triespecific proteins and methods of use

专利摘要:
B cell maturation agent (BCMA) targeting specific proteins comprising a CD3 binding domain, a half-life extension domain and a BCMA binding domain are provided herein. Their pharmaceutical compositions are also provided, as well as nucleic acids, recombinant expression vectors and host cells to produce such BCMA targeting specific proteins. Also disclosed are methods of using BCMA aimed at specific proteins in the prevention and / or treatment of diseases, conditions and disorders.
公开号:BR112020007196A2
申请号:R112020007196-0
申请日:2018-10-12
公开日:2020-12-01
发明作者:Holger Wesche；Bryan D. LEMON；Richard J. Austin
申请人:Harpoon Therapeutics, Inc.；
IPC主号:

专利说明:

[001] [001] This claim claims the benefit of Provisional U.S. Order No. 62 / 572,381 filed on October 13, 2017, which is incorporated by reference into this specification in its entirety. SEQUENCE LISTING
[002] [002] The present application contains a List of strings that was submitted electronically in ASCII format and is incorporated in this specification by reference in its entirety. Said ASCII copy, created on October 11, 2018, is called 47517- 723 601 SL.txt and is 752,020 in size. BACKGROUND OF THE INVENTION
[003] [003] Cancer is the second leading cause of human death, right after death from coronary heart disease. Worldwide, millions of people die from cancer each year. in the United States alone, as reported by the American Cancer Society, cancer causes the death of more than half a million people annually, with more than 1.4 million new cases diagnosed each year. While deaths from heart disease are declining significantly, those resulting from cancer are generally on the rise. It is predicted that in the early part of the next century, cancer is expected to become the leading cause of death.
[004] [004] Furthermore, even for those cancer patients who initially survive their primary cancers, common experience has shown that their lives are dramatically altered. Many cancer patients have strong anxieties driven by an awareness of the potential for treatment recurrence or failure. Many cancer patients experience physical weakness after treatment.
[005] [005] In general, the fundamental problem in the management of the most deadly cancers is the absence of effective and non-toxic systemic therapies. Cancer is a complex disease characterized by genetic mutations that lead to uncontrolled cell growth. Cancer cells are present in all organisms and, under normal circumstances, their excessive growth is closely regulated by various physiological factors. SUMMARY OF THE INVENTION
[006] [006] The selective destruction of a specific cell or individual cell type is often desirable in several clinical settings. For example, it is a primary goal of cancer therapy to specifically destroy tumor cells while leaving healthy cells and tissue intact and undamaged. One of these methods is by inducing an immune response against the tumor, to cause immune effector cells, such as natural killer cells (NK) or cytotoxic T lymphocytes (CTLs), to attack and destroy tumor cells.
[007] [007] In this specification, a specific B cell maturation agent (BCMA) binding protein is provided comprising: (a) a first domain (A) that specifically binds to human CD3; (b) a second domain (B) which is a half-life extension domain; and (c) a third domain (C) that specifically binds to BCMA, where the domains are linked in the order H2N- (A) - (C) - (B) - COOH, H2N- (B) - (A) - (C) -COOH, H2N- (C) - (B) - (A) -COOH, H2N- (C) -
[008] [008] In some cases, the first domain may comprise a variable light domain and a variable heavy domain, each being able to specifically bind to human CD3. The first domain can be humanized or human.
[009] [009] In some cases, the second domain binds to albumin. The second domain may comprise a single chain variable fragment (scFv), a variable heavy domain (VH), a variable light domain (VL), a binding domain of the single chain antibody devoid of a light chain (a VHH domain), a peptide, a linker or a small molecule.
[010] [010] The third domain is, in some cases, a single chain binding domain devoid of a light chain (a VHH domain), a scFv, a VH domain, a VL domain, a non-Ig domain, a linker , a knotin, or a small molecule entity that specifically binds to BCMA. In some non-limiting cases, the third domain comprises a VHH domain.
[011] [011] In this specification a specific BCMA-binding protein is provided in which the VHH domain comprises CDR1, CDR2 and CDR3 complementarity determining regions, where (a) the amino acid sequence of CDR1 is as shown in X1X2X3X4aXsXeX7PXsG (ID. DE SEQ. Nº: 1), where X1 is Tou S; Xo is N, Dou S; X; is I, D, Q, H, V or E; Xa is F, S, E, A, T, M, V, IT, D, Q, P, R or G; Xs is S, M, R or N; X; It is I, K, S, T, R, E, D, N, V, H, L, A, Q Or G; X7 is S, T, Y, Rou N; and X; s is M, G or Y; (b) the amino acid sequence of CDR2 is as shown in AIXsGX: oX11 TX12YADSVK (SEQ ID. NO .: 2), where X; is H, N or S; X10 is F, G, K, R, P, D, OQ, H, E, N, T, S, A, I, L or V; Xu is S, Q, E, T, K or D; and X12 is L, V, I, F, Y or W; and (c) the amino acid sequence of CDR3 is as shown in VPWGX: 3YHPX: 4aX1sVX16 (SEQ ID. NO .: 3), where X13 is D, I, T, K, R, A, E, S or Y; Xu is R, G, L, K, T, OQ, S or N; X15 is N, K, E, V, R, M or D; and X1k is Y, A, V, K, H, L, M, T, R, Q, C, S or N.
[012] [012] In one embodiment, CDR1 does not comprise an amino acid sequence from ID. SEQ. No. 599. In one embodiment, CDR2Q does not comprise an amino acid sequence from ID. SEQ. No. 600. In one embodiment, CDR3 does not comprise an amino acid sequence from ID. SEQ. No. 601. In one embodiment, CDRII and CDR2 do not comprise ID amino acid sequences. SEQ. No. 599 and 600, respectively. In one embodiment, CDR1 and CDR3 do not comprise ID amino acid sequences. SEQ. No. 599 and 601, respectively. In one embodiment, CDR2 and CDR3 do not comprise ID amino acid sequences. SEQ. No. 600 and 601, respectively. In one embodiment, CDR1, CDR2 and CDR3 do not comprise ID amino acid sequences. SEQ. No. 599, 600 and 601, respectively.
[013] [013] A specific BCMA-binding protein is provided in this specification, in which the VHH domain comprises the following formula: fl-rl-f2-r2-f3-r3-f4; where, rl is the ID. SEQ. No.: 1; r2 is the ID. SEQ. No.: 2; and r3 is the ID. SEQ. No.: 3; and where fi, fo, f3 and fa are structural residues (framework) selected so that the said protein is from about eighty percent (80%) to about 99% identical to the amino acid sequence shown in
[014] [014] In some non-limiting examples, rl comprises an amino acid sequence presented as any of the IDS. SEQ. No. 4-117.
[015] [015] In some non-limiting examples, r2 comprises an amino acid sequence presented as any of the IDS. SEQ. No. 118-231.
[016] [016] In some non-limiting examples, r3 comprises an amino acid sequence presented as any of the IDS. SEQ. Nº: 232-345.
[017] [017] In other non-limiting examples, the protein comprises an amino sequence presented as any of the IDS. SEQ. No. 346-460.
[018] [018] In a single domain BCMA-binding protein, fl comprises, in some cases, ID. SEQ. No. 461 or 462.
[019] [019] In a single domain BCMA binding protein, f2 comprises, in some cases, the ID. SEQ. No.
[020] [020] In a single domain BCMA-binding protein, f3 comprises, in some cases, ID. SEQ. No. 464 or 465.
[021] [021] In a single domain BCMA-binding protein, where f4 comprises, in some cases, ID. SEQ. No. 466 OR 467.
[022] [022] In a non-limiting example, rl comprises the ID. SEQ. No. 76, 114, 115, 116 or 117. In a non-limiting example, rl comprises the ID. SEQ. No. 76.
[023] [023] In a non-limiting example, rl comprises the ID. SEQ. No. 76, r2 is the ID. SEQ. No. 190, er3éo1ID. SEQ. No. 304.
[024] [024] In a non-limiting example, rl comprises the ID. SEQ. No. 114, r2 comprises the ID. SEQ. No.: 228 and r3 comprises the ID. SEQ. No. 342.
[025] [025] In a non-limiting example, rl comprises the ID. SEQ. No. 115, r2 comprises the ID. SEQ. No.: 229 and r3 comprises the ID. SEQ. No. 343.
[026] [026] In a non-limiting example, rl comprises the ID. SEQ. No: 117, r2 comprises the ID. SEQ. No.: 231 and r3 comprises the ID. SEQ. No. 345.
[027] [027] In a non-limiting example, rl comprises the ID. SEQ. No. 116, r2 comprises the ID. SEQ. Nº: 230 and r3 comprises the ID. SEQ. No. 344.
[028] [028] The third domain, in some cases, is a human VHH domain, a humanized VHH domain, a matured affinity VHH domain, or a combination of these.
[029] [029] The specific BCMA-binding protein, in some cases, has an elimination half-life of at least 12 hours, at least 20 hours, at least 25 hours, at least 30 hours, at least 35 hours, at least 40 hours, at least 45 hours, at least 50 hours or at least 100 hours.
[030] [030] A specific BCMA-binding protein is provided in this specification that is a VHH domain, in which the VHH domain comprises a CDR1, a CDR2 and a CDR3, and in which the protein comprises the sequence shown as the ID. SEQ. No. 346 or 598, where one or more amino acid residues selected from amino acid positions 26, 27, 28, 29, 30, 31, 32 and / or 34 of CDR1; positions 52, 54, 55 and / or 57 of CDR2; and positions 101, 105, 106 and / or 108 of CDR3 are substituted, wherein the amino acid position 26, if substituted, is substituted with S; amino acid position 27, if substituted, is replaced with D or S; amino acid position 28, if substituted, is replaced with D, Q, H, V or E; amino acid position 29, if substituted, is replaced with S, E, A, T, M, V, I, D, Q, P, R or G; amino acid position 30, if substituted, is replaced with M, R or N; the amino acid position 31, if substituted, is replaced with K, S, T, R, E, D, N, V, H, L, A, Q or G; amino acid position 32, if substituted, is replaced with T, Y, R or N; amino acid position 34, if substituted, is replaced with G or Y; amino acid position 52, if substituted, is replaced with N or S; amino acid position 54, if substituted, is replaced with G, K, R, P, D, OQ, H, E, N, T, S, A, I, L or V; amino acid position 55, if substituted, is replaced with Q, E, T, K or D; amino acid position 57, if substituted, is replaced with V, I, F, Y or W; the amino acid position 101, if substituted, is replaced with I, T, K, R, A, E, S or Y; amino acid position 105, if substituted, is replaced with G, L, K, T, Q, S or N; amino acid position 106, if substituted, is replaced with K, E, V, R, M or D; and amino acid position 108, if substituted, is replaced with A, V, K, H, L, M, T, R, Q, C, S or N. In a non-limiting example, the VHH domain is human, humanized, with mature affinity, or a combination of these.
[031] [031] In this specification a specific BCMA-binding protein is provided, in which the third domain binds to a human BCMA protein that comprises a sequence shown as the ID. SEQ. No. 468. In some cases, the third domain binds to a BCMA epitope, where that epitope comprises the extracellular BCMA domain. In some cases, the third domain binds to a BCMA epitope, wherein said epitope comprises amino acid residues 5-51 of the ID. SEQ. No.
[032] [032] In these specific BCMA-binding proteins, L1 and L2 linkers are each selected independently from (GS) n (SEQ ID. No.: 472), (GGS) n (SEQ ID. No.: 473), (GGGS) n (SEQ ID NO: 474), (GGSG) n (SEQ ID NO: 475), (GGSGG) n (SEQ ID NO: 476), (GGGGS ) n (SEQ ID NO: 477), (GGGGG) n (SEQ ID NO: 478) or (GGG) n (SEQ ID NO: 479) where n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
[033] [033] In a non-limiting example, in these specific BCMA-binding proteins, the Ll and L2 linkers are each independently (GGGGS). (SEQ ID. NO .: 480) or (GGGGS); (SEQ ID. NO .: 481).
[034] [034] The domains of a specific BCMA-binding protein can be linked in the order H2N- (C) - (B) - (A) - COOH.
[035] [035] In some cases, a specific BCMA-binding protein is less than about 80 kDa. In other cases, a specific BCMA-binding protein may be about 50 to about 75 kDa. In other cases, a specific BCMA-binding protein has less than about 60 kDa.
[036] [036] A specific BCMA-binding protein described in that specification, in some cases, has an elimination half-life of at least about 50 hours, about 100 hours or more.
[037] [037] A specific BCMA-binding protein, in some cases, exhibits increased tissue penetration compared to an IgG for the same BCMA.
[038] [038] A try-specific BCMA-binding protein, in some cases, comprises an amino acid sequence selected from the group consisting of the IDS. SEQ. No.: 483-
[039] [039] In that specification, in a modality, a B-cell maturing agent (BCMA) triespecific binding protein comprising: (a) a first domain (A) that specifically binds to human CD3; (b) a second domain (B) which is a half-life extension domain; and (c) a third domain (C) that specifically binds to BCMA, where the third domain comprises an amino sequence presented as any of the IDS. SEQ. No. 346-460.
[040] [040] In this specification, in one embodiment, a B-cell maturing agent (BCMA) triespecific binding protein comprising: (a) a first domain (A) that specifically binds to human CD3; (b) a second domain (B) which is a half-life extension domain; and (c) a third domain (C) that specifically binds to BCMA, where the third domain comprises complementarity determining regions CDR1, CDR2 and CDR3, where CDR1 comprises an amino acid sequence presented as any of the IDS. SEQ. No. 4-117, CDR2 comprises an amino acid sequence presented as any of the IDS. SEQ. No. 118-231, and CDR3 comprises an amino acid sequence presented as any of the IDS. SEQ. No.: 232-345.
[041] [041] A pharmaceutical composition is provided in this specification that comprises a specific BCMA-binding protein as described in that specification and a pharmaceutically acceptable carrier.
[042] [042] Also provided in that specification is a process for producing a specific BCMA-binding protein described in that specification, said process comprising culturing a host transformed or transfected with a vector comprising a nucleic acid sequence that encodes a BCMA triespecific binding protein under conditions that allow expression of the BCMA triespecific binding protein and recovery and purification of the protein produced by the culture.
[043] [043] One embodiment provides a method for treating or ameliorating a tumor disease, an autoimmune disease or an infectious disease associated with BCMA in a needy subject, which comprises administering to the individual a pharmaceutical composition comprising a protein binding to BCMA triespecific, wherein the BCMA-binding protein comprises: (a) a first domain (A) that specifically binds to human CD3; (b) a second domain (B) which is a half-life extension domain; and (c) a third domain (C) that specifically binds to BCMA, where the domains are linked in the order H2N- (A) - (C) - (B) -COOH, H2N- (B) - (A) - (C) -COOH, H2N- (C) - (B) - (A) -COOH, H2N- (C) - (A) - (B) -COOH, H2N- (A) - (B) - ( C) -COOH, H2N- (B) - (C) - (A) COOH, where the domains are connected by L1 and L2 linkers.
[044] [044] This specification provides a method for treating or ameliorating a tumor disease, an autoimmune disease or an infectious disease associated with BCMA in a needy individual, which comprises administering to the individual a pharmaceutical composition as described in that specification. .
[045] [045] An individual to be treated is, in some cases, a human.
[046] [046] In some cases, the method further comprises the administration of one or more additional agents in combination with the specific BCMA-binding protein.
[047] [047] The methods described in this specification are useful for treating or ameliorating a tumor disease, in which the specific BCMA-binding protein selectively binds to tumor cells that express BCMA.
[048] [048] A tumor disease to be treated with the described methods comprises a primary cancer or a metastasis thereof. In one case, the tumor disease comprises cancer of the B cell lineage.
[049] [049] Cancer of the B cell lineage to be treated with the aforementioned methods includes, without limitation, multiple myeloma, leukemia, lymphoma, or metastasis. INCORPORATION BY REFERENCE
[050] [050] All publications, patents and patent applications mentioned in this specification are incorporated into this specification by reference to the same degree as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS
[051] [051] The new features of the invention are presented with particularity in the appended claims. A better understanding of the characteristics and advantages of the present invention will be obtained by reference to the following detailed description which presents illustrative modalities, in which the principles of the invention are used, and in the accompanying drawings, of which:
[052] [052] Fig. 1 is a schematic representation of an exemplary BCMA-specific antigen-binding protein in which the protein has a constant central element comprising an anti-CD3e single chain variable (scFv) fragment and a region of the anti-ALB variable heavy chain; and an anti-BCMA binding domain which can be a VHH, a VH, scFv, a non-Ig binder or a linker.
[053] [053] Fig. 2 illustrates the effect of exemplary BCMA-directed molecules (01H08, 01F07, 02F02 and BH253), containing an anti-BCMA binding protein according to the present disclosure, on the death of purified human T cells that express BCMA compared to a negative control.
[054] [054] Fig. 3 is a SDS-PAGE image of representative purified BCMA-specific molecules. Lane 1: 01FO7-M34Y TriTAC not reduced; Lane 2: O01FO7-M34G-TriTAC not reduced; Lane 3: 02B05 TriTAC not reduced; Lane 4: 02G0O2-M34Y TriTAC not reduced; Lane 5: 02GO0O2 M34G TriTAC not reduced; Lane 6: Wide Range SDS-PAGE Standard (Bio-Rad $ 1610317); Lane 7: O1FO7-M34Y TriTAC not reduced; Lane 8: 01FO7-M34G-TriTAC not reduced; Lane 9: 02B05 TriTAC not reduced; Lane 10: 02G02-M34Y TriTAC not reduced; Lane 11: 02G02 M34G TriTAC not reduced; Lane 12: Wide Range SDS-PAGE Standard (Bio-Rad $ 1610317).
[055] [055] Figs. 4A-41I illustrate the effect of exemplary BCMA-directed molecule-specific molecules that contain an anti-BCMA binding protein according to the present disclosure on the death of Jekol, MOLP-8 or OPM-2 cells that express BCMA compared to a negative control.
[056] [056] Figs. 5A-5D illustrates the binding of a specific specific protein directed to the exemplary BCMA (02B05) to purified T cells from four different human donors, donor 02 (Fig. 5A), donor 35 (Fig. 5B), donor 81 (Fig. 5C) , donor 86 (Fig. 5D).
[057] [057] Figs. 6A-6F illustrates the binding of an attempted-specific protein directed to the exemplary BCMA (02B05) to cells expressing BCMA, NCI-H929 (Fig. 6A), EJM (Fig. 6B), OPM2 (Fig. 6D), RPMI8226 (Fig. 6E); or cell lines devoid of BCMA expression, NCI-H510A (Fig.
[058] [058] Fig. 7 illustrates the results of a TDCC assay using an exemplary BCMA-specific protein (02B05) and BCMA-expressing EJM cells, in the presence or absence of human serum albumin (HSA).
[059] [059] Fig. 8 illustrates the results of a TDCC assay using an exemplary BCMA-targeted protein (02B05) and BCMA-expressing EJM cells, using a varying ratio of effector cells to target cells.
[060] [060] Fig. 9 illustrates the results of a TDCC assay using an exemplary BCMA-targeted protein (02B05) and BCMA-expressing OPM2 cells, using a varying ratio of effector cells to target cells.
[061] [061] Fig. 10 illustrates the results of a TDCC assay using an exemplary BCMA-specific directed protein (02B05) and BCMA-expressing NCI-H929 cells, using variable time points and a 1: 1 ratio from effector cells to target cells.
[062] [062] Fig. 11 illustrates the results of a TDCC assay using an exemplary BCMA-targeted protein (02B05), BCMA-expressing EJM cells and T cells from four different donors, in the presence of human serum albumin ( HSA).
[063] [063] Fig. 12 illustrates the results of a TDCC assay using an exemplary BCMA-targeted protein (02B05), NCI-H929 cells that express BCMA and T cells from four different donors, in the presence of serum albumin (HSA).
[064] [064] Fig. 13 illustrates the results of a TDCC assay using an exemplary BCMA-targeted protein (02B05), BCMA-expressing OPM2 cells and T cells from four different donors, in the presence of human serum albumin ( HSA).
[065] [065] Fig. 14 illustrates the results of a TDCC assay using an exemplary BCMA-specific protein (02B05), RPMI8226 cells that express BCMA and T cells from four different donors, in the presence of human serum albumin ( HSA).
[066] [066] Fig. 15 illustrates the results of a TDCC assay using an exemplary BCMA-targeted protein (02B05), OVCAR8 cells that do not express BCMA and T cells from four different donors in the presence of human serum albumin (HSA).
[067] [067] Fig. 16 illustrates the results of a TDCC assay using an exemplary BCMA-targeted protein (02B05), NCI-H510A cells that do not express BCMA and T cells from four different donors, in the presence of albumin human serum (HSA).
[068] [068] Fig. 17 illustrates the results of a TDCC assay using an exemplary BCMA-targeted protein (02B05), BCCI-expressing NCI-H929 cells and peripheral blood mononuclear cells (PBMC) from two Cynomolgus donors different in the presence of human serum albumin (SAH).
[069] [069] Fig. 18 illustrates the results of a TDCC assay using an exemplary BCMA-targeted protein (02B05), BCMA-expressing RPMI8226 cells and peripheral blood mononuclear cells (PBMC) from two different Cynomolgus donors, in the presence of human serum albumin (HSA).
[070] [070] Fig. 19 illustrates the expression level of the CD69 T cell activation biomarker, after a TDCC assay using an exemplary BCMA-directed protein (02B05) and BCMA-expressing EJM cells.
[071] [071] Fig. 20 illustrates the expression level of the CD25 T cell activation biomarker, after a TDCC assay with the use of a specific BCMA-specific protein (02B05) and BCMA-expressing EJM cells.
[072] [072] Fig. 21 illustrates the expression level of the CD69 T cell activation biomarker, after a TDCC assay using an exemplary BCMA-directed protein (02B05) and BCMA-expressing OPM2 cells.
[073] [073] Fig. 22 illustrates the expression level of the CD25 T cell activation biomarker, after a TDCC assay using an exemplary BCMA-specific protein (02B05) and BCM-expressing OPM2 cells.
[074] [074] Fig. 23 illustrates the expression level of the CD69 T cell activation biomarker, after a TDCC assay with the use of a specific BCMA-directed protein (02B05) and BCMA-expressing RPMI8226 cells.
[075] [075] Fig. 24 illustrates the expression level of the CD25 T cell activation biomarker, after a TDCC assay using an exemplary BCMA-directed protein (02B05) and BCMA-expressing RPMI8226 cells.
[076] [076] Fig. 25 illustrates the expression level of the CD69 T cell activation biomarker, after a TDCC assay with the use of a specific BCMA-specific protein (02B05) and OVCAR8 cells that do not express BCMA.
[077] [077] Fig. 26 illustrates the expression level of the CD25 T cell activation biomarker, after a TDCC assay using an exemplary BCMA-specific protein (02B05) and OVCAR8 cells that do not express BCMA.
[078] [078] Fig. 27 illustrates the level of expression of the CD69 T cell activation biomarker, after a TDCC assay using an exemplary BCMA-specific protein (02B05) and NCI-H5S10A cells that do not express BCMA.
[079] [079] Fig. 28 illustrates the expression level of the CD25 T cell activation biomarker, after a TDCC assay using an exemplary BCMA-targeted protein (02B05) and NCI-H5S10A cells that do not express BCMA.
[080] [080] Fig. 29 illustrates the level of expression of a cytokine, TNF-a, in cocultures of T cells and target cells that express BCMA (EJM cells) treated with increasing concentrations of a trypecific protein (02B05) directed to the exemplary BCMA or with a negative specific GFP protein tries control.
[081] [081] Fig. 30 illustrates the reduction of tumor growth in a xenograft model of RPMI8226, treated with a triespecific protein (02B05) directed to the exemplary BCMA, in varying concentrations, or with a control vehicle.
[082] [082] Fig. 31 illustrates the reduction of tumor growth in a Jekol xenograft model, treated with a triespecific protein (02B05) directed to the exemplary BCMA, in varying concentrations, or with a control vehicle.
[083] [083] Fig. 32 illustrates the concentration of triespecific protein targeting BCMA in serum samples from Cynomolgus monkeys dosed with varying concentrations of a trypecific protein (02B05) targeting exemplary BCMA.
[084] [084] Fig. 33 the results of a TDCC assay using BCMA-specific triespecific protein obtained from serum samples from Cynomolgus monkeys collected 168 hours after dosing with varying concentrations of a trypecific protein (02B05) directed to the exemplary BCMA , BCMA-expressing EJM cells and purified human T cells, in the presence of serum from Cynomolgus monkeys that were not exposed to a specific BCMA-directed protein. DETAILED DESCRIPTION OF THE INVENTION
[085] [085] Although preferred embodiments of the present invention have been shown and described in this specification, it will be obvious to those skilled in the art that these modalities are provided by way of example only. Several variations, changes and substitutions will now occur to those skilled in the art without departing from the invention. It will be understood that several alternatives to the modalities of the invention described in this specification can be employed in the practice of the invention. It is intended that the following claims define the scope of the invention and that the methods and structures within the scope of those claims and their equivalents are covered by them.
[086] [086] In this specification, specific proteins that target the B cell maturation antigen (BCMA), pharmaceutical compositions of these (referred to in that specification, try specific BCMA-binding protein, try-specific BCMA-directed protein or trypecific antigen-specific protein, are described in this specification. directed to BCMA), as well as nucleic acids, recombinant expression vectors and host cells for the production of these proteins. Also provided are methods of using the specific BCMA-directed proteins revealed in the prevention, and / or treatment of diseases, conditions and disorders. The specific proteins targeting BCMA are able to specifically bind to BCMA, as well as to CD3, and have a half-life extension domain, for example, a human albumin binding (ALB) domain. Fig. 1 depicts a non-limiting example of a specific BCMA-binding protein.
[087] [087] An "antibody" typically refers to a "Y" shaped tetrameric protein that comprises two heavy polypeptide chains (HE) and two light polypeptide chains (L) held together by covalent disulfide bonds and non-covalent interactions. Human light chains comprise a variable domain (VL) and a constant domain (CL) in which the constant domain can be readily classified as kappa or lambda based on the sequence of amino acids and loci. Each heavy chain comprises a variable domain (VH) and a constant region, which, in the case of IgG, IgA and IgD, comprises three domains called CH1, CH2 and CH3 (IgM and IgE have a fourth domain, CH4). In the IgG, IgA and IgD classes, the CH1 and CH2 domains are separated by a flexible hinge region, which is a segment rich in proline and cysteine of variable length (usually from about 10 to about 60 amino acids in IgG). The variable domains in both the light and heavy chains are joined to the constant domains by a "J" region of about 12 or more amino acids and the heavy chain also has a "D" region of about additional amino acids.
[088] [088] As used in this specification, the term "antibody" includes polyclonal antibodies, multiclonal antibodies, monoclonal antibodies, chimeric antibodies, humanized and primatized antibodies, antibodies with grafted CDR, human antibodies, recombinantly produced antibodies, intrabodies, multispecific antibodies, antibodies bispecific, monovalent antibodies, multivalent antibodies, anti-idiotypic antibodies, synthetic antibodies, including muteins and variants thereof, immunospecific antibody fragments, for example, Fd, Fab, F (ab ')', F (ab ') fragments, fragments of single chain (for example, ScFv and ScFvFc), disulfide-linked Fvs (sdFv), an FD fragment consisting of the VH and CH1 domains, linear antibodies, single domain antibodies such as sdãAb (VH, VL or VHH domains ); and derivatives thereof, including Fe fusions and other modifications, and any other immunoreactive molecule, as long as it comprises a domain that has a binding site for association or preferential binding with a BCMA protein. In addition, unless otherwise determined by contextual restrictions, the term still includes all classes (ie IgA, IgD, IgE, IgG and IgM) and all subclasses (ie IgGl, IgG2, IgG3, IgG4, IgAl and IgaA2) of antibodies. Heavy chain constant domains that correspond to different classes of antibodies are typically represented by the lowercase Greek letters corresponding to alpha, delta, epsilon, gamma and mu, respectively. Light chains of antibodies of any vertebrate species can be assigned to one of two distinctly distinct types, called kappa (kappa) and lambda (lambda), based on the amino acid sequences of their constant domains.
[089] [089] In some embodiments, the BCMA-binding domain of the specific BCMA-directed proteins of that disclosure comprises a heavy chain only antibody, for example, a VH domain or a VHH domain. In some cases, BCMA-binding proteins comprise a heavy chain-only antibody that is a genetically modified human VH domain. In some examples, the genetically modified human VH domain is produced by screening phage display libraries. In some embodiments, the BCMA-binding domain of the specific BCMA-directed proteins of this disclosure comprises a VHH. The term "VHH", as used in this specification, refers to the binding domain of the single chain antibody devoid of light chain. In some cases, a VHH is derived from an antibody of the type that can be found in Camelidae or cartilaginous fish that are naturally devoid of light chains or from a synthetic, non-immunized VHH that can be constructed accordingly. Each heavy chain comprises a variable region encoded by exons V, D and J. A VHH, in some cases, is a natural VHH, for example, a camelid-derived VHH, or a recombinant protein comprising a variable domain of the heavy chain. In some modalities, VHH is derived from a species selected from the group consisting of camels, llamas, vicuñas, guanacos and cartilaginous fish (for example, without limitation, sharks). In another modality, VHH is derived from an alpaca (for example, without limitation, a Huacaya Alpaca or a Suri alpaca).
[090] [090] As used in this specification, the term “variable region” or “variable domain” refers to the fact that certain portions of the variable domains differ markedly in sequence between antibodies and are used in the binding and specificity of each particular antibody due to its particular antigen. However, variability is not distributed equally across all variable domains of antibodies. It is concentrated in three segments called complementarity determining regions (CDRs) or hypervariable regions in the variable domains of both the light chain (VL) and the heavy chain (VH). The most highly conserved portions of variable domains are called the framework (FR). Each of the variable domains of native heavy and light chains comprises four FR regions, which largely adopt an RB leaf configuration, connected by three CDRs, which form loops that connect, and in some cases form part of, the f & leaf structure. The CDRs in each chain are held together in close proximity by the FR regions and, with the CDRs in the other chain, contribute to the formation of the antibody antigen binding site (see, Kabat et al., “Sequences of Proteins of Immunological Interest ”, Fifth Edition,“ National Institute of Health ”, Bethesda, Md. (1991)). The constant domains are not directly involved in the binding of an antibody to an antigen, but exhibit various effector functions, for example, participation of the antibody in antibody-dependent cell toxicity. ScFv fragments (or single-chain variable fragment), which in some cases are obtained by genetic engineering, are associated in a single polypeptide chain, the VH region and the VL region of an antibody, separated by a peptide linker.
[091] [091] In some embodiments of this disclosure, the BCMA-binding domain of the specific BCMA-directed proteins comprises heavy chain antibodies only, for example, VH or VHH domains, and comprises three CDRs. These heavy chain-only antibodies, in some modalities, bind to BCMA as a monomer without dimerization dependence with a VL (variable light chain) region for optimal binding affinity. In some embodiments of this disclosure, the CD3-binding domain of the specific BCMA-directed proteins comprises an scFv. In some embodiments of this disclosure, the albumin-binding domain of the specific BCMA-directed proteins comprises a heavy chain only antibody, for example, a single domain antibody comprising a VH domain or a VHH domain.
[092] [092] The designation of amino acids for each domain, framework region and CDR is, in some modalities, in accordance with one of the numbering schemes provided by Kabat et al. (1991) “Sequences of Proteins of Immunological Interest” (5th Edition), “US Dept. of Health and Human Services ”, PHS, NIH, NIH Publication No. 91-3242; Chothia et al., 1987, PMID: 3681981; Chothia et al., 1989, PMID: 2687698; MacCallum et al, 1996, PMID: 8876650; or Dubel, Ed. (2007) “Handbook of Therapeutic Antibodies”, 3rd Edition, Wily-VCH Verlag GmbH and “Co or AbM” (Oxford Molecular / MSI Pharmacopia), unless otherwise noted. CDRs of the present disclosure are not intended to necessarily correspond to the Kabat numbering convention.
[093] [093] The term residues (or regions) “framework” or “FR” refer to residues from the variable domain other than the residues of the CDR or hypervariable region as defined in this specification. A “human consensus framework” is a framework that represents the amino acid residue that most commonly occurs in a selection of human immunoglobulin VL or VH framework sequences.
[094] [094] As used in this specification, the term "percentage (%) of amino acid sequence identity" with respect to a sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to amino acid residues in the specific sequence, after aligning the sequences and inserting gaps, if necessary, to obtain the maximum sequence identity percentage, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining the percent amino acid sequence identity can be achieved in a number of ways that are part of the skill in the art, for example, using publicly available computer software such as EMBOSS MATCHER, EMBOSS WATER, EMBOSS software STRETCHER, EMBOSS NEEDLE, EMBOSS LALIGN, BLAST, BLAST-2, ALIGN or Megalign (DNASTAR). Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms necessary to obtain maximum alignment over the total length of the sequences being compared.
[095] [095] As used in this specification, the term “elimination half-life” is used in its common sense, as described in “Goodman and Gillman's The Pharmaceutical Basis of Therapeutics” 21-25 (Alfred Goodman Gilman, Louis S. Goodman and Alfred Gilman, eds., 6th Edition, 1980). Briefly, the term is intended to encompass a quantitative measure of the time course of drug elimination. The elimination of most drugs is exponential (that is, it accompanies first-order kinetics), as the drug concentrations do not normally approach those necessary for the elimination process. The rate of an exponential process can be expressed by its speed constant, k, which expresses the fractional change per unit of time, or by its half-life, ti, the time required for 50% of the end of the process. The units of these two constants are time! and time, respectively. A first order velocity constant and the reaction half-life are simply related (kK x ti / 27 = 0.693) and can be interchanged accordingly. Since first order elimination kinetics dictates that a constant drug fraction is lost per unit of time, a graph of the drug concentration log versus time is linear at all times after the initial distribution phase (ie after absorption and drug distribution are complete). The drug elimination half-life can be accurately determined from such a graph.
[096] [096] As used in this specification, the term "binding affinity" refers to the affinity of the proteins described in the disclosure to their binding targets, and is expressed numerically using "Kd" values. If two or more proteins are indicated to have comparable binding affinities for their binding targets, then the Kd values for binding the respective proteins to their binding targets are within + 2 times between them.
[097] [097] The term “about” or “approximately” means within an acceptable error range for the particular value, as determined by those skilled in the art, which will depend, in part on how the value is measured or determined, by example, the limitations of the measurement system. For example, "about" may mean within 1 or more than 1 standard deviation, by practicing at a certain value. When particular values are described in the application and in the claims, unless otherwise stated, the term "about" should be assumed to mean an acceptable error range for the particular value.
[098] [098] The terms "patient" or "individual" are used interchangeably. None of the terms requires or is limited to the situation characterized by the supervision (for example, constant or intermittent) of a health professional (for example, a doctor, a registered nurse, a nursing assistant, an assistant physician, a hospital servant or a nursing home employee).
[099] [099] The terminology used in this specification is intended to describe only particular cases and is not intended to be limiting. As used in this specification, the singular forms “um”, “o”, “umaã” and “a” aim to include the plural forms as well, unless the context clearly indicates otherwise. In addition, insofar as the terms "including", "includes", "who owns", "owns", "with", or variants of these are used in the detailed description and / or in the claims, these terms are intended to be inclusive of a form similar to the term “that comprises”.
[100] [100] In one aspect, the BCMA-directed trypecific proteins comprise a domain (A) that specifically binds to CD3, a domain (B) that specifically binds to human albumin (ALB) and a domain (C) that binds specifically to BCMA. The three domains in the specific proteins targeting BCMA are arranged in any order. Thus, it is contemplated that the order of domains of the specific proteins directed to BCMA are: H2N- (A) - (B) - (C) -COOH, HaN- (A) - (C) - (B) -COOH, H2N- (B) - (A) - (C) -COOH, HaoN- (B) - (C) - (A) -COOH, HoN- (C) - (B) - (A) -COOH, or HaN - (C) - (A) - (B) -COOH.
[101] [101] In some embodiments, the specific proteins targeting BCMA have an order of H2N- (A) - (B) - (C) -COOH domains. In some embodiments, the specific BCMA-directed proteins have an order of HN- (A) - (C) - (B) -COOH domains. In some embodiments, the specific proteins targeted to BCMA have an order of H2N- (B) - (A) - (C) -COOH domains. In some embodiments, the specific proteins targeted to BCMA have an order of HoN- (B) - (C) - (A) -COO0OH domains. In some embodiments, the specific proteins targeted to BCMA have an order of H2N- (C) - (B) - (A) -COOH domains. In some embodiments, the specific proteins targeted to BCMA have an order of HN- (C) - (A) - (B) -COOH domains. In some embodiments, the anti-BCMA domain (the anti-target domain, T), the anti-CD3 domain (C) and the anti-ALB domain (A) are in an anti-CD3 orientation: anti-ALB: anti- BCMA (CAT). In some embodiments, the anti-BCMA domain (the anti-target domain, T) the anti-CD3 domain (C) and the anti-ALB domain (A) are in an anti-BCMA orientation: anti-ALB: anti-CD3 (TAC).
[102] [102] In some embodiments, the specific BCMA-targeted proteins have the HSA-binding domain as the middle domain, so that the order of domains is HoN- (A) - (B) - (C) -COOH or HAN- (C) - (B) - (A) -COOH. It is contemplated that in the modalities in which the ALB binding domain is the middle domain, the CD3 and BCMA binding domains generate additional flexibility to link to their respective targets.
[103] [103] In some embodiments, the BCMA-directed trypecific proteins described in that specification comprise a polypeptide that has a sequence described in the Sequence Table (IDS. SEQ.
[104] [104] The tries specific to BCMA proteins described in this specification are designed to allow specific targeting of cells that express BCMA by recruiting cytotoxic T cells. This increases the effectiveness compared to ADCC (antibody-dependent cell mediated cytotoxicity), which uses full-length antibodies directed at a single antigen and is not able to directly recruit cytotoxic T cells. In contrast, by engaging CD3 molecules specifically expressed in these cells, BCMA-directed specific proteins can cross-link cytotoxic T cells with cells that express BCMA in a highly specific way, thereby directing the T cell's cytotoxic potential against the cell- target. The BCMA-directed trypecific proteins described in this specification engage cytotoxic T cells by binding to the CD3 proteins expressed on the surface, which form part of the TCR. The simultaneous binding of various specific antigen-binding proteins targeting BCMA to CD3 and BCMA expressed on the surface of particular cells causes T cell activation and mediates subsequent lysis of the cell that expresses particular BCMA. Thus, specific proteins targeted at BCMA are contemplated to exhibit strong, specific and efficient target cell death. In some embodiments, the specific BCMA-directed proteins described in this specification stimulate the death of the target cell by cytotoxic T cells to eliminate pathogenic cells (for example, tumor cells that express BCMA). In some of these modalities, cells are selectively eliminated, thereby reducing the potential for toxic side effects.
[105] [105] The BCMA-directed trypecific proteins described in this specification provide additional therapeutic advantages over traditional monoclonal antibodies and other minor bispecific molecules. Generally, the effectiveness of recombinant protein pharmaceutical products depends largely on the intrinsic pharmacokinetics of the protein itself. One of these benefits here is that the specific BCMA-directed proteins described in this specification have an extended pharmacokinetic elimination half-life because they have a half-life extension domain, such as an HSA-specific domain. In this regard, the BCMA-targeted specific proteins described in this specification have an extended serum elimination half-life of about two, three, about five, about seven, about 10, about 12 or about 14 days , in some modalities. This contrasts with other binding proteins, such as BiTE or DART molecules, which have relatively shorter elimination half-lives. For example, the bispecific scFv-scFv fusion molecule CD19 x CD3 BiTE requires drug release by continuous intravenous (i.v.) infusion as a function of its short elimination half-life. The longer intrinsic half-lives of the BCMA-targeted trypecific proteins address this issue, thereby allowing for increased therapeutic potential, such as low-dose pharmaceutical formulations, decreased periodic administration and / or new pharmaceutical compositions.
[106] [106] The BCMA-directed triespecific proteins described in this specification also have an optimal size for increased tissue penetration and tissue distribution. Larger sizes limit or prevent the penetration or distribution of the protein in the target tissues. The specific BCMA-directed proteins described in this specification prevent this by having a small size that allows increased tissue penetration and distribution. Consequently, the specific BCMA-directed proteins described in this specification, in some embodiments, have a size of about 50 kD to about 80 kD, about 50 kD to about 75 kD, about 50 kD to about 70 kD or about 50 kD to about 65 kD. Thus, the size of the specific proteins directed to BCMA is advantageous in relation to IgG antibodies that have about 150 kD and to the diabody molecules BiTE and DART that have about 55 kD, but do not have an extended half-life and, therefore, are cleared quickly through the kidney.
[107] [107] In additional modalities, the BCMA-directed trypecific proteins described in this “descriptive report have an optimal size for increased tissue penetration and distribution. In these modalities, the specific proteins targeting BCMA are built to be as small as possible while retaining specificity for their targets.
[108] [108] In yet other modalities, the BCMA-binding domain of BCMA-directed specific proteins described in this specification includes a knotin peptide for BCMA binding. Knotins are disulfide-stabilized peptides with a cysteine knot framework and have average sizes of about 3.5 kD. Knotins have been contemplated for binding to certain tumor molecules, such as BCMA. In additional embodiments, the BCMA-binding domain of BCMA-directed specific proteins described in this specification comprises a natural BCMA ligand.
[109] [109] Another characteristic of the BCMA-directed trypecific proteins described in this specification is that they are of a unique polypeptide design with flexible binding of their domains. This allows for easy production and manufacture of the specific proteins targeted to BCMA, as they can be encoded by a single cDNA molecule to be easily incorporated into a vector. In addition, since the BCMA-directed triespecific proteins described in this specification are a single monomeric polypeptide chain, there are no issues related to chain matching or the need for dimerization. It is contemplated that the specific BCMA-directed proteins described in this specification have a reduced tendency to aggregate, unlike other molecules reported, for example, bispecific proteins with Fc-gamma immunoglobulin domains.
[110] [110] In the BCMA-directed triespecific proteins described in this specification, the domains are linked by internal linkers Ll1 and L2, where Ll binds the first and second domains of the specific proteins directed to BCMA and L2 links the second and third domains of proteins tries specific to BCMA. The L1 and L2 linkers have an optimized length and / or amino acid composition. In some embodiments, the L1 and L2 linkers are of the same length and amino acid composition. In other modalities, Ll and L2 are different. In certain embodiments, the internal linkers Ll1 and / or L2 are "short", that is, they consist of O, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 amino acid residues . Thus, in certain cases, the internal linkers consist of about 12 or less amino acid residues. In the case of The amino acid residue, the internal linker is a peptide bond. In certain embodiments, the internal linkers L1 and / or L2 are "long", that is, "consist of" 15, 20 or 25 amino acid residues. In some embodiments, these internal linkers consist of about 3 to about 15, for example, 8, 9 or 10 contiguous amino acid residues. Regarding the amino acid composition of the internal linkers Ll1 and L2, the peptides are selected with properties that give flexibility to the specific proteins directed to BCMA, do not interfere with the binding domains, as well as resist cleavage by proteases. For example, glycine and serine residues generally provide protease resistance. Examples of suitable internal linkers for binding domains in BCMA-targeted trypecific proteins include, without limitation, (GS) n (SEQ ID NO: 472), (GGS) n (SEQ ID NO: 473), (GGGS) n (SEQ ID NO: 474), (GGSG) N (SEQ ID NO: 475), (GGSGG) n (SEQ ID NO: 476), (GGGGS) n ( SEQ ID NO: 477), (GGGGG) n (SEQ ID NO: 478), or (GGG) n (SEQ ID NO: 479), where n is 1, 2, 3 , 4, 5, 6, 7, 8, 9 or 10. In one embodiment, the internal linker L1 and / or L2 is (GGGGS) 4 (SEQ ID. No.: 480) or (GGGGS) 3 (ID. SEQ. No.: 481).
[111] [111] The specificity of the T cell response is mediated by the recognition of an antigen (displayed in the context of a major histocompatibility complex, MHC) by the TCR. As part of the TCR, CD3 is a protein complex that includes a CD3y chain (gamma), a CD35 chain (delta) and two CD3e chains (epsilon) that are present on the cell surface. CD3 associates with the a (alpha) and B (beta) chains of the TCR, as well as CD3 7 (zeta) together, to understand the complete TCR. Clustering of CD3 into T cells, for example, by immobilized anti-CD3 antibodies, leads to T cell activation, similar to T cell receptor engagement, but regardless of its typical clone specificity.
[112] [112] In one aspect, the BCMA-directed trypecific proteins described in this specification comprise a domain that specifically binds to CD3. In one aspect, the BCMA-targeted proteins described in this specification comprise a domain that specifically binds to human CD3. In some embodiments, the specific BCMA-directed proteins described in this specification comprise a domain that specifically binds to CD3y. In some modalities, the specific BCMA-directed proteins described in this specification comprise a domain that specifically binds to CD35. In some embodiments, the specific BCMA-directed proteins described in this specification comprise a domain that specifically binds to CD3re.
[113] [113] In additional embodiments, the BCMA-directed trypecific proteins described in this specification comprise a domain that specifically binds to the TCR. In certain cases, the specific BCMA-directed proteins described in this specification comprise a domain that specifically binds to the TCR a chain. In certain cases, the specific BCMA-directed proteins described in this specification comprise a domain that specifically binds to the B chain of the TCR.
[114] [114] In some embodiments, the CDMA-binding antigen-specific protein CD3-binding domain may be any domain that binds to CD3 including, without limitation, domains of a monoclonal antibody, a polyclonal antibody, a recombinant antibody , a human antibody, a humanized antibody. In some cases, it is beneficial for the CD3-binding domain to be derived from the same species in which the BCMA-directed trypecific antigen-binding protein will ultimately be used. For example, for use in humans, it may be beneficial that the CDMA-binding domain of the specific BCMA-directed antigen-binding protein comprises human or humanized residues from the antigen-binding domain of an antibody or antibody fragment.
[115] [115] Thus, in one aspect, the antigen-binding domain comprises a humanized or human antibody or antibody fragment, or a murine antibody or antibody fragment. In one embodiment, the humanized or human anti-CD3 binding domain comprises one or more (for example, all three) of the complementary determining region of light chain 1 (LC CDR1), the complementary determining region of light chain 2 (LC CDR2) and light chain 3 complementarity determining region (LC CDR3) of a humanized or human anti-CD3 binding domain described in that specification, and / or one or more (for example, all three) of the complementarity determining region heavy chain 1 (HC CDR1), heavy chain 2 complementarity determining region (HC CDR2) and heavy chain 3 complementarity determining region (HC CDR3) of a humanized or human anti-CD3 binding domain described in that specification, for example, a humanized or human anti-CD3 binding domain comprising one or more, for example, all three, LC CDRs and one or more, for example, all three, HC CDRs.
[116] [116] In some embodiments, the humanized or human anti-CD3 binding domain comprises a CD3-specific humanized or human light chain variable region, where the CD3-specific light chain variable region comprises human or non-human CDRs human resources in a framework region of the human light chain. In certain cases, the light chain framework region is a light chain A (lambda) framework. In other cases, the light chain framework region is a light chain x (kappa) framework.
[117] [117] In some embodiments, the humanized or human anti-CD3 binding domain comprises a CD3 specific humanized or human heavy chain variable region, where the CD3 specific heavy chain variable region comprises human or non-human heavy chain CDRs human resources in a framework region of the human heavy chain.
[118] [118] In certain cases, the complementarity determining regions of the heavy chain and / or the light chain are derived from anti-CD3 antibodies known, for example, muromonab-CD3 (OKT3), otelixizumab (TRX4), teplizumab (MGAO31) , visilizumab (Nuvion), SP34, TR-66 or Xx35-3, VIT3, BMAO30O (BW264 / 56), CLB-T3 / 3, CRIS7, YTH12.5, F111-409, CLB-T3.4.2, TR-66 , WT32, SPv-T3b, 11D8, XIII-l41, XIII-46, XIII-87, 12F6, T3 / RW2-8C8, T3 / RW2-4B6, OKT3D, M-T301, SMC2, F101.01, UCHT-1 and WT-31.
[119] [119] In one embodiment, the anti-CD3 binding domain is a single chain variable fragment (scFv) comprising a light chain and a heavy chain of an amino acid sequence provided in that specification.
[120] [120] In some cases, scFvs that bind to CD3 are prepared according to known methods. For example, scFv molecules can be produced by linking VH and VL regions together with the use of flexible polypeptide linkers. The scFv molecules comprise an scFv linker (e.g., a Ser-Gly linker) with an optimized length and / or amino acid composition. Consequently, in some embodiments, the length of the scFv linker is such that the VH or VL domain can associate intermolecularly with the other variable domain to form the CD3 binding site. In certain embodiments, these scFv linkers are "short", that is, they consist of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 amino acid residues. Thus, in certain cases, scFv linkers consist of about 12 or less amino acid residues. In the case of The amino acid residue, the scFv linker is a peptide bond. In some embodiments, these scFv linkers consist of about 3 to about 15, for example, 8, 9 or 10 contiguous amino acid residues. Regarding the amino acid composition of the scFv linkers, peptides are selected that confer flexibility, do not interfere with variable domains, as well as allow inter-chain folding to join the two variable domains to form a functional CD3 binding site. For example, scFv linkers that comprise glycine and serine residues generally provide protease resistance. In some embodiments, linkers in an scFv comprise glycine and serine residues. The amino acid sequence of scFv linkers can be optimized, for example, by phage display methods to increase binding to CD3 and the production yield of scFv. Examples of suitable peptide scFv linkers for binding a variable light domain and a variable heavy domain in an scFv include, without limitation, (GS) n (SEQ ID. NO: 472), (GGS) n (ID. SEQ. NO .: 473), (GGGS) n (SEQ ID. NO .: 474), (GGSG) n (SEQ ID. NO .: 475), (GGSGG) n (SEQ ID. 476), (GGGGS) n (SEQ ID NO: 477), (GGGGG) n (SEQ ID NO: 478), or (GGG) n (SEQ ID NO: 479), in that n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In one embodiment, the internal linker L1 and / or L2 is (GGGGS) s (SEQ ID.: 480) or (GGGGS); (SEQ ID. NO .: 481). Variation in the length of the linker can retain or increase activity, giving rise to superior effectiveness in activity studies.
[121] [121] In some embodiments, the BCMA-directed antigen-binding protein CD3 binding domain has an affinity for CD3 in cells that express CD3 with a Kp of 1,000 nM or less, 500 nM or less, 200 nM or less , 100 nM or less, 80 nM or less, 50 nM or less, 20 nM or less, 10 nM or less, 5 nM or less,
[122] [122] The affinity to bind to CD3 can be determined, for example, by the ability of the triespecific antigen-binding protein to target BCMA itself or its CD3-binding domain to bind to CD3 coated on an assay plate. ; displayed on the surface of a microbial cell; in solution etc. The binding activity of the BCMA-specific antigen-binding protein itself or its CD3-binding domain of the present disclosure to CD3 can be tested by immobilizing the ligand (eg, CD3) or the specific antigen-binding protein directed to BCMA itself or its CD3 binding domain, to a microparticle, substrate, cell etc. Agents can be added in an appropriate buffer and the binding partners incubated for a period of time at a certain temperature. After washing to remove unbound material, the bound protein can be released with, for example, SDS, high pH buffers, and the like, and analyzed, for example, by Surface Plasmon Resonance (SPR).
[123] [123] This specification describes domains that extend the half-life of an antigen-binding domain. Such domains are contemplated to include, without limitation, albumin-binding domains, Fc domains, small molecules, and other half-life extension domains known in the art.
[124] [124] Human albumin (ALB) (molecular mass of about 67 kDa) is the most abundant protein in plasma, present at about 50 mg / ml (600 µM), and has a half-life of about 20 days in humans. ALB serves to maintain the pH of the plasma, contributes to colloidal blood pressure, functions as a carrier for many metabolites and fatty acids, and serves as an important drug transport protein in the plasma.
[125] [125] The non-covalent association with albumin extends the elimination half-life of short-lived proteins. For example, a recombinant fusion of an albumin-binding domain to a Fab fragment resulted in an in vivo clearance of 25- and 58-fold and a half-life extension of 26 and 37-fold when administered intravenously to mice and rabbits, respectively, when compared to the administration of the Fab fragment alone. In another example, when insulin is acylated with fatty acids to promote the association with albumin, a prolonged effect was observed when injected subcutaneously in rabbits or pigs. Taken together, these studies demonstrate a link between binding to albumin and prolonged action.
[126] [126] In one respect, the BCMA-directed trypecific proteins described in this specification include a half-life extension domain, for example,
[127] [127] The BCMA-directed antigen-specific protein half-life extension domain provides altered pharmacodynamics and pharmacokinetics of the BCMA-specific antigen-binding protein itself. As above, the half-life extension domain extends the elimination half-life. The half-life extension domain also alters pharmacodynamic properties, including alteration of tissue distribution, penetration and diffusion of the triespecific antigen-binding protein. In some embodiments, the half-life extension domain provides tissue targeting (including tumor), increased tissue distribution, tissue penetration, diffusion into the tissue, and increased efficacy when compared to a protein without a half-extension domain life. In one embodiment, therapeutic methods effectively and efficiently use a reduced amount of the trypecific antigen-binding protein, resulting in reduced side effects, for example, reduced cytotoxicity to non-tumor cells.
[128] [128] In addition, the binding affinity of the half-life extension domain can be selected to target a specific elimination half-life in a particular specific antigen-binding protein. Thus, in some modalities, the half-life extension domain has a high bonding affinity. In other modalities, the half-life extension domain has a medium bonding affinity. In yet other modalities, the half-life extension domain has a low or marginal bonding affinity. Exemplary binding affinities include KD concentrations of 10 nM or less (high), between 10 nM and 100 nM (medium), and greater than 100 nM (low). As above, binding affinities to ALB are determined by methods known as, for example, Surface Plasmon Resonance (SPR).
[129] [129] In some embodiments, the ALB-binding domains described in that specification comprise a single domain antibody.
[130] [130] B cell maturation antigen (BCMA, TNFRSF17, CD269) is a transmembrane protein that belongs to the superfamily of the tumor necrosis receptor (TNFR) family that is expressed primarily in terminally differentiated B cells. BCMA expression is restricted to the B cell line and is present mainly in plasma cells and plasmoblasts and, to some degree, in memory B cells, but is practically absent in peripheral and naive B cells. BCMA is also expressed in multiple myeloma (MM) cells, in leukemia cells and lymphoma cells.
[131] [131] BCMA was identified by means of molecular analysis of a t (4; 16) translocation (926; p13 found in a human intestinal T cell lymphoma and an in frame sequence was mapped to the chromosome band 16p13.1.
[132] [132] The human BCMA cDNA has a 552 bp open reading frame that encodes a 184 amino acid polypeptide. The BCMA gene is organized into three exons that are separated by two introns, each flanked by GT donor and AG acceptor splicing sites, and encodes a 1.2 kb transcript. The structure of the BCMA protein includes an integral transmembrane protein based on a central hydrophobic region of 24 amino acids in an alpha helix structure.
[133] [133] The murine BCMA gene is located on synthetic chromosome 16 to the human 16pl3 region, and also includes three exons that are separated by two introns. The gene encodes a 185-amino acid protein. The murine BCMA mRNA is expressed as a 404 bp transcript at the highest levels in plasmacytoma cells (J558) and at modest levels in the A20 B cell lymphoma lineage. Murine BCMA mRNA transcripts have also been detected at low levels in T cell lymphoma (EL4, BW5147) and dendritic cell lines (CB1ID6, D2SCl) in contrast to human cell lines originating from T cells and dendritic cells. The murine BCMA cDNA sequence has 69.3% nucleotide identity with the human BCMA cDNA sequence and slightly higher identity (73.7%) when the coding regions between these two cDNA sequences are compared. The mouse BCMA protein is 62% identical to the human BCMA protein and, like human BCMA, contains a single hydrophobic region, which can be an internal transmembrane segment. The N-terminal 40 amino acid domain of both murine BCMA protein and human BCMA protein has six conserved cysteine residues consistent with the formation of a cysteine repeat motif found in the extracellular domain of TNFRs. Similar to members of the TNFR superfamily, the BCMA protein contains an aromatic residue conserved four to six C-terminal residues from the first cysteine.
[134] [134] BCMA is not expressed on the cell surface, but is instead located on the Golgi apparatus. The amount of BCMA expression is proportional to the stage of cell differentiation (the largest in plasma cells).
[135] [135] He is involved in the development and homeostasis of B cells due to their interaction with their BAFF ligands (cell activation factor B, also called TALL-l or TNFSF13B) and APRIL (proliferation-inducing ligand A).
[136] [136] BCMA regulates different aspects of humoral immunity, development and B cell homeostasis in conjunction with its members of the family TACI (transmembrane and interacting activator of the cyclophilin ligand) and BAFF-R (receptor for cell activation factor B, also known as a 13C member of the tumor necrosis factor receptor superfamily). BCMA expression appears late in B cell differentiation and contributes to long-term survival of plasmoblasts and plasma cells in bone marrow. BCMA also supports the growth and survival of multiple myeloma (MM) cells.
[137] [137] BCMA is known primarily for its functional activity in mediating the survival of plasma cells that maintain long-term humoral immunity.
[138] [138] There is a need for treatment options for diseases of solid tumors related to BCMA overexpression, for example, cancer, multiple myeloma, leukemias and lymphomas. The present disclosure provides, in certain embodiments, single domain proteins that specifically bind to BCMA on the surface of tumor target cells.
[139] [139] The design of the specific BCMA-directed proteins described in this specification allows the BCMA-binding domain to be flexible, where the BCMA-binding domain can be any type of binding domain including, without limitation, domains of one monoclonal antibody, a polyclonal antibody, a recombinant antibody, a human antibody, a humanized antibody.
[140] [140] In some embodiments, the BCMA-binding domain binds to a protein that comprises the ID sequence. SEQ. No. 469, 470 or 471. In some embodiments, the BCMA-binding domain binds to a protein that comprises a truncated sequence compared to ID. SEQ. No. 469, 470 or 471.
[141] [141] In some embodiments, the BCMA-binding domain is an antibody or an anti-BCMA antibody variant. As used in this specification, the term "antibody variant" refers to variants and derivatives of an antibody described in this specification. In certain embodiments, variants of the amino acid sequence of the anti-BCMA antibodies described in this specification are contemplated. For example, in certain embodiments, variants of the anti-BCMA antibody amino acid sequence described in that specification are contemplated to increase the binding affinity and / or other biological properties of the antibodies. An exemplary method for the preparation of amino acid variants includes, without limitation, the introduction of appropriate modifications to the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions of, and / or insertions in and / or substitutions of residues within the antibody's amino acid sequences.
[142] [142] Any combination of deletion, insertion and substitution can be done to arrive at the final construction, as long as the final construction has the desired characteristics, for example, antigen binding. In certain embodiments, antibody variants are provided that have one or more amino acid substitutions. Sites of interest for substitution mutagenesis include CDRs and framework regions. Examples of such substitutions are described below. Amino acid substitutions can be introduced into an antibody of interest and the products evaluated for desired activity, for example, retained / increased antigen binding, decreased immunogenicity or increased T-cell-mediated cytotoxicity (TDCC). Both conservative and non-conservative amino acid substitutions are contemplated for the preparation of antibody variants.
[143] [143] In another example of a substitution to create a variant anti-BCMA antibody, one or more residues from the hypervariable region of a parental antibody are replaced. In general, variants are then selected based on improvements in desired properties, compared to a parent antibody, for example, increased affinity, reduced affinity, reduced immunogenicity, increased dependence on pH binding.
[144] [144] In some embodiments, the BCMA binding domain of the tries specific to BCMA is a single domain antibody, for example, a heavy chain variable (VH) domain, a variable domain (VHH) of an sdAb derived from llama, a peptide, a linker or a small molecule entity specific to BCMA. In some embodiments, the BCMA-binding domain of the specific BCMA-directed protein described in this specification is any domain that binds to BCMA including, without limitation, domains of a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a human antibody , a humanized antibody. In certain embodiments, the BCMA-binding domain is a single domain antibody. In other embodiments, the BCMA-binding domain is a peptide. In additional embodiments, the BCMA-binding domain is a small molecule.
[145] [145] It should generally be noted that the term “single domain antibody”, as used in this specification in its broadest sense, is not limited to a specific biological source or a specific preparation method. Single domain antibodies are antibodies whose complementarity-determining regions are part of a single domain polypeptide. Examples include, without limitation, heavy chain antibodies, antibodies naturally devoid of light chains, single domain antibodies derived from conventional 4-chain antibodies, genetically modified antibodies and single domain frameworks other than those derived from antibodies. Single domain antibodies can be any of the art, or any future single domain antibodies. Single-domain antibodies can be derived from any species including, without limitation, mice, humans, camels, llama, goats, rabbits, cattle. For example, in some embodiments, the single domain antibodies of the disclosure are obtained: (1) by isolating the VHH domain from a naturally occurring heavy chain antibody; (2) by expression of a nucleotide sequence that encodes a naturally occurring VHH domain; (3) by "humanizing" a naturally occurring VHH domain or by expressing a nucleic acid encoding such a humanized VHH domain; (4) by “camelizing” a naturally occurring VH domain of any animal species and, in particular, a mammalian species, for example, a human being, or by expression of a nucleic acid encoding a camelized VH domain of this type; (5) by "camelizing" a "domain antibody" or "Dab", or by expression of a nucleic acid encoding such a camelized VH domain; (6) by using synthetic or semi-synthetic techniques for the preparation of proteins, polypeptides or other amino acid sequences; (7) by preparing a nucleic acid that encodes a single domain antibody using techniques for nucleic acid synthesis known in the field, followed by expression of the nucleic acid thus obtained; and / or (8) by any combination of one or more of those mentioned above.
[146] [146] In one embodiment, a single domain antibody corresponds to the VHH domains of naturally occurring heavy chain antibodies directed against BCMA. As further described in that specification, these VHH sequences can generally be generated or obtained by properly immunizing a species of Llama with BCMA, (ie, in order to elicit an immune response and / or heavy chain antibodies directed against BCMA), by obtaining an appropriate biological sample from said Llama (for example, a blood sample, serum sample or B cell sample), and by generating VHH sequences directed against BCMA from that sample, using any suitable technique known in the field.
[147] [147] In another embodiment, these naturally occurring VHH domains against BCMA are obtained from naive libraries of camelid VHH sequences, for example, by evaluating that library using BCMA, or at least part, fragment, antigenic determinant or epitope using one or more assessment techniques known in the field. Such libraries and techniques are described, for example, in WO 99/37681, WO 01/90190, WO 03/025020 and WO 03/035694. Alternatively, enhanced synthetic or semi-synthetic libraries derived from naive VHH libraries are used, for example, VHH libraries obtained from naive VHH libraries by techniques such as, for example, random mutagenesis and / or CDR shuffling such as, for example, described in WO 00/43507.
[148] [148] In an additional embodiment, yet another technique for obtaining VHH sequences directed against BCMA, involves adequate immunization of a transgenic mammal that is capable of expressing heavy chain antibodies (ie,
[149] [149] In some embodiments, a single-domain anti-BCMA antibody to the BCMA-directed protein tries to comprise a single-domain antibody with an amino acid sequence that corresponds to the amino acid sequence of a naturally occurring VHH domain, but which was “ humanized ”, that is, by replacing one or more amino acid residues in the amino acid sequence of the said naturally occurring VHH sequence (and, in particular, in the framework sequences) with one or more of the amino acid residues that occur in the position (or positions) corresponding to a VH domain of a conventional 4-chain antibody from a human (for example, as indicated above). This can be done in a manner known in the field, which will be evident to those skilled in the art, for example, based on the additional description in this specification. Again, it should be noted that these single-domain, humanized anti-BCMA antibodies from the disclosure are obtained in any way known to you (i.e., as indicated under points (1) - (8) above) and are therefore not strictly limited to the polypeptides that were obtained using a polypeptide that comprises a naturally occurring VHH domain as a starting material.
[150] [150] Other methods and techniques suitable for obtaining the anti-BCMA single domain antibody of the disclosure and / or nucleic acids encoding it, starting from naturally occurring VH sequences or VHH sequences, for example, comprise the combination of one or more more parts of one or more naturally occurring VH sequences (for example, one or more framework sequences (FR) and / or sequences of the complementarity determining region (CDR)), one or more parts of one or more naturally occurring VHH sequences (for example, one or more FR sequences or CDR sequences), and / or one or more synthetic or semi-synthetic sequences, in a suitable manner, to provide a single domain anti-BCMA antibody from the disclosure or a sequence nucleotides or nucleic acid encoding it.
[151] [151] In some embodiments, the BCMA binding domain is a specific anti-BCMA antibody comprising a variable complementarity determining region of the CDR1 heavy chain, a CDR2 variable heavy chain, a CDR3 variable heavy chain, a CDR1l variable light chain , a CDR2 variable light chain and a CDR3 variable light chain. In some embodiments, the BCMA-binding domain comprises any domain that binds to BCMA including, without limitation, domains of a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a human antibody, a humanized antibody, or fragments binding to the antigens such as single domain antibodies (sdAb), Fab, Fab ', F (ab) fragments, and Fv, fragments composed of one or more CDRs, single chain antibodies (e.g., single chain Fv fragments ( scFv)), disulfide stabilized Fv fragments (dsEFv), heteroconjugate antibodies (for example, bispecific antibodies), pFv fragments, heavy chain monomers or dimers, light chain monomers or dimers, and dimers consisting of one heavy chain and one light chain. In some embodiments, the BCMA-binding domain is a single domain antibody. In some embodiments, the anti-BCMA single domain antibody comprises variable complementarity determining regions of the heavy chain (CDR), CDR1, CDR2 and CDR3.
[152] [152] In some embodiments, the BCMA-binding protein of the present disclosure is a polypeptide that comprises an amino acid sequence that is composed of four framework regions / sequences (f1-f4) interrupted by three complementarity determining regions / sequences, such as represented by the formula: fl-rl-f2-r2-f3-r3-f4, where rl, r2 and r3 are complementarity determining regions CDR1, CDR2 and CDR3, respectively, and fl, f £ 2, £ 3 and f4 are structural waste. The rl residues of the BCMA-binding protein of the present disclosure comprise, for example, amino acid residues 26, 27, 28, 29, 30, 31, 32, 33 and 34; the r2 residues of the BCMA-binding protein of the present disclosure comprise, for example, amino acid residues, for example, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59.60, 61, 62 and 63; and the r3 residues of the BCMA-binding protein of the present disclosure comprise, for example, amino acid residues, for example, 97, 98, 99, 100, 101, 102, 103 104, 105, 106, 107 and 108. In some modalities, the BCMA-binding protein comprises an amino acid sequence selected from the IDS. SEQ. No. 346-460.
[153] [153] In one embodiment, CDR1 does not comprise an amino acid sequence from ID. SEQ. No. 599. In one embodiment, CDR2Q does not comprise an amino acid sequence from ID. SEQ. No. 600. In one embodiment, CDR3 does not comprise an amino acid sequence from ID. SEQ. No.: 601.
[154] [154] In some embodiments, CDR1 comprises the amino acid sequence as shown in the ID. SEQ. Nº: 1 or a variant of this that has one, two, three, four, five, six, seven, eight, nine or ten amino acid substitutions. An exemplary CDR1 comprises the amino acid sequence as shown in the ID. SEQ. No.: 4. Another exemplary CDR1l comprises the amino acid sequence as shown in the ID. SEQ. No.: 5. Another exemplary CDRl1l comprises the amino acid sequence as shown in the ID. SEQ. No.: 6. Another exemplary CDR1 comprises the amino acid sequence as shown in the ID. SEQ. No.: 7. Another exemplary CDR1l comprises the amino acid sequence as shown in the ID. SEQ. No.: 8. Another exemplary CDR1 comprises the amino acid sequence as shown in the ID. SEQ. No.: 9. Another exemplary CDR1 comprises the amino acid sequence as shown in the ID. SEQ. No.: 10. Another exemplary CDR1l comprises the amino acid sequence as shown in the ID. SEQ. No.: 11. Another exemplary CDR1 comprises the amino acid sequence as shown in the ID. SEQ. No.: 12. Another exemplary CDR1 comprises the amino acid sequence as shown in the ID. SEQ. No.
[155] [155] In some embodiments, CDR2 comprises a sequence as shown in the ID. SEQ. Nº: 2 or a variant that has one, two, three, four, five, six, seven, eight, nine or ten amino acid substitutions in the ID. SEQ. No.: 2. Another exemplary CDR2 comprises the amino acid sequence as shown in the ID. SEQ. No. 118. Another exemplary CDR2 comprises the amino acid sequence as shown in the ID. SEQ. No. 119. Another exemplary CDR2 comprises the amino acid sequence as shown in the ID. SEQ. No. 120. Another exemplary CDR2 comprises the amino acid sequence as shown in the ID. SEQ. No.
[156] [156] In some embodiments, CDR3 comprises a sequence as shown in the ID. SEQ. Nº: 3 or a variant that has one, two, three, four, five, six, seven, eight, nine or ten amino acid substitutions in the ID. SEQ. No.: 3. Another exemplary CDR3 comprises the amino acid sequence as shown in the ID. SEQ. No.: 232. Another exemplary CDR3 comprises the amino acid sequence as shown in the ID. SEQ. No.: 233. Another exemplary CDR3 comprises the amino acid sequence as shown in the ID. SEQ. No.: 234. Another exemplary CDR3 comprises the amino acid sequence as shown in the ID. SEQ. No.
[157] [157] In various embodiments, the BCMA-binding protein of the present disclosure has a CDR1 that has an amino acid sequence that is at least about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% identical to an amino acid sequence selected from the IDS. SEQ. No. 4-117.
[158] [158] In various embodiments, the BCMA-binding protein of the present disclosure has a CDR2 that has an amino acid sequence that is at least about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% identical to an amino acid sequence selected from the IDS. SEQ. No. 118-231.
[159] [159] In various embodiments, a BCMA-binding protein complementarity determining region of the present disclosure has a CDR3 that has an amino acid sequence that is at least about 10%, about 20%, about 30%, about about 40%, about 50%, about 60%, about 70%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to an amino acid sequence selected from the IDS. SEQ. No.: 232-345.
[160] [160] In various embodiments, a BCMA-binding protein of the present disclosure has an amino acid sequence that is at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to an amino acid sequence selected from the IDS. SEQ. No. 346-460.
[161] [161] In various embodiments, a BCMA-binding protein of the present disclosure has a framework 1 (fl) that has an amino acid sequence that is at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%,
[162] [162] In various embodiments, a BCMA-binding protein of the present disclosure has a framework 2 (f £ 2) that has an amino acid sequence that is at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% identical to the amino acid sequence shown in the ID. SEQ. No. 463.
[163] [163] In various embodiments, a BCMA-binding protein of the present disclosure has a framework 3 (f £ 3) that has an amino acid sequence that is at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100% identical to the amino acid sequence shown in the ID. SEQ. No. 464 or ID. SEQ. No. 465.
[164] [164] In various embodiments, a BCMA-binding protein of the present disclosure has a framework 4 (f4) that has an amino acid sequence that is at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 81%,
[165] [165] In some embodiments, the BCMA-binding protein is a single domain antibody that comprises the ID sequence. SEQ. No. 346. In some embodiments, the BCMA-binding protein is a single domain antibody that comprises the ID sequence. SEQ. No. 347. In some embodiments, the BCMA-binding protein is a single domain antibody that comprises the ID sequence. SEQ. No.
[166] [166] In some embodiments, the BCMA-binding protein is a single domain antibody that comprises the ID sequence. SEQ. No. 360. In some embodiments, the BCMA-binding protein is a single domain antibody that comprises the ID sequence. SEQ. No. 361. In some embodiments, the BCMA-binding protein is a single domain antibody that comprises the ID sequence. SEQ. No.
[167] [167] In some embodiments, the BCMA-binding protein is a single domain antibody that comprises the ID sequence. SEQ. No. 370. In some embodiments, the BCMA-binding protein is a single domain antibody that comprises the ID sequence. SEQ. No. 371. In some embodiments, the BCMA-binding protein is a single domain antibody that comprises the ID sequence. SEQ. No.
[168] [168] In some embodiments, the BCMA-binding protein is a single domain antibody comprising the ID sequence. SEQ. No. 380. In some embodiments, the BCMA-binding protein is a single domain antibody that comprises the ID sequence. SEQ. No. 381. In some embodiments, the BCMA-binding protein is a single domain antibody that comprises the ID sequence. SEQ. No.
[169] [169] In some embodiments, the BCMA-binding protein is a single domain antibody that comprises the ID sequence. SEQ. No. 390. In some embodiments, the BCMA-binding protein is a single domain antibody that comprises the ID sequence. SEQ. No. 391. In some embodiments, the BCMA-binding protein is a single domain antibody that comprises the ID sequence. SEQ. No.
[170] [170] In some embodiments, the BCMA-binding protein is a single domain antibody that comprises the ID sequence. SEQ. No. 400. In some embodiments, the BCMA-binding protein is a single domain antibody that comprises the ID sequence. SEQ. No. 401. In some embodiments, the BCMA-binding protein is a single domain antibody that comprises the ID sequence. SEQ. No.
[171] [171] In some embodiments, the BCMA-binding protein is a single domain antibody comprising the ID sequence. SEQ. No. 410. In some embodiments, the BCMA-binding protein is a single domain antibody that comprises the ID sequence. SEQ. No. 411. In some embodiments, the BCMA-binding protein is a single domain antibody that comprises the ID sequence. SEQ. No.
[172] [172] In some embodiments, the BCMA-binding protein is a single domain antibody that comprises the ID sequence. SEQ. No. 420. In some embodiments, the BCMA-binding protein is a single domain antibody that comprises the ID sequence. SEQ. No. 421. In some embodiments, the BCMA-binding protein is a single domain antibody that comprises the ID sequence. SEQ. No.
[173] [173] In some embodiments, the BCMA-binding protein is a single domain antibody comprising the ID sequence. SEQ. No. 430. In some embodiments, the BCMA-binding protein is a single domain antibody that comprises the ID sequence. SEQ. No. 431. In some embodiments, the BCMA-binding protein is a single domain antibody that comprises the ID sequence. SEQ. No.
[174] [174] In some embodiments, the BCMA-binding protein is a single domain antibody that comprises the ID sequence. SEQ. No. 440. In some embodiments, the BCMA-binding protein is a single domain antibody that comprises the ID sequence. SEQ. No. 441. In some embodiments, the BCMA-binding protein is a single domain antibody that comprises the ID sequence. SEQ. No.
[175] [175] In some embodiments, the BCMA-binding protein is a single domain antibody that comprises the ID sequence. SEQ. No. 450. In some embodiments, the BCMA-binding protein is a single domain antibody that comprises the ID sequence. SEQ. No. 451. In some embodiments, the BCMA-binding protein is a single domain antibody that comprises the ID sequence. SEQ. No.
[176] [176] A BCMA-binding protein described in this specification can bind to human BCMA with an hKd range of about 0.1 nM to about 500 nM. In some embodiments, hKd ranges from about 0.1 nM to about 450 nM. In some embodiments, hKd ranges from about 0.1 nM to about 400 nM. In some embodiments, hKd ranges from about 0.1 nM to about 350 nM. In some embodiments, hKd ranges from about 0.1 nM to about 300 nM. In some embodiments, hKd ranges from about 0.1 nM to about 250 nM. In some embodiments, hKd ranges from about 0.1 nM to about 200 nM. In some embodiments, hKd ranges from about 0.1 nM to about 150 nM. In some embodiments, hKd ranges from about 0.1 nM to about 100 nM. In some embodiments, hKd ranges from about 0.1 nM to about 90 nM. In some embodiments, hKd ranges from about 0.2 nM to about 80 nM. In some embodiments, hKd ranges from about 0.3 nM to about 70 nM. In some embodiments, hKd ranges from about 0.4 nM to about 50 nM. In some embodiments, hKd ranges from about 0.5 nM to about 30 nM. In some embodiments, hKd ranges from about 0.6 nM to about 10 nM. In some embodiments, hKd ranges from about 0.7 nM to about 8 nM. In some embodiments, hKd ranges from about 0.8 nM to about 6 nM. In some embodiments, hKd ranges from about 0.9 nM to about 4 nM. In some embodiments, hKd ranges from about 1 nM to about 2 nM.
[177] [177] In some embodiments, any of the aforementioned BCMA binding domains are labeled with an affinity peptide to facilitate purification. In some embodiments, the affinity peptide marker consists of six consecutive histidine residues, also called a His tag or 6X-his (His-His-His-His-His-His; SEQ ID NO: 471) .
[178] [178] In certain embodiments, the BCMA-binding domains of the present disclosure preferentially bind to membrane-bound BCMA over soluble BCMA. Membrane-bound BCMA refers to the presence of BCMA on the cell membrane surface of a cell that expresses BCMA. Soluble BCMA refers to BCMA that is no longer on the cell membrane surface of a cell that expresses or expressed BCMA. In certain cases, soluble BCMA is present in the blood and / or lymphatic circulation in an individual. In one embodiment, BCMA-binding domains bind to membrane-bound BCMA at least 5 times, 10 times, 15 times, 20 times, times, 30 times, 40 times, 50 times, 100 times, 500 times, or 1,000 times more than soluble BCMA. In one embodiment, the specific antigen-binding proteins directed to the BCMA of the present disclosure preferentially bind to membrane-bound BCMA 30 times more than soluble BCMA. The determination of the preferential binding of an antigen-binding protein to membrane-bound BCMA over soluble BCMA can be readily determined using assays well known in the art.
[179] [179] A specific BCMA-binding protein comprises an amino acid sequence selected from the group consisting of IDS. SEQ. No. 483-597.
[180] [180] In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No. 483. In one example, a specific BCMA-binding protein comprises a sequence of ID amino acids. SEQ. No. 484. In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No. 485. In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No. 486. In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No.
[181] [181] In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No. 500. In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No. 501. In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No. 502. In one example, a specific BCMA-binding protein comprises a sequence of ID amino acids. SEQ. No. 503. In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No.
[182] [182] In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No. 510. In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No. 511. In one example, a specific BCMA-binding protein comprises an ID amino acid sequence. SEQ. No. 512. In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No. 513. In one example, a specific BCMA-binding protein comprises a sequence of ID amino acids. SEQ. No.
[183] [183] In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No. 520. In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No. 521. In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No. 522. In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No. 523. In one example, a specific BCMA-binding protein comprises an ID amino acid sequence. SEQ. No.
[184] [184] In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No. 530. In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No. 531. In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No. 532. In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No. 533. In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No.
[185] [185] In one example, a specific BCMA-binding protein comprises an ID amino acid sequence. SEQ. No. 541. In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No. 542. In one example, a specific BCMA-binding protein comprises an ID amino acid sequence. SEQ. No. 543. In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No. 544. In one example, a specific BCMA-binding protein comprises a sequence of ID amino acids. SEQ. No.
[186] [186] In one example, a specific BCMA-binding protein comprises an amino acid sequence of ID. SEQ. No. 551. In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No. 552. In one example, a specific BCMA-binding protein comprises a sequence of ID amino acids. SEQ. No. 553. In one example, a specific BCMA-binding protein comprises an amino acid sequence of the ID. SEQ. No. 554. In one example, a specific BCMA-binding protein comprises an ID amino acid sequence. SEQ. No.
[187] [187] In one example, a specific BCMA-binding protein comprises an amino acid sequence of ID. SEQ. No. 560. In one example, a specific BCMA-binding protein comprises a sequence of ID amino acids. SEQ. No. 561. In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No. 562. In one example, a specific BCMA-binding protein comprises a sequence of ID amino acids. SEQ. No. 563. In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No.
[188] [188] In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No. 570. In one example, a protein binding to
[189] [189] In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No. 580. In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No. 581. In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No. 582. In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No. 583. In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No.
[190] [190] In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No. 590. In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No. 591. In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No. 592. In one example, a specific BCMA-binding protein comprises an ID amino acid sequence. SEQ. No. 593. In one example, a specific BCMA-binding protein comprises an amino acid sequence from ID. SEQ. No.
[191] [191] Polynucleotide molecules encoding an anti-BCMA triespecific binding protein described in this specification are also provided in some embodiments. In some embodiments, polynucleotide molecules are provided as a DNA construct. In other embodiments, the polynucleotide molecules are provided as a messenger RNA transcript.
[192] [192] Polynucleotide molecules are constructed by known methods, for example, by combining the genes encoding the three binding domains separated by peptide linkers or, in other modalities directly linked by a peptide link, into a single linked genetic construct operatively to a suitable promoter and, optionally, a suitable transcription terminator, and expressing it in bacteria or another appropriate expression system such as, for example, CHO cells. In modalities in which the BCMA-binding domain is a small molecule, polynucleotides contain genes that encode the CD3-binding domain and the half-life extension domain. In modalities in which the half-life extension domain is a small molecule, polynucleotides contain genes that encode domains that bind to CD3 and BCMA. Depending on the host and vector system used, any number of suitable transcription and translation elements, including constitutive and inducible promoters, can be used. The promoter is selected in such a way that it directs the expression of the polynucleotide in the respective host cell.
[193] [193] In some embodiments, the polynucleotide is inserted into a vector, preferably an expression vector, which represents an additional modality. This recombinant vector can be constructed according to known methods. Vectors of particular interest include plasmids, phagemids, phage derivatives, viruses (e.g., retroviruses, adenoviruses, adeno-associated viruses, herpes viruses, lentiviruses and the like) and cosmids.
[194] [194] Several expression vector / host systems can be used to contain and express the polynucleotide encoding the described specific antigen binding protein polypeptide. Examples of expression vectors for expression in E. coli are pSKK (Le Gall et al., J. Immunol. Methods. (2004) 285 (1): 111-27) or PpcDNAS (Invitrogen) for expression in mammalian cells.
[195] [195] Thus, the specific BCMA-targeted proteins as described in this specification, in some embodiments, are produced by introducing a vector that encodes the protein as described above into a host cell and culturing that host cell under conditions under which protein domains are expressed, can be isolated and, optionally, further purified.
[196] [196] The specific BCMA-directed antigen-binding proteins of the present disclosure may, in certain instances, be incorporated into a chimeric antigen (CAR) receptor. A genetically modified effector immune cell, for example, a T cell or NK cell, can be used to express a CAR that includes a specific anti-BCMA protein that contains a single domain anti-BCMA antibody as described in that specification. In one embodiment, the CAR that includes a specific anti-BCMA protein as described in this specification is connected to a transmembrane domain by means of a hinge region, plus a co-stimulatory domain, for example, a functional signaling domain obtained from OX40 , CD27, CD28, CD5, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278) or 4-1BB. In some embodiments, the CAR further comprises a sequence that encodes an intracellular signaling domain, for example, 4-1BB and / or CD3 zeta.
[197] [197] The specific BCMA-directed proteins described in this specification include derivatives or analogues in which: (i) an amino acid is replaced with an amino acid residue that is not encoded by the genetic code, (ii) the mature polypeptide is fused with another compound such as, for example, polyethylene glycol, or (iii additional amino acids are fused to the protein, for example, a leader or secretory sequence or a sequence for purifying the protein.
[198] [198] Typical modifications include, without limitation, acetylation, acylation, ADP-ribosylation, amidation, covalent adhesion of flavin, covalent adhesion of a heme portion, covalent adhesion of a nucleotide or nucleotide derivative, covalent adhesion of a lipid or derivative of lipid, covalent phosphatidylinositol adhesion, cross-linking, cyclization, disulfide bond formation,
[199] [199] Modifications are made anywhere in the specific BCMA-directed proteins described in this specification, including the peptide framework, the amino acid side chains and the amino or carboxyl termini. Certain modifications of common peptides that are useful for the modification of BCMA-directed trypecific proteins include glycosylation, lipid adhesion, sulfatization, gamma-carboxylation of glutamic acid residues, hydroxylation, blocking of the amino or carboxyl group on a polypeptide, or both, by a covalent modification, and ADP-ribosylation.
[200] [200] Pharmaceutical compositions comprising an anti-BCMA triespecific binding protein described in that specification, a vector comprising the polynucleotide encoding the polypeptide of the specific proteins targeting BCMA or a host cell transformed by this vector is at least one pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" includes, without limitation, any carrier that does not interfere with the effectiveness of the biological activity of the ingredients and that is not toxic to the patient to whom it is administered. Examples of suitable pharmaceutical carriers are well known in the art and include phosphate buffered saline solutions, water, emulsions, for example, oil / water emulsions, various types of wetting agents, sterile solutions, etc. These carriers can be formulated by conventional methods and can be administered to the individual in an appropriate dose. Preferably, the compositions are sterile. Such compositions can also contain adjuvants such as, for example, preservative agents, emulsifying agents and dispersing agents. The prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents. An additional embodiment provides one or more of the specific BCMA-directed proteins described above packaged in lyophilized form, or packaged in an aqueous medium.
[201] [201] In some modalities of pharmaceutical compositions, the specific BCMA-directed proteins described in this specification are encapsulated in nanoparticles. In some embodiments, nanoparticles are fullerenes, liquid crystals, liposomes, quantum dots, superparamagnetic nanoparticles, dendrimers or nanobonds. In other modalities of pharmaceutical compositions, the BCMA-directed antigen-specific protein is attached to liposomes. In some cases, the specific BCMA-directed antigen-binding proteins are conjugated to the surface of liposomes. In some cases, the specific BCMA-directed antigen-binding proteins are encapsulated within a liposome shell. In some cases, the liposome is a cationic liposome.
[202] [202] The specific BCMA-directed proteins described in this specification are contemplated for use as a medicine. Administration is carried out in different ways, for example, by intravenous, intraperitoneal, subcutaneous, intramuscular, topical or intradermal administration. In some embodiments, the route of administration depends on the type of therapy and the type of compound contained in the pharmaceutical composition. The dosage regimen will be determined by the attending physician and other clinical factors. Dosages for any patient depend on many factors, including size, body surface area, age, sex of the patient, the particular compound to be administered, the time and route of administration, the type of therapy, general health and others drugs that are being administered concurrently. An "effective dose" refers to the amounts of the active ingredient that are sufficient to affect the course and severity of the disease, leading to a reduction or remission of this pathology, and can be determined using known methods.
[203] [203] In some embodiments, the specific BCMA-directed proteins of this disclosure are administered at a dosage of up to 10 mg / kg at a frequency of once a week. In some cases, the dosage ranges from about 1 ng / kg to about 10 mg / kg. In some embodiments, the dose is from about 1 ng / kg to about 10 ng / kg, about 5 ng / kg to about 15 ng / kg, about 12 ng / kg to about 20 ng / kg, about 18 ng / kg to about ng / kg, about 25 ng / kg to about 50 ng / kg, about ng / kg to about 60 ng / kg, about 45 ng / kg to about 70 ng / kg, about 65 ng / kg to about 85 ng / kg, about 80 ng / kg to about 1 npg / kg, about 0.5 upg / kg to about 5 ug / kg, about 2 ug / kg to about 10 ug / kg, about 7 ug / kg to about 15 ug / kg, about 12 ug / kg to about 25 ug / kg, about 20 ug / kg to about 50 vg / kg, about 35 ug / kg to about 70 ug / kg, about 45 vg / kg to about 80 vg / kg, about 65 ug / kg to about 290 ug / kg, about 85 ug / kg to about 0.1 mg / kg, about 0.095 mg / kg to about 10 mg / kg. In some cases, the dosage is from about 0.1 mg / kg to about 0.2 mg / kg; about 0.25 mg / kg to about 0.5 mg / kg, about 0.45 mg / kg to about 1 mg / kg, about 0.75 mg / kg to about 3 mg / kg, about 2.5 mg / kg to about 4 mg / kg, about 3.5 mg / kg to about 5 mg / kg, about 4.5 mg / kg to about 6 mg / kg, about 5.5 mg / kg to about 7 mg / kg, about 6.5 mg / kg to about 8 mg / kg, about 7.5 mg / kg to about 9 mg / kg or about 8, 5 mg / kg to about 10 mg / kg. The frequency of administration, in some modalities, is about less than daily, on alternate days, less than once a day, twice a week, weekly, once in 7 days, once in two weeks, once in two weeks, once in three weeks, once in four weeks or once a month. In some cases, the frequency of administration is weekly. In some cases, the frequency of administration is weekly and the dosage is up to 10 mg / kg. In some cases, the duration of administration is from about 1 day to about 4 weeks or longer.
[204] [204] In certain embodiments, the BCMA-targeted proteins of the disclosure reduce tumor cell growth in vivo when administered to an individual who has BCMA-expressing tumor cells. The measurement of tumor cell growth reduction can be determined by multiple different methodologies well known in the art. Non-limiting examples include direct measurement of tumor size, measurement of removed tumor mass and comparison with control subjects, measurement using imaging techniques (eg CT or MRI) that may or may not use isotopes or luminescent molecules (eg , luciferase) for enhanced analysis and the like. In specific embodiments, administration of the trypspecific proteins of the staining results in a reduction of tumor cell growth in vivo, when compared to a control antigen binding agent by at least about 10%, 20%, 30%, 40% , 50%, 60%, 70%, 80%, 90% or 100%, with a reduction of approximately 100% in tumor growth, indicating a complete response and disappearance of the tumor. In additional embodiments, administration of the trypspecific proteins of the staining results in a reduction of tumor cell growth in vivo, when compared to a control antigen binding agent by about 50-100%, about 75-100% or about 90-100%. In additional embodiments, administration of the trypspecific proteins of the disclosure results in a reduction of tumor cell growth in vivo, when compared to a control antigen binding agent by about 50-60%, about 60-70%, about 70-80%, about 80-90% or about 90-100%.
[205] [205] They are also provided in this specification,
[206] [206] Also provided in this specification, in some modalities, methods and uses for stimulating the immune system of an individual in need, which include the administration of a BCMA-binding protein as described in that specification. In some cases, administration of a BCMA-binding protein described in that specification induces and / or sustains cytotoxicity against a cell that expresses a target antigen. In some cases, the cell that expresses a target antigen is a terminally differentiated B cell that is a cancer or tumor cell, or a metastatic cancer or tumor cell.
[207] [207] Also included in this specification are methods and uses for treating a BCMA-associated disease, disorder or condition, which include administering to an individual who needs a BCMA-binding protein or a multispecific binding protein that comprises the BCMA-binding protein described in that specification.
[208] [208] Diseases, disorders or conditions associated with BCMA include, without limitation, cancer or metastasis that is from a B cell line.
[209] [209] Cancers that can be treated, prevented, or managed by the BCMA-binding proteins of the present disclosure, and methods of their use, include, without limitation, a primary cancer or metastatic cancer.
[210] [210] Examples of such leukemias include, without limitation: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML), as well as several less common types, for example, hair cell leukemia (HCL), pro-lymphocytic T-cell leukemia (T-PLL), large granular lymphocytic leukemia and adult T-cell leukemia, etc. The subtypes of acute lymphoblastic leukemia (ALL) to be treated include, without limitation, precursor B acute lymphoblastic leukemia, T precursor acute lymphoblastic leukemia, Burkitt's leukemia and acute biphenotypic leukemia. Subtypes of chronic lymphocytic leukemia (CLL) to be treated include, without limitation, B-cell pro-lymphocytic leukemia (AML) Subtypes of acute myelogenous leukemia (AML) to be treated include, without limitation, acute pro-myelocytic leukemia, acute myeloblastic leukemia and acute megacarioblastic leukemia. Subtypes of chronic myelogenous leukemia (CML) to be treated include, without limitation, chronic myelomonocytic leukemia.
[211] [211] Examples of a lymphoma to be treated with the methods in question include, without limitation, Hodgkin's disease, non-Hodgkin's disease, or any lymphoma subtype.
[212] [212] Examples of such multiple myelomas include, without limitation, a multiple myeloma of bone or other tissues including, for example, an indolent multiple myeloma, a non-secretory myeloma, an osteosclerotic myeloma, etc.
[213] [213] For a review of these disorders, see Fishman et al., 1985, Medicine, 2nd Edition, JB Lippincott Co., Philadelphia and Murphy et al., 1997, “Informed Decisions: The Complete Book of Cancer Diagnosis, Treatment, and Recovery ”, Viking Penguin, Penguin Books USA, TInc., United States of America).
[214] [214] As used in this specification, in some modalities, the term "treatment" or "treating" or "treated" refers to therapeutic treatment in which the objective is to slow down (alleviate) an unwanted physiological condition, disorder or disease, or obtain beneficial or desired clinical results. For the purposes described in this specification, beneficial or desired clinical results include, without limitation, symptom relief; decrease in the extent of the condition, disorder or disease; stabilization (that is, it does not worsen) the state of the condition, disorder or disease; delay the onset or slow down the progression of the condition, disorder or disease; improvement of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or improvement of the condition, disorder or disease. Treatment includes developing a clinically significant response, without excessive levels of side effects. Treatment also includes prolonging survival when compared to expected survival if you do not receive treatment. In other modalities, “treatment” or “that treats” or “treated” refers to prophylactic measures, in which the objective is to delay the onset or reduce the severity of an unwanted physiological condition, disorder or disease such as, for example, in a person predisposed to a disease (for example, an individual who carries a genetic marker for a disease such as breast cancer).
[215] [215] In some modalities of the methods described in that specification, the BCMA-targeted proteins as described in that specification are administered in combination with an agent for the treatment of the particular disease, disorder or condition. Agents include, but are not limited to, therapies involving antibodies, small molecules (for example, chemotherapy), hormones (steroidal, peptide and the like), radiotherapy (y-rays, X-rays and / or the targeted release of radioisotopes, microwaves, radiation UV and the like), gene therapies (for example, antisense, retroviral and the like) and other immunotherapies. In some embodiments, a specific anti-BCMA protein as described in this specification is administered in combination with antidiarrheal agents, antiemetic agents, analgesics, opioids and / or non-steroidal anti-inflammatory agents. In some embodiments, a specific anti-BCMA protein as described in that specification is administered in combination with anti-cancer agents.
[216] [216] Non-limiting examples of anticancer agents that can be used in the various disclosure modalities, including pharmaceutical compositions and dosage forms and disclosure kits, include: acivicin; aclarrubicin; acodazole hydrochloride; acronin; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutetimide; amsacrine; anastrozole; anthramycin; asparaginase; asperline; azacytidine; azetepa; azotomycin;
[217] [217] In some embodiments, the anti-BCMA-specific protein as described in that specification is administered before, during, or after surgery.
[218] [218] In some embodiments, the anticancer agent is conjugated via any means suitable to the specific protein.
[219] [219] According to another embodiment of the disclosure, kits are provided for detecting BCMA expression in vitro or in vivo. The kits include the BCMA-directed triespecific proteins presented above (for example, a triespecific protein that contains a labeled anti-BCMA single domain antibody, or antigen-binding fragments thereof), and one or more compounds for detection of the marker. In some embodiments, the marker is selected from the group consisting of a fluorescent marker, an enzyme marker, a radioactive marker, an active nuclear magnetic resonance marker, a luminescent marker and a chromophore marker.
[220] [220] In some cases, BCMA expression is detected in a biological sample. The sample can be any sample including, without limitation, tissue from biopsies, autopsies and pathology samples. Biological samples also include tissue cuts, for example, frozen cuts for histological purposes. Biological samples also include body fluids, for example, blood, serum, plasma, sputum, cerebrospinal fluid or urine. A biological sample is typically obtained from a mammal, for example, a human or non-human primate.
[221] [221] Samples to be obtained for use in an assay described in this specification include body tissues and fluids that can be processed using conventional means in the art (eg homogenization, serum isolation, etc.). Consequently, a sample obtained from a patient is transformed before use in an assay described in this specification. BCMA, if present in the sample, is further transformed into the methods described in that specification by virtue of binding, for example, to an antibody.
[222] [222] In one embodiment, a method is provided to determine whether an individual has cancer by contacting a sample of the individual with a single domain anti-BCMA antibody as disclosed in that specification; and detecting the binding of the single domain antibody to the sample. An increase in antibody binding to the sample, compared to antibody binding to a control sample, identifies the individual as having cancer.
[223] [223] In another embodiment, a method of confirming a diagnosis of cancer in an individual is provided by contacting a sample of an individual diagnosed with cancer with a single domain anti-BCMA antibody as disclosed in that specification; and detecting the binding of the antibody to the sample. An increase in the binding of the antibody to the sample, compared to the binding of the antibody to a control sample, confirms the diagnosis of cancer in the individual.
[224] [224] In some examples of the disclosed methods, the single domain antibody against BCMA of the triespecific protein is directly labeled.
[225] [225] In some examples, the methods even include contacting a second antibody that specifically binds the anti-BCMA single domain antibody to the sample; and detecting the binding of the second antibody. An increase in the binding of the second antibody to the sample, compared to the binding of the second antibody to a control sample, detects cancer in the individual or confirms the diagnosis of cancer in the individual.
[226] [226] In some cases, the cancer is leukemia, lymphoma, multiple myeloma, or any other type of cancer that expresses BCMA.
[227] [227] In some instances, the control sample is a sample from an individual without cancer. In particular examples, the sample is a blood or tissue sample.
[228] [228] In some cases, the antibody that binds (for example, that specifically binds) to BCMA is marked directly with a detectable marker. In another embodiment, the antibody that binds (for example, that specifically binds) to BCMA (the first antibody) is not labeled and a second antibody or other molecule that can bind to the antibody that specifically binds to BCMA is labeled. A second antibody is chosen so that it is able to specifically bind to the specific species and class of the first antibody. For example, if the first antibody is a llama IgG, then the secondary antibody can be a llama anti-IgG. Other molecules that can bind to antibodies include, without limitation, Protein A and Protein G, both commercially available. Suitable markers for the antibody or secondary antibody are described above, and include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, magnetic agents and radioactive materials. Non-limiting examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, beta-
[229] [229] In an alternative embodiment, BCMA can be tested on a biological sample by a competition immunoassay that uses BCMA standards marked with a detectable substance and an unlabeled antibody that specifically binds to BCMA. In this assay, the biological sample, the labeled BCMA standards and the antibody that specifically binds to the BCMA are combined and the amount of labeled BCMA standard bound to the unlabeled antibody is determined. The amount of BCMA in the biological sample is inversely proportional to the amount of labeled BCMA standard bound to the antibody that specifically binds to BCMA.
[230] [230] The immunoassays and methods revealed in this specification can be used for a variety of purposes. In one embodiment, the antibody that specifically binds to BCMA can be used to detect BCMA production in cells in the cell culture. In another embodiment, the antibody can be used to detect the amount of BCMA in a biological sample, for example, a tissue sample, or a blood or serum sample. In some instances, BCMA is BCMA on the cell surface. In other examples, BCMA is BCMA soluble (for example, BCMA in a cell culture supernatant or BCMA soluble in a sample of body fluid, for example, a blood or serum sample).
[231] [231] In one embodiment, a kit for detecting BCMA in a biological sample, for example, a blood sample or a tissue sample, is provided. For example, to confirm a diagnosis of cancer in an individual, a biopsy may be performed to obtain a tissue sample for histological examination. Alternatively, a blood sample can be obtained to detect the presence of a soluble BCMA protein or fragment. Kits for detecting a polypeptide will typically comprise a single domain antibody according to the present disclosure, which specifically binds to BCMA. In some embodiments, an antibody fragment, for example, an scFv fragment, a VH domain or a Fab, is included in the kit. In an additional embodiment, the antibody is labeled (for example, with a fluorescent, radioactive, or enzyme marker).
[232] [232] In one embodiment, a kit includes instructional materials that reveal ways to use an antibody that binds to BCMA. Instructional materials can be written in electronic form (for example, a computer diskette or compact disc) or can be visual (for example, video files), or provided over an electronic network, for example, on the Internet, World Wide Web, an intranet, or another network. Kits can also include additional components to facilitate the particular application for which the kit is designed. Thus, for example, the kit may additionally contain means for detecting a marker (for example, enzyme substrates for enzyme markers, filter sets for detecting fluorescent markers, appropriate secondary markers such as, for example, a secondary antibody, or the like) . The kits may additionally include buffers and other reagents routinely used to practice a particular method. These kits and appropriate content are well known to those skilled in the art.
[233] [233] In one embodiment, the diagnostic kit comprises an immunoassay. Although the details of the immunoassays may vary with the particular format employed, the method of detecting BCMA in a biological sample generally includes the steps of contacting the biological sample with an antibody that reacts specifically, under immunologically reactive conditions, with a BCMA polypeptide. The antibody is allowed to bind specifically under immunologically reactive conditions to form an immune complex, and the presence of the immune complex (antibody bound) is detected directly or indirectly.
[234] [234] Methods of determining the presence or absence of a cell surface marker are well known in the art. For example, antibodies can be conjugated to other compounds including, without limitation, enzymes, magnetic microparticles, colloidal magnetic microparticles, haptens, fluorochromes, metal compounds, radioactive compounds or drugs. Antibodies can also be used in immunoassays, such as, without limitation, radioimmunoassays (RIAS), ELISA or immunohistochemical assays. Antibodies can also be used for fluorescence-activated cell separation (FACS). FACS employs several color channels, obtuse and low-angle light scattering detection channels, and impedance channels, among other more sophisticated levels of detection, to separate or classify cells (see U.S. Patent No. 5,061,620). Any of the single domain antibodies that bind to BCMA, as revealed in this specification, can be used in these assays. In this way, antibodies can be used in a conventional immunoassay including, without limitation, an ELISA, an RIA, FACS, tissue immunohistochemistry, Western blot or immunoprecipitation. EXAMPLES
[235] [235] The application can be better understood by reference to the following non-limiting examples, which are provided as exemplary modalities of the application. The following examples are presented in order to more fully illustrate modalities and should not be considered in any way, however, as limiting the broad scope of the application. Example 1 Protein production
[236] [236] Sequences of specific molecules targeting the BCMA, containing a BCMA-binding protein according to the present disclosure, were cloned into the mammalian expression vector pcDNA 3.4 (Invitrogen), preceded by a leader sequence and followed by a tag Histidine 6x (SEQ ID. No.: 471). Expi293 cells (Life Technologies Al4527) were kept in suspension in Optimum Growth Vials (Thomson) between 0.2 to 8 x l and 6 cells / ml in Expi293 media. Purified plasmid DNA was transfected into Expi293 cells according to the “Expi293 Expression System Kit” protocols (Life Technologies, Al4635), and maintained for 4-6 days post-transfection. The amount of the exemplary triespecific proteins being tested, in the conditioned media, of the transfected Expi293 cells, was quantified using an Octet instrument with Protein A tips and using a specific trying control protein for a standard curve.
[237] [237] Conditioned media titrations have been added to TDCC assays (T Cell Dependent Cell Cytotoxicity assays) to assess whether the anti-BCMA single domain antibody is capable of forming a synapse between T cells and a cell line that express BCMA and direct T cells to kill the cell line that express BCMA. In this assay (Nazarian et al., 2015. JU. Biomol. Screen., 20: 519-27), T cells and target cells of the cancer cell line are mixed together in a 10: 1 ratio on a 384 wells, and varying amounts of the specific trying proteins being tested have been added. The tumor cell lines were genetically modified to express the luciferase protein. After 48 hours, to quantify the remaining viable tumor cells, the Steady-Glo6 Luminescent Assay (Promega) was used.
[238] [238] In this example, EJM cells were used, which is a cell line that serves as an in vitro model for multiple myelin and plasma cell leukemia. The viability of EJM cells is measured after 48 hours. It was observed that the specific proteins mediated death by T cells. Fig. 2 shows an exemplary cell viability assay with test proteins 01H08, 01F07, 02F02 and BH253 compared to a negative control. The ECso for the TDCC activity of several other triespecific test proteins is listed below in Table 1.
[239] [239] In the present study, the binding affinity for human BCMA protein of the BCMA-directed specific proteins containing a BCMA binding protein according to the present disclosure was determined. The affinity measurements are listed in Table 1. Table 1: Binding affinity and TDCC activity of several specific proteins targeting BCMA. ne metes TDCC EC50 (M) construction (M) | - pray
[240] [240] Molecules 01H08, O1FO0O7, O1H06, 02GO02, 02B05, 01C01, 02F02, 0O2EO05, O1EO8, 02COl, O02EO6, 02B06, 02F04, 01GO08, 02CO6, 01H09, 0O1FO4, 02OOOO, 02O0O1, 02H09, O1EO03, 02F0O5, O1BO05, O1CO5, 02F12, 01H11, 02GO6, O1EO6, O1G11, 02A05, O1A08, 02GO5, 01B09, 01GO1, O1B06, O1F10, O1EO5, 02GOl, O1A0, 021, 06, 02 O1DO3, O1A05, O2Fll1, O1DO4, O1B04, 02CO05, 02E03, 0O1DO5, O1CO4, O1EO7, O1GO6, 02FO6, O1B01, O01DO7, 0O2A08, 0O1A02, 0O2G11, O1GO4, 021 at least twice and also exhibit increased affinity, compared to a molecule with parental CDRs, 253BH10.
[241] [241] Molecules 01H08, O1FO0O7, O1H06, 02GO02, 02B05, 01CO01, 02F02, O2EO5, O1EO8, 02COl, 02E06, 02B06, 02F04, 01G08, 02CO6, 01H09, 0O1FO4, 02O1O0O4, 0O1O0O2, 02H09, O1EO03, 02FO5, O1BO5, O1CO5, 0O2F12, 01H11, 02GO6, O1E0O6, O1G11, O2AO5, O1A08, 0O2GO5, 0O1B09 have an increase in TDCC power of at least ten times and also exhibit an increased affinity with compared to a molecule with increased, compared to a higher affinity parental CDRs, 253BH10.
[242] [242] An attempted specific anti-GFP molecule, included in these assays as a negative control, had no detectable BCMA binding and no effect on cell viability in the TDCC assay (data not shown).
[243] [243] Sequences of specific molecules targeting the BCMA, containing a BCMA-binding protein according to the present disclosure, preceded by a leader sequence and followed by a 6x Histidine Tag (SEQ ID. No. 471), were expressed using the vectors and methods described previously (Running Deer and Allison, 2004. Biotechnol Prog. 20: 880-9), except that lipid-based reagents and non-linearized plasmid DNA were used for cell transfection. Recombinant triespecific proteins were purified using affinity chromatography, ion exchange chromatography and / or size exclusion. The purified protein was quantified using theoretical extinction coefficients and absorption spectroscopy. An image from an SDS-PAGE stained with Coomassie demonstrates the purity of the proteins (Fig. 3).
[244] [244] A human T cell-dependent cell cytotoxicity (TDCC) assay was used to measure the ability of T cell engagers, including specific molecules, to target T cells to kill tumor cells (Nazarian et al 2015. J. Biomol Screen 20: 519-27). In this assay, T cells and target cells from the cancer cell line are mixed together in a 10: 1 ratio in a 384-well plate, and varying amounts of the specific proteins being tested are added. Tumor cell lines are genetically modified to express the luciferase protein. After 48 hours, to quantify the remaining viable tumor cells, the Steady-Glo6 & Luminescent Assay (Promega) was used.
[245] [245] In the present study, purified protein titrations were added to the TDCC assays (T Cell Dependent Cell Cytotoxicity assays) to assess whether the anti-BCMA single domain antibody was able to form a synapse between T cells and strains of cancer cells that express BCMA Jekol, MOLP8 and OPM2. Jekol is a B-cell lymphoma cell line. MOLP-8 is a myeloma cell line. OPM-2 is a human myeloma cell line.
[246] [246] Cell viability was measured after 48 hours.
[247] [247] In the present study, the binding affinity for human BCMA protein of the specific BCMA-directed proteins containing a BCMA binding protein according to the present disclosure was determined. Table 3: Binding affinity of purified triespecific targeting proteins containing a BCMA binding protein according to the present disclosure.
[248] [248] The data in Fig. 3, Fig. 4, Table 2 and Table 3 indicate that the specific proteins targeting BCMA can be expressed and purified to a purity above 90%. Purified proteins exhibit TDCC activity about 13 times to 213 times more potent, compared to a specific protein with the sequence directed to the parental BCMA. The purified tried-specific proteins bind to BCMA with an affinity of about 3 to 7 nM.
[249] [249] An exemplary BCMA-targeted protein described in this specification was evaluated in a xenograft model.
[250] [250] On day 0, NCG mice were inoculated subcutaneously with RPMI-8226 cells, and also implanted intraperitoneally with normal human peripheral blood mononuclear cells (PBMCs). Treatment with a specimen-specific BCMA-directed protein (02B05) (SEQ ID. No.: 520) was also started on day O (gdx10) (once daily for 10 days). The administration dosage was vpg / kg, 50 pg / kg or 500 vpg / kg of the specific protein directed to BCMA 02B05, or a vehicle as a control. Tumor volumes were determined for 25 days. As shown in Fig. 30, mean tumor volumes were significantly lower in mice treated with the exemplary BCMA-directed protein specific (02B05) (at 50 µg / kg, or 500 µg / kg), compared to vehicle-treated mice. or the smallest dose of BCMA-targeted protein (02B05) (at 5 µg / kg).
[251] [251] On day 0, NCG mice were inoculated subcutaneously with Jeko 1 cells, and also implanted intraperitoneally with normal human peripheral blood mononuclear cells (PBMCs). Treatment with a specimen-specific BCMA-directed protein (02B05) (SEQ ID. No.: 520) was started on day 3 (gdx10) (once daily for 10 days). The administration dosage was 5 nug / kg, 50 pg / kg or 500 ug / kg of the specific protein directed to BCMA 02B05, or a vehicle as a control. Tumor volumes were determined for 25 days. As shown in Fig. 31, mean tumor volumes were significantly lower in mice treated with the exemplary BCMA-directed protein (02B05) (at 500 ug / kg), compared to mice treated with the vehicle or lower doses of protein tries specific to BCMA (02B05) (at 5 1ug / kg or 50 ug / kg).
[252] [252] This is a Phase I / II clinical trial for the study of the BCMA-directed antigen-specific protein targeting Example 1 as a treatment for multiple myeloma.
[253] [253] Primary: Maximum tolerated dose of BCMA directed specific proteins from previous examples
[254] [254] Secondary: Determine whether the in vitro response of BCMA-directed proteins specific proteins from previous examples is associated with Phase I clinical response
[255] [255] The maximum tolerated dose (BAT) will be determined in the Phase I section of the experiment.
[256] [256] 1.1 The maximum tolerated dose (BAT) will be determined in the Phase I section of the experiment.
[257] [257] 1.2 Patients who meet the eligibility criteria will be included in the experiment for the specific BCMA-targeted proteins in the previous examples.
[258] [258] 1.3 The objective is to identify the highest dose of specific proteins directed to BCMA from previous examples that can be safely administered without severe or intractable side effects in participants. The dose given will depend on the number of participants who were included in the previous study and how well the dose was tolerated. Not all participants will receive the same dose.
[259] [259] 2.1 A subsequent Phase II section will be dealt with in the BAT with the aim of determining whether treatment with BCMA-directed protein-specific protein therapy from the previous examples results in a response rate of at least 20%.
[260] [260] Primary endpoint for Phase II - Determine whether previous specific examples of BCMA-targeted protein therapy results in at least 20% of those obtaining a clinical response (blast response, small response, partial response or complete response) Eligibility
[261] [261] The eligibility criteria for inclusion in the studies are as follows:
[262] [262] Patients with multiple myeloma not previously treated and without serious or impending complications (eg, imminent pathological fracture, hypercalcemia, renal failure). All asymptomatic patients with low or intermediate tumor mass will qualify.
[263] [263] Patients with elevated tumor mass, symptomatic or impending fractures, hypercalcemia (corrected calcium> 11.5 mg%), anemia (Hgb <8.5 g9 / dl), renal failure (creatinine> 2.0 mg / dl) , elevated serum lactate dehydrogenase (> 300 U / l1) or plasma cell leukemia (> 1,000 / ul) are ineligible.
[264] [264] Visible infections or unexplained fever should be resolved before treatment. Adequate liver function (including SGPT, bilirubin and LDH) is required.
[265] [265] Patients should have a Zubrod performance of 1 or less.
[266] [266] Patients must provide written informed consent indicating that they are aware of the investigative nature of this study.
[267] [267] Life expectancy must exceed 1 year.
[268] [268] Patients with idiopathic monoclonal gammopathy and non-secreting multiple myeloma are ineligible. Patients whose only previous therapy was with local radiotherapy, alpha-IFN or ATRA are eligible. Patients previously exposed to high-dose glucocorticoids or alkylating agents are not eligible.
[269] [269] The purpose of this study was to assess the affinity of a specific BCMA-directed protein exemplary of this disclosure (02B05) (SEQ ID. No.: 520), for human BCMA, Cynomolgus BCMA, human CD3e, Cynomolgus CD3re, human albumin , Cynomolgus albumin and mouse albumin. Affinities were measured using an Octet instrument. For these measurements, streptavidin tips were first loaded with 2.5 nM human BCMA-Fc, 2.5 nM BCMA from Cynomolgus-Fc, 2.5 nM human CD3re-Fc, 2.5 nM CD3e from Cynomolgus- Fc, 50 nM human serum albumin (HSA), 50 nM Cynomolqgus serum albumin, or 50 nM mouse serum albumin. Subsequently, the specimen-specific BCMA-directed protein 02B05 was incubated with the tips and, after a period of association, the tips were moved to a buffer solution to allow the specimen-specific BCMA-directed protein (02B05) to disassociate. Affinities for binding to human BCMA and Cynomolgus and CD3e were measured in the presence of mg / ml of human serum albumin. The calculated average K values for these studies are given in Table 4 (n indicates the number of independent measurements, n / d indicates no link detected under the conditions tested). Binding was detected to human BCMA, human CD3e, Cynomolgus CD3e, human serum albumin, Cynomolgus serum albumin and mouse serum albumin. Under the conditions tested, no binding was detected to Cynomolgus BCMA. Table 4. Kp values ”measured for specific tries directed to exemplary BCMA 02B05 to protein ligands. Protein ligand Species [men | 0 |
[270] [270] The exemplary BCMA-targeted protein 02B05 (SEQ ID. No.: 520) has been tested for its ability to bind to purified T cells. Briefly, the BCMA-specific protein or phosphate-buffered saline (PBS) was incubated with cells
[271] [271] The exemplary BCMA-directed protein 02B05 (SEQ ID. No.: 520) has been tested for its ability to bind to BCMA-expressing cells. Briefly, the BCMA 02B05 antigen-specific antigen-binding protein was incubated with cell lines expressing BCMA (NCI-H929; EJIM; RPMI-8226; OPM2) or devoid of BCMA (NCI-H510A; DMS-153). The BCMA RNA expression in these cells is indicated by the FPKM values (fragments per million kilobases) listed in Figs. 6A-F: FPKM RNA values are from the Cancer Cell Line Encyclopedia (Broad Institute, Cambridge, MA, USA). After washing unbound protein, the cells were then incubated with an antibody conjugated to Alexa Fluorine 647 that recognizes the anti-albumin domain in the try-specific antigen binding protein directed to BCMA 02B05. The cells were then analyzed by flow cytometry. As a negative control, the cells were incubated with a GFP-targeted protein. Cells that express BCMA RNA and incubated with the BCMA triespecific protein had notable changes associated with staining with Alexa Fluorine 647, compared to cells that were incubated with GFP specific proteins (as in Figs. 6A, 6B, 6D and 6E). Meanwhile, cells devoid of BCMA RNA produced staining with Alexa Fluorine 647 equivalent to the BCMA-specific protein and the GFP-specific protein (as seen in Figs. 6C and 6F). Thus, this study indicated that binding to the exemplary BCMA-specific antigen was able to selectively bind to cells that express BCMA. Example 8 Ability of an exemplary BCMA-targeted protein to mediate death by T cells from cancer cells expressing BCMA
[272] [272] The exemplary BCMA-specific protein 02B05 (SEQ ID. NO .: 520) was tested for its ability to direct T cells to kill BCMA-expressing cells in the presence and absence of human serum albumin (HSA) using an assay of standardized TDCC as described in Example 1. Since the exemplary BCMA-specific protein contains an anti-albumin domain, this experiment was performed to confirm that binding to albumin would prevent the BCMA-directed antigen-specific protein from targeting T cells to kill cells that express BCMA. Five cell lines expressing BCMA were tested: EJM, Jeko, OPM2, MOLP8 and NCI-H929. Representative data for an experiment with the EJM cells are shown in Fig.
[273] [273] In the standardized TDCC assay (as described in Example 1), a ratio of 1 target cell (EJM cells or OPM2 cells) to 10 effector cells (T cells) is used in a 48 hour assay. In this experiment, the ability of the exemplary BCMA tries-specific protein 02B0O5 (SEQ ID: 520) to test T cells to kill target cells with smaller ratios of target cell to effector cell was tested. The expectation was that less death would be observed when fewer effector cells were used. Two cell lines expressing BCMA were tested, EJM and OPM2, using target cell to effector cell ratios of 1: 1, 1: 3 and 1:10, and the experiment was carried out in the presence of 15 mg / ml HSA . The specific protein directed to GFP was used as a negative control. Data from this experiment are shown in Fig. 8 (TDCC assay with EJM cells) and Fig. 9 (TDCC assay with OPM2 cells). As expected, almost complete death of the target cells was observed with a target cell to effector cell ratio of 1:10. The amount of death was reduced with a decrease in effector cells. ECso values for cell death with each proportion are listed in Table 6 (n / a indicates insufficient death was observed to calculate an ECso value). ECso values increased when fewer effector cells were present. Thus, as expected, the reduction in the number of effector cells for target cells reduced the TDCC activity of the BCMA-specific protein. Table 6. Values of TDCC ECs for an exemplary BCMA directed specific protein (02B05) with varying ratios from target cell (EJM cells) to effector cell (T cells) (tested in the presence of 15 mg / ml HSA). Ratio of target cell to T cell EJM ECso (PM) OPM2 ECso (pM) 1:10 154 371 1: 3 523 1896 1: 1 1147 n / a Example 10 Ability of an exemplary BCMA-targeted protein to mediate death by T cells from cancer cells expressing BCMA, in a time evolution study, using a lower ratio of target cell to effector cell
[274] [274] In the standardized TDCC assay (Example 1), a ratio of 1 target cell to 10 effector cells (T cells) is used in a 48-hour assay. In this experiment, time evolution was performed using a 1: 1 ratio of target cells (EJM cells) to effector cells (T cells). The expectation was that, with time increased, a 1 to 1 ratio would result in death of the target cell. The experiment was carried out in the presence of 15 mg / ml of HSA. The specific protein directed to GFP was used as a negative control. The viability of the target cell was measured on days 1, 2, 3 and 4 after incubation of the target cells and effector cells, in a 1: 1 ratio, in the presence of the trypecific antigen-binding protein directed to the
[275] [275] The exemplary BCMA-specific protein 02B05 (ID. SEQ.
[276] [276] The exemplary BCMA-targeted protein 02B05 (SEQ ID NO: 520) was tested for its ability to target T cells from Cynomolgus monkeys to kill cells that express BCMA in the presence of 15 mg / ml serum albumin (HSA). The experimental conditions were the same as described in Example 1, except that peripheral blood mononuclear cells (PBMC) from Cynomolgus monkeys were used as a T cell source. Two cell lines expressing BCMA were tested, RPMI8226 and NCI-H929. As shown in Figs. 17 and 18, the BCMA-specific protein was able to direct T cells present in Cynomolgus PBMCs to kill the two cell lines that express BCMA. ECso values for cell death are listed in Table 9. The GFP-specific protein did not affect the viability of cells expressing BCMA. In this way, cells that express BCMA-specific protein, which can bind to Cynomolgus CD3e (as shown in Example 5), can direct Cynomolgus T cells to kill cells that express human BCMA.
[277] [277] The exemplary BCMA-directed protein 02B05 (SEQ ID. No.: 520) has been tested for its ability to activate T cells in the presence of BCMA-expressing cells. The cell lines expressing BCMA were EJM, OPM2 and RPMI8226. As negative controls, two cell lines that lack BCMA expression were also included, OVCAR8 and NCI-H510A. T cells were obtained from four different anonymous human donors. The assays were set up using the conditions of a standardized TDCC assay as described in Example 1, except that the assay was adapted to the 96-well format and the assay was performed in the presence of 15 mg / ml HSA. After the 48-hour assay, T cell activation was assessed using flow cytometry to measure the expression of CD25 and CD69 T cell activation biomarkers on the surface of T cells. With increasing concentrations of the specific antigen-binding protein directed to exemplary BCMA 02B05, increased expression of CD69 and CD25 was observed in T cells when co-cultured with cells expressing BCMA (as shown in Figs. 19-24). Thus, the increased expression observed was dependent on the interaction of the BCMA binding sequence within the triespecific antigen binding protein directed to the exemplary BCMA 02B05 with BCMA, insofar as little or no activation was observed with a GFP specific protein of control (as shown in Figs. 19-24) or with target cells with no BCMA expression (as shown in Figs. 25-28). Therefore, the exemplary BCMA-directed antigen-binding protein 02B05 activated T cells in cocultures containing cells that express BCMA.
[278] [278] Cynomolgus monkeys were administered single intravenous doses of an exemplary BCMA-directed protein (02B05) (SEQ ID. No.: 520), at 0.01 mg / kg, 0.1 mg / kg or 1 mg / kg. Two animals were included per dose group. After administration, serum samples were collected and analyzed by two different electrochemiluminescent assays. One assay used biotinylated CD3re as a capture reagent and detected with sulfo-labeled BCMA (called the functional assay). Another assay used as a capture reagent a biotinylated antibody that recognizes the anti-albumin domain in the exemplary BCMA-directed protein and used as a detection reagent a sulfo-labeled antibody that recognizes the anti-CD3 binding domain in the BCMA-directed protein example (ie, an anti-idiotype antibody). the results of the electrochemiluminescent assays are plotted in Fig. 32. As seen in Fig. 32, the exemplary BCMA-directed protein was detected in the Cynomolgus serum samples, even after 504 hours after administration. The specimen-specific BCMA-directed protein was identified using both sulfo-labeled BCMA (strains labeled using the term "functional" in Fig. 32) and the anti-idiotype antibody (strains labeled using the term "anti-idiotype" in Fig. 32).
[279] [279] To confirm that the exemplary BCMA-targeted protein retained the ability to target T cells to kill BCMA-expressing EJM cells, after in vivo administration, 168-hour time point serum samples were tested in a TDCC assay (as described in Example 1) in the presence of 16.7% serum from a Cynomolgus monkey that was not exposed to a BCMA-directed trypecific protein, titrating the exemplary BCMA-directed trypecific protein using the protein concentrations determined using the electrochemiluminescent assays (shown in Fig. 33). Fresh diluted tryma specific BCMA 02B05 protein was compared with tryma specific BCMA protein collected from test Cynomolgus monkeys at 168 h. A GFP-specific protein was included as a negative control. That study demonstrated that the exemplary BCMA-targeted protein collected from the serum of the test Cynomolgus monkeys had activity identical to the newly diluted protein, and that the protein in the serum samples retained the ability to direct T cells to kill target cells that express BCMA.
[280] [280] Although preferred embodiments of the present invention have been shown and described in this specification, it will be obvious to those skilled in the art that these modalities are provided by way of example only. Several variations, changes and substitutions will now occur to those skilled in the art, without departing from the invention. It should be understood that several alternatives to the modalities of the invention described in this specification can be used in the practice of the invention. It is desired that the following claims define the scope of the invention and that the methods and structures within the scope of those claims and their equivalents are encompassed by them.
Sequence Table SEQ ID Description Sequence NO: T. CDRI1 Exemplary | X: iXX3XaXsXeX; PXsG where X; is T or S; X, is N, D, or S; X; is 1, D, OQ, H, V, or E; Xa is F, S, E, A, T, M, V, 1, D, Q, P, R, or G; Xs is S, M, R, or N; Xs is 1, K, S, T, R, E, D, N, V, H, L, A, OQ, or G; X; is S, T, Y, R, or N; and Xs is M, G, or Y
2. Exemplary CDR2 | AIXSGX: oX1: TX: 2YADSVK where Xs is H, N, or S; X1o is F, G, K, R, P, D, Q, H, E, N, T, S, A, IT, L, or V; Xu is 5, O, E, T, K, or D; and X17 is L, V, LI, E, Y, or W
3. Exemplary CDR3 | VPWGX:; YHPX1sX1sVX1s where X :; is D, T, T, K, R, A, E, S, or Y; Xu is R, G, L, K, T, OQ, S, or N; Xis is N, K, E, V, R, M, or D; and Xi is Y, A, V, K, H, L, M, T, R, Q, C, S, or N SEQ ID Name HCDR1 NO: | 4 om TDIFSISPMG 01A02 TNIFSSSPMG 01A03 TNIFSISPGG 01A04 TNIFMISPMG [& 01A05 TNIFSSSPMG NNE 01A06 TNIFSIRPMG 01A07 TNISSISPMG 01A08 TNIFSSSPMG 01A09 TNIFSITPMG 01B01 TNIPSISPMGPMBPM TNT 01 218 TNIFSISPMG 01B07 TNIFSRSPMG 01B08 TNIESISPMG 01B09 SNIFSISPMG | 22 joy TNIFSTSPMG 01C01 TNIVSISPMG 01C02 TNIESISPMG 01C04 TNIPSISPMG 01cC05 TNIFSSSPMG 01C06 TNIFSISPMG
Fr Je ss FE JE E
FRA RA FP Je mes
PETER FP Je ss E PP EPE E AND EE
SEQ ID Sequence Name VHH NO Construction
346. BH2T EVOLVESGGGLVQPGRSLTLSCAASTNIFSISPMGWYRQOAPGK QRELVAAIHGFSTLYADSVKGRFTISRDNAKNSIYLQOMNSLRP EDTALYYCNKVPWGDYHPRNVYWGQGTQOVTVSS
347. 01A01 EVOLVESGGGLVOPGRSLTLSCAASTDIFSISPMGWYROAPGK QRELVAAIHGGSTLYADSVKGRFTISRDNAKNSIYLQOMNSLRP EDTALYYCNKVPWGDYHPRNVANGQOGTQVTVSS
348. 02E09 EVQOLVESGGGLVQPGRSLTLSCAASTNDFSISPMGWYROAPGK QRELVAAIHGGSTLYADSVKGRFTISRDNAKNSIYLQOMNSLRP EDTALYYCNKVPWGDYHPRNVANGQOGTQVTVSS
349. 01B03 EVQOLVESGGGLVQOPGRSLTLSCAASTNIFSKSPMGWYRQOAPGK QRELVAAIHGKSTLYADSVKGRFTISRDNAKNSIYLQOMNSLRP EDTALYYCNKVPWGDYHPRNVVWGQOGTQVTVSS
350. O01B04 EVOLVESGGGLVQPGRSLTLSCAASTNDFSISPMGWYRQOAPGK QRELVAAIHGKSTLYADSVKGRFTISRDNAKNSIYLQMNSLRP EDTALYYCNKVPWGDYHPRNVKWGQGTQVTVSS
351. 02H05 EVQLVESGGGLVOPGRSLTLSCAASTNQFSISPMGWYROAPGK QRELVAAIHGKSTLYADSVKGRFTISRDNAKNSIYLQOMNSLRP EDTALYYCNKVPWGDYHPRNVVWGQOGTQVTVSS
352. 01A02 EVOLVESGGGLVQPGRSLTLSCAASTNIFSSSPMGWYRQOAPGK QRELVAAINGFSTLYADSVKGRFTISRDNAKNSIYLQOMNSLRP EDTALYYCNKVPWGDYHPRNVHWGQOGTQVTVSS
353. 01A05 EVOLVESGGGLVQPGRSLTLSCAASTNIFSSSPMGWYRQAPGK QRELVAAIHGFSTLYADSVKGRFTISRDNAKNSIYLQMNSLRP EDTALYYCNKVPWGDYHPRNVYWGQOGTQVTVSS
354. 01B12 EVOLVESGGGLVQPGRSLTLSCAASTNIFSTSPMGWYRQOAPGK QRELVAAIHGFOTLYADSVKGRFTISRDNAKNSIYLQOMNSLRP EDTALYYCNKVPWGDYHPRNVVWGQOGTQVTVSS
355. 01606 EVOLVESGGGLVOPGRSLTLSCAASTNIFSRSPMGWYRQAPGK QRELVAAIHGFETLYADSVKGRFTISRDNAKNSIYLQMNSLRP EDTALYYCNKVPWGDYHPRNVLWGQGTQVTVSS
356. 02C05 EVOLVESGGGLVQPGRSLTLSCAASTNIFSESPMGWYRQOAPGK QRELVAAIHGFTTLYADSVKGRFTISRDNAKNSIYLQOMNSLRP EDTALYYCNKVPWGDYHPRNVTWGQOGTQOVTVSS
357. 02609 EVOLVESGGGLVQPGRSLTLSCAASTNIFSDSPMGWYRQAPGK QRELVAAIHGFSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPRNVANGOGTQOVTVSS
358. 01C08 EVOLVESGGGLVQPGRSLTLSCAASTNIFSNSPMGWYRQAPGK QRELVAAIHGGSTLYADSVKGRFTISRDNAKNSIYLQOMNSLRP EDTALYYCNKVPWGDYHPRNVHWGQOGTQOVTVSS
359. 02B01 EVOLVESGGGLVQPGRSLTLSCAASTNIFSNSPMGWYRQAPGK QORELVAAIHGRSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPRNVMWGQOGTQOVTVSS
360. 02E03 EVOLVESGGGLVQPGRSLTLSCAASTNIFSNSPMGWYRQAPGK QRELVAAIHGPSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPRNVTWGQOGTQOVTVSS
361. 01D03 EVQOLVESGGGLVQPGRSLTLSCAASTNIFSNSPMGWYRQOAPGK QRELVAAIHGDSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPRNVRWGQOGTQOVTVSS
362. 01D06 EVQOLVESGGGLVQPGRSLTLSCAASTNIFSRSPMGWYRQOAPGK QRELVAAIHGDSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPRNVTWGQOGTQVTVSS
363. 01H04 EVQOLVESGGGLVQPGRSLTLSCAASTNIFSKSPMGWYRQOAPGK QORELVAAIHGOSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPRNVTWGQOGTQOVTVSS
364. 02B07 EVOLVESGGGLVQPGRSLTLSCAASTNIFSSSPMGWYRQOAPGK QRELVAAIHGHSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPRNVTWGOGTOVTVSS
365. 01A08 EVOLVESGGGLVQPGRSLTLSCAASTNIFSSSPMGWYRQAPGK QRELVAAIHGESTLYADSVKGRFTISRDNAKNSIYLQMNSLRP EDTALYYCNKVPWGDYHPRKVYWGQOGTQOVTVSS
366. 01B07 EVOLVESGGGLVQPGRSLTLSCAASTNIFSRSPMGWYRQOAPGK QRELVAAIHGNSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGIYHPRNVYWGOGTOVTVSS
367. 01FO03 EVOLVESGGGLVQPGRSLTLSCAASTNIFSESPMGWYRQAPGK ORELVAAIHGNSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGTYHPRNVYWGQOGTOVTVSS
368. 02F05 EVQOLVESGGGLVQPGRSLTLSCAASTNIFSVSPMGWYRQAPGK QORELVAAIHGNSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGKYHPRNVYWGQOGTQVTVSS
369. 02H04 EVQOLVESGGGLVQPGRSLTLSCAASTNIFSVSPMGWYRQAPGK ORELVAAIHGNSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPRNVYWGQOGTQOVTVSS
370. 02A07 EVQOLVESGGGLVQPGRSLTLSCAASTNIFSKSPMGWYRQAPGK QORELVAAIHGNSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPREVYWGQOGTQOVTVSS
371. 01DO5 EVQLVESGGGLVQPGRSLTLSCAASTNIFSDSPMGWYRQOAPGK ORELVAAIHGTSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPRNVYWGQOGTQOVTVSS
372. 01E05 EVQOLVESGGGLVQPGRSLTLSCAASTNIFSRSPMGWYRQOAPGK QORELVAAIHGTSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGKYHPRNVYWGQOGTQOVTVSS
373. 01F02 EVOLVESGGGLVQPGRSLTLSCAASTNIFSHSPMGWYRQOAPGK ORELVAAIHGTSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGRYHPRNVYWGQOGTQOVTVSS
374. 02C06 EVQOLVESGGGLVQPGRSLTLSCAASTNIFSTSPMGWYRQOAPGK QORELVAAIHGTSTLYADSVKGRFTISRDNAKNSIYLQOMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQGTQVTVSS
375. 02F11 EVOLVESGGGLVOPGRSLTLSCAASTNIFSTSPMGWYROAPGK QRELVAAIHGTSTLYADSVKGRFTISRDNAKNSIYLQMNSLRP EDTALYYCNKVPWGDYHPRNVQWGOGTQOVTVSS
376. 01E06 EVQLVESGGGLVQPGRSLTLSCAASTNIFSLSPMGWYROAPGK QRELVAAIHGDSTLYADSVKGRFTISRDNAKNSIYLQOMNSLRP EDTALYYCNKVPWGDYHPRNVYWGQGTOVTVSS
377. 01A03 EVOLVESGGGLVQOPGRSLTLSCAASTNIFSISPGGWYROAPGK QRELVAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQOMNSLRP EDTALYYCNKVPWGDYHPRNVYWGQOGTQVTVSS
378. 02A11 EVQOLVESGGGLVOPGRSLTLSCAASTNHFSISPMGWYRQOAPGK QRELVAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQMNSLRP EDTALYYCNKVPWGDYHPRVVYWGQOGTQOVTVSS
379. 01DO7 EVOLVESGGGLVQPGRSLTLSCAASTNIFSASPMGWYRQOAPGK QRELVAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQOMNSLRP EDTALYYCNKVPWGDYHPRNVNWGQOGTQOVTVSS
380. 01D10 EVOLVESGGGLVQPGRSLTLSCAASTNIFSASPMGWYRQOAPGK QRELVAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQMNSLRP EDTALYYCNKVPWGRYHPRNVYWGQOGTOVTVSS
381. 01A07 EVOLVESGGGLVQPGRSLTLSCAASTNISSISPMGWYRQOAPGK QRELVAAIHGTSTLYADSVKGRFTISRDNAKNSIYLQMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQGTQOVTVSS
382. 02F12 EVOLVESGGGLVQPGRSLTLSCAASTNIESISPMGWYROAPGK QRELVAAIHGTSTLYADSVKGRFTISRDNAKNSIYLQOMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQOGTQOVTVSS
383. 02B05 EVOLVESGGGLVQPGRSLTLSCAASTNIFSISPYGWYRQOAPGK QRELVAAIHGTSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQOGTQOVTVSS
384. O01EO04 EVOLVESGGGLVQPGRSLTLSCAASTNIASISPMGWYROAPGK QRELVAAIHGTSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQOGTQOVTVSS
385. 02A05 EVOLVESGGGLVQPGRSLTLSCAASTNIASISPMGWYRQAPGK QRELVAAIHGKSTLYADSVKGRFTISRDNAKNSIYLQMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQOGTQOVTVSS
386. 02C03 EVOLVESGGGLVQPGRSLTLSCAASTNIASISPMGWYRQOAPGK QRELVAAIHGSSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQOGTQOVTVSS
387. 01E03 EVOLVESGGGLVQPGRSLTLSCAASTNITSISPMGWYRQAPGK ORELVAAIHGDSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQOGTOVTVSS
388. 01H09 EVQOLVESGGGLVQPGRSLTLSCAASTNIMSISPMGWYRQAPGK QORELVAAIHGNSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQOGTQVTVSS
389. 02GO05 EVQOLVESGGGLVQPGRSLTLSCAASTNITSISPMGWYRQAPGK ORELVAAIHGNSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQOGTQOVTVSS
390. 01C01 EVQOLVESGGGLVQPGRSLTLSCAASTNIVSISPMGWYRQAPGK QORELVAAIHGHSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQOGTQOVTVSS
391. 01DO02 EVQOLVESGGGLVQPGRSLTLSCAASTNIVSISPMGWYRQAPGK ORELVAAIHGKSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQOGTQOVTVSS
392. 02D09 EVQOLVESGGGLVQPGRSLTLSCAASTNVVSISPMGWYRQOAPGK QORELVAAIHGKSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPNNVYWGQOGTQOVTVSS
393. 02C01 EVOLVESGGGLVQPGRSLTLSCAASTNIISISPMGWYRQOAPGK ORELVAAIHGASTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQGTQOVTVSS
394. 02G02 EVQOLVESGGGLVQPGRSLTLSCAASTNIFSITPMGWYRQOAPGK QORELVAAIHGASTLYADSVKGRFTISRDNAKNSIYLQOMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQGTQVTVSS
395. 01B05 EVOLVESGGGLVOPGRSLTLSCAASTNITSISPMGWYROAPGK QRELVAAIHGFETLYADSVKGRFTISRDNAKNSIYLQMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQOGTOVTVSS
396. 01GO08 EVOLVESGGGLVQPGRSLTLSCAASTNIQSISPMGWYROAPGK QRELVAAIHGFETLYADSVKGRFTISRDNAKNSIYLQOMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQGTQOVTVSS
397. 01H06 EVOLVESGGGLVQPGRSLTLSCAASTSDFSISPMGWYROAPGK QRELVAAIHGFETLYADSVKGRFTISRDNAKNSIYLQOMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQOGTQVTVSS
398. 01FO4 EVQOLVESGGGLVOPGRSLTLSCAASTNIDSISPMGWYRQOAPGK QRELVAAIHGFOTLYADSVKGRFTISRDNAKNSIYLQMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQGTQOVTVSS
399. 01H08 EVOLVESGGGLVQPGRSLTLSCAASTNIMSISPMGWYRQOAPGK QRELVAAIHGFSTVYADSVKGRFTISRDNAKNSIYLQOMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQGTQOVTVSS
400. 02F07 EVOLVESGGGLVQPGRSLTLSCAASTNIESISPMGWYRQOAPGK QRELVAAIHGFSTLYADSVKGRFTISRDNAKNSIYLQOMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQGTQOVTVSS
401. 01C05 EVOLVESGGGLVQPGRSLTLSCAASTNIFSSSPMGWYRQOAPGK QRELVAAIHGFKTLYADSVKGRFTISRDNAKNSIYLQMNSLRP EDTARYYCNKVPWGDYHPGNVYWGQGTQOVTVSS
402. 02F04 EVOLVESGGGLVQPGRSLTLSCAASTNIFSSSPMGWYROAPGK QRELVAAIHGFSTLYADSVKGRFTISRDNAKNSIYLQOMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQOGTQOVTVSS
403. 02B06 EVOLVESGGGLVQPGRSLTLSCAASTNIFSNSPMGWYRQAPGK QRELVAAIHGFSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQOGTQOVTVSS
404. 01FO07 EVOLVESGGGLVQPGRSLTLSCAASTNIFSTSPMGWYRQOAPGK QRELVAAIHGFSTIYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQOGTQOVTVSS
405. 02B04 EVOLVESGGGLVQPGRSLTLSCAASTNIFSTSPMGWYRQAPGK QRELVAAIHGFSTIYADSVKGRFTISRDNAKNSIYLQMNSLRP
EDTALYYCNKVPWGDYHPLNVYWGQOGTQOVTVSS 01H11 EVQOLVESGGGLVQPGRSLTLSCVASTNIFSTSPMGWYRQOAPGK QRELVAAIHGFSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQOGTQOVTVSS
407. 02E06 EVOLVESGGGLVQPGRSLTLSCAASTNIFSDSPMGWYRQAPGK ORELVAAIHGFSTFYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQOGTOVTVSS
408. 01EO08 EVOLVESGGGLVQPGRSLTLSCAASTNIFSQSPMGWYRQAPGK QRELVAAIHGDSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPGNVCWGQOGTQOVTVSS
409. 02A04 EVOLVESGGGLVQPGRSLTLSCAASTNIFSQSPMGWYRQAPGK ORELVAAIHGKSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPSNVYWGKGTQVTVSS
410. 02A08 EVOLVESGGGLVQPGRSLTLSCAASTNIFSRSPMGWYRQAPGK QRELVAAIHGESTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGRYHPGNVYWGQOGTQVTVSS
411. 02E05 EVQLVESGGGLVQPGRSLTLSCAASTNIFSRSPMGWYRQOAPGK ORELVAAIHGISTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQOGTQOVTVSS
412. 02H09 EVQOLVESGGGLVQPGRSLTLSCAASTNIFSRSPMGWYRQOAPGK QORELVAAIHGSSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQOGTQOVTVSS
413. 02G06 EVQOLVESGGGLVQPGRSLTLSCAASTNIFSGSPMGWYRQOAPGK ORELVAAIHGNSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQOGTQOVTVSS
414. 01B09 EVQOLVESGGGLVQPGRSLTLSCAASSNIFSISPMGWYRQOAPGK QORELVAAIHGSSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQOGTQVTVSS
415. 02F03 EVOLVESGGGLVQPGRSLTLSCAASTNIFSIYPMGWYROAPGK QRELVAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQMNSLRP EDTALYYCNKVPWGDYHPKNVYWGQGTQVTVSS
416. 02F02 EVOLVESGGGLVQPGRSLTLSCAASTNIFSKSPMGWYRQOAPGK QRELVAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQOMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQGTQOVTVSS
417. 02H01 EVQLVESGGGLVQPGRSLTLSCAASTNIFSKSPMGWYRQAPGK ORELVAAIHGSSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPRNVYWGQOGTQOVTVSS
418. 01G10 EVOLVESGGGLVQPGRSLTLSCAASTNEFSISPMGWYROAPGK QRELVAAIHGLSTLYADSVKGRFTISRDNAKNSIYLQOMNSLRP EDTALYYCNKVPWGAYHPRNVYWGQOGTOVTVSS
419. 02D11 EVQLVESGGGLVQPGRSLTLSCAASTNEFSISPMGWYRQOAPGK QRELVAAIHGESTLYADSVKGRFTISRDNAKNSIYLQOMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQGTQVTVSS
420. O01B01 EVOLVESGGGLVQPGRSLTLSCAASTNIPSISPMGWYRQOAPGK QRELVAAIHGESTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPRNVANWGOGTQOVTVSS
421. 01611 EVQOLVESGGGLVOPGRSLTLSCAASTNIPSISPMGWYRQAPGK QRELVAAIHGASTLYADSVKGRFTISRDNAKNSIYLQMNSLRP EDTALYYCNKVPWGDYHPRNVANWGQOGTQOVTVSS
422. 01H10 EVOLVESGGGLVQPGRSLTLSCAASTNIPSISPMGWYRQOAPGK QRELVAAIHGESTLYADSVKGRFTISRDNAKNSIYLQOMNSLRP EDTALYYCNKVPWGDYHPRNVYWGQOGTQOVTVSS OVER THERE
423. 01C04 EVOLVESGGGLVQPGRSLTLSCAASTNIPSISPMGWYRQAPGK QORELVAAIHGDSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP
EDTALYYCNKVPWGDYHPRNVYWGQGTQVTVSS 424, 01D04 EVOLVESGGGLVQPGRSLTLSCAASTNITSISPMGWYRQAPGK QORELVAAIHGVSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPRNVQWGOGTQOVTVSS
425. 01E07 EVOLVESGGGLVQPGRSLTLSCAASTNIPSISPMGWYRQAPGK QORELVAAIHGOSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPRNVQWGOGTOVTVSS
426. 02B11 EVOLVESGGGLVQPGRSLTLSCAASTNIVSISPMGWYRQAPGK QORELVAAIHGDSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPRNVSWGQOGTQOVTVSS
427. O01F10 EVOLVESGGGLVQPGRSLTLSCAASSNIFSISPMGWYRQAPGK QORELVAAIHGESTLYADSVKGRFTISRDNAKNSIYLQMNSLRP EDTALYYCNKVPWGDYHPRNVTWGQOGTQOVTVSS
428. 02GO08 EVOLVESGGGLVQPGRSLTLSCAASTNIDSISPMGWYRQOAPGK QORELVAAIHGESTLYADSVKGRFTISRDNAKNSIYLQOMNSLRP EDTALYYCNKVPWGDYHPRNVTWGQOGTQVTVSS
429. 02G11 EVOLVESGGGLVQPGRSLTLSCAASTNIDSISPMGWYRQAPGK QRELVAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQMNSLRP EDTALYYCNKVPWGDYHPRNVTWGQOGTQOVTVSS
430. 02H06 EVOLVESGGGLVQPGRSLTLSCAASTNIRSISPMGWYRQAPGK QRELVAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQMNSLRP EDTALYYCNKVPWGDYHPRNVVWGOGTQOVTVSS
431. 01B02 EVOLVESGGGLVQPGRSLTLSCAASTNITSISPMGWYRQAPGK QRELVAAISGFSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNEVPWGDYHPRNVYWGQOGTOVTVSS
432. 02H11 EVQOLVESGGGLVQPGRSLTLSCAASTNITSISPMGWYRQAPGK QRELVAAIHGESTLYADSVKGRFTISRDNAKNSIYLQOMNSLRP EDTALYYCNKVPWGDYHPRNVYWGQOGTQVTVSS
433. 01FO08 EVQLVESGGGLVQPGRSLTLSCAASTNITSVSPMGWYRQAPGK QRELVAAIHGPSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP
EDTALYYCNKVPWGDYHPTNVYWGQOGTQVTVSS 434, 01H01 EVQLVESGGGLVQPGRSLTLSCAASTNIGSISPMGWYRQAPGK QRELVAAIHGOSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPQONVYWGOGTQOVTVSS
435. O01E10 EVOLVESGGGLVQPGRSLTLSCAASTNIESISPMGWYRQAPGK OQORELVAAIHGKSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPRRVYWGQOGTQVTVSS
436. 01GO01 EVQOLVESGGGLVQPGRSLTLSCAASTNIVSISPMGWYRQAPGK QRELVAAIHGDSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPRRVYWGQOGTQOVTVSS
437. 01G04 EVOLVESGGGLVQPGRSLTLSCAASTNIDSISPMGWYRQAPGK QORELVAAIHGNSTLYADSVKGRFTISRDNAKNSIYLQMNSLRP EDTALYYCNKVPWGDYHPRMVYWGQOGTQOVTVSS
438. 01A04 EVOLVESGGGLVQPGRSLTLSCAASTNIFMISPMGWYRQAPGK QRELVAAIHGDSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGRYHPRNVYWGQOGTQOVTVSS
439. 01F12 EVOLVESGGGLVQPGRSLTLSCAASTNIFRISPMGWYRQAPGK QRELVAAIHGDSTLYADSVKGRFTISRDNAKNSIYLQMNSLRP EDTALYYCNKVPWGRYHPRNVYWGQOGTQOVTVSS
440. 01B06 EVOLVESGGGLVQPGRSLTLSCAASTNIFSISPMGWYRQOAPGK QRELVAAIHGDSTLYADSVKGRFTISRDNAKNSIYLQOMNSLRP EDTALYYCNKVPWGEYHPRNVYWGQOGTOVTVSS
441. 01C06 EVOLVESGGGLVQPGRSLTLSCAASTNIFSISPMGWYRQAPGK QRELVAAIHGDSTLYADSVKGRFTISRDNAKNSIYLQMNSLRP EDTALYYCNKVPWGKYHPRNVYWGOGTQOVTVSS
442. 01B08 EVOLVESGGGLVQPGRSLTLSCAASTNIESISPMGWYRQOAPGK QRELVAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQOMNSLRP EDTALYYCNKVPWGRYHPRNVYWGQOGTOVTVSS
443. 01cC02 EVOLVESGGGLVQPGRSLTLSCAASTNIESISPMGWYRQAPGK QRELVAAIHGNSTLYADSVKGRFTISRDNAKNSIYLQMNSLRP EDTALYYCNKVPWGRYHPRNVYWGQOGTOVTVSS
444. 01C10 EVOLVESGGGLVQPGRSLTLSCAASTNISSISPMGWYRQOAPGK QRELVAAIHGFSTLYADSVKGRFTISRDNAKNSIYLQOMNSLRP EDTALYYCNKVPWGYYHPRNVYWGQOGTQVTVSS
445. 01FO09 EVOLVESGGGLVQOPGRSLTLSCAASTNISSISPMGWYRQAPGK QRELVAAIHGHSTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGRYHPRNVYWGQOGTOVTVSS
446. 02D06 EVQLVESGGGLVQPGRSLTLSCAASTNISSISPMGWYRQAPGK QRELVAAIHGFSTVYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGRYHPRNVYWGQOGTQVTVSS
447. 01A06 EVQOLVESGGGLVQPGRSLTLSCAASTNIFSIRPMGWYRQAPGK QORELVAAIHGFSTVYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPRNVYWGQOGTQVTVSS
448. 01C07 EVQOLVESGGGLVQPGRSLTLSCAASTNIFSIYPMGWYRQAPGK QRELVAAIHGFSTYYADSVKGRFTISRDNAKNSIYLOMNSLRP
EDTALYYCNKVPWGSYHPRNVYWGQOGTQVTVSS 01G09 EVQOLVESGGGLVQPGRSLTLSCAASTNIFNISPMGWYRQAPGK QORELVAAIHGFSTYYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGRYHPRNVYWGQOGTQOVTVSS
450. 01FO5 EVOLVESGGGLVQPGRSLTLSCAASTNIFSSSPMGWYRQAPGK QRELVAAIHGFSTWYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGRYHPRNVYWGQOGTQVTVSS
451. 02B12 EVOLVESGGGLVQPGRSLTLSCAASTNISSISPMGWYRQAPGK QRELVAAIHGFDTLYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPRNVYWGQOGTQOVTVSS
452. 02G01 EVOLVESGGGLVQPGRSLTLSCAASTNIFSINPMGWYRQAPGK QRELVAAIHGFDTLYADSVKGRFTISRDNAKNSIYLQOMNSLRP EDTALYYCNKVPWGDYHPRNVSWGQOGTQVTVSS
453. 01A09 EVOLVESGGGLVQPGRSLTLSCAASTNIFSITPMGWYRQAPGK QRELVAAIHGRSTLYADSVKGRFTISRDNAKNSIYLQMNSLRP
EDTALYYCNKVPWGSYHPRNVYWGQOGTQOVTVSS 454, 01H05 EVOLVESGGGLVQPGRSLTLSCAASTNIFSITPMGWYRQAPGK QORELVAAIHGTSTLYADSVKGRFTISRDNAKNSIYLQMNSLRP EDTALYYCNKVPWGRYHPRNVYWGQOGTQOVTVSS
455. 02F06 EVOLVESGGGLVQPGRSLTLSCAASTNIFSITPMGWYRQAPGK QRELVAAIHGESTLYADSVKGRFTISRDNAKNSIYLQMNSLRP EDTALYYCNKVPWGRYHPRNVYWGQOGTOVTVSS
456. 02G07 EVOLVESGGGLVQPGRSLTLSCAASTNIFSITPMGWYRQAPGK QRELVAAIHGESTLYADSVKGRFTISRDNAKNSIYLQMNSLRP EDTALYYCNKVPWGDYHPRDVYWGQOGTQOVTVSS
457. O1FO7-M34Y EVOLVESGGGLVQPGRSLTLSCAASTNIFSTSPYGWYRQOAPGK QRELVAAIHGFSTIYADSVKGRFTISRDNAKNSIYLQMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQOGTQOVTVSS
458. O01FO01-M34G EVQOLVESGGGLVQPGRSLTLSCAASTNIFSTSPGGWYRQAPGK QORELVAAIHGFSTIYADSVKGRFTISRDNAKNSIYLOMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQOGTQOVTVSS
459. 02G02-M34Y EVOLVESGGGLVQPGRSLTLSCAASTNIFSITPYGWYROAPGK QRELVAAIHGASTLYADSVKGRFTISRDNAKNSIYLQMNSLRP EDTALYYCNKVPWGDYHPGNVYWGQOGTOVTVSS
02G02-M34G | EVOLVESGGGLVOPGRSLTLSCAASTNIFSITPGGWYROAPGK QRELVAAIHGASTLYADSVKGRFTISRDNAKNSIYLQOMNSLRP
EDTALYYCNKVPWGDYHPGNVYWGQGTOVTVSS F1 EVOLVESGGGLVQPGRSLTLSCAAS EVOLVESGGGLVQPGRSLTLSCVAS F1 F2 F3 WYROAPGKORELVA GRFTISRDNAKNSIYLQMNSLRPEDTALYYCNK GRETISRDNAKNSIYLQOMNSLRPEDTALYYCNE F3 F4 F4 WGQOGTQVTVSS WGKGTQVTVSS
468. Human BCMA MLQOMAGQCSQNEYFDSLLHACIPCQOLRCSSNTPPLTCORYCNA SVTNSVKGTNAILWTCLGLSLIISLAVFVLMFLLRKINSEPLK DEFKNTGSGLLGMANIDLEKSRTGDEIILPRGLEYTVEECTCE DCIKSKPKVDSDHCFPLPAMEEGATILVTTKTNDYCKSLPAAL SATETEKSISAR
469. Murine BCMA | MAQOCFHSEYFDSLLHACKPCHLRCSNPPATCQPYCDPSVTSS VKGTYTVLWIFLGLTLVLSLALFTISFLLRKMNPEALKDEPQS PGQLDGSAQLDKADTELTRIRAGDDRIFPRSLEYTVEECTCED CVKSKPKGDSDHFFPLPAMEEGATILVTTKTGDYGKSSVPTAL QSVMGMEKPTHTR
470. Cynomolgus | MLOMAROCSQNEYFDSLLHDCKPCOLRCSSTPPLTCORYCNAS
BCMA MTNSVKGMNAILWTCLGLSLIISLAVFVLTFLLRKMSSEPLKD o EFKNTGSGLLGMANIDLEKGRTGDEIVLPRGLEYTVEECTCED CIKNKPKVDSDHCFPLPAMEEGATILVTTKTNDYCNSLSAALS
VTEIEKSISAR His-His-His-His-His-His SEQ ID NO Sequence Name Construction
472. Exemplary n-link (GS) sequence
473. Exemplary n-linker sequence (GGS)
474. Exemplary n-linker sequence (GEGS)
475. Exemplary linker (GGSG) sequence
476. Exemplary n-linker sequence (GGSGG)
477. Exemplary linker (GGGGS) sequence
478. Exemplary linker (GGGGG) sequence
479. Exemplary linker (GGG) sequence
SEQ ID NO Sequence Name o fetet
480. Sequence (GGGGS) 4th rem
481. Sequence (GGGGS) 3 FAITH
482. LPETG o E string
483. String BH2T EVOLVESGGGLVOPGRSLTLSCAASTNIFSISPM exemplary TriTAC GWYROAPGKORELVAAIHGFSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPRNVYWGQOGTQVTVSSGGGGSGGESEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQOAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGEGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQOAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGEGGESCEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED
EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 484, String 01A01 EVOLVESGGGLVQPGRSLTLSCAASTDIFSISPM TriTAC copy GWYROAPGKORELVAAIHGGSTLYADSVKGRFTI SRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDY HPRNVAWGOGTQOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGEGGSCGEESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQKPGQOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
485. Sequence 02FE09 EVOLVESGGGLVQPGRSLTLSCAASTNDFSISPM [PT these
SEQ ID NO Sequence Name E et SRDNAKNSIYLOMNSLRPEDTALYYCNKVPWGDY HPRNVAWGQOGTQOVTVSSGGGESCEESEVOLVESGE GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGEGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADOVKDRFTISRDDSKNTAYLOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGESGEGESGEGESQTVVTEEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQKPGQOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
486. String 01B03 EVOLVESGGGLVQPGRSLTLSCAASTNIFSKSPM TriTAC exemplary GWYRQOAPGKQORELVAAIHGKSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPRNVVWGQOGTQVTVSSGGEGGSCCGESEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQOAPGKGLEWVARIRSK YNNYATYYADOVKDRFTISRDDSKNTAYLOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGEGESCEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQKPGOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
487. String 01B04 EVQOLVESGGGLVQPGRSLTLSCAASTNDFSISPM TriTAC exemplary GWYROAPGKQORELVAAIHGKSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPRNVKWGQGTQVTVSSGGGGSGGESEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT
SEQ ID NO Sequence Name 22 VSSGGGGSGEGESCEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
488. Sequence 02H05 EVOLVESGGGLVQPGRSLTLSCAASTNQFSISPM TriTAC exemplary GWYRQOAPGKORELVAAIHGKSTLYADSVKGRFTI SRDNAKNSIYLOMNSLRPEDTALYYCNKVPWGDY HPRNVVWGOGTOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VIVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQAPGKGLEWVARIRSK YNNYATYYADQOQVKDRFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVT VSSGGGGSGEGESCEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQOQKPGQOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
489. String 01A02 EVQLVESGGGLVQPGRSLTLSCAASTNIFSSSPM TriTAC exemplary GWYRQOAPGKORELVAAINGFSTLYADSVKGRFTI SRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDY HPRNVHWGOGTOVTVSSGGGGSGGGSEVQOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQOAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQOAPGKGLEWVARIRSK YNNYATYYADQVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGEGESCECGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQKPGOAAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
490. String 01A05 EVQOLVESGGGLVQPGRSLTLSCAASTNIFSSSPM TriTAC exemplary GWYRQOAPGKORELVAAIHGFSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPRNVYWGQOGTQOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG
SEQ ID NO Sequence Name E et KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQOAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGOGTLVT VSSGGGGSGGGESCEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQKPGQOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
491. Sequence 01B12 EVOLVESGGGLVQPGRSLTLSCAASTNIFSTSPM TriTAC exemplary GWYROAPGKORELVAAIHGFOTLYADSVKGRFTI SRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDY HPRNVVWGOGTQOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGEGGGSCGECGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQKPGQOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
492. Sequence 01G06 EVQOLVESGGGLVQPGRSLTLSCAASTNIFSRSPM TriTAC exemplary GWYROAPGKQORELVAAIHGFETLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPRNVLWGQGTQOVTVSSGGGESCGEESEVOLVESGE GGLVOPGNSLRLSCAASGFTFSKFGMSWVRQOAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGEGSGEGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGEGEGSCGEGESCEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQOQOKPGQOAPRGLI
SEQ ID NO Sequence Name E et GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED CTA
493. Sequence 02C05 EVQOLVESGGGLVQOPGRSLTLSCAASTNIFSESPM TriTAC exemplary GWYRQOAPGKORELVAAIHGEFTTLYADSVKGRFTI SRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDY HPRNVTWGQOGTQVTVSSGGGGSGCGESEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGEGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQOAPGKGLEWVARIRSK YNNYATYYADOQVKDRFTISRDDSKNTAYLOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGEGESCEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQOKPGQOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED
EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 494, String 02G09 EVOLVESGGGLVQPGRSLTLSCAASTNIFSDSPM TriTAC copy GWYROAPGKORELVAAIHGFSTLYADSVKGRFTI SRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDY HPRNVANWGOGTQVTVSSGGGGSGGEGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQOAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGEGCGSCGECESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
495. Sequence 01CO8 EVQOLVESGGGLVQPGRSLTLSCAASTNIFSNSPM TriTAC exemplary GWYROAPGKORELVAAIHGGSTLYADSVKGRFTI SRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDY HPRNVHWGOGTQOVTVSSGGGGSGGGSEVOLVESG GGLVOPGNSLRLSCAASGFTFSKFGMSWVRQOAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL
SEQ ID NO Sequence Name E et VTVSSGGGGSGEGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQOAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGEGESCEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQOKPGQOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED
EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH String 02B01 EVQOLVESGGGLVQPGRSLTLSCAASTNIFSNSPM exemplary TriTAC GWYROAPGKORELVAAIHGRSTLYADSVKGRFTI SRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDY HPRNVMWGQGTQVTVSSGGGGSCGCGESEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGEGESCEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQOKPGOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
497. String 02E03 EVQOLVESGGGLVQOPGRSLTLSCAASTNIFSNSPM TriTAC copy GWYROAPGKQORELVAAIHGPSTLYADSVKGRFTI SRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDY HPRNVTWGOGTQOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGEGESCEGESQTVVTQOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQKPGQOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
SEQ ID NO Sequence Name o et
498. String 01D03 EVOLVESGGGLVOPGRSLTLSCAASTNIFSNSPM exemplary TriTAC GWYRQOAPGKQORELVAAIHGDSTLYADSVKGRFTI SRDNAKNSIYLOMNSLRPEDTALYYCNKVPWGDY HPRNVRWGQOGTQVTVSSGGGGSCGESEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGEGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQOAPGKGLEWVARIRSK YNNYATYYADOVKDRFTISRDDSKNTAYLOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGESGEGESGEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQOAPRGLTI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED
EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH String 01D06 EVQOLVESGGGLVQPGRSLTLSCAASTNIFSRSPM exemplary TriTAC GWYROAPGKORELVAAIHGDSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPRNVTWGQGTQVTVSSGGGGSCGGESEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGEGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQOAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGOGTLVT VSSGGGGSCGEGESCEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQOQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
500. String 01H04 EVQOLVESGGGLVQPGRSLTLSCAASTNIFSKSPM TriTAC exemplary GWYROAPGKQORELVAAIHGOSTLYADSVKGRFTI SRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDY HPRNVTWGOGTQOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK
SEQ ID NO Sequence Name 22 YNNYATYYADOVKDRFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVT VSSGGGGSGGGESGGGEGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
501. Sequence 02B07 EVOLVESGGGLVOPGRSLTLSCAASTNIFSSSPM exemplary TriTAC GWYRQAPGKORELVAAIHGHSTLYADSVKGRFTI SRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDY HPRNVTWGOGTOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQAPGKGLEWVARIRSK YNNYATYYADQVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGESGGGEGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQKPGOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
502. String 01A08 EVQLVESGGGLVQPGRSLTLSCAASTNIFSSSPM TriTAC exemplary GWYRQOAPGKORELVAAIHGESTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPRKVYWGQOGTQOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQOMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQOPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGEGGGSCGECGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
503. String 01B07 EVOLVESGGGLVQPGRSLTLSCAASTNIFSRSPM exemplary TriTAC GWYRQAPGKORELVAAIHGNSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGIY
SEQ ID NO Sequence Name E et HPRNVYWGQOGTQVTVSSGGGGSGGESEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGEGCGSCGEESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQOKPGOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
504. Sequence 01F03 EVQOLVESGGGLVQPGRSLTLSCAASTNIFSESPM TriTAC exemplary GWYROAPGKQORELVAAIHGNSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGTY HPRNVYWGOGTOVTVSSGGGGSCGEGGSEVOLVESG GGLVOPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGEGSGEGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGEGEGSCGEGESCEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQOKPGQOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
505. Sequence 02F05 EVQOLVESGGGLVQOPGRSLTLSCAASTNIFSVSPM TriTAC exemplary GWYRQOAPGKQORELVAAIHGNSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGKY HPRNVYWGQOGTOVTVSSGGGESCEESEVOLVESGE GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQOAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGEGSCGEGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADOVKDRFTISRDDSKNTAYLOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGESGEGESGEGESQTVVTEEPSLTVSPGG
SEQ ID NO Sequence Name 22 TVTLTCASSTGAVTSGNYPNWVQOQOKPGQOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
506. Sequence 02H04 EVOLVESGGGLVQPGRSLTLSCAASTNIFSVSPM TriTAC exemplary GWYRQOAPGKORELVAAIHGNSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPRNVYWGOGTQOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLOMNSLRPEDTAVYYCTIGGSLSVSSQOGTL VTVSSGGGGSGGGSEVQOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDREFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGGSGGGGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
507. String 02A07 EVOLVESGGGLVQPGRSLTLSCAASTNIFSKSPM TriTAC exemplary GWYRQAPGKQRELVAAIHGNSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPREVYWGQOGTQOVTVSSGGGGSGGGSEVQOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQOAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQOMNSLRPEDTAVYYCTIGGSLSVSSQOGTL VTVSSGGGGSGGGSEVQOLVESGGGLVQPGGSLKL SCAASGFTFENKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQOVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGGSGGGGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQOQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
508. Sequence 01DO5 EVOLVESGGGLVQPGRSLTLSCAASTNIFSDSPM TriTAC exemplary GWYRQAPGKQORELVAAIHGTSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPRNVYWGOGTOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQOAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK
SEQ ID NO Sequence Name 22 TTLYLOMNSLRPEDTAVYYCTIGGSLSVSSQOGTL VTVSSGGGGSGGGSEVOLVESGGGLVQOPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGGSGGGGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQOQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
509. Sequence O01EO5 EVOLVESGGGLVOQPGRSLTLSCAASTNIFSRSPM TriTAC copy GWYRQAPGKQRELVAAIHGTSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGKY HPRNVYWGQOGTQAVTVSSGGGGSGGGSEVQOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQOAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVQOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGESGGGEGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
510. String 01F02 EVOLVESGGGLVQPGRSLTLSCAASTNIFSHSPM TriTAC exemplary GWYRQAPGKQRELVAAIHGTSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGRY HPRNVYWGOGTOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGESCGGGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQOQOKPGOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
SEQ ID NO Sequence Name [E et
511. Sequence 02C06 EVOLVESGGGLVOPGRSLTLSCAASTNIFSTSPM exemplary TriTAC GWYRQOAPGKQORELVAAIHGTSTLYADSVKGRFTI SRDNAKNSIYLOMNSLRPEDTALYYCNKVPWGDY HPGNVYWGQOGTQVTVSSGGGGSCGESEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGEGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQOAPGKGLEWVARIRSK YNNYATYYADOVKDRFTISRDDSKNTAYLOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGESGEGESGEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQOAPRGLTI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
512. Sequence 02F11 EVOLVESGGGLVOPGRSLTLSCAASTNIFSTSPM exemplary TriTAC GWYROAPGKORELVAAIHGTSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPRNVQWGQOGTQVTVSSGGGGSCGGESEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGEGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQOAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGOGTLVT VSSGGGGSCGEGESCEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQOQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
513. Sequence 01E06 EVQOLVESGGGLVQPGRSLTLSCAASTNIFSLSPM TriTAC exemplary GWYROAPGKQORELVAAIHGDSTLYADSVKGRFTI SRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDY HPRNVYWGQOGTQOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK
SEQ ID NO Sequence Name 22 YNNYATYYADOVKDRFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVT VSSGGGGSGGGESGGGEGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
514. String 01A03 EVOLVESGGGLVOQPGRSLTLSCAASTNIFSISPG TriTAC exemplary GWYRQAPGKQORELVAAIHGSSTLYADSVKGRFTI SRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDY HPRNVYWGOGTOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQAPGKGLEWVARIRSK YNNYATYYADQVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGESGGGEGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQKPGOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
515. String 02A11 EVQLVESGGGLVQPGRSLTLSCAASTNHFSISPM TriTAC exemplary GWYRQOAPGKORELVAAIHGSSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPRVVYWGOGTQOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQOMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQOPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGEGGGSCGECGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
516. Sequence 01DO07 EVOLVESGGGLVQPGRSLTLSCAASTNIFSASPM TriTAC exemplary GWYRQAPGKQORELVAAIHGSSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY
SEQ ID NO Sequence Name 22 HPRNVNWGOGTQOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQOGTL VTVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFENKYAINWVROAPGKGLEWVARIRSK YNNYATYYADOVKDRFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGEGCGSCGEESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQOKPGOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
517. String 01D10 EVQLVESGGGLVQPGRSLTLSCAASTNIFSASPM TriTAC exemplary GWYRQAPGKORELVAAIHGSSTLYADSVKGRFTI SRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGRY HPRNVYWGOGTOVTVSSGGGGSCGEGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLOMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQOPGGSLKL SCAASGFTFENKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGGSGGGGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
518. String 01A07 EVOLVESGGGLVQPGRSLTLSCAASTNISSISPM exemplary TriTAC GWYRQAPGKQRELVAAIHGTSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPGNVYWGQOGTQAVTVSSGGGGSGGGSEVQOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQOMNSLRPEDTAVYYCTIGGSLSVSSQOGTL VTVSSGGGGSGGGSEVQOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADOVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGGSGGGGSQTVVTOEPSLTVSPGG
SEQ ID NO Sequence Name 22 TVTLTCASSTGAVTSGNYPNWVQOQOKPGQOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
519. Sequence 02F12 EVOLVESGGGLVQPGRSLTLSCAASTNIESISPM exemplary TriTAC GWYRQOAPGKORELVAAIHGTSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPGNVYWGQOGTQOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLOMNSLRPEDTAVYYCTIGGSLSVSSQOGTL VTVSSGGGGSGGGSEVQOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDREFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGGSGGGGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
520. Sequence 02B05 EVOLVESGGGLVQPGRSLTLSCAASTNIFSISPY TriTAC exemplary GWYRQAPGKQRELVAAIHGTSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPGNVYWGQOGTQAVTVSSGGGGSGGGSEVQOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQOAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQOMNSLRPEDTAVYYCTIGGSLSVSSQOGTL VTVSSGGGGSGGGSEVQOLVESGGGLVQPGGSLKL SCAASGFTFENKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQOVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGGSGGGGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQOQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
521. Sequence O01EO04 EVOLVESGGGLVQPGRSLTLSCAASTNIASISPM TriTAC copy GWYRQAPGKQORELVAAIHGTSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPGNVYWGOGTOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQOAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK
SEQ ID NO Sequence Name 22 TTLYLOMNSLRPEDTAVYYCTIGGSLSVSSQOGTL VTVSSGGGGSGGGSEVOLVESGGGLVQOPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGGSGGGGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQOQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
522. Sequence 02A05 EVOLVESGGGLVOQPGRSLTLSCAASTNIASISPM exemplary TriTAC GWYRQAPGKQRELVAAIHGKSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPGNVYWGQOGTQAVTVSSGGGGSGGGSEVQOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQOAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVQOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGESGGGEGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
523. Sequence 02C03 EVOLVESGGGLVQPGRSLTLSCAASTNIASISPM exemplary TriTAC GWYRQAPGKQRELVAAIHGSSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPGNVYWGOGTOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGESCGGGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQOQOKPGOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
SEQ ID NO Sequence Name [E et
524. String 01FE03 EVOLVESGGGLVOPGRSLTLSCAASTNITSISPM exemplary TriTAC GWYRQOAPGKQORELVAAIHGDSTLYADSVKGRFTI SRDNAKNSIYLOMNSLRPEDTALYYCNKVPWGDY HPGNVYWGQOGTQVTVSSGGGGSCGESEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGEGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQOAPGKGLEWVARIRSK YNNYATYYADOVKDRFTISRDDSKNTAYLOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGESGEGESGEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQOAPRGLTI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
525. String 01H09 EVQLVESGGGLVQPGRSLTLSCAASTNIMSISPM TriTAC copy GWYRQOAPGKORELVAAIHGNSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPGNVYWGQGTQVTVSSGGGGSCGGESEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGEGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQOAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGOGTLVT VSSGGGGSCGEGESCEGGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQOQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
526. Sequence 02GO05 EVQOLVESGGGLVQPGRSLTLSCAASTNITSISPM TriTAC exemplary GWYROAPGKQORELVAAIHGNSTLYADSVKGRFTI SRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDY HPGNVYWGQOGTQOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK
SEQ ID NO Sequence Name 22 YNNYATYYADOVKDRFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVT VSSGGGGSGGGESGGGEGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
527. Sequence 01CO01 EVOLVESGGGLVOPGRSLTLSCAASTNIVSISPM exemplary TriTAC GWYRQAPGKORELVAAIHGHSTLYADSVKGRFTI SRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDY HPGNVYWGOGTOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQAPGKGLEWVARIRSK YNNYATYYADQVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGESGGGEGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQKPGOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
528. String 01D02 EVQLVESGGGLVQPGRSLTLSCAASTNIVSISPM TriTAC exemplary GWYRQOAPGKORELVAAIHGKSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPGNVYWGOGTQOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQOMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQOPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGEGGGSCGECGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
529. Sequence 02D09 EVOLVESGGGLVQPGRSLTLSCAASTNVVSISPM TriTAC exemplary GWYRQAPGKORELVAAIHGKSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY
SEQ ID NO Sequence Name E et HPNNVYWGQOGTQVTVSSGGGGSGGESEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGEGCGSCGEESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQOKPGOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
530. Sequence 02C0O01 EVQOLVESGGGLVQPGRSLTLSCAASTNIISISPM TriTAC exemplary GWYROAPGKQORELVAAIHGASTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPGNVYWGOGTOVTVSSGGGGSCGEGSEVOLVESG GGLVOPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGEGSGEGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGEGEGSCGEGESCEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQOKPGQOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
531. Sequence 02G02 EVQOLVESGGGLVOPGRSLTLSCAASTNIFSITPM exemplary TriTAC GWYRQOAPGKQORELVAAIHGASTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPGNVYWGQOGTOVTVSSGGGESCGEESEVOLVESGE GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQOAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGEGSCGEGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADOVKDRFTISRDDSKNTAYLOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGESGEGESGEGESQTVVTEEPSLTVSPGG
SEQ ID NO Sequence Name 22 TVTLTCASSTGAVTSGNYPNWVQOQOKPGQOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
532. String 01B05 EVOLVESGGGLVQPGRSLTLSCAASTNITSISPM TriTAC exemplary GWYRQOAPGKORELVAAIHGFETLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPGNVYWGQOGTQOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLOMNSLRPEDTAVYYCTIGGSLSVSSQOGTL VTVSSGGGGSGGGSEVQOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDREFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGGSGGGGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
533. String 01GO8 EVOLVESGGGLVQPGRSLTLSCAASTNIQSISPM TriTAC copy GWYRQAPGKQRELVAAIHGFETLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPGNVYWGQOGTQAVTVSSGGGGSGGGSEVQOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQOAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQOMNSLRPEDTAVYYCTIGGSLSVSSQOGTL VTVSSGGGGSGGGSEVQOLVESGGGLVQPGGSLKL SCAASGFTFENKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQOVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGGSGGGGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQOQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
534. String 01H06 EVOLVESGGGLVQPGRSLTLSCAASTSDFSISPM TriTAC copy GWYRQAPGKQORELVAAIHGFETLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPGNVYWGOGTOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQOAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK
SEQ ID NO Sequence Name 22 TTLYLOMNSLRPEDTAVYYCTIGGSLSVSSQOGTL VTVSSGGGGSGGGSEVOLVESGGGLVQOPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGGSGGGGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQOQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
535. Sequence 01F04 EVOLVESGGGLVOQPGRSLTLSCAASTNIDSISPM exemplary TriTAC GWYRQAPGKQRELVAAIHGFQOTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPGNVYWGQOGTQAVTVSSGGGGSGGGSEVQOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQOAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVQOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGESGGGEGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
536. String 01H08 EVOLVESGGGLVQPGRSLTLSCAASTNIMSISPM TriTAC exemplary GWYRQAPGKQRELVAAIHGFSTVYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPGNVYWGOGTOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGESCGGGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQOQOKPGOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
SEQ ID NO String Name [E Jet O
537. Sequence 02F07 EVOLVESGGGLVOPGRSLTLSCAASTNIESISPM exemplary TriTAC GWYRQOAPGKQORELVAAIHGFSTLYADSVKGRFTI SRDNAKNSIYLOMNSLRPEDTALYYCNKVPWGDY HPGNVYWGQOGTQVTVSSGGGGSCGESEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGEGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQOAPGKGLEWVARIRSK YNNYATYYADOVKDRFTISRDDSKNTAYLOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGESGEGESGEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQOAPRGLTI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
538. Sequence 01CO5 EVQLVESGGGLVQPGRSLTLSCAASTNIFSSSPM TriTAC exemplary GWYROAPGKORELVAAIHGFKTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTARYYCNKVPWGDY HPGNVYWGQGTQVTVSSGGGGSCGGESEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGEGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQOAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGOGTLVT VSSGGGGSCGEGESCEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQOQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
539. Sequence 02F04 EVOLVESGGGLVQOPGRSLTLSCAASTNIFSSSPM TriTAC exemplary GWYROAPGKQORELVAAIHGFSTLYADSVKGRFTI SRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDY HPGNVYWGQOGTQOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK
SEQ ID NO Sequence Name 22 YNNYATYYADOVKDRFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVT VSSGGGGSGGGESGGGEGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
540. Sequence 02B06 EVOLVESGGGLVOPGRSLTLSCAASTNIFSNSPM exemplary TriTAC GWYRQAPGKQORELVAAIHGFSTLYADSVKGRFTI SRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDY HPGNVYWGOGTOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQAPGKGLEWVARIRSK YNNYATYYADQVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGESGGGEGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQKPGOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
541. Sequence 01F07 EVQLVESGGGLVQPGRSLTLSCAASTNIFSTSPM exemplary TriTAC GWYRQOAPGKORELVAAIHGFSTIYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPGNVYWGOGTQOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQOMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQOPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGEGGGSCGECGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
542. Sequence 02B04 EVOLVESGGGLVQPGRSLTLSCAASTNIFSTSPM TriTAC exemplary GWYRQAPGKQORELVAAIHGFSTIYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY
SEQ ID NO Sequence Name 22 HPLNVYWGOGTQOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQOGTL VTVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFENKYAINWVROAPGKGLEWVARIRSK YNNYATYYADOVKDRFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGEGCGSCGEESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQOKPGOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
543. String 01H11 EVQLVESGGGLVQPGRSLTLSCVASTNIFSTSPM TriTAC exemplary GWYRQAPGKORELVAAIHGFSTLYADSVKGRFTI SRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDY HPGNVYWGOGTOVTVSSGGGGSCGEGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLOMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQOPGGSLKL SCAASGFTFENKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGGSGGGGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
544. String 02E06 EVOLVESGGGLVQPGRSLTLSCAASTNIFSDSPM TriTAC exemplary GWYRQAPGKQRELVAAIHGFSTFYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPGNVYWGQOGTQAVTVSSGGGGSGGGSEVQOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQOMNSLRPEDTAVYYCTIGGSLSVSSQOGTL VTVSSGGGGSGGGSEVQOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADOVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGGSGGGGSQTVVTOEPSLTVSPGG
SEQ ID NO Sequence Name 22 TVTLTCASSTGAVTSGNYPNWVQOQOKPGQOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
545. Sequence O01EO08 EVOLVESGGGLVQPGRSLTLSCAASTNIFSQSPM TriTAC exemplary GWYRQOAPGKORELVAAIHGDSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPGNVCWGQOGTQOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLOMNSLRPEDTAVYYCTIGGSLSVSSQOGTL VTVSSGGGGSGGGSEVQOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDREFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGGSGGGGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
546. String 02A04 EVOLVESGGGLVQPGRSLTLSCAASTNIFSQSPM TriTAC exemplary GWYRQAPGKQRELVAAIHGKSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPSNVYWGKGTQVTVSSGGGGSGGGSEVQOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQOAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQOMNSLRPEDTAVYYCTIGGSLSVSSQOGTL VTVSSGGGGSGGGSEVQOLVESGGGLVQPGGSLKL SCAASGFTFENKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQOVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGGSGGGGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQOQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
547. String 02A08 EVOLVESGGGLVQPGRSLTLSCAASTNIFSRSPM TriTAC exemplary GWYRQAPGKQORELVAAIHGESTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGRY HPGNVYWGOGTOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQOAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK
SEQ ID NO Sequence Name 22 TTLYLOMNSLRPEDTAVYYCTIGGSLSVSSQOGTL VTVSSGGGGSGGGSEVOLVESGGGLVQOPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGGSGGGGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQOQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
548. Sequence 02E05 EVOLVESGGGLVOQPGRSLTLSCAASTNIFSRSPM exemplary TriTAC GWYRQAPGKQRELVAAIHGISTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPGNVYWGQOGTQAVTVSSGGGGSGGGSEVQOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQOAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVQOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGESGGGEGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
549. Sequence 02H09 EVOLVESGGGLVQPGRSLTLSCAASTNIFSRSPM TriTAC copy GWYRQAPGKQRELVAAIHGSSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPGNVYWGOGTOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGESCGGGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQOQOKPGOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
SEQ ID NO String Name [E fest
550. String 02GO06 EVOLVESGGGLVOPGRSLTLSCAASTNIFSGSPM TriTAC exemplary GWYRQOAPGKQORELVAAIHGNSTLYADSVKGRFTI SRDNAKNSIYLOMNSLRPEDTALYYCNKVPWGDY HPGNVYWGQOGTQVTVSSGGGGSCGESEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGEGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQOAPGKGLEWVARIRSK YNNYATYYADOVKDRFTISRDDSKNTAYLOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGESGEGESGEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQOAPRGLTI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
551. Sequence 01B09 EVQLVESGGGLVQPGRSLTLSCAASSNIFSISPM TriTAC exemplary GWYROAPGKORELVAAIHGSSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPGNVYWGQGTQVTVSSGGGGSCGGESEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGEGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQOAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGOGTLVT VSSGGGGSCGEGESCEGGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQOQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
552. String 02F03 EVQOLVESGGGLVQPGRSLTLSCAASTNIFSIYPM TriTAC exemplary GWYROAPGKQORELVAAIHGSSTLYADSVKGRFTI SRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDY HPKNVYWGQOGTQOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK
SEQ ID NO Sequence Name 22 YNNYATYYADOVKDRFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVT VSSGGGGSGGGESGGGEGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
553. Sequence 02F02 EVOLVESGGGLVOPGRSLTLSCAASTNIFSKSPM TriTAC exemplary GWYRQAPGKQORELVAAIHGSSTLYADSVKGRFTI SRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDY HPGNVYWGOGTOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQAPGKGLEWVARIRSK YNNYATYYADQVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGESGGGEGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQKPGOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED
EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 554, String 02H01 EVQLVESGGGLVQPGRSLTLSCAASTNIFSKSPM TriTAC copy GWYRQOAPGKORELVAAIHGSSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPRNVYWGOGTQOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQOMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQOPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGEGGGSCGECGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
555. Sequence 01G10 EVOLVESGGGLVQPGRSLTLSCAASTNEFSISPM exemplary TriTAC GWYRQAPGKORELVAAIHGLSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGAY
SEQ ID NO Sequence Name 22 HPRNVYWGOGTQOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQOGTL VTVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFENKYAINWVROAPGKGLEWVARIRSK YNNYATYYADOVKDRFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGEGCGSCGEESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQOKPGOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
556. Sequence 02D11 EVQLVESGGGLVQPGRSLTLSCAASTNEFSISPM exemplary TriTAC GWYRQAPGKORELVAAIHGESTLYADSVKGRFTI SRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDY HPGNVYWGOGTOVTVSSGGGGSCGEGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLOMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQOPGGSLKL SCAASGFTFENKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGGSGGGGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
557. String 01B01 EVOLVESGGGLVQPGRSLTLSCAASTNIPSISPM TriTAC copy GWYRQAPGKQRELVAAIHGESTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPRNVAWGQOGTQVTVSSGGGGSGGGSEVQOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQOMNSLRPEDTAVYYCTIGGSLSVSSQOGTL VTVSSGGGGSGGGSEVQOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADOVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGGSGGGGSQTVVTOEPSLTVSPGG
SEQ ID NO Sequence Name 22 TVTLTCASSTGAVTSGNYPNWVQOQOKPGQOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
558. Sequence 01G11 EVOLVESGGGLVQPGRSLTLSCAASTNIPSISPM TriTAC exemplary GWYRQOAPGKORELVAAIHGASTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPRNVAWGOGTQOVTVSSGGGGSGGGSEVQOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLOMNSLRPEDTAVYYCTIGGSLSVSSQOGTL VTVSSGGGGSGGGSEVQOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDREFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGGSGGGGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
559. Sequence 01H10 EVOLVESGGGLVQPGRSLTLSCAASTNIPSISPM TriTAC exemplary GWYRQAPGKQRELVAAIHGESTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPRNVYWGQOGTQAVTVSSGGGGSGGGSEVQOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQOAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQOMNSLRPEDTAVYYCTIGGSLSVSSQOGTL VTVSSGGGGSGGGSEVQOLVESGGGLVQPGGSLKL SCAASGFTFENKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQOVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGGSGGGGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQOQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
560. Sequence 01CO4 EVOLVESGGGLVQPGRSLTLSCAASTNIPSISPM TriTAC exemplary GWYRQAPGKQORELVAAIHGDSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPRNVYWGOGTOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQOAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK
SEQ ID NO Sequence Name 22 TTLYLOMNSLRPEDTAVYYCTIGGSLSVSSQOGTL VTVSSGGGGSGGGSEVOLVESGGGLVQOPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGGSGGGGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQOQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
561. Sequence 01D04 EVOLVESGGGLVOQPGRSLTLSCAASTNITSISPM exemplary TriTAC GWYRQAPGKQRELVAAIHGVSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPRNVQWGQOGTQAVTVSSGGGGSGGGSEVQOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQOAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVQOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGESGGGEGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
562. Sequence 01E07 EVOLVESGGGLVQPGRSLTLSCAASTNIPSISPM TriTAC exemplary GWYRQAPGKQRELVAAIHGOSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPRNVQOWGOGTAOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGESCGGGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQOQOKPGOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
SEQ ID NO String Name E fest
563. Sequence 02B11 EVOLVESGGGLVOPGRSLTLSCAASTNIVSISPM exemplary TriTAC GWYRQOAPGKQORELVAAIHGDSTLYADSVKGRFTI SRDNAKNSIYLOMNSLRPEDTALYYCNKVPWGDY HPRNVSWGQGTQVTVSSGGGEGSCGESEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGEGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQOAPGKGLEWVARIRSK YNNYATYYADOVKDRFTISRDDSKNTAYLOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGESGEGESGEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQOAPRGLTI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
564. String O01F10 EVQLVESGGGLVQPGRSLTLSCAASSNIFSISPM TriTAC copy GWYROAPGKORELVAAIHGESTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPRNVTWGQOGTQVTVSS GGGGSGGGSEVOLVESGGGLVQPGNSLRLSCAAS GFTFSKFGMSWVROAPGKGLEWVSSISGSGRDTL YADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAV YYCTIGGSLSVSSQOGTLVTVSSGGGGSCEGSEVO LVESGGGLVQPGGSLKLSCAASGFTFNKYAINWV ROAPGKGLEWVARIRSKYNNYATYYADQVKDRFT ISRDDSKNTAYLOMNNLKTEDTAVYYCVRHANFG NSYISYWAYWGQOGTLVTVSSGGGGSCGGGESCEGE SQOTVVTOEPSLTVSPGGTVTLTCASSTGAVTSGN YPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGS LLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFG GGTKLTVLHHHHHH
565. Sequence 02G08 EVQOLVESGGGLVQOPGRSLTLSCAASTNIDSISPM exemplary TriTAC GWYRQAPGKQORELVAAIHGESTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPRNVTWGQOGTQVTVSSGGGGSCGESEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGEGSEVOLVESGGGLVQPGGSLKL
SEQ ID NO Sequence Name 22 SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDREFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGGSGGGGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQOQKPGQOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
566. Sequence 02G11 EVOLVESGGGLVQPGRSLTLSCAASTNIDSISPM exemplary TriTAC GWYRQAPGKQRELVAAIHGSSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPRNVTWGQOGTQOVTVSSGGGGSGGGSEVQOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLOMNSLRPEDTAVYYCTIGGSLSVSSQOGTL VTVSSGGGGSGGGSEVQOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQAPGKGLEWVARIRSK YNNYATYYADQOVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGGSGGGGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
567. Sequence 02H06 EVOLVESGGGLVQPGRSLTLSCAASTNIRSISPM TriTAC exemplary GWYRQAPGKQORELVAAIHGSSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPRNVVWGOGTOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQOAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VIVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQAPGKGLEWVARIRSK YNNYATYYADQOVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGESGGGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
568. Sequence 01B02 EVOLVESGGGLVQPGRSLTLSCAASTNITSISPM Fo [ETERNAL]
SEQ ID NO Sequence Name E et SRDNAKNSIYLOMNSLRPEDTALYYCNEVPWGDY HPRNVYWGQGTOVTVSSEGGEGESCEESEVOLVESGE GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGEGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADOVKDRFTISRDDSKNTAYLOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGESGEGESGEGESQTVVTEEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQKPGQOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
569. Sequence 02H11 EVOLVESGGGLVOQPGRSLTLSCAASTNITSISPM TriTAC exemplary GWYRQOAPGKQORELVAAIHGESTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPRNVYWGQOGTQVTVSSGGEGGSCCGESEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQOAPGKGLEWVARIRSK YNNYATYYADOVKDRFTISRDDSKNTAYLOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGEGESCEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQKPGOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
570. Sequence 01FO08 EVQOLVESGGGLVQPGRSLTLSCAASTNITSVSPM TriTAC exemplary GWYROAPGKQORELVAAIHGPSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPTNVYWGQOGTQVTVSSGGGGSGGESEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT
SEQ ID NO Sequence Name 22 VSSGGGGSGEGESCEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
571. String 01H01 EVOLVESGGGLVQPGRSLTLSCAASTNIGSISPM TriTAC copy GWYRQOAPGKQORELVAAIHGOSTLYADSVKGRFTI SRDNAKNSIYLOMNSLRPEDTALYYCNKVPWGDY HPQONVYWGOGTOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VIVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQAPGKGLEWVARIRSK YNNYATYYADQOQVKDRFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVT VSSGGGGSGEGESCEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQOQKPGQOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
572. String 01E10 EVQLVESGGGLVQPGRSLTLSCAASTNIESISPM exemplary TriTAC GWYRQOAPGKORELVAAIHGKSTLYADSVKGRFTI SRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDY HPRRVYWGOGTOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQOAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQOAPGKGLEWVARIRSK YNNYATYYADQVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGEGESCECGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQKPGOAAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
573. String 01GO01 EVOLVESGGGLVQPGRSLTLSCAASTNIVSISPM TriTAC exemplary GWYRQOAPGKORELVAAIHGDSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPRRVYWGQOGTQOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG
SEQ ID NO Sequence Name E et KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQOAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGOGTLVT VSSGGGGSGGGESCEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQOKPGQOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED
EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 574, String 01GO04 EVQOLVESGGGLVQPGRSLTLSCAASTNIDSISPM exemplary TriTAC GWYROAPGKORELVAAIHGNSTLYADSVKGRFTI SRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDY HPRMVYWGQOGTQOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGEGGGSCGECGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQOQOKPGQOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
575. String 01A04 EVQLVESGGGLVQPGRSLTLSCAASTNIFMISPM TriTAC copy GWYROAPGKQORELVAAIHGDSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGRY HPRNVYWGQOGTOVTVSSGGGESCGEESEVOLVESGE GGLVOPGNSLRLSCAASGFTFSKFGMSWVRQOAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGEGSGEGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGEGEGSCGEGESCEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQOQKPGQOAPRGLTI
SEQ ID NO Sequence Name E et GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED CTA
576. String 01F12 EVQOLVESGGGLVOPGRSLTLSCAASTNIFRISPM TriTAC copy GWYRQOAPGKQORELVAAIHGDSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGRY HPRNVYWGQOGTQVTVSSGGGGSGCGESEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGEGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQOAPGKGLEWVARIRSK YNNYATYYADOQVKDRFTISRDDSKNTAYLOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGEGESCEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQOKPGQOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
577. String 01B06 EVOLVESGGGLVQPGRSLTLSCAASTNIFSISPM TriTAC copy GWYROAPGKORELVAAIHGDSTLYADSVKGRFTI SRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGEY HPRNVYWGQOGTQVTVSSGGGGSGGESEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQOAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGEGCGSCGECESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
578. Sequence 01C06 EVQOLVESGGGLVQPGRSLTLSCAASTNIFSISPM TriTAC exemplary GWYROAPGKORELVAAIHGDSTLYADSVKGRFTI SRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGKY HPRNVYWGOGTQOVTVSSGGGGSGGGSEVOLVESG GGLVOPGNSLRLSCAASGFTFSKFGMSWVRQOAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL
SEQ ID NO Sequence Name E et VTVSSGGGGSGEGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQOAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGEGESCEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQOKPGQOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
579. Sequence 01B08 EVQOLVESGGGLVQPGRSLTLSCAASTNIESISPM TriTAC copy GWYROAPGKORELVAAIHGSSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGRY HPRNVYWGQGTQVTVSSGGGGSCGCGESEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGEGESCEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQOKPGOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
580. Sequence 01C02 EVQOLVESGGGLVQOPGRSLTLSCAASTNIESISPM TriTAC exemplary GWYROAPGKQORELVAAIHGNSTLYADSVKGRFTI SRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGRY HPRNVYWGQOGTQOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGEGESCEGESQTVVTQOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQKPGQOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
SEQ ID NO Sequence Name [Jet
581. Sequence 01C10 EVOLVESGGGLVOPGRSLTLSCAASTNISSISPM exemplary TriTAC GWYRQOAPGKQORELVAAIHGFSTLYADSVKGRFTI SRDNAKNSIYLOMNSLRPEDTALYYCNKVPWGYY HPRNVYWGQOGTQVTVSSGGGGSCGESEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGEGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQOAPGKGLEWVARIRSK YNNYATYYADOVKDRFTISRDDSKNTAYLOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGESGEGESGEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQOAPRGLTI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
582. String 01F09 EVQLVESGGGLVQPGRSLTLSCAASTNISSISPM TriTAC exemplary GWYROAPGKORELVAAIHGHSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGRY HPRNVYWGQGTQVTVSSGGGGSCGGESEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGEGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQOAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGOGTLVT VSSGGGGSCGEGESCEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQOQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
583. String 02D06 EVOLVESGGGLVQOPGRSLTLSCAASTNISSISPM exemplary TriTAC GWYROAPGKQORELVAAIHGFSTVYADSVKGRFTI SRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGRY HPRNVYWGQOGTQOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK
SEQ ID NO Sequence Name E et YNNYATYYADOVKDRFTISRDDSKNTAYLOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGEGGESCEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
584. String 01A06 EVOLVESGGGLVOPGRSLTLSCAASTNIFSIRPM TriTAC exemplary GWYROAPGKORELVAAIHGFSTVYADSVKGRFTI SRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDY HPRNVYWGQOGTQVTVSSGGGGSCGGESEVOLVESG GGLVOPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQOAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGOGTLVT VSSGGGGSGEGGESCEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQKPGQOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
585. String 01C07 EVOLVESGGGLVQPGRSLTLSCAASTNIFSIYPM exemplary TriTAC GWYROAPGKORELVAAIHGFSTYYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGSY HPRNVYWGOGTQOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGEGSGEGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGEGGGSCGECGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQOKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
586. Sequence 01G09 EVQOLVESGGGLVOPGRSLTLSCAASTNIFNISPM TriTAC exemplary GWYRQOAPGKQORELVAAIHGFSTYYADSVKGRFTI SRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGRY
SEQ ID NO Sequence Name E et HPRNVYWGQOGTQVTVSSGGGGSGGESEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGEGCGSCGEESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQOKPGOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
587. Sequence 01FO05 EVQOLVESGGGLVQPGRSLTLSCAASTNIFSSSPM TriTAC exemplary GWYROAPGKQORELVAAIHGFSTWYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGRY HPRNVYWGOGTOVTVSSGGGGSCGEGGSEVOLVESG GGLVOPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGEGSGEGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGEGEGSCGEGESCEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVOQOKPGQOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
588. Sequence 02B12 EVQOLVESGGGLVQOPGRSLTLSCAASTNISSISPM TriTAC copy GWYRQOAPGKQORELVAAIHGFDTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPRNVYWGQOGTOVTVSSGGGESCEESEVOLVESGE GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQOAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGEGSCGEGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADOVKDRFTISRDDSKNTAYLOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGESGEGESGEGESQTVVTEEPSLTVSPGG
SEQ ID NO Sequence Name 22 TVTLTCASSTGAVTSGNYPNWVQOQOKPGQOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
589. Sequence 02G01 EVOLVESGGGLVQPGRSLTLSCAASTNIFSINPM TriTAC exemplary GWYRQOAPGKORELVAAIHGFDTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPRNVSWGQOGTQVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLOMNSLRPEDTAVYYCTIGGSLSVSSQOGTL VTVSSGGGGSGGGSEVQOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDREFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGGSGGGGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
590. String 01A09 EVOLVESGGGLVQPGRSLTLSCAASTNIFSITPM exemplary TriTAC GWYRQAPGKQRELVAAIHGRSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGSY HPRNVYWGQOGTQAVTVSSGGGGSGGGSEVQOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQOAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQOMNSLRPEDTAVYYCTIGGSLSVSSQOGTL VTVSSGGGGSGGGSEVQOLVESGGGLVQPGGSLKL SCAASGFTFENKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQOVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGGSGGGGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQOQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
591. Sequence 01H05 EVOLVESGGGLVQPGRSLTLSCAASTNIFSITPM TriTAC exemplary GWYRQAPGKQORELVAAIHGTSTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGRY HPRNVYWGOGTOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQOAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK
SEQ ID NO Sequence Name 22 TTLYLOMNSLRPEDTAVYYCTIGGSLSVSSQOGTL VTVSSGGGGSGGGSEVOLVESGGGLVQOPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGGSGGGGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQOQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
592. Sequence 02F06 EVOLVESGGGLVOQPGRSLTLSCAASTNIFSITPM TriTAC exemplary GWYRQAPGKQRELVAAIHGESTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGRY HPRNVYWGQOGTQAVTVSSGGGGSGGGSEVQOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQOAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVQOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADQVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGESGGGEGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
593. Sequence 02G07 EVOLVESGGGLVQPGRSLTLSCAASTNIFSITPM TriTAC exemplary GWYRQAPGKQRELVAAIHGESTLYADSVKGRFTI SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPRDVYWGOGTAOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGESCGGGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQOQOKPGOAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
SEQ ID NO String Name [E Jet
594. String 01F07- EVOLVESGGGLVOQPGRSLTLSCAASTNIFSTSPY M34Y TriTAC GWYRQOAPGKQORELVAAIHGFSTIYADSVKGRFTI exemplary SRDNAKNSIYLOMNSLRPEDTALYYCNKVPWGDY HPGNVYWGQOGTQVTVSSGGGGSCGESEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGEGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQOAPGKGLEWVARIRSK YNNYATYYADOVKDRFTISRDDSKNTAYLOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGESGEGESGEGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQOAPRGLTI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
595. Sequence 01F01- | EVOLVESGGGLVOPGRSLTLSCAASTNIFSTSPG M34G TriTAC GWYROAPGKORELVAAIHGFSTIYADSVKGRFTI copy SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPGNVYWGQGTQVTVSSGGGGSCGGESEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGEGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVRQOAPGKGLEWVARIRSK YNNYATYYADQVKDRFTISRDDSKNTAYLQOMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGOGTLVT VSSGGGGSCGEGESCEGGESQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQOQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
596. Sequence 02G02- EVQOLVESGGGLVQPGRSLTLSCAASTNIFSITPY M34Y TriTAC GWYROAPGKQORELVAAIHGASTLYADSVKGRFTI exemplary SRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDY HPGNVYWGQOGTQOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRFTISRDNAK TTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTL VTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK
SEQ ID NO Sequence Name 22 YNNYATYYADOVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQOGTLVT VSSGGGGSGGGESGGGEGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
597. Sequence 02G02- EVOLVESGGGLVOQPGRSLTLSCAASTNIFSITPG M34G TriTAC GWYRQAPGKQRELVAAIHGASTLYADSVKGRFTI copy SRDNAKNSIYLQOMNSLRPEDTALYYCNKVPWGDY HPGNVYWGOGTOVTVSSGGGGSGGGSEVOLVESG GGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPG KGLEWVSSISGSGRDTLYADSVKGRETISRDNAK TTLYLQOMNSLRPEDTAVYYCTIGGSLSVSSQOGTL VIVSSGGGGSGGGSEVOLVESGGGLVQPGGSLKL SCAASGFTFNKYAINWVROAPGKGLEWVARIRSK YNNYATYYADOVKDRETISRDDSKNTAYLQMNNL KTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVT VSSGGGGSGGGGSGGGGSQTVVTOEPSLTVSPGG TVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLI GGTKFLVPGTPARFSGSLLGGKAALTLSGVQPED EAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH
598. 253BH10 QVOLVESGGGLVQPGESLRLSCAASTNIFSISPM (anti- llama | GWYROAPGKQORELVAAIHGFSTLYADSVKGRFTI BCMA) SRDNAKNTIYLQOMNSLKPEDTAVYYCNKVPWGDY HPRNVYWGOGTQOVTVSS

权利要求:
Claims (52)
[1]
1. B cell maturation agent (BCMA) binding protein tries specific, comprising: (a) a first domain (A) that specifically binds to human CD3; (b) a second domain (B) which is a half-life extension domain; and (c) a third domain (C) that specifically binds to BCMA, where the domains are linked in the order H2N- (A) - (C) - (B) -COOH, H2N- (B) - (A) - (C) -COOH, H2oN- (C) - (B) - (A) -COOH, HoN- (C) - (A) - (B) -COOH, HIN- (A) - (B) - ( C) -COOH or H2N- (B) - (C) - (A) - COOH, where the domains are connected by L1 and L2 linkers.
[2]
2. Try-specific BCMA-binding protein according to claim 1, characterized by the fact that the first domain comprises a variable light domain and a variable heavy domain each of which is capable of specifically binding to human CD3.
[3]
3. BCMA triespecific binding protein according to claim 1, characterized by the fact that the first domain is humanized or human.
[4]
4, BCMA triespecific binding protein, according to claim 1, characterized by the fact that the second domain binds to albumin.
[5]
5. BCMA triespecific binding protein according to claim 1, characterized by the fact that the second domain comprises a scFv, a variable heavy domain (VH), a light variable domain (VL), a VHH domain, a peptide , a ligand or a small molecule.
[6]
6. BCMA triespecific binding protein according to claim 1, characterized by the fact that the third domain comprises a VHH domain, a scFv, a VH domain, a VL domain, a non-Ig domain, a ligand, a knotina, or a small molecule entity that specifically binds to BCMA.
[7]
7. BCMA triespecific binding protein according to claim 6, characterized by the fact that the third domain comprises a VHH domain.
[8]
8. The specific BCMA-binding protein of claim 7, characterized by the fact that said VHH domain comprises complementarity determining regions CDR1, CDR2 and CDR3, in which: (a) the amino acid sequence of CDR1 is as shown in X: X2X3XaXsXeX7PXgG (SEQ ID. No.: 1), where X1 is TouS; X is N, Dou S; X; is I, D, OQ, H, Vou E; Xa is EF, S, E, A, T, M, V, I, D, O, P, R or G; Xs is S, M, R or N; X; It is 1, K, S, T, R, E, D, N, V, H, L, A, Q or G; X7 is S, T, Y, R or N; and Xs is M, G or Y; (b) the amino acid sequence of CDR2 is as shown in AIXsGX10X11TX12YADSVK (SEQ ID. NO .: 2), where X; is H, N or S; X1o IS F, G, K, R, P, D, OQ, H, E, N, T, S, A, IT, Lou V; X1 is S, OQ, E, T, Kou D; and X172 is L, V, 1, EF, Y or W; and (Cc) the amino acid sequence of CDR3 is as shown in VPWGX: 3YHPX: 4aX15sVX16 (SEQ ID. NO .: 3), where X13 is D, 1, T, K, R, A, E, S or Y; Xu is R, G, L, K, T, O, S or N; X15 is N, K, E, V, R, M or D; and X1 is Y, A, V, K, H, L, M, T, R, OQ, C, S or N; and where CDR1 is not the ID. SEQ. No. 599, where CDR2 is not the ID. SEQ. No.: 600, and where CDR3 is not the ID. SEQ. No.: 601.
[9]
9. Try-specific BCMA-binding protein according to claim 8, characterized in that the VHH domain comprises the following formula: fl-rl-f2-r2-f3-r3-f4 where, rl is the ID. SEQ. No.: 1; r2 is the ID. SEQ. No.: 2; erôéol1ID. SEQ. No.: 3; and where fi, fo, f3 and fa are structural residues selected so that said protein is from about eighty percent (80%) to about 99% identical to an amino acid sequence shown in the ID. SEQ. No. 346 or 598.
[10]
10. Try-specific BCMA-binding protein according to claim 9, characterized in that rl comprises an amino acid sequence presented as any of the IDS. SEQ. No.: 4-117.
[11]
11. BCMA triespecific binding protein according to claim 9, characterized in that r2 comprises an amino acid sequence presented as any of the IDS. SEQ. No. 118-231.
[12]
12. Try-specific BCMA-binding protein according to claim 9, characterized in that r3 comprises an amino acid sequence presented as any of the IDS. SEQ. No.: 232-345.
[13]
13. Try-specific BCMA-binding protein according to claim 9, characterized by the fact that the VHH domain comprises an amino sequence presented as any of the IDS. SEQ. No. 346-460.
[14]
14. Try-specific BCMA-binding protein according to claim 9, characterized by the fact that F1 comprises ID. SEQ. No. 461 or 462.
[15]
15. Try-specific BCMA-binding protein according to claim 9, characterized by the fact that F2 comprises the ID. SEQ. No. 463.
[16]
16. BCMA triespecific binding protein according to claim 9, characterized by the fact that F3 comprises the ID. SEQ. No. 464 or 465.
[17]
17. BCMA triespecific binding protein according to claim 9, characterized by the fact that F4 comprises the ID. SEQ. No. 466 or 467.
[18]
18. Try-specific BCMA-binding protein according to claim 9, characterized by the fact that rl comprises the ID. SEQ. No. 76, 114, 115, 116 or 117.
[19]
19. Try-specific BCMA-binding protein according to claim 9, characterized by the fact that rl comprises the ID. SEQ. No. 76, r2 is the ID. SEQ. No.: 190, and r3éo1ID. SEQ. No. 304.
[20]
20. Try-specific BCMA-binding protein according to claim 9, characterized by the fact that rl comprises the ID. SEQ. No. 114, r2 comprises the ID. SEQ. Nº: 228 and r3ô comprises the ID. SEQ. No. 342.
[21]
21. Try-specific BCMA-binding protein according to claim 9, characterized by the fact that rl comprises the ID. SEQ. No. 115, r2 comprises the ID. SEQ. Nº: 229 and r3ô comprises the ID. SEQ. No. 343.
[22]
22. Try-specific BCMA-binding protein according to claim 9, characterized by the fact that rl comprises the ID. SEQ. No: 117, r2 comprises the ID. SEQ. No.: 231 and r3 comprises the ID. SEQ. No. 345.
[23]
23. Try-specific BCMA-binding protein according to claim 9, characterized by the fact that rl comprises the ID. SEQ. No. 116, r2 comprises the ID. SEQ. Nº: 230 and r3 comprises the ID. SEQ. No. 344.
[24]
24. BCMA triespecific binding protein according to any one of claims 1-23, characterized in that the third domain is a human VHH domain, a humanized VHH domain, a matured affinity VHH domain, or a combination of these .
[25]
25. Try-specific BCMA-binding protein according to any of claims 1-24, characterized in that said protein has an elimination half-life of at least 12 hours, at least 20 hours, at least 25 hours , at least 30 hours, at least 35 hours, at least 40 hours, at least 45 hours, at least 50 hours or at least 100 hours.
[26]
26. BCMA triespecific binding protein according to claim 7, characterized in that the VHH domain comprises a CDR1, a CDR2 and a CDR3, and wherein the protein comprises a sequence shown as the ID. SEQ. No. 598 or 346, wherein one or more amino acid residues selected from amino acid positions 26, 27, 28, 29, 30, 31, 32 and 34 of CDR1; positions 52, 54, 55 and 57 of CDR2; and positions 101, 105, 106 and 108 of CDR3 are substituted, wherein: amino acid position 26, if substituted, is substituted with S; amino acid position 27, if substituted, is replaced with D or S; amino acid position 28, if substituted, is replaced with D, Q, H, V or E; amino acid position 29, if substituted, is replaced with S, E, A, T, M, T, V, I, D, Q, D, P, Rou G; amino acid position 30, if substituted, is replaced with M, R or N; the amino acid position 31, if substituted, is replaced with K, S, T, R, E, D, N, V, H, L, A, Q or G; amino acid position 32, if substituted, is replaced with T, Y, R or N; amino acid position 34, if substituted, is replaced with G or Y; amino acid position 52, if substituted, is replaced with N or S; amino acid position 54, if substituted, is replaced with G, K, R, P, D, Q, H, E, N, T, S, A, 1, L or V; amino acid position 55, if substituted, is replaced with Q, E, T, K or D; amino acid position 57, if substituted, is replaced with V, I, F, Y or W; the amino acid position 101, if substituted, is replaced with I, T, K, R, A, E, S or Y; amino acid position 105, if substituted, is replaced with G, L, K, T, Q, S or N; amino acid position 106, if substituted, is replaced with K, E, V, R, M or D; amino acid position 108, if substituted, is replaced with A, V, K, H, L, M, T, R, Q, C, S or N.
[27]
27. Try-specific BCMA-binding protein according to claim 26, characterized by the fact that the VHH domain is human, humanized, with mature affinity, or a combination of these.
[28]
28. The specific BCMA-binding protein according to any one of claims 1-27, characterized in that the third domain binds to a human BCMA protein comprising the sequence shown as the ID. SEQ. No. 468.
[29]
29. Try-specific BCMA-binding protein according to any of claims 1-27, characterized in that the third domain binds to an extracellular domain of BCMA.
[30]
30. BCMA triespecific binding protein according to any one of claims 1-29, characterized by the fact that the L1 and L2 linkers are each selected independently from (GS) n (SEQ ID. NO: 472), (GGS) n (SEQ ID NO: 473), (GGGS) n (SEQ ID NO: 474), (GGSG) n (SEQ ID NO: 475), (GGSGG ) n (SEQ ID NO: 476), (GGGGS) n (SEQ ID NO: 477), (GGGGG) n (SEQ ID NO: 478) or (GGG) n (ID. DE SEQ. Nº: 479) where n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
[31]
31. Try-specific BCMA-binding protein according to any of claims 1-30, characterized by the fact that the L1 and L2 linkers are each independently (GGGGS) s. (SEQ ID. NO .: 480) or (GGGGS); 3 (SEQ ID. NO .: 481).
[32]
32. BCMA triespecific binding protein according to any one of claims 1-31, characterized by the fact that the domains are linked in the order H2oN- (C) - (B) - (A) -COOH.
[33]
33. The specific BCMA-binding protein according to any one of claims 1-32, characterized by the fact that the protein has less than about 80 kDa.
[34]
34. The specific BCMA-binding protein according to any one of claims 1-32, characterized by the fact that the protein is about 50 to about 75 kDa.
[35]
35. BCMA triespecific binding protein according to any one of claims 1-32, characterized by the fact that the protein has less than about 60 kDa.
[36]
36. The specific BCMA-binding protein according to any one of claims 1-35, characterized by the fact that the protein has an elimination half-life of at least about 50 hours.
[37]
37. BCMA triespecific binding protein according to any one of claims 1-36, characterized in that the protein has an elimination half-life of at least about 100 hours.
[38]
38. Try-specific BCMA-binding protein according to any of claims 1-37, characterized by the fact that the protein has increased tissue penetration compared to an IgG for the same BCMA.
[39]
39. BCMA triespecific binding protein according to any one of claims 1-38, characterized in that the protein comprises a sequence selected from the group consisting of IDS. SEQ. No. 483-597.
[40]
40. BCMA triespecific binding protein according to any one of claims 1-39, characterized in that the protein comprises a sequence as shown in ID. SEQ. No. 520.
[41]
41. Pharmaceutical composition characterized in that it comprises a specific BCMA-binding protein as defined in any one of claims 1-40 and a pharmaceutically acceptable carrier.
[42]
42. Process for producing a specific BCMA-binding protein as defined in any one of claims 1-40, said process comprising cultivating a host transformed or transfected with a vector comprising a nucleic acid sequence that encodes a BCMA triespecific binding protein as defined in any of claims 1-40 under conditions that allow expression of the BCMA triespecific binding protein and recovery and purification of the protein produced by the culture.
[43]
43. Method for treating or ameliorating a tumor disease, an autoimmune disease or an infectious disease associated with BCMA in a needy individual, characterized in that it comprises administering to the individual a pharmaceutical composition as defined in claim 41.
[44]
44, Method, according to claim 43, characterized by the fact that the individual is human.
[45]
45. The method of claim 43 or 44, characterized in that the method further comprises the administration of one or more additional agents in combination with the specific BCMA-binding protein.
[46]
46. Method according to any one of claims 43-45, characterized in that it comprises the treatment or amelioration of a tumor disease, wherein the specific BCMA-binding protein selectively binds to tumor cells that express BCMA.
[47]
47. Method according to any of claims 43-46, characterized in that it comprises treatment or amelioration of a tumor disease, wherein the tumor disease comprises a primary cancer or a metastasis thereof.
[48]
48. Method according to claim 47, characterized by the fact that the tumor disease comprises a cancer of the B cell lineage.
[49]
49. Method according to claim 48, characterized by the fact that cancer of the B cell lineage is a multiple myeloma, leukemia, lymphoma, or metastasis of these.
[50]
50. B cell maturation agent (BCMA) binding protein tries specific, characterized by comprising: (a) a first domain (A) that specifically binds to human CD3; (b) a second domain (B) which is a half-life extension domain; and (c) a third domain (C) that specifically binds to BCMA, where the third domain comprises an amino sequence presented as any of the IDS. SEQ. No. 346-460.
[51]
51. B cell maturation agent (BCMA) binding protein tries specific, characterized by comprising: (a) a first domain (A) that specifically binds to human CD3; (b) a second domain (B) which is a half-life extension domain; and (c) a third domain (C) that specifically binds to BCMA, where the third domain comprises complementarity determining regions CDR1, CDR2 and CDR3, where CDR1 comprises an amino acid sequence presented as any of the IDS. SEQ. Nº: 4-117, CDR2 comprises an amino acid sequence presented as any of the IDS. SEQ. No. *: 118-231, and CDR3 comprises an amino acid sequence presented as any of the IDS. SEQ. No. 232-345.
[52]
52. Method for treating or ameliorating a tumor disease, an autoimmune disease or an infectious disease associated with BCMA in a needy individual, characterized by comprising administering to the individual a pharmaceutical composition comprising a specific BCMA-binding protein, in particular whereas the BCMA-binding protein comprises: (a) a first domain (A) that specifically binds to human CD3; (b) a second domain (B) which is a half-life extension domain; and (c) a third domain (C) that specifically binds to BCMA, where the domains are linked in the order H2N- (A) - (C) - (B) -COOH, H2N- (B) - (A) - (C) -COOH, H2N- (C) - (B) - (A) -COOH, H2N- (C) -— (A) - (B) -COOH, H2N- (A) - (B) - (C) -COOH, H2N- (B) - (C) - (A) - COOH, where the domains are connected by L1 and L2 linkers.

类似技术:

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公开号 | 公开日 | 专利标题

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CL2020000991A1|2020-10-23|

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US11136403B2|2021-10-05|

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JP2020537644A|2020-12-24|

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CO2020005645A2|2020-05-15|

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EP3694529A1|2020-08-19|

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AU2018347582A1|2020-05-07|

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IL273918D0|2020-05-31|

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PE20201183A1|2020-11-03|

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WO2019075359A1|2019-04-18|

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US20190112381A1|2019-04-18|

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EP3694529A4|2021-11-10|

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DOP2020000071A|2020-08-15|

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KR20200066343A|2020-06-09|

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ECSP20025070A|2020-06-30|

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SG11202003359UA|2020-05-28|

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CA3078969A1|2019-04-18|

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CN111630070A|2020-09-04|

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PH12020550258A1|2021-03-01|

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EA202090817A1|2020-09-08|

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CR20200196A|2020-06-05|

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法律状态:
2021-12-07| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US201762572381P| true| 2017-10-13|2017-10-13|

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US62/572,381|2017-10-13|

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PCT/US2018/055659|WO2019075359A1|2017-10-13|2018-10-12|Trispecific proteins and methods of use|

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