Thymic stromal lympho PO I ET (TLSP) antibodies and uses thereof

专利摘要:

公开号:AU2007218165A1
申请号:U2007218165
申请日:2007-02-21
公开日:2007-08-30
发明作者:Michael Bardroff；Matthew Edwards；Olaf Ratsch；Mehmet Tur
申请人:Novartis AG；
IPC主号:C07K16-24

专利说明:
WO 2007/096149 PCT/EP2007/001506 THYMIC STROMAL LYMPHOPOIETIN (TSLP) ANTIBODIES AND USES THEREOF Field of Use The present invention relates to human thymic stromal lymphopoietin (hTSLP) antibodies and especially those which neutralize hTSLP activity. It further relates to methods 5 for using anti- hTSLP antibody molecules in diagnosis or treatment of hTSLP related disorders, such as asthma, atopic dermatitis, allergic rhinitis, fibrosis, inflammatory bowel disease and Hodgkin's lymphoma. Background of the invention 10 Human thymic stromal lymphopoietin (hTSLP) (GenBank accession number: NM_033035), an interleukin-7 (IL-7) like cytokine, which is produced by human epithelial stroma and mast cells, initiates the allergic response by the stimulation of dendritic cells (DC)'. The deduced 159-amino acid protein is 43% identical to mouse TSLP, contains a 28 residue signal sequence, 6 cysteines, and 2 putative N-glycosylation sites. Native Sodium 15 Dodecyl Sulfate Polyacrylamide Gel Electrophoresis (SDS-PAGE) analysis showed expression of a 23 kilo Dalton (kDa) protein, whereas the calculated molecular mass of the mature protein is 14,9 kDa, suggesting that hTSLP is glycosylated. hTSLP contains 7 basic C-terminal amino acids (aa) N-Lysine-Lysine-Arginine-Arginine-Lysine-Arginine-Lysine-C (KKRRKRK) and 6 cysteins probably involved in disulfide bond formation. 20 hTSLP is highly expressed by epithelial cells of inflamed tonsils and keratinocytes of atopic dermatitis and its expression is associated with Langerhans cell migration and 2 activation The TSLP receptor complex is a heterodimer comprised of the TSLP receptor (TSLPR) and IL-7 receptor alpha (IL-7Ra) chain. The receptor is expressed primarily on 25 monocytes and myeloid-derived DC, as well as on B lymphocytes3. Allergy is the result of a complex immune cascade leading to the dysregulated production of the Thymus-derived helper cell type 2 (Th2) subset lymphocyte cytokines, the generation of allergen-specific IgE-producing B lymphocytes and the subsequent activation and degranulation of mast cells upon allergen challenge. 30 DC play an important role in several models of allergy whereby TSLP-activated human DC produce Th2-attracting chemokines but no IL-12, and induce naive CD4-and CD8- antigen-positive T lymphocyte differentiation into effector cells with a typical pro allergic phenotype. 1 WO 2007/096149 PCT/EP2007/001506 Atopic dermatitis (AD) represents a chronic, relapsing inflammatory skin disease with characteristic clinical features. Genetic background, environmental exposures such as food allergens, aeroallergens, microbial antigens, or stress, and distinct immunological predispositions all contribute to the development of periodic, itchy eczematous skin lesions in 5 afflicted patients. Several soluble factors have been shown to be increased in the peripheral blood of patients with AD. These cytokines and chemokines play an important role in regulating DC differentiation, activation and migration and are important in coordinating the trafficking of immune cells. hTSLP, which is produced by human epithelial stroma and mast cells, initiates the allergic response by the stimulation of DC. TSLP activated DC produce the 10 CC chemokines that induce the chemotaxis and polarization of allergen-specific effector lymphocytes 5 . Thus, epithelial- and stromal-cell-derived TSLP might represent one of the factors initiating the allergic responses, and could be a target for a curative therapeutic approach to allergy. In recent studies, one anti-human TSLP polyclonal antibody was described (R&D 15 Systems, AF 1398). This antibody was produced in sheep immunized with purified E. coli derived recombinant TSLP. Human TSLP specific sheep IgG was purified by hTSLP affinity chromatography. This polyclonal antibody was selected for its ability to neutralize hTSLP bioactivity and showed less than 1% cross-reactivity with recombinant murine TSLP. The Neutralization Dose 5 o (ND 5 o) for this antibody was defined as that concentration of antibody 20 required to yield one-half maximal inhibition of the recombinant hTSLP activity on the responsive cell line mouse BaF/3 cells co-transfected with IL-7Ra and hTSLPR chains, as an assay. The ND 50 was determined to be approximately 0.05 - 0.25 pg/ml in the presence of 0.5 ng/ml recombinant hTSLP. The disadvantage of polyclonal antibodies is that they are in a limited supply as there is a restricted supply of serum from the same treated animal. In 25 addition, polyclonal antibodies recognize multiple epitopes on the same antigen and may have undesired cross-reactivity. While polyclonal serum contains a mixture of both high and low affinity binders, targeting also a range of epitopes, a monoclonal antibody approach make sure to select the most useful candidate for a therapeutic use. Animal-derived polyclonal antibodies when injected in humans constitute a foreign 30 protein in a human host, they often elicit an antiglobulin response due to their immunogenicity in human. This antiglobulin response, which is predominantly directed against the constant domains of the animal antibodies, usually precludes treatment after repeated administration. 2 WO 2007/096149 PCT/EP2007/001506 Summary of the invention An embodiment of the invention herein provides an isolated human or humanized antibody or functional fragment thereof with an antigen-binding region that is specific for target protein hTSLP and the antibody or functional fragment thereof binds to hTSLP. In a 5 related embodiment, the binding to hTSLP is determined at least by cell surface hTSLP receptor binding preventing inflammatory mediator release. In still another embodiment, the invention provides an isolated antigen-binding region of an antibody or functional fragment thereof. In certain embodiments, the isolated antigen binding region includes an H-CDR1 region having an amino acid sequence selected from 10 SEQ ID NOs: 1-7, and conservative variants thereof. As described herein, the conservative variants include amino acid residues in any of the amino acid sequences identified. In a related embodiment, the isolated antigen-binding region is an H-CDR2 region having an amino acid sequence selected from SEQ ID NOs: 8-25, and conservative variants thereof. In another related embodiment, the isolated antigen-binding region is an H-CDR3 region having 15 an amino acid sequence selected from SEQ ID NO: 26-31, and conservative variants thereof. In another embodiment, the isolated antigen-binding region is an L-CDR1 region having an amino acid sequence selected from SEQ ID NOs: 32-40., and conservative variants thereof. In still another related embodiment, the isolated antigen-binding region is an L-CDR2 region having an amino acid sequence selected from SEQ ID NOs: 41-49, and 20 conservative variants thereof. In yet another related embodiment, the isolated antigen binding region is an L-CDR3 region having an amino acid sequence selected from SEQ ID NOs: 50-66, and conservative variants thereof. In another embodiment, the isolated antigen-binding region is a heavy chain having an amino acid sequence selected from one to three of SEQ ID 1-31, and a sequence having at 25 least 60, 70, 80, 90 or 95 percent sequence identity in the CDR regions with the CDR regions having SEQ ID NOs: 1-31. In a related embodiment, the isolated antigen-binding region is a light chain having an amino acid sequence selected from one to three of SEQ ID NOs: 32-66, and a sequence having at least 60, 70, 80, 90 or 95 percent sequence identity in the CDR regions with the CDR regions having SEQ ID NOs: 32-66. 30 In a certain embodiment, the isolated antibody is an IgG. In another embodiment, the isolated antibody is an IgG 1, IgG2 or an IgG4. In yet another embodiment, the invention provides an isolated human or humanized antibody or functional fragment thereof, having an antigen-binding region that is specific for an epitope of hTSLP, and the antibody or functional fragment binds to hTSLP surface 3 WO 2007/096149 PCT/EP2007/001506 receptors on a cell. In a related embodiment, the invention provides an isolated human or humanized antibody or functional fragment thereof, having an antigen-binding region that is specific for an epitope of target hTSLP, and the epitope contains one or more amino acid residues of amino acid residues 1-112 of target hTSLP. In a related embodiment, the epitope 5 is a conformational epitope. In yet another embodiment, the antibody or functional fragment is a Fab or scFv antibody fragment. In a related embodiment, the isolated antibody is an IgG. In another related embodiment, the isolated antibody is an IgGI, IgG2 or an IgG4. In another embodiment, the invention provides a pharmaceutical composition having 10 at least one of any of the above antibodies or functional fragments or conservative variants, and a pharmaceutically acceptable carrier or excipient therefor. In still another embodiment, the invention provides for a transgenic animal carrying a gene encoding any of the above antibodies or functional fragments thereof. In certain embodiments, the invention provides a method for treating a disorder or 15 condition associated with the presence of a cell having a receptor target hTSLP. The method involves administering to a subject in need thereof an effective amount of any of the above pharmaceutical compositions. In a related embodiment, the disorder or condition to be treated is a respiratory disorder. In another embodiment, the disorder or condition to be treated is bronchial asthma, 20 which is a common persistent inflammatory disease of the lung characterised by airways hyper-responsiveness (AHR), mucus overproduction, fibrosis and raised serum IgE levels. A significant role for TSLP has been demonstrated in a mouse model in which lung specific expression of TSLP transgene induced allergic inflammation, goblet cell hyperplasia, subepithelial fibrosis and increased IgE levels (Zhou B, et al Nat. Immunol. 6: 1047-1053). 25 Also mice lacking the TSLP-receptor were protected from allergic responses when exposed to aerosolized antigen challenge. In addition a link between TSLP expression levels in lung epithelial cells and asthmatic disease severity has been described in humans ( Ying, S.B. et al. J. Immunol. 174: 8183-8190). In another embodiment, the disorder or condition to be treated is atopic 30 (allergic) dermatitis, which is the most common skin disease in childhood and is characterized by intense pruritus and chronic eczematous plaques. A significant role for TSLP has been demonstrated in a mouse model in which skin specific expression of TSLP transgene induced eczematous skin lesions containing inflammatory cell infiltrates, an increase in circulating Th2 cells and an increase in serum IgE (Yoo, J. et al. J. Exp. Med. 202: 4 WO 2007/096149 PCT/EP2007/001506 541-549). Also in humans TSLP has been found to be highly expressed in tissue sections of atopic dermatitis lesions which was associated with Langerhans cell migration and activation (Soumelis, V. et al. Nat. Immunol. 3: 673-680). In another embodiment, the disorder or condition to be treated is selected from other 5 inflammatory or obstructive airways diseases and conditions such as COPD, acute lung injury (ALI), acute/adult respiratory distress syndrome (ARDS), dyspnea, allergic airway inflammation, small airway disease, lung carcinoma, acute chest syndrome in patients with sickle cell disease and pulmonary hypertension, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy. 10 In another embodiment, the disorder or condition to be treated is bronchitis of whatever type or genesis including, e.g., acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis. In another embodiment, the disorder or condition to be treated includes pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently 15 accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis. In another embodiment, the disorder or condition to be treated is selected from atopic rhinitis (hay fever) and chronic sinusitis. 20 In another embodiment, the disorder or condition to be treated is selected from other inflammatory conditions of the skin, for example, psoriasis or lupus erythematosus. In another embodiment, the disorder or condition to be treated is inflammatory bowel disease, such as ulcerative colitis and Crohn's disease. In another embodiment, the disorder or condition to be treated is selected from other 25 fibrotic conditions, such as systemic scelrosis, liver fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis or fibroid lung. In another embodiment, the disorder or condition to be treated is tumour recurrence or metastasis. Inhibition of Th2 cytokines has been shown to enhance anti-viral vaccines in animal models and may be beneficial in the treatment of HIV and other infectious diseases 30 [Ahlers, J. D. , et al. Proc NatI Acad Sci U S A, 2002]. In another embodiment, the disorder or condition to be treated is a respiratory viral infection, which exacerbates underlying chronic conditions such as asthma, chronic bronchitis, COPD, otitis media, and sinusitis. The respiratory viral infection treated may be associated with secondary bacterial infection, such as otitis media, sinusitis or pneumonia. 5 WO 2007/096149 PCT/EP2007/001506 In another embodiment, the disorder or condition to be treated is selected from other diseases or conditions, in particular diseases or conditions having an inflammatory component, for example, diseases of the bone and joints including rheumatoid arthritis, psoriatic arthritis, and other diseases such as atherosclerosis, multiple sclerosis, and acute and 5 chronic allograft rejection, e.g. following transplantation of heart, kidney, liver, lung or bone marrow. In another embodiment, the disorder or condition to be treated is endotoxic shock, glomerulonephritis, cerebral and cardiac ischemia, Alzheimer's disease, cystic fibrosis, virus infections and the exacerbations associated with them, acquired immune deficiency syndrome 10 (AIDS), multiple sclerosis (MS), Helicobacterpylori associated gastritis, and cancers, particularly the growth of ovarian cancer. In another embodiment, the disorder or condition to be treated is the symptoms caused by viral infection in a human which is caused by the human rhinovirus, other enterovirus, coronavirus, herpes viruses, influenza virus, parainfluenza virus, respiratory syncytial virus or 15 an adenovirus. Treatment in accordance with the present invention may be symptomatic or prophylactic. The effectiveness of an agent of the invention in inhibiting inflammatory conditions, for example in inflammatory airways diseases, may be demonstrated in an animal 20 model, e.g. mouse, rat or rabbit model, of airway inflammation or other inflammatory conditions, for example as described by Wada et al, J. Exp. Med (1994) 180:1135-40; Sekido et al, Nature (1993) 365:654-57; Modelska et al., Am. J. Respir. Crit. Care. Med (1999) 160:1450-56; and Laffon et al (1999) Am. J. Respir. Crit. Care Med. 160:1443-49. In yet another embodiment, the invention provides a method for identifying a cell 25 having a receptor for hTSLP. This method involves contacting the cell with any of the above antibodies or antibody fragments further having a detectable label. The label is radioactive, fluorescent, magnetic, paramagnetic, or chemiluminescent. The method further can involve any of the above imaging or separating the labeled cell. In another embodiment, any of the above human or humanized antibodies or antibody 30 fragments are synthetic. In another embodiment, the invention provides a pharmaceutical composition and an additional therapeutic agent. The additional therapeutic agent can be selected from the group consisting of 6 WO 2007/096149 PCT/EP2007/001506 anti-inflammatory, bronchodilatory, antihistamine or anti-tussive drug substances, particularly in the treatment of obstructive or inflammatory airways diseases such as those mentioned hereinbefore, for example as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs. A 5 therapeutic agent of the invention may be mixed with the other drug substance in a fixed pharmaceutical composition or it may be administered separately, before, simultaneously with or after the other drug substance. Accordingly the invention includes a combination of an agent of the invention as hereinbefore described with an anti-inflammatory, bronchodilatory, antihistamine or anti-tussive drug substance, said agent of the invention and 10 said drug substance being in the same or different pharmaceutical composition. Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate, or steroids described in WO 02/88167, WO 02/12266, WO 02/100879, WO 02/00679 (especially those of Examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, 60, 67, 72, 15 73, 90, 99 and 101), WO 03/35668, WO 03/48181, WO 03/62259, WO 03/64445, WO 03/72592, WO 04/39827 and WO 04/66920; non-steroidal glucocorticoid receptor agonists, such as those described in DE 10261874, WO 00/00531, WO 02/10143, WO 03/82280, WO 03/82787, WO 03/86294, WO 03/104195, WO 03/101932, WO 04/05229, WO 04/18429, WO 04/19935 and WO 04/26248; LTB4 antagonists such as BIlL 284, CP 20 195543, DPC1 1870, LTB4 ethanolamide, LY 293111, LY 255283, CGS025019C, CP 195543, ONO-4057, SB 209247, SC-53228 and those described in US 5451700; LTD4 antagonists such include montelukast, pranlukast, zafirlukast, accolate, SR2640, Wy-48,252, ICI 198615, MK-571, LY-171883, Ro 24-5913 and L-648051; PDE4 inhibitors such cilomilast (Ariflo@ GlaxoSmithKline), Roflumilast (Byk Gulden),V-1 1294A (Napp), 25 BAY 19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline (Almirall Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID(TM) CC-10004 (Celgene), VM554/UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo), and those disclosed in WO 92/19594, WO 93/19749, WO 93/19750, WO 93/1975 1, WO 98/18796, WO 99/16766, WO 01/13953, WO 03/104204, WO 30 03/104205, WO 03/39544, WO 04/000814, WO 04/000839, WO 04/005258, WO 04/018450, WO 04/018451, WO 04/018457, WO 04/018465, WO 04/018431, WO 04/018449, WO 04/018450, WO 04/018451, WO 04/018457, WO 04/018465, WO 04/019944, WO 04/019945, WO 04/045607 and WO 04/037805; A 2 A agonists such as those described in EP 1052264, EP 1241176, EP 409595A2, WO 94/17090, WO 96/02543, WO 96/02553, WO 7 WO 2007/096149 PCT/EP2007/001506 98/28319, WO 99/24449, WO 99/24450, WO 99/2445 1, WO 99/38877, WO 99/41267,~WO 99/67263, WO 99/67264, WO 99/67265, WO 99/67266, WO 00/23457, WO 00/77018, WO 00/78774, WO 01/23399, WO 01/27130, WO 01/27131, WO 01/60835, WO 01/94368, WO 02/00676, WO 02/22630, WO 02/96462, and WO 03/086408; and A2B antagonists such as 5 those described in WO 02/42298. Suitable bronchodilatory drugs include anticholinergic or antimuscarinic agents, in particular ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate, but also those described in EP 424021, US 3714357, US 5171744, WO 01/04118, WO 02/00652, WO 02/51841, WO 02/53564, WO 03/00840, WO 10 03/33495, WO 03/53966, WO 03/87094, WO 04/018422 and WO 04/05285; and beta-2 adrenoceptor agonists such as albuterol (salbutamol), metaproterenol, terbutaline, salmeterol fenoterol, procaterol, and especially, formoterol, carmoterol and pharmaceutically acceptable salts thereof, and compounds (in free or salt or solvate form) of formula I of WO 00/75114, which document is incorporated herein by reference, preferably compounds of the Examples 15 thereof, e.g. (5-[(R)-2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1 H quinolin-2-one) and pharmaceutically acceptable salts thereof, as well as compounds (in free or salt or solvate form) of formula I of WO 04/16601, and also compounds of EP 1440966, JP 05025045, WO 93/18007, WO 99/64035, US 2002/0055651, WO 01/42193, WO 01/83462, WO 02/66422, WO 02/ 70490, WO 02/76933, WO 03/24439, WO 03/42160, WO 20 03/42164, WO 03/72539, WO 03/91204, WO 03/99764, WO 04/16578, WO 04/22547, WO 04/32921, WO 04/33412, WO 04/37768, WO 04/37773, WO 04/37807, WO 04/39762, WO 04/39766, WO 04/45618 WO 04/46083 , WO 04/80964, EP1460064, WO 04/087142, WO 04/089892, EP 01477167, US 2004/0242622, US 2004/0229904, WO 04/108675, WO 04/108676, WO 05/033121, WO 05/040103 and WO 05/044787. 25 Suitable dual anti-inflammatory and bronchodilatory drugs include dual beta-2 adrenoceptor agonist / muscarinic antagonists such as those disclosed in US 2004/0167167, WO 04/74246 and WO 04/74812. Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, 30 diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine as well as those disclosed in JP 2004107299, WO 03/099807 and WO 04/026841. Combinations of therapeutic agents of the invention and anticholinergic or antimuscarinic agents, steroids, beta-2 agonists, PDE4 inhibitors, dopamine receptor agonists, 8 WO 2007/096149 PCT/EP2007/001506 LTD4 antagonists or LTB4 antagonists may also be used. Other useful combinations of agents of the invention with anti-inflammatory drugs are those with other antagonists of chemokine receptors, e.g. CCR-1, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR1O, CXCRI, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonists 5 such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, Takeda antagonists such as N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzocyclohepten-8 yl]carbonyl]amino]phenyl]-methyl]-tetrahydro-N,N-dimethyl-2H-pyran-4-aminium chloride (TAK-770), CCR-5 antagonists described in US 6166037 (particularly claims 18 and 19), WO 0066558 (particularly claim 8), WO 0066559 (particularly claim 9), WO 04/018425 and 10 WO 04/026873. The additional therapeutic agent may also be selected from the group consisting of other cytokine binding molecules, particularly antibodies of other cytokines, in particular a combination with an anti-IL4 antibody, such as described in PCT/EP2005/00836, an anti-IgE antibody, such as Xolair@, an anti-1L31 antibody, an anti-IL3 IR antibody, an anti-IL 13 15 antibody, such as described in WO05/007699, an anti-endoglin antibody, an anti-IL lb antibody, an anti-TSLPR antibody or another anti-hTSLP antibody. In a certain embodiment, the invention provides an antibody having a first amino acid sequence which is a heavy chain selected from one to three of SEQ ID NOs: 1-31, and a sequence having at least 60, 70, 80, 90 or 95 percent sequence identity in the CDR regions 20 with the CDR regions having SEQ ID NOs: 1-31; and a second amino acid sequence which is a light chain selected from one to three of SEQ ID NOs: 32-66, and a sequence having at least 60, 70, 80, 90 or 95 percent sequence identity in the CDR regions with the CDR regions shown in SEQ ID NOs: 32-66. In still another embodiment, the invention provides an immunoconjugate made out of 25 a first component which is an antibody or fragment thereof and a second component having a second amino acid sequence. For example, the immunoconjugate is a cytotoxin, or the immunoconjugate is a binding protein or antibody having a binding specificity for a target that is different from hTSLP. In certain embodiments, the invention provides for a bispecific antibody. 30 In another embodiment, the invention provides a kit having an antibody or antibody fragment thereof. In some embodiments, the kit further contains a pharmaceutically acceptable carrier or excipient therefore. In other related embodiments, the antibody in the kit is present in a unit dose. In yet another related embodiment, the kit includes instructions for use in administering to a subject. 9 WO 2007/096149 PCT/EP2007/001506 Brief Description of the figures Figure 1 describes the HuCAL* Fab expression vector pMORPH*X9_FabFH (carrying anti-TSLP Fab MOR04494)F 5 Detailed description of the invention The present invention relates to isolated antibodies, particularly human antibodies, that bind specifically to hTSLP and that inhibit functional properties of hTSLP. In certain embodiments, the antibodies of the invention are derived from particular heavy and light 10 chain sequences and/or comprise particular structural features such as CDR regions comprising particular amino acid sequences. The invention provides isolated antibodies, methods of making such antibodies, immunoconjugates and bispecific molecules comprising such antibodies and pharmaceutical compositions containing the antibodies, immunconjugates or bispecific molecules of the invention. The invention also relates to 15 methods of using the antibodies to inhibit a disorder or condition associated with the presence of cell receptor target hTSLP, for example, in the treatment of an inflammatory or allergic condition, particularly an inflammatory or obstructive airways disease. In order that the present invention may be more readily understood, certain terms are 20 first defined. Additional definitions are set forth throughout the detailed description. The term 'hTSLP' is a reference to human TSLP. The present invention provides antibodies to human TSLP, especially human antibodies, that are cross-reactive with non human primate TSLP, including cynomolgus and rhesus monkey TSLP. Antibodies in accordance with some embodiments of the present invention may recognise a variant 25 truncated isoform of TSLP in which the protein terminates at the alanine at residue 99 resulting in the last 60 amino acids of the C-terminus being deleted and also an single nucleotide polymorphism (SNP) of TSLP in which the cysteine residue at amino acid position 90 is replaced by tyrosine. The term "immune response" refers to the action of, for example, lymphocytes, antigen presenting cells, phagocytic cells, granulocytes, and soluble 30 macromolecules produced by the above cells or the liver (including antibodies, cytokines, and complement) that results in selective damage to, destruction of, or elimination from the human body of invading pathogens, cells or tissues infected with pathogens, cancerous cells, or, in cases of autoimmunity or pathological inflammation, normal human cells or tissues. 10 WO 2007/096149 PCT/EP2007/001506 A "signal transduction pathway" refers to the biochemical relationship between a variety of signal transduction molecules that play a role in the transmission of a signal from one portion of a cell to another portion of a cell. As used herein, the phrase "cell surface receptor" includes, for example, molecules and complexes of molecules capable of 5 receiving a signal and capable of the transmission of such a signal across the plasma membrane of a cell. An example of a "cell surface receptor" of the present invention is the hTSLP receptor to which the hTSLP protein molecule binds. The term "antibody" as referred to herein includes whole antibodies and any antigen binding fragment (i. e., "antigen-binding portion") or single chains thereof. A naturally 10 occurring "antibody" is a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbrebyted herein as VH) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, CHI, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbrebyted herein as VL) and a light chain 15 constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is, composed of three CDRs and four FRs arranged from amino-terminus to carboxy-terminus in the following order: FRI, 20 CDRI, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system. 25 The term "antigen-binding portion" of an antibody (or simply "antigen portion"), as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., hTSLP). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments encompassed within the term "antigen-binding portion" of an antibody 30 include a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains; a F(ab) 2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; a Fd fragment consisting of the VH and CHl domains; a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; a dAb 11 WO 2007/096149 PCT/EP2007/001506 fragment (Ward et al., 1989 Nature 341:544-546), which consists of a VH domain; and an isolated complementarity determining region (CDR). Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that 5 enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al., 1988 Science 242:423-426; and Huston et al., 1988 Proc. NatI. Acad. Sci. 85:5879-5883). Such single chain antibodies are also intended to be encompassed within the term "antigen-binding portion" of an antibody. These antibody fragments are obtained using conventional 10 techniques known to those of skill in the art, and the fragments are screened for utility in the same manner as are intact antibodies. An "isolated antibody", as used herein, refers to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds hTSLP is substantially free of antibodies that specifically bind antigens 15 other than hTSLP). An isolated antibody that specifically binds hTSLP may, however, have cross-reactivity to other antigens, such as TSLP molecules from other species. Moreover, an isolated antibody may be substantially free of other cellular material and/or chemicals. "Isolated antibody" also refers to an antibody to the target that cross-reacts with known homologs/orthologs, as well as antibodies to the target that do not cross react with known 20 homologs/orthologs. The terms "monoclonal antibody" or "monoclonal antibody composition" as used herein refer to a preparation of antibody molecules of single molecular composition. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope. 25 The term "human antibody", as used herein, is intended to include antibodies having variable regions in which both the framework and CDR regions are derived from sequences of human origin. Furthermore, if the antibody contains a constant region, the constant region also is derived from such human sequences, e.g., human germline sequences, or mutated versions of human germline sequences. The human antibodies of the invention may include 30 amino acid residues not encoded by human sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. CDR grafted antibodies, or alternative 12 WO 2007/096149 PCT/EP2007/001506 technology designed to minimize the Human Anti-murine Antibody response (humaneering technology of Kalobios, or humanization technology of PDL). Xoma also has "human engineering" technology; see e.g., US patent 5766886. The term "human monoclonal antibody" refers to refers to an antibody obtained from 5 a substantially homogeneous population of antibodies that recognizes and binds to a determinant (or epitope) on the antigen. Monoclonal antibodies displaying a single binding specificity which have variable regions in which both the framework and CDR regions are derived from human sequences. In one embodiment, the human monoclonal antibodies are produced by a hybridoma which includes a B cell obtained from a transgenic nonhuman 10 animal, e.g., a transgenic mouse, having a genome comprising a human heavy chain transgene and a light chain transgene fused to an immortalized cell. The term "recombinant human antibody", as used herein, includes all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies isolated from an animal (e.g., a mouse) that is transgenic or transchromosomal for 15 human immunoglobulin genes or a hybridoma prepared therefrom, antibodies isolated from a host cell transformed to express the human antibody, e.g., from a transfectoma, antibodies isolated from a recombinant, combinatorial human antibody library, and antibodies prepared, expressed, created or isolated by any other means that involve splicing of all or a portion of a human immunoglobulin gene, sequences to other DNA sequences. Such recombinant human 20 antibodies have variable regions in which the framework and CDR regions are derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies can be subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, 25 while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo. As used herein, "isotype" refers to the antibody class (e.g., IgM, IgE, IgG such as IgGI, IgG2 or IgG4) that is encoded by the heavy chain constant region genes. The phrases "an antibody recognizing an antigen" and " an antibody specific for an 30 antigen" are used interchangeably herein with the term "an antibody which binds specifically to an antigen." As used herein, an antibody that "specifically binds to hTSLP " is intended to refer to an antibody that binds to human TSLP with a KD of I x 10~9 M or less. An antibody that "cross-reacts with an antigen other than hTSLP " is intended to refer to an antibody that binds 13 WO 2007/096149 PCT/EP2007/001506 that antigen with a 1 x 10-9 M or less. An antibody that "does not cross-react with a particular antigen" is intended to refer to an antibody that binds to that antigen, with a KD of 1.5 x 10-8 M or greater, or a KD of 5-10 x 10~8 M or 1 x 10-7 M or greater. In certain embodiments, such antibodies that do not cross-react with the antigen exhibit essentially undetectable binding 5 against these proteins in standard binding assays. As used herein, an antibody that "inhibits binding of hTSLP to the hTSLP receptor" refers to an antibody that inhibits hTSLP binding to the receptor with a KD of 5 nM or less. As used herein, an antibody that "inhibits inflammatory mediator release" is intended to refer to an antibody that inhibits hTSLP induced luciferase expression from a Baf-3 cell 10 line transfected with the TSLP-receptor and a luciferase reporter system and hTSLP induced TARC secretion from human primary monocytes isolated from PBMCs with an IC 5 0 less than 1.0 nM. The term "Kasc" or "Ka", as used herein, is intended to refer to the association rate of a particular antibody-antigen interaction, whereas the term "Kdis" or "KD," as 15 used herein, is intended to refer to the dissociation rate of a particular antibody antigen interaction. The term "KD", as used herein, is intended to refer to the dissociation constant, which is obtained from the ratio of Kj to Ka (i.e. Kd/Ka) and is expressed as a molar concentration (M). KD values for antibodies can be determined using methods well established in the art. A method for determining the KD of an antibody is by using surface 20 plasmon resonance, or using a biosensor system such as a Biacore* system. As used herein, the term "high affinity" for an IgG antibody refers to an antibody having a KD Of 10-9 M or less for a target antigen. As used herein, the term "subject" includes any human or nonhuman animal. The term "nonhuman animal" includes all vertebrates, e.g., mammals and non 25 mammals, such as nonhuman primates, sheep, dogs, cats, horses, cows chickens, amphibians, reptiles, etc. Various aspects of the invention are described in further detail in the following subsections. Standard assays to evaluate the binding ability of the antibodies toward hTSLP of 30 various species are known in the art, including for example, ELISAs, western blots and RIAs. Suitable assays are described in detail in the Examples. The binding kinetics (e.g., binding affinity) of the antibodies also can be assessed by standard assays known in the art, such as by Biacore analysis. Assays to evaluate the effects of the antibodies on functional properties of hTSLP are described in further detail in the Examples. 14 WO 2007/096149 PCT/EP2007/001506 Accordingly, an antibody that "inhibits" one or more of these hTSLP functional properties (e.g., biochemical, immunochemical, cellular, physiological or other biological activities, or the like) as determined according to methodologies known to the art and described herein, will be understood to relate to a statistically significant decrease in the 5 particular activity relative to that seen in the absence of the antibody (e.g., or when a control antibody of irrelevant specificity is present). An antibody that inhibits hTSLP activity effects such a statistically significant decrease by at least 10% of the measured parameter, by at least 50%, 80% or 90%, and in certain embodiments an antibody of the invention may inhibit greater than 95%, 98% or 99% of hTSLP functional activity. 10 Monoclonal antibodies Antibodies of the invention are the human monoclonal antibodies, isolated and structurally characterized as described, in Examples 1-5. The VH amino acid sequences of the antibodies are shown in SEQ ID NOs: 1-31 respectively. The VL amino acid sequences of 15 the antibodies are shown in SEQ ID NOs: 32-66 respectively. Other antibodies of the invention include amino acids that have been mutated, yet have at least 60, 70, 80, 90 or 95 percent identity in the CDR regions with the CDR regions depicted in the sequences described above. Since each of these antibodies can bind to hTSLP, the VH and VL sequences can be 20 "mixed and matched" to create other anti- hTSLP binding molecules of the invention. hTSLP binding of such "mixed and matched" antibodies can be tested using the binding assays described above and in the Examples (e.g., ELISAs). When VH and VL chains are mixed and matched, a VH sequence from a particular VHVL pairing should be replaced with a structurally similar VH sequence. Likewise, a VL sequence from a particular VH/L pairing 25 should be replaced with a structurally similar VL sequence. The VH and VL sequences of the antibodies of the present invention are particularly amenable for mixing and matching, since these antibodies use VH and VL sequences derived from the same germline sequences and thus exhibit structural similarity. In another aspect, the invention provides antibodies that comprise the heavy chain and 30 light chain CDRIs, CDR2s and CDR3s of the antibodies, or combinations thereof. The amino acid sequences of the VH CDRIs of the antibodies are shown in SEQ ID NOs: 1-7. The amino acid sequences of the VH CDR2s of the antibodies and are shown in SEQ ID NOs: 8 25. The amino acid sequences of the VH CDR3s of the antibodies are shown in SEQ ID NOs: 26-31. The amino acid sequences of the VL CDRls of the antibodies are shown in SEQ ID 15 WO 2007/096149 PCT/EP2007/001506 NOs: 32-40. The amino acid sequences of the VL CDR2s of the antibodies are shown in SEQ ID NOs: 41-49. The amino acid sequences of the VL CDR3s of the antibodies are shown in SEQ ID NOs: 50-66. The CDR regions are delineated using the Kabat system (Kabat, E. A., et al., 1991 Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department 5 of Health and Human Services, NIH Publication No. 91-3242). Given that each of these antibodies can bind to hTSLP and that antigen-binding specificity is provided primarily by the CDR1, 2 and 3 regions, the VH CDRI, 2 and 3 sequences and VL CDR1, 2 and 3 sequences can be "mixed and matched" (i.e., CDRs from different antibodies can be mixed and match, although each antibody must contain a VH 10 CDRI, 2 and 3 and a VL CDR1, 2 and 3) to create other anti-hTSLP binding molecules of the invention. hTSLP binding of such "mixed and matched" antibodies can be tested using the binding assays described above and in the Examples (e.g., ELISAs). When VH CDR sequences are mixed and matched, the CDR1, CDR2 and/or CDR3 sequence from a particular VH sequence should be replaced with a structurally similar CDR sequence(s). 15 Likewise, when VL CDR sequences are mixed and matched, the CDRI, CDR2 and/or CDR3 sequence from a particular VL sequence should be replaced with a structurally similar CDR sequence(s). It will be readily apparent to the ordinarily skilled artisan that novel VH and VL sequences can be created by substituting one or more VH and/or VL CDR region sequences with structurally similar sequences from the CDR sequences shown herein for monoclonal 20 antibodies of the present invention. An isolated monoclonal antibody, or antigen binding portion thereof has: a heavy chain variable region CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-7; a heavy chain variable region CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 8-25; a heavy chain 25 variable region CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 26-31; a light chain variable region CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 32-40; a light chain variable region CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 41-49; and a light chain variable region CDR3 comprising an amino acid sequence 30 selected from the group consisting of SEQ ID NOs: 50-66; wherein the antibody specifically binds hTSLP. In a certain embodiment, the antibody consists of: a heavy chain variable region CDRI comprising SEQ ID NO: 3; a heavy chain variable region CDR2 comprising SEQ ID NO: 15; a heavy chain variable region CDR3 comprising SEQ ID NO: 28; a light chain 16 WO 2007/096149 PCT/EP2007/001506 variable region CDR1 comprising SEQ ID NO: 38; a light chain variable region CDR2 comprising SEQ ID NO: 47; and a light chain variable region CDR3 comprising SEQ ID NO: 60. In another embodiment, the antibody consists of: a heavy chain variable region CDR1 5 comprising SEQ ID NO: 3; a heavy chain variable region CDR2 comprising SEQ ID NO: 17; a heavy chain variable region CDR3 comprising SEQ ID NO: 28; a light chain variable region CDRI comprising SEQ ID NO: 38; a light chain variable region CDR2 comprising SEQ ID NO: 47; and a light chain variable region CDR3 comprising SEQ ID NO: 60. In yet another embodiment, the antibody consists of: a heavy chain variable region 10 CDR1 comprising SEQ ID NO: 3; a heavy chain variable region CDR2 comprising SEQ ID NO: 18; a heavy chain variable region CDR3 comprising SEQ ID NO: 28; a light chain variable region CDR1 comprising SEQ ID NO: 38; a light chain variable region CDR2 comprising SEQ ID NO: 47; and a light chain variable region CDR3 comprising SEQ ID NO: 60. 15 In another embodiment, the antibody consists of: a heavy chain variable region CDRI comprising SEQ ID NO: 3; a heavy chain variable region CDR2 comprising SEQ ID NO: 19; a heavy chain variable region CDR3 comprising SEQ ID NO: 28; a light chain variable region CDR1 comprising SEQ ID NO: 38; a light chain variable region CDR2 comprising SEQ ID NO: 47; and a light chain variable region CDR3 comprising SEQ ID NO: 60. 20 In another embodiment, the antibody consists of: a heavy chain variable region CDR1 comprising SEQ ID NO: 3; a heavy chain variable region CDR2 comprising SEQ ID NO: 20; a heavy chain variable region CDR3 comprising SEQ ID NO: 28; a light chain variable region CDR1 comprising SEQ ID NO: 38; a light chain variable region CDR2 comprising SEQ ID NO: 47; and a light chain variable region CDR3 comprising SEQ ID NO: 60. 25 As used herein, a human antibody comprises heavy or light chain variable regions that is "the product of" or "derived from" a particular germline sequence if the variable regions of the antibody are obtained from a system that uses human germline immunoglobulin genes. Such systems include immunizing a transgenic mouse carrying human immunoglobulin genes with the antigen of interest or screening a human immunoglobulin gene library displayed on 30 phage with the antigen of interest. A human antibody that is "the product of" or "derived from" a human germline immunoglobulin sequence can be identified as such by comparing the amino acid sequence of the human antibody to the amino acid sequences of human germline immunoglobulins and selecting the human germline immunoglobulin sequence that is closest in sequence (i.e., greatest % identity) to the sequence of the human antibody. A 17 WO 2007/096149 PCT/EP2007/001506 human antibody that is "the product of' or "derived from" a particular human germline immunoglobulin sequence may contain amino acid differences as compared to the germline sequence, due to, for example, naturally occurring somatic mutations or intentional introduction of site-directed mutation. However, a selected human antibody typically is at 5 least 90% identical in amino acids sequence to an amino acid sequence encoded by a human germline immunoglobulin gene and contains amino acid residues that identify the human antibody as being human when compared to the germline immunoglobulin amino acid sequences of other species (e.g., murine germline sequences). In certain cases, a human antibody may be at least 60%, 70%, 80%, 90%, or at least 95%, or even at least 96%, 97%, 10 98%, or 99% identical in amino acid sequence to the amino acid sequence encoded by the germline immunoglobulin gene. Typically, a human antibody derived from a particular human germline sequence will display no more than 10 amino acid differences from the amino acid sequence encoded by the human germline immunoglobulin gene. In certain cases, the human antibody may display no more than 5, or even no more than 4, 3, 2, or 1 amino 15 acid difference from the amino acid sequence encoded by the gennline immunoglobulin gene. Homologous antibodies In yet another embodiment, an antibody of the invention has heavy and light chain variable regions having amino acid sequences that are homologous to the amino acid 20 sequences of the antibodies described herein, and wherein the antibodies retain the desired functional properties of the anti-hTSLP antibodies of the Invention. For example, the invention provides an isolated monoclonal antibody, or antigen binding portion thereof, comprising a heavy chain variable region and a light chain variable region, wherein: the heavy chain variable region comprises an amino acid sequence that is at 25 least 80% homologous to an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-31; the light chain variable region comprises an amino acid sequence that is at least 80% homologous to an amino acid sequence selected from the group consisting of SEQ ID NOs: 32-66; the antibody specifically binds to hTSLP, and the antibody exhibits at least one of the following functional properties: the antibody inhibits binding hTSLP protein to the 30 hTSLP receptor or the antibody inhibits hTSLP receptor binding preventing or ameliorating an inflammatory or allergic condition, particularly an inflammatory or obstructive airways disease, or the antibody inhibits hTSLP receptor binding preventing or ameliorating asthma or the antibody inhibits hTSLP receptor binding preventing or ameliorating COPD. 18 WO 2007/096149 PCT/EP2007/001506 In various embodiments, the antibody may exhibit one or more, two or more, or three of the functional properties discussed above. The antibody can be, for example, a human antibody, a humanized antibody or a chimeric antibody. In other embodiments, the V and/or VL amino acid sequences may be 60%, 70%, 5 80%, 90%, 95%, 96%, 97%, 98% or 99% homologous to the sequences set forth above. An antibody having VH and VL regions having high (i.e., 80% or greater) homology to the VH and VL regions of SEQ ID NOs: 1-31 and 32-66 respectively, can be obtained by mutagenesis (e.g., site-directed or PCR-mediated mutagenesis) of nucleic acid molecules encoding SEQ ID NOs: 1-31 and/or 32-66, followed by testing of the encoded altered antibody for retained 10 function (i. e., the functions set forth above) using the functional assays described herein. As used herein, the percent homology between two amino acid sequences is equivalent to the percent identity between the two sequences. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i. e., % homology = # of identical positions/total # of positions x 100), taking into account 15 the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm, as described in the non-limiting examples below. The percent identity between two amino acid sequences can be determined using the 20 algorithm of E. Meyers and W. Miller (Comput. Apple. Biosci., 4:11-17, 1988) which has been incorporated into the ALIGN program (version 2.0), using a PAM 120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. In addition, the percent identity between two amino acid sequences can be determined using the Needleman and Wunsch (J. Mol, Biol. 48:444-453, 1970) algorithm which has been incorporated into the GAP program 25 in the GCG software package (available at http://www.geg.com), using either a Blossom 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. Additionally or alternatively, the protein sequences of the present invention can further be used as a "query sequence" to perform a search against public databases to, for 30 example, identify related sequences. Such searches can be performed using the XBLAST program (version 2.0) of Altschul, et al., 1990 J.Mol. Biol. 215:403-10. BLAST protein searches can be performed with the XBLAST program, score = 50, wordlength = 3 to obtain amino acid sequences homologous to the antibody molecules of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in 19 WO 2007/096149 PCT/EP2007/001506 Altschul et al., 1997 Nucleic Acids Res. 25(17):3389-3402. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. See http:www.ncbi.nlm.nih.gov. 5 Antibodies with conservative modifications In certain embodiments, an antibody of the invention has a heavy chain variable region consist of CDR1, CDR2, and CDR3 sequences and a light chain variable region consisting of CDRI, CDR2, and CDR3 sequences, wherein one or more of these CDR sequences have specified amino acid sequences based on the antibodies described herein or 10 conservative modifications thereof, and wherein the antibodies retain the desired functional properties of the anti- hTSLP antibodies of the invention. Accordingly, the invention provides an isolated monoclonal antibody, or antigen binding portion thereof, consisting of a heavy chain variable region consisting of CDRI, CDR2, and CDR3 sequences and a light chain variable region consisting of CDR1, CDR2, and CDR3 sequences, wherein: the heavy chain 15 variable regions of CDR1 is sequences consisting of amino acid sequences selected from the group consisting of amino acid sequences of SEQ ID NOs: 1-7, and conservative modifications thereof; the heavy chain variable region of CDR2 is sequences consisting of amino acid sequences selected from the group consisting of amino acid sequences of SEQ ID NOs: 8-25, and conservative modifications thereof; the heavy chain variable region of CDR3 20 is sequences consisting of amino acid sequences selected from the group consisting of amino acid sequences of SEQ ID NOs: 26-31, and conservative modifications thereof; the light chain variable regions of CDRI is sequences consisting of amino acid sequences selected from the group consisting of amino acid sequences of SEQ ID NOs: 32-40, and conservative modifications thereof; the light chain variable regions of CDR2 is sequences consisting of 25 amino acid sequences selected from the group consisting of amino acid sequences of SEQ ID NOs: 41-49, and conservative modifications thereof; the light chain variable regions of CDR3 is sequences consisting of amino acid sequences selected from the group consisting of amino acid sequences of SEQ ID NOs: 50-66, and conservative modifications thereof; the antibody specifically binds to hTSLP; and the antibody inhibits hTSLP receptor binding preventing 30 inflammatory mediator release. In various embodiments, the antibody may exhibit one or more, two or more, or three or more of the functional properties listed discussed above. Such antibodies can be, for example, human antibodies, humanized antibodies or chimeric antibodies. 20 WO 2007/096149 PCT/EP2007/001506 As used herein, the term "conservative sequence modifications" is intended to refer to amino acid modifications that do not significantly affect or alter the binding characteristics of the antibody containing the amino acid sequence. Such conservative modifications include amino acid substitutions, additions and deletions. Modifications can be introduced into an 5 antibody of the invention by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions are ones in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino 10 acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, 15 histidine). Thus, one or more amino acid residues within the CDR regions of an antibody of the invention can be replaced with other amino acid residues from the same side chain family, and the altered antibody can be tested for retained function using the functional assays described herein. 20 Antibodies that bind to the same epitope as anti- hTSLP antibodies of the invention In another embodiment, the invention provides antibodies that bind to the same epitope as do the various anti- hTSLP antibodies of the invention provided herein. Such additional antibodies can be identified based on their ability to cross-compete (e.g., to competitively inhibit the binding of, in a statistically significant manner) with other 25 antibodies of the invention in standard hTSLP binding assays. The ability of a test antibody to inhibit the binding of antibodies of the present invention to human hTSLP demonstrates that the test antibody can compete with that antibody for binding to hTSLP; such an antibody may, according to non-limiting theory, bind to the same or a related (e.g., a structurally similar or spatially proximal) epitope on hTSLP as the antibody with which it competes. In a 30 certain embodiment, the antibody that binds to the same epitope on hTSLP as the antibodies of the present invention is a human monoclonal antibody. Such human monoclonal antibodies can be prepared and isolated as described in the Examples. Engineered and modified antibodies 21 WO 2007/096149 PCT/EP2007/001506 An antibody of the invention further can be prepared using an antibody having one or more of the VH and/or VL sequences shown herein as starting material to engineer a modified antibody, which modified antibody may have altered properties from the starting antibody. An antibody can be engineered by modifying one or more residues within one or both 5 variable regions (i.e., VH and/or V), for example within one or more CDR regions and/or within one or more framework regions. Additionally or alternatively, an antibody can be engineered by modifying residues within the constant region(s), for example to alter the effector function(s) of the antibody. One type of variable region engineering that can be performed is CDR grafting. 10 Antibodies interact with target antigens predominantly through amino acid residues that are located in the six heavy and light chain complementarity determining regions (CDRs). For this reason, the amino acid sequences within CDRs are more diverse between individual antibodies than sequences outside of CDRs. Because CDR sequences are responsible for most antibody-antigen interactions, it is possible to express recombinant antibodies that 15 mimic the properties of specific naturally occurring antibodies by constructing expression vectors that include CDR sequences from the specific naturally occurring antibody grafted onto framework sequences from a different antibody with different properties (see, e.g., Riechmann, L. et al., 1998 Nature 332:323-327; Jones, P. et al., 1986 Nature 321:522-525; Queen, C. et al., 1989 Proc. Natl. Acad. See. U.S.A. 86:10029-10033; U.S. Patent No. 20 5,225,539 to winter, and U.S. Patent Nos. 5,530,101; 5,585,089; 5,693,762 and 6,180,370 to Queen et al.) Accordingly, another embodiment of the invention pertains to an isolated monoclonal antibody, or antigen binding portion thereof, comprising a heavy chain variable region comprising CDR1 sequences having an amino acid sequence selected from the group 25 consisting of SEQ ID NOs: 1-7; CDR2 sequences having an amino acid sequence selected from the group consisting of SEQ ID NOs: 8-25; CDR3 sequences having an amino acid sequence selected from the group consisting of SEQ ID NOs: 26-31, respectively; and a light chain variable region having CDRI sequences having an amino acid sequence selected from the group consisting of SEQ ID NOs: 32-40; CDR2 sequences having an amino acid 30 sequence selected from the group consisting of SEQ ID NOs: 41-49; and CDR3 sequences consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 50 66, respectively. Thus, such antibodies contain the VH and VL CDR sequences of monoclonal antibodies, yet may contain different framework sequences from these antibodies. 22 WO 2007/096149 PCT/EP2007/001506 Such framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences. For example, germline DNA sequences for human heavy and light chain variable region genes can be found in the "VBase" human germline sequence database (available on the Internet at www.mrc 5 cpe.cam.ac.uk/vbase), as well as in Kabat, E. A., et al., 1991 Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242; Tomlinson, I. M., et al., 1992 J. fol. Biol. 227:776-798; and Cox, J. P. L. et al., 1994 Eur. J Immunol. 24:827-836; the contents of each of which are expressly incorporated herein by reference. 10 An example of framework sequences for use in the antibodies of the invention are those that are structurally similar to the framework sequences used by selected antibodies of the invention, e.g., consensus sequences and/or framework sequences used by monoclonal antibodies of the invention. The VH CDR1, 2 and 3 sequences, and the VL CDRI, 2 and 3 sequences, can be grafted onto framework regions that have the identical sequence as that 15 found in the germline immunoglobulin gene from which the framework sequence derive, or the CDR sequences can be grafted onto framework regions that contain one or more mutations as compared to the germline sequences. For example, it has been found that in certain instances it is beneficial to mutate residues within the framework regions to maintain or enhance the antigen binding ability of the antibody (see e.g., U.S. Patent Nos. 5,530,101; 20 5,585,089; 5,693,762 and 6,180,370 to Queen et al). Another type of variable region modification is to mutate amino acid residues within the VH and/or VL CDR1, CDR2 and/or CDR3 regions to thereby improve one or more binding properties (e.g., affinity) of the antibody of interest, known as "affinity maturation." Site-directed mutagenesis or PCR-mediated mutagenesis can be performed to introduce the 25 mutation(s) and the effect on antibody binding, or other functional property of interest, can be evaluated in in vitro or in vivo assays as described herein and provided in the Examples. Conservative modifications (as discussed above) can be introduced. The mutations may be amino acid substitutions, additions or deletions. Moreover, typically no more than one, two, three, four or five residues within a CDR region are altered. 30 Accordingly, in another embodiment, the invention provides isolated anti- hTSLP monoclonal antibodies, or antigen binding portions thereof, consisting of a heavy chain variable region having: a VH CDRI region consisting of an amino acid sequence selected from the group having SEQ ID NOs: 1-7 or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NOs: 1-7; 23 WO 2007/096149 PCT/EP2007/001506 a VH CDR2 region having an amino acid sequence selected from the group consisting of SEQ ID NOs: 8-25, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NOs: 8-25; a VH CDR3 region having an amino acid sequence selected from the group consisting of SEQ ID NOs: 26-31, or 5 an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NOs: 26-3 1; a VL CDRI region having an amino acid sequence selected from the group consisting of SEQ ID NOs: 32-40, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NOs: 32-40; a VL CDR2 region having an amino acid 10 sequence selected from the group consisting of SEQ ID NOs: 41-49, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to SEQ ID NOs: 41-49; and a VL CDR3 region having an amino acid sequence selected from the group consisting of SEQ ID NOs: 50-66, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions as compared to 15 SEQ ID NOs: 50-66. Engineered antibodies of the invention include those in which modifications have been made to framework residues within VH and/or VL, e.g. to improve the properties of the antibody. Typically such framework modifications are made to decrease the immunogenicity of the antibody. For example, one approach is to "backmutate" one or more framework 20 residues to the corresponding germline sequence. More specifically, an antibody that has undergone somatic mutation may contain framework residues that differ from the germline sequence from which the antibody is derived. Such residues can be identified by comparing the antibody framework sequences to the germline sequences from which the antibody is derived. To return the framework region sequences to their germline configuration, the 25 somatic mutations can be "backmutated" to the germline sequence by, for example, site directed mutagenesis or PCR-mediated mutagenesis. Such "backmutated" antibodies are also intended to be encompassed by the invention. Another type of framework modification involves mutating one or more residues within the framework region, or even within one or more CDR regions, to remove T cell 30 epitopes to thereby reduce the potential immunogenicity of the antibody. This approach is also referred to as "deimmunization" and is described in further detail in U.S. Patent Publication No. 20030153043 by Carr et al. In addition or alternative to modifications made within the framework or CDR regions, antibodies of the invention may be engineered to include modifications within the Fc 24 WO 2007/096149 PCT/EP2007/001506 region, typically to alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding, and/or antigen-dependent cellular cytotoxicity. Furthermore, an antibody of the invention may be chemically modified (e.g., one or more chemical moieties can be attached to the antibody) or be modified to alter its 5 glycosylation, again to alter one or more functional properties of the antibody. Each of these embodiments is described in further detail below. The numbering of residues in the Fc region is that of the EU index of Kabat. In one embodiment, the hinge region of CHI is modified such that the number of cysteine residues in the hinge region is altered, e.g., increased or decreased. This approach is 10 described further in U.S. Patent No. 5,677,425 by Bodmer et al. The number of cysteine residues in the hinge region of CH1 is altered to, for example, facilitate assembly of the light and heavy chains or to increase or decrease the stability of the antibody. In another embodiment, the Fc hinge region of an antibody is mutated to decrease the biological half-life of the antibody. More specifically, one or more amino acid mutations are 15 introduced into the CH2-CH3 domain interface region of the Fc-hinge fragment such that the antibody has impaired Staphylococcyl protein A (SpA) binding relative to native Fc-hinge domain SpA binding. This approach is described in further detail in U.S. Patent No. 6,165,745 by Ward et al. In another embodiment, the antibody is modified to increase its biological half-life. 20 Various approaches are possible. For example, one or more of the following mutations can be introduced: T252L, T254S, T256F, as described in U.S. Patent No. 6,277,375 to Ward. Alternatively, to increase the biological half life, the antibody can be altered within the CHI or CL region to contain a salvage receptor binding epitope taken from two loops of a CH2 domain of an Fc region of an IgG, as described in U.S. Patent Nos. 5,869,046 and 6,121,022 25 by Presta et al. The Fc constant region of an antibody is critical for determining serum half life and effector functions, i.e., antibody dependent cell cytotoxicity (ADCC) or complement dependent cytotoxicity (CDC) activities. One can engineer specific mutants of the Fc fragment to alter the effector function and/or serum half-life (see Xencor technology for example) (See e.g., W02004029207). 30 One method to alter effector function and serum half-life of an antibody is to graft the variable region of an antibody fragment with an Fc fragment having the appropriate effector function. IgGI or IgG4 isotypes can be selected for cell killing activity, whereas IgG2 isotype can be used for silent antibodies (with no cell killing activity). 25 WO 2007/096149 PCT/EP2007/001506 Silent antibodies with long serum half-life can be obtained by making chimeric fusion of variable regions of an antibody with a serum protein such as HSA or a protein binding to such serum protein, such HSA - binding protein. In yet other embodiments, the Fc region is altered by replacing at least one amino acid 5 residue with a different amino acid residue to alter the effector functions of the antibody. For example, one or more amino acids can be replaced with a different amino acid residue such that the antibody has an altered affinity for an effector ligand but retains the antigen-binding ability of the parent antibody. The effector ligand to which affinity is altered can be, for example, an Fc receptor or the Cl component of complement. This approach is described in 10 further detail in U.S. Patent Nos. 5,624,821 and 5,648,260, both by Winter et al. In another embodiment, one or more amino acids selected from amino acid residues can be replaced with a different amino acid residue such that the antibody has altered Clq binding and/or reduced or abolished complement dependent cytotoxicity (CDC). This approach is described in further detail in U.S. Patent Nos. 6,194,551 by Idusogie et at. 15 In another embodiment, one or more amino acid residues are altered to thereby alter the ability of the antibody to fix complement. This approach is described further in PCT Publication WO 94/29351 by Bodmer et al. In yet another embodiment, the Fc region is modified to increase the ability of the antibody to mediate antibody dependent cellular cytotoxicity (ADCC) and/or to increase the 20 affinity of the antibody for an Fc-y receptor by modifying one or more amino acids. This approach is described further in PCT Publication WO 00/42072 by Presta. Moreover, the binding sites on human IgGI for FcyRl, FcyRII, FcyRIII and FcRn have been mapped and variants with improved binding have been described (see Shields, R.L. et al., 2001 J. Biol. Chen. 276:6591-6604). 25 In still another embodiment, the glycosylation of an antibody is modified. For example, an aglycoslated antibody can be made (i.e., the antibody lacks glycosylation). Glycosylation can be altered to, for example, increase the affinity of the antibody for "antigen'. Such carbohydrate modifications can be accomplished by; for example, altering one or more sites of glycosylation within the antibody sequence. For example, one or 30 more amino acid substitutions can be made that result in elimination of one or more variable region framework glycosylation sites to thereby eliminate glycosylation at that site. Such aglycosylation may increase the affinity of the antibody for antigen. Such an approach is described in further detail in U.S. Patent Nos. 5,714,350 and 6,350,861 by Co et al. 26 WO 2007/096149 PCT/EP2007/001506 Additionally or alternatively, an antibody can be made that has an altered type of glycosylation, such as a hypofucosylated antibody having reduced amounts of fucosyl residues or an antibody having increased bisecting GlcNac structures. Such altered glycosylation patterns have been demonstrated to increase the ADCC ability of antibodies. 5 Such carbohydrate modifications can be accomplished by, for example, expressing the antibody in a host cell with altered glycosylation machinery. Cells with altered glycosylation machinery have been described in the art and can be used as host cells in which to express recombinant antibodies of the invention to thereby produce an antibody with altered glycosylation. For example, EP 1,176,195 by Hang et al. describes a cell line with a 10 functionally disrupted FUT8 gene, which encodes a fucosyl transferase, such that antibodies expressed in such a cell line exhibit hypofucosylation. PCT Publication WO 03/035835 by Presta describes a variant CHO cell line, Lecl3 cells, with reduced ability to attach fucose to Asn(297)-linked carbohydrates, also resulting in hypofucosylation of antibodies expressed in that host cell (see also Shields, R.L. et al., 2002 J. Biol. Chem. 277:26733-26740). PCT 15 Publication WO 99/54342 by Umana et al. describes cell lines engineered to express glycoprotein-modifying glycosyl transferases (e.g., beta(1,4)-N acetylglucosaminyltransferase III (GnTIII)) such that antibodies expressed in the engineered cell lines exhibit increased bisecting GlcNac structures which results in increased ADCC activity of the antibodies (see also Umana et al., 1999 Nat. Biotech. 17:176-180). 20 Another modification of the antibodies herein that is contemplated by the invention is pegylation. An antibody can be pegylated to, for example, increase the biological (e.g., serum) half-life of the antibody. To pegylate an antibody, the antibody, or fragment thereof, typically is reacted with polyethylene glycol (PEG), such as a reactive ester or aldehyde derivative of PEG, under conditions in which one or more PEG groups become attached to 25 the antibody or antibody fragment. The pegylation can be carried out by an acylation reaction or an alkylation reaction with a reactive PEG molecule (or an analogous reactive water soluble polymer). As used herein, the term "polyethylene glycol" is intended to encompass any of the forms of PEG that have been used to derivatize other proteins, such as mono (Cl C10) alkoxy- or aryloxy-polyethylene glycol or polyethylene glycol-maleimide. In certain 30 embodiments, the antibody to be pegylated is an aglycosylated antibody. Methods for pegylating proteins are known in the art and can be applied to the antibodies of the invention. See for example, EP 0 154 316 by Nishimura et al. and EP 0 401 384 by Ishikawa et al. Effector functions can also be altered by modulating the glycosylation pattern of the antibody. Glycart (e.g., US6,602,684), Biowa (e.g., US6,946,292) and Genentech (e.g 27 WO 2007/096149 PCT/EP2007/001506 W003/035835) have engineered mammalian cell lines to produce antibodies with increased or decreased effector function. Especially, non fucosylated antibodies will have enhanced ADCC activities. Glycofi has also developed yeast cell lines capable of producing specific glycoforms of antibodies. Also Kyowa Hakka/Biowa technology to reduce fucose. See, e.g., 5 WO 03/085102. A wide variety of antibody/ immunoglobulin frameworks or scaffolds can be employed so long as the resulting polypeptide includes one or more binding region which is specific for the hTSLP protein. Such frameworks or scaffolds include the 5 main idiotypes of human immunoglobulins, or fragments thereof (such as those disclosed elsewhere herein), 10 and include immunoglobulins of other animal species, preferably having humanized aspects. Single heavy-chain antibodies such as those identified in camelids are of particular interest in this regard. Novel frameworks, scaffolds and fragments continue to be discovered and developed by those skilled in the art. Alternatively, known or future non-immunoglobulin frameworks and scaffolds may 15 be employed, as long as they comprise a binding region specific for the hTSLP protein. Such compounds are known herein as "polypeptides comprising a cMAC-specific binding region". Known non-immunoglobulin frameworks or scaffolds include Adnectins (fibronectin) (Compound Therapeutics, Inc., Waltham, MA), ankyrin (Molecular Partners AG, Zurich, Switzerland), domain antibodies (Domantis, Ltd (Cambridge, MA) and Ablynx nv 20 (Zwijnaarde, Belgium)), lipocalin (Anticalin) (Pieris Proteolab AG, Freising, Germany), small modular immuno-pharmaceuticals (Trubion Pharmaceuticals Inc., Seattle, WA), maxybodies (Avidia, Inc. (Mountain View, CA)), Protein A (Affibody AG, Sweden) and affilin (gamma-crystallin or ubiquitin) (Scil Proteins GmbH, Halle, Germany). According to the instant invention, the anti-hTSLP antibody or fragment 25 thereof, or the polypeptide comprising a hTSLP-specific binding region, regardless of the framework or scaffold employed, may be bound, either covalently or non-covalently, to an additional moiety. The additional moiety may be a polypeptide, an inert polymer such as PEG, small molecule, radioisotope, metal, ion, nucleic acid or other type of biologically relevant molecule. Such a construct, which may be known as an immunoconjugate, 30 immunotoxin, or the like, is also included in the meaning of antibody, antibody fragment or polypeptide comprising ahTSLP-specific binding region, as used herein. Methods of engineering antibodies 28 WO 2007/096149 PCT/EP2007/001506 As discussed above, the anti- hTSLP antibodies having VH and VL sequences shown herein can be used to create new anti- hTSLP antibodies by modifying the VH and/or VL sequences, or the constant region(s) attached thereto. Thus, in another aspect of the invention, the structural features of an anti- hTSLP antibody of the invention are used to create 5 structurally related anti- hTSLP antibodies that retain at least one functional property of the antibodies of the invention, such as binding to hTSLP and also inhibiting one or more functional properties of hTSLP (e.g., receptor binding, inhibition of mediator release). For example, one or more CDR regions of the antibodies of the present invention, or mutations thereof, can be combined recombinantly with known framework regions and/or 10 other CDRs to create additional, recombinantly-engineered, anti- hTSLP antibodies of the invention, as discussed above. Other types of modifications include those described in the previous section. The starting material for the engineering method is one or more of the VH and/or VL sequences provided herein, or one or more CDR regions thereof. To create the engineered antibody, it is not necessary to actually prepare (i.e., express as a protein) an 15 antibody having one or more of the VH and/or VL sequences provided herein, or one or more CDR regions thereof. Rather, the information contained in the sequence(s) is used as the starting material to create a "second generation" sequence(s) derived from the original sequence(s) and then the "second generation" sequence(s) is prepared and expressed as a protein. 20 Accordingly, in another embodiment, the invention provides a method for preparing an anti- hTSLP antibody consisting of: a heavy chain variable region antibody sequence having a CDRI sequence selected from the group consisting of SEQ ID NOs: 1-7, a CDR2 sequence selected from the group consisting of SEQ ID NOs: 8-25 and/or a CDR3 sequence selected from the group consisting of SEQ ID NOs: 26-31 and a light chain variable region 25 antibody sequence having a CDR1 sequence selected from the group consisting of SEQ ID NOs: 32-40, a CDR2 sequence selected from the group consisting of SEQ ID NOs: 41-49 and/or a CDR3 sequence selected from the group consisting of SEQ ID NOs: 50-66; altering at least one amino acid residue within the heavy chain variable region antibody sequence and/or the light chain variable region antibody sequence to create at least one altered antibody 30 sequence; and expressing the altered antibody sequence as a protein. Standard molecular biology techniques can be used to prepare and express the altered antibody sequence. The antibody encoded by the altered antibody sequence(s) is one that retains one, some or all of the functional properties of the anti- hTSLP antibodies described herein, which functional properties include, but are not limited to, specifically binding to 29 WO 2007/096149 PCT/EP2007/001506 hTSLP; and the antibody exhibits at least one of the following functional properties: the antibody inhibits binding of hTSLP protein to the hTSLP receptor, or the antibody inhibits hTSLP receptor binding preventing or ameliorating an inflammatory, fibrotic or allergic condition, particularly an inflammatory or obstructive airways disease, or the antibody 5 inhibits hTSLP receptor binding thereby preventing or ameliorating asthma. The altered antibody may exhibit one or more, two or more, or three or more of the functional properties discussed above. The functional properties of the altered antibodies can be assessed using standard assays available in the art and/or described herein, such as those set forth in the Examples 10 (e.g., ELISAs). In certain embodiments of the methods of engineering antibodies of the invention, mutations can be introduced randomly or selectively along all or part of an anti- hTSLP antibody coding sequence and the resulting modified anti- hTSLP antibodies can be screened for binding activity and/or other functional properties as described herein. Mutational 15 methods have been described in the art. For example, PCT Publication WO 02/092780 by Short describes methods for creating and screening antibody mutations using saturation mutagenesis, synthetic ligation assembly, or a combination thereof. Alternatively, PCT Publication WO 03/074679 by Lazar et al. describes methods of using computational screening methods to optimize physiochemical properties of antibodies. 20 Nucleic acid molecules encoding antibodies of the invention Another aspect of the invention pertains to nucleic acid molecules that encode the antibodies of the invention. The nucleic acids may be present in whole cells, in a cell lysate, or may be nucleic acids in a partially purified or substantially pure form. A nucleic acid is 25 "isolated" or "rendered substantially pure" when purified away from other cellular components or other contaminants, e.g., other cellular nucleic acids or proteins, by standard techniques, including alkaline/SDS treatment, CsCI banding, column chromatography, agarose gel electrophoresis and others well known in the art. See, F. Ausubel, et al., ed. 1987 Current Protocols in Molecular Biology, Greene Publishing and Wiley Interscience, New 30 York. A nucleic acid of the invention can be, for example, DNA or RNA and may or may not contain intronic sequences. In an embodiment, the nucleic acid is a cDNA molecule. The nucleic acid may be present in a vector such as a phage display vector, or in a recombinant plasmid vector. 30 WO 2007/096149 PCT/EP2007/001506 Nucleic acids of the invention can be obtained using standard molecular biology techniques. For antibodies expressed by hybridomas (e.g., hybridomas prepared from transgenic mice carrying human immunoglobulin genes as described further below), cDNAs encoding the light and heavy chains of the antibody made by the hybridoma can be obtained 5 by standard PCR amplification or cDNA cloning techniques. For antibodies obtained from an immunoglobulin gene library (e.g., using phage display techniques), nucleic acid encoding the antibody can be recovered from various phage clones that are members of the library. Once DNA fragments encoding VH and VL segments are obtained, these DNA fragments can be further manipulated by standard recombinant DNA techniques, for example 10 to convert the variable region genes to full-length antibody chain genes, to Fab fragment genes or to an scFv gene. In these manipulations, a VL- or VH-encoding DNA fragment is operatively linked to another DNA molecule, or to a fragment encoding another protein, such as an antibody constant region or a flexible linker. The term "operatively linked", as used in this context, is intended to mean that the two DNA fragments are joined in a functional 15 manner, for example, such that the amino acid sequences encoded by the two DNA fragments remain in-frame, or such that the protein is expressed under control of a desired promoter. The isolated DNA encoding the VH region can be converted to a full-length heavy chain gene by operatively linking the VH-encoding DNA to another DNA molecule encoding heavy chain constant regions (CHI, CH2 and CH3). The sequences of human heavy chain 20 constant region genes are known in the art (see e.g., Kabat, E. A., el al., 1991 Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242) and DNA fragments encompassing these regions can be obtained by standard PCR amplification. The heavy chain constant region can be an IgGI, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region. For a Fab fragment heavy chain 25 gene, the VH-encoding DNA can be operatively linked to another DNA molecule encoding only the heavy chain CHI constant region. The isolated DNA encoding the VL region can be converted to a full-length light chain gene (as well as to a Fab light chain gene) by operatively linking the VL-encoding DNA to another DNA molecule encoding the light chain constant region, CL. The sequences of 30 human light chain constant region genes are known in the art (see e.g., Kabat, E. A., et al., 1991 Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242) and DNA fragments encompassing these regions can be obtained by standard PCR amplification. The light chain constant region can be a kappa or a lambda constant region. 31 WO 2007/096149 PCT/EP2007/001506 To create an scFv gene, the VH- and VL-encoding DNA fragments are operatively linked to another fragment encoding a flexible linker, e.g., encoding the amino acid sequence (Gly4 -Ser) 3 , such that the VH and VL sequences can be expressed as a contiguous single chain protein, with the VL and VH regions joined by the flexible linker (see e.g., Bird et al., 5 1988 Science 242:423-426; Huston et at., 1988 Proc. Nati. Acad. Sci. USA 85:5879-5883; McCafferty et al., 1990 Nature 348:552-554). Production of monoclonal antibodies of the invention Monoclonal antibodies (mAbs) can be produced by a variety of techniques, including 10 conventional monoclonal antibody methodology e.g., the standard somatic cell hybridization technique of Kohler and Milstein, 1975 Nature 256: 495. Many techniques for producing monoclonal antibody can be employed e.g., viral or oncogenic transformation of B lymphocytes. An animal system for preparing hybridomas is the murine system. Hybridoma 15 production in the mouse is a well established procedure. Immunization protocols and techniques for isolation of immunized splenocytes for fusion are known in the art. Fusion partners (e.g., murine myeloma cells) and fusion procedures are also known. Monolconal antibodies can also be produced using a specific hybridoma, which has been deposited in a strain collection. 20 Chimeric or humanized antibodies of the present invention can be prepared based on the sequence of a murine monoclonal antibody prepared as described above. DNA encoding the heavy and light chain immunoglobulins can be obtained from the murine hybridoma of interest and engineered to contain non-murine (e.g.,. human) immunoglobulin sequences using standard molecular biology techniques. For example, to create a chimeric antibody, the 25 murine variable regions can be linked to human constant regions using methods known in the art (see e.g., U.S. Patent No. 4,816,567 to Cabilly et al.). To create a humanized antibody, the murine CDR regions can be inserted into a human framework using methods known in the art (see e.g., U.S. Patent No. 5,225,539 to Winter, and U.S. Patent Nos. 5,530,101; 5,585,089; 5,693,762 and ,6;180;370 to.Queen.et al. 30 In a certain embodiment, the antibodies of the invention are human monoclonal antibodies. Such human monoclonal antibodies directed against hTSLP can be generated using transgenic or transchromosomic mice carrying parts of the human immune system rather than the mouse system. These transgenic and transchromosomic mice include mice 32 WO 2007/096149 PCT/EP2007/001506 referred to herein as HuMAb mice and KM mice, respectively, and are collectively referred to herein as "human Ig mice." The HuMAb mouse* (Medarex, Inc.) contains human immunoglobulin gene miniloci that encode un-rearranged human heavy (p and y) and K light chain immunoglobulin 5 sequences, together with targeted mutations that inactivate the endogenous i and K chain loci (see e.g., Lonberg, et al., 1994 Nature 368(6474): 856-859). Accordingly, the mice exhibit reduced expression of mouse IgM or K, and in response to immunization, the introduced human heavy and light chain transgenes undergo class switching and somatic mutation to generate high affinity human IgGK monoclonal (Lonberg, N. et al., 1994 supra; reviewed in 10 Lonberg, N., 1994 Handbook of Experimental Pharmacology 113:49-101; Lonberg, N. and Huszar, D., 1995 Intern. Rev. Immunol.13: 65-93, and Harding, F. and Lonberg, N., 1995 Ann. N. Y. Acad. Sci. 764:536-546). The preparation and use of HuMAb mice, and the genomic modifications carried by such mice, is further described in Taylor, L. et al., 1992 Nucleic Acids Research 20:6287-6295; Chen, J. et at., 1993 International Immunology 5: 15 647-656; Tuaillon et al., 1993 Proc. Nati. Acad. Sci. USA 94:3720-3724; Choi et al., 1993 Nature Genetics 4:117-123; Chen, J. et al., 1993 EMBO J. 12: 821-830; Tuaillon et al., 1994 J. Immunol. 152:2912-2920; Taylor, L. et al., 1994 International Immunology 579-591; and Fishwild, D. et al., 1996 Nature Biotechnology 14: 845-85 1, the contents of all of which are hereby specifically incorporated by reference in their entirety. See further, U.S. Patent Nos. 20 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,789,650; 5,877,397; 5,661,016; 5,814,318; 5,874,299; and 5,770,429; all to Lonberg and Kay; U.S. Patent No. 5,545,807 to Surani et al.; PCT Publication Nos. WO 92103918, WO 93/12227, WO 94/25585, WO 97113852, WO 98/24884 and WO 99/45962, all to Lonberg and Kay; and PCT Publication No. WO 01/14424 to Korman et al. 25 In another embodiment, human antibodies of the invention can be raised using a mouse that carries human immunoglobulin sequences on transgenes and transchomosomes such as a mouse that carries a human heavy chain transgene and a human light chain transchromosome. Such mice, referred to herein as "KM mice", are described in detail in PCT Publication WO 02/43478 to Ishida et al. 30 Still further, alternative transgenic animal systems expressing human immunoglobulin genes are available in the art and can be used to raise anti- hTSLP antibodies of the invention. For example, an alternative transgenic system referred to as the Xenomouse (Abgenix, Inc.) can be used; such mice are described in, for example, U.S. Patent Nos. 5,939,598; 6,075,181; 6,114,598; 6, 150,584 and 6,162,963 to Kucherlapati et al. 33 WO 2007/096149 PCT/EP2007/001506 Moreover, alternative transchromosomic animal systems expressing human immunoglobulin genes are available in the art and can be used to raise anti- hTSLP antibodies of the invention. For example, mice carrying both a human heavy chain transchromosome and a human light chain tranchromosome, referred to as "TC mice" can be 5 used; such mice are described in Tomizuka et al., 2000 Proc. Natl. Acad. Sci. USA 97:722 727. Furthermore, cows carrying human heavy and light chain transchromosomes have been described in the art (Kuroiwa et al., 2002 Nature Biotechnology 20:889-894) and can be used to raise anti - hTSLP antibodies of the invention. Human monoclonal antibodies of the invention can also be prepared using phage 10 display methods for screening libraries of human immunoglobulin genes. Such phage display methods for isolating human antibodies are established in the art. See for example: U.S. Patent Nos. 5,223,409; 5,403,484; and 5,571,698 to Ladner et al.; U.S. Patent Nos. 5,427,908 and 5,580,717 to Dower et al.; U.S. Patent Nos. 5,969,108 and 6,172,197 to McCafferty et al.; and U.S. Patent Nos. 5,885,793; 6,521,404; 6,544,731; 6,555,313; 6,582,915 and 15 6,593,081 to Griffiths et al. Human monoclonal antibodies of the invention can also be prepared using SCID mice into which human immune cells have been reconstituted such that a human antibody response can be generated upon immunization. Such mice are described in, for example, U.S. Patent Nos. 5,476,996 and 5,698,767 to Wilson et al. 20 Antibodies obtained from screening of antibody human libraries, (e.g. phage display with Morphosys), from libraries such as HuCal library from Morphosys, affinity maturation technology and further codon optimization sequence technologies can also be used. Affinity maturation can also be used on antibodies made in other ways (e.g., hybridomas). 25 Generation of transfectomas producing monoclonal antibodies Antibodies of the invention also can be produced in a host cell transfectoma using, for example, a combination of recombinant DNA techniques and gene transfection methods as is well known in the art (e.g., Morrison, S. (1985) Science 229:1202). For example, to express the antibodies, or antibody fragments thereof, DNAs 30 encoding partial or full-length light and heavy chains, can be obtained by standard molecular biology techniques (e.g., PCR amplification or cDNA cloning using a hybridoma that expresses the antibody of interest) and the DNAs can be inserted into expression vectors such that the genes are operatively linked to transcriptional and translational control sequences. In this context, the term "operatively linked" is intended to mean that an antibody gene is ligated 34 WO 2007/096149 PCT/EP2007/001506 into a vector such that transcriptional and translational control sequences within the vector serve their intended function of regulating the transcription and translation of the antibody gene. The expression vector and expression control sequences are chosen to be compatible with the expression host cell used. The antibody light chain gene and the antibody heavy 5 chain gene can be inserted into separate vector or, more typically, both genes are inserted into the same expression vector. The antibody genes are inserted into the expression vector by standard methods (e.g., ligation of complementary restriction sites on the antibody gene fragment and vector, or blunt end ligation if no restriction sites are present). The light and heavy chain variable regions of the antibodies described herein can be used to create full 10 length antibody genes of any antibody isotype by inserting them into expression vectors already encoding heavy chain constant and light chain constant regions of the desired isotype such that the VH segment is operatively linked to the CH segment(s) within the vector and the VL segment is operatively linked to the CL segment within the vector. Additionally or alternatively, the recombinant expression vector can encode a signal peptide that facilitates 15 secretion of the antibody chain from a host cell. The antibody chain gene can be cloned into the vector such that the signal peptide is linked in frame to the amino terminus of the antibody chain gene. The signal peptide can be an immunoglobulin signal peptide or a heterologous signal peptide (i.e., a signal peptide from a non-immunoglobulin protein). In addition to the antibody chain genes, the recombinant expression vectors of the 20 invention carry regulatory sequences that control the expression of the antibody chain genes in a host cell. The term "regulatory sequence" is intended to include promoters, enhancers and other expression control elements (e.g., polyadenylation signals) that control the transcription or translation of the antibody chain genes. Such regulatory sequences are described, for example, in Goeddel (Gene Expression Technology. Methods in Enzymology 25 185, Academic Press, San Diego, CA 1990). It will be appreciated by those skilled in the art that the design of the expression vector, including the selection of regulatory sequences, may depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc. Regulatory sequences for mammalian host cell expression include viral elements that direct high levels of protein expression in mammalian cells, such as 30 promoters and/or enhancers derived from cytomegalovirus (CMV), Simian Virus 40 (SV40), adenovirus (e.g., the adenovirus major late promoter (AdMLP)), and polyoma. Alternatively, nonviral regulatory sequences may be used, such as the ubiquitin promoter or P-globin promoter. Still further, regulatory elements composed of sequences from different sources, such as the SRa promoter system, which contains sequences from the SV40 early promoter 35 WO 2007/096149 PCT/EP2007/001506 and the long terminal repeat of human T cell leukemia virus type 1 (Takebe, Y. et al., 1988 Mol. Cell. Biol. 8:466-472). In addition to the antibody chain genes and regulatory sequences, the recombinant expression vectors of the invention may carry additional sequences, such as sequences that 5 regulate replication of the vector in host cells (e.g., origins of replication) and selectable marker genes. The selectable marker gene facilitates selection of host cells into which the vector has been introduced (see, e.g., U.S. Pat. Nos. 4,399,216, 4,634,665 and 5,179,017, all by Axel et al.). For example, typically the selectable marker gene confers resistance to drugs, such as G418, hygromycin or methotrexate, on a host cell into which the vector has been 10 introduced. Selectable marker genes include the dihydrofolate reductase (DHFR) gene (for use in dhfr- host cells with methotrexate selection/amplification) and the neo gene (for G418 selection). For expression of the light and heavy chains, the expression vector(s) encoding the heavy and light chains is transfected into a host cell by standard techniques. The various 15 forms of the term "transfection" are intended to encompass a wide variety of techniques commonly used for the introduction of exogenous DNA into a prokaryotic or eukaryotic host cell, e.g., electroporation, calcium-phosphate precipitation, DEAE-dextran transfection and the like. It is theoretically possible to express the antibodies of the invention in either prokaryotic or eukaryotic host cells. Expression of antibodies in eukaryotic cells, in 20 particular mammalian host cells, is discussed because such eukaryotic cells, and in particular mammalian cells, are more likely than prokaryotic cells to assemble and secrete a properly folded and immunologically active antibody. Prokaryotic expression of antibody genes has been reported to be ineffective for production of high yields of active antibody (Boss, M. A. and Wood, C. R., 1985 Immunology Today 6:12-13). 25 Mammalian host cells for expressing the recombinant antibodies of the invention include Chinese Hamster Ovary (CHO cells) (including dhfr- CHO cells, described Urlaub and Chasin, 1980 Proc. Nati. Acad. Sci. USA 77:4216-4220 used with a DH FR selectable marker, e.g., as described in R.J. Kaufman and P.A. Sharp, 1982 Mol. Biol. 159:601-621, NSO myeloma cells, COS cells and SP2 cells. When recombinant expression vectors 30 encoding antibody genes are introduced into mammalian host cells, the antibodies are produced by culturing the host cells for a period of time sufficient to allow for expression of the antibody in the host cells or secretion of the antibody into the culture medium in which the host cells are grown. Antibodies can be recovered from the culture medium using standard protein purification methods. 36 WO 2007/096149 PCT/EP2007/001506 Sequences encoding partial or full-length light and heavy chains are expressed by transfecting the expression vector(s) carrying such sequences into a host cell by standard transfection techniques. Typically, eukaryotic host cells are used for expressing antibodies, as antibodies are generally glycoproteins and prokaryotic cells are therefore not appropriate. 5 Mammalian host cells which can be used for expressing the recombinant antibodies include Chinese Hamster Ovary (CHO cells) (including dhfr- CHO cells), NSO myeloma cells, COS cells and SP2 cells. Alternatively, one can use a host cell engineered to produce glycoproteins with mammalian-like glycosylation patterns, including yeast, fungi or plant cell lines. The antibodies can be produced for example in glycoengineered yeast cell lines, including Pichia, 10 Saccharomyces or Kluyveromyces species, and preferably, Pichia pastoris or Saccharomyces cerevisae or Kluyveromyces lactis, see for example EP1297172B1 (Glycofi). The antibodies can also be produced in glycoengineered plant cell lines, and preferably bryophyte cell lines as described in W02004057002 (Greenovation). Antibodies are produced by culturing the host cells for a period of time sufficient to allow for expression of the antibody in the host 15 cells or secretion of the antibody into the culture medium. Antibodies are recovered from the culture medium using standard protein purification methods. Immunoconjugates In another aspect, the present invention features an anti- hTSLP antibody, or a 20 fragment thereof, conjugated to a therapeutic moiety, such as a cytotoxin, a drug (e.g., an immunosuppressant) or a radiotoxin. Such conjugates are referred to herein as "immunoconjugates". Immunoconjugates that include one or more cytotoxins are referred to as "immunotoxins." A cytotoxin or cytotoxic agent includes any agent that is detrimental to (e.g., kills) cells. Examples include taxon, cytochalasin B, gramicidin D, ethidium bromide, 25 emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, t. colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, I dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof. Therapeutic agents also include, for example, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5 30 fluorouracil decarbazine), ablating agents (e.g., mechlorethamine, thioepa chloraxnbucil, meiphalan, carmustine (BSNU) and lomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP) cisplatin, anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), 37 WO 2007/096149 PCT/EP2007/001506 antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents (e.g., vincristine and vinblastine). Other examples of therapeutic cytotoxins that can be conjugated to an antibody of the invention include duocarmycins, calicheamicins, maytansines and auristatins, and derivatives 5 thereof. An example of a calicheamicin antibody conjugate is commercially available (MylotargTm; Wyeth-Ayerst). Cytotoxins can be conjugated to antibodies of the invention using linker technology available in the art. Examples of linker types that have been used to conjugate a cytotoxin to an antibody include, but are not limited to, hydrazones, thioethers, esters, disulfides and 10 peptide-containing linkers. A linker can be chosen that is, for example, susceptible to cleavage by low pH within the lysosomal compartment or susceptible to cleavage by proteases, such as proteases preferentially expressed in tumor tissue such as cathepsins (e.g., cathepsins B, C, D). For further discussion of types of cytotoxins, linkers and methods for conjugating 15 therapeutic agents to antibodies, see also Saito, G. et al., 2003 Adv. Drug Deliv. Rev. 55:199 215; Trail, P.A. et al., 2003 Cancer Immunol. Immunother. 52:328-337; Payne, G., 2003 Cancer Cell 3:207-212; Allen, T.M., 2002 Nat. Rev. Cancer 2:750-763; Pastan, I. and Kreitman, R. J., 2002 Curr. Opin. Investig. Drugs 3:1089-1091; Senter, P.D. and Springer, C.J., 2001 Adv. Drug Deliv. Rev. 53:247-264. 20 Antibodies of the present invention also can be conjugated to a radioactive isotope to generate cytotoxic radiopharmaceuticals, also referred to as radioimmunoconjugates. Examples of radioactive isotopes that can be conjugated to antibodies for use diagnostically 131 90 or therapeutically include, but are not limited to, iodine, indium", yttrium , and lutetium'm. Method for preparing radioimmunconjugates are established in the art. Examples 25 of radioimmunoconjugates are commercially available, including ZevalinTM (DEC Pharmaceuticals) and Bexxarh (Corixa Pharmaceuticals), and similar methods can be used to prepare radioimmunoconjugates using the antibodies of the invention. The antibody conjugates of the invention can be used to modify a given biological response, and the drug moiety is not to be construed as limited to classical chemical 30 therapeutic agents. For example, the drug moiety may be a protein or polypeptide possessing a desired biological activity. Such proteins may include, for example, an enzymatically active toxin, or active fragment thereof, such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin; a protein such as tumor necrosis factor or interferon-Y; or, biological response modifiers such as, for example, lymphokines, interleukin- I ("IL-I"), interleukin-2 ("IL-2"), 38 WO 2007/096149 PCT/EP2007/001506 interleukin-6 ("IL-6"), granulocyte macrophage colony stimulating factor ("GM-CSF"), granulocyte colony stimulating factor ("G-CSF"), or other growth factors. Techniques for conjugating such therapeutic moiety to antibodies are well known, see, e.g., Amon et al., "Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer 5 Therapy", in Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss, Inc. 1985); Hellstrom et at., "Antibodies For Drug Delivery", in Controlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp. 623-53 (Marcel Dekker, Inc. 1987); Thorpe, "Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review", in Monoclonal Antibodies '84: Biological And Clinical Applications, Pinchera et al. (eds.), pp. 10 475-506 (1985); "Analysis, Results, And Future Prospective Of The Therapeutic Use Of Radiolabeled Antibody In Cancer Therapy", in Monoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al. (eds.), pp. 303-16 (Academic Press 1985), and Thorpe et al., "The Preparation And Cytotoxic Properties Of Antibody-Toxin Conjugates", Inmunol. Rev., 62:119-58 (1982). 15 Bispecific molecules In another aspect, the present invention features bispecific molecules comprising an anti- hTSLP antibody, or a fragment thereof, of the invention. An antibody of the invention, or antigen-binding portions thereof, can be derivatized or linked to another functional 20 molecule, e.g., another peptide or protein (e.g., another antibody or ligand for a receptor) to generate a bispecific molecule that binds to at least two different binding sites or target molecules. The antibody of the invention may in fact be derivatized or linked to more than one other functional molecule to generate multi-specific molecules that bind to more than two different binding sites and/or target molecules; such multi-specific molecules are also 25 intended to be encompassed by the term "bispecific molecule" as used herein. To create a bispecific molecule of the invention, an antibody of the invention can be functionally linked (e.g., by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other binding molecules, such as another antibody, antibody fragment, peptide or binding mimetic, such that a bispecific molecule results. 30 Accordingly, the present invention includes bispecific molecules comprising at least one first binding specificity for hTSLP and a second binding specificity for a second target epitope. For example, the second target epitope is an Fc receptor, e.g., human FcyRI (CD64) or a human Fca receptor (CD89). Therefore, the invention includes bispecific molecules capable of binding both to FcyR, FcaR or FcR expressing effector cells (e.g., monocytes, 39 WO 2007/096149 PCT/EP2007/001506 macrophages or polymorphonuclear cells (PMNs), and to target cells expressing hTSLP. These bispecific molecules target hTSLP expressing cells to effector cell and trigger Fc receptor-mediated effector cell activities, such as phagocytosis of an hTSLP expressing cells, antibody dependent cell-mediated cytotoxicity (ADCC), cytokine release, or generation of 5 superoxide anion. Additionally, for the invention in which the bispecific molecule is multi-specific, the molecule can further include a third binding specificity, in addition to an anti-Fc binding specificity and an anti- hTSLP binding specificity. For example, the third binding specificity could be an anti-enhancement factor (EF) portion, e.g., a molecule which binds to a surface 10 protein involved in cytotoxic activity and thereby increases the immune response against the target cell. The "anti-enhancement factor portion" could be an antibody, functional antibody fragment or a ligand that binds to a given molecule, e.g., an antigen or a receptor, and thereby results in an enhancement of the effect of the binding determinants for the Fc receptor or target cell antigen. 15 The "anti-enhancement factor portion" can bind an Fc receptor or a target cell antigen. Alternatively, the anti-enhancement factor portion could bind to an entity that is different from the entity to which the first and second binding specificities bind. For example, the anti enhancement factor portion can bind a cytotoxic T-cell (e.g. by CD2, CD3, CD8, CD28, CD4, CD44, ICAM-I or other immune cell that results in an increased immune response 20 against the target cell). In one embodiment, the bispecific molecules of the invention comprise as a binding specificity at least one antibody, or an antibody fragment thereof, including, e.g., an Fab, Fab', F(ab') 2 , Fv, or a single chain Fv. The antibody may also be a light chain or heavy chain dimer, or any minimal fragment thereof such as a Fv or a single chain construct as described 25 in Ladner et al. U.S. Patent No. 4,946,778, the contents of which is expressly incorporated by reference. In one embodiment, the binding specificity for an Fcy receptor is provided by a monoclonal antibody, the binding of which is not blocked by human immunoglobulin G (IgG). As used herein, the term "IgG receptor" refers to any of the eight y-chain genes located 30 on chromosome 1. These genes encode a total of twelve transmembrane or soluble receptor isoforms which are grouped into three Fy receptor classes: FcyRl (CD64), FcyRII(CD32), and FcyRIII (CD 16). In another embodiment, the Fey receptor is a human high affinity FcyRI. The human Fc-yRI is a 72 kDa molecule, which shows high affinity for monomeric IgG (108 10 9 M-1). 40 WO 2007/096149 PCT/EP2007/001506 The production and characterization of certain anti-Fcy monoclonal antibodies are described by Fanger et at. in PCT Publication WO 88/00052 and in U.S. Patent No. 4,954,617, the teachings of which are fully incorporated by reference herein. These antibodies bind to an epitope of FcyRI, FcyRII or FcyRII at a site which is distinct from the 5 Fcy binding site of the receptor and, thus, their binding is not blocked substantially by physiological levels of IgG. Specific anti-FcyRI antibodies useful in this invention are mAb 22, mAb 32, mAb 44, mAb 62 and mAb 197. The hybridoma producing mAb 32 is available from the American Type Culture Collection, ATCC Accession No. HB9469. In other embodiments, the anti-Fcy receptor antibody is a humanized form of monoclonal antibody 22 10 (H22). The production and characterization of the H22 antibody is described in Graziano, R.F. et al., 1995 J. Immunol 155 (10): 4996-5002 and PCT Publication WO 94/10332. The 1122 antibody producing cell line was deposited at the American Type Culture Collection under the designation HA022CL 1 and has the accession no. CRL 11177. In still other embodiments, the binding specificity for an Fc receptor is provided by an 15 antibody that binds to a human IgA receptor, e.g., an Fc-alpha receptor (FcaRI (CD89), the binding of which does not have to be blocked by human immunoglobulin A (IgA). The term "IgA receptor" is intended to include the gene product of one a gene (FcaRI) located on chromosome 19. This gene is known to encode several alternatively spliced transmembrane isoforms of 55 to 110 kDa. FcaRI (CD89) is constitutively expressed on 20 monocytes/macrophages, eosinophilic and neutrophilic granulocytes, but not on non-effector cell populations. FcaRI has medium affinity ( 5 x 107 M') for both IgAl and IgA2, which is increased upon exposure to cytokines such as G-CSF or GM-CSF (Morton, H.C. et al., 1996 Critical Reviews in Immunology 116:423-440). Four FcaRI-specific monoclonal antibodies, identified as A3, A59, A62 and A77, which bind FcaRl outside the IgA ligand binding 25 domain, have been described (Monteiro, R.C. et al., 1992 J. Immunol. 148:1764). FcaRI and FcyRI are trigger receptors for use in the bispecific molecules of the invention because they are expressed primarily on immune effector cells, e.g., monocytes, PMNs, macrophages and dendritic cells; expressed at high levels (e.g., 5,000-100,000 per cell); mediators of cytotoxic activities (e.g., ADCC, phagocytosis); mediate enhanced antigen 30 presentation of antigens, including self-antigens, targeted to them. Other antibodies which can be employed in the bispecific molecules of the invention are murine, chimeric and humanized monoclonal antibodies. The bispecific molecules of the present invention can be prepared by conjugating the constituent binding specificities, e.g., the anti-FcR and anti- hTSLP binding specificities, 41 WO 2007/096149 PCT/EP2007/001506 using methods known in the art. For example, each binding specificity of the bispecific molecule can be generated separately and then conjugated to one another. When the binding specificities are proteins or peptides, a variety of coupling or cross-linking agents can be used for covalent conjugation. Examples of cross-linking agents include protein A, carbodiimide, 5 N-succinimidyl-S-acetyl-thioacetate (SATA), 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB), o phenylenedimaleimide (oPDM), N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), and sulfosuccinimidyl 4-(N-maleimidomethyl) cyclohaxane-l-carboxylate (sulfo-SMCC) (see e.g., Karpovsky et al., 1984 J. Exp. Med. 160:1686; Liu, MA et al., 1985 Proc. Natl. Acad. Sci. USA 82:8648). Other methods include those described in Paulus, 1985 Behring Ins. Mitt. 10 No. 78,118-132; Brennan et al., 1985 Science 229:81-83), and Glennie et al., 1987 J. Immunol. 139: 2367-2375). Conjugating agents are SATA and sulfo-SMCC, both available from Pierce Chemical Co. (Rockford, IL). When the binding specificities are antibodies, they can be conjugated by sulfhydryl bonding of the C-terminus hinge regions of the two heavy chains. In a particularly 15 embodiment, the hinge region is modified to contain an odd number of sulfhydryl residues, for example one, prior to conjugation. Alternatively, both binding specificities can be encoded in the same vector and expressed and assembled in the same host cell. This method is particularly useful where the bispecific molecule is a mAb x mAb, mAb x Fab, Fab x F(ab') 2 or ligand x Fab 20 fusion protein. A bispecific molecule of the invention can be a single chain molecule comprising one single chain antibody and a binding determinant, or a single chain bispecific molecule comprising two binding determinants. Bispecific molecules may comprise at least two single chain molecules. Methods for preparing bispecific molecules are described for example in U.S. Patent Number 5,260,203; U.S. Patent Number 5,455,030; U.S. Patent 25 Number 4,881,175; U.S. Patent Number 5,132,405; U.S. Patent Number 5,091,513; U.S. Patent Number 5,476,786; U.S. Patent Number 5,013,653; U.S. Patent Number 5,258,498; and U.S. Patent Number 5,482,858. Binding of the bispecific molecules to their specific targets can be confirmed by, for example, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (REA), FACS 30 analysis, bioassay (e.g., growth inhibition), or Western Blot assay. Each of these assays generally detects the presence of protein-antibody complexes of particular interest by employing a labeled reagent (e.g., an antibody) specific for the complex of interest. For example, the FcR-antibody complexes can be detected using e.g., an enzyme-linked antibody or antibody fragment which recognizes and specifically binds to the antibody-FcR 42 WO 2007/096149 PCT/EP2007/001506 complexes. Alternatively, the complexes can be detected using any of a variety of other immunoassays. For example, the antibody can be radioactively 4 labeled and used in a radioimmunoassay (RIA) (see, for example, Weintraub; B., Principles of Radioimmunoassays, Seventh Training Course on Radioligand Assay Techniques, The 5 Endocrine Society, March, 1986, which is incorporated by reference herein). The radioactive isotope can be detected by such means as the use of a y counter or a scintillation counter or by autoradiography. Non-Immunoglobulin Scaffolds 10 A wide variety of antibody/ immunoglobulin frameworks or scaffolds can be employed so long as the resulting polypeptide includes at least one binding region which is specific for the target protein. Such frameworks or scaffolds include the 5 main idiotypes of human immunoglobulins, or fragments thereof (such as those disclosed elsewhere herein), and include immunoglobulins of other animal species, preferably having humanized aspects. 15 Single heavy-chain antibodies such as those identified in camelids are of particular interest in this regard. Novel frameworks, scaffolds and fragments continue to be discovered and developed by those skilled in the art. In one aspect, the invention pertains to generating non-immunoglobulin based 20 antibodies using non- immunoglobulin scaffolds onto which CDRs of the invention can be grafted. Known or future non-immunoglobulin frameworks and scaffolds may be employed, as long as they comprise a binding region specific for the target protein. Such compounds are known herein as "polypeptides comprising a target-specific binding region". Known non immunoglobulin frameworks or scaffolds include, but are not limited to, Adnectins 25 (fibronectin) (Compound Therapeutics, Inc., Waltham, MA), ankyrin (Molecular Partners AG, Zurich, Switzerland), domain antibodies (Domantis, Ltd (Cambridge, MA) and Ablynx nv (Zwijnaarde, Belgium)), lipocalin (Anticalin) (Pieris Proteolab AG, Freising, Germany), small modular immuno-pharmaceuticals (Trubion Pharmaceuticals Inc., Seattle, WA), maxybodies (Avidia, Inc. (Mountain View, CA)), Protein A (Affibody AG, Sweden) and 30 affilin (gamma-crystallin or ubiquitin) (Scil Proteins GmbH, Halle, Germany). (i) Adnectins - Compound Therapeutics The adnectin scaffolds are based on fibronectin type III domain (e.g., the tenth module of the fibronectin type III (10 Fn3 domain). The fibronectin type III domain has 7 or 43 WO 2007/096149 PCT/EP2007/001506 8 beta strands which are distributed between two beta sheets, which themselves pack against each other to form the core of the protein, and further containing loops (analogous to CDRs) which connect the beta strands to each other and are solvent exposed. There are at least three such loops at each edge of the beta sheet sandwich, where the edge is the boundary of the 5 protein perpendicular to the direction of the beta strands. (US 6,818,418). These fibronectin-based scaffolds are not an immunoglobulin, although the overall fold is closely related to that of the smallest functional antibody fragment, the variable region of the heavy chain, which comprises the entire antigen recognition unit in camel and llama 10 IgG. Because of this structure, the non-immunoglobulin antibody mimics antigen binding properties that are similar in nature and affinity to those of antibodies. These scaffolds can be used in a loop randomization and shuffling strategy in vitro that is similar to the process of affinity maturation of antibodies in vivo. These fibronectin-based molecules can be used as scaffolds where the loop regions of the molecule can be replaced with CDRs of the invention 15 using standard cloning techniques. (ii) Ankyrin - Molecular Partners The technology is based on using proteins with ankyrin derived repeat modules as scaffolds for bearing variable regions which can be used for binding to different targets. The 20 ankyrin repeat module is a 33 amino acid polypeptide consisting of two anti-parallel a-helices and a s-turn. Binding of the variable regions is mostly optimized by using ribosome display. (iii) Maxybodies/Avimers - Avidia Avimers are derived from natural A-domain containing protein such as LRP-1. These 25 domains are used by nature for protein-protein interactions and in human over 250 proteins are structurally based on A-domains. Avimers consist of a number of different "A-domain" monomers (2-10) linked via amino acid linkers. Avimers can be created that can bind to the target antigen using the methodology described in, for example, 20040175756; 20050053973; 20050048512; and 20060008844. 30 (vi) Protein A - Affibody Affibody@ affinity ligands are small, simple proteins composed of a three-helix bundle based on the scaffold of one of the IgG-binding domains of Protein A. Protein A is a surface protein from the bacterium Staphylococcus aureus. This scaffold domain consists of 44 WO 2007/096149 PCT/EP2007/001506 58 amino acids, 13 of which are randomized to generate Affibody@ libraries with a large number of ligand variants (See e.g., US 5,831,012). Affibody@ molecules mimic antibodies, they have a molecular weight of 6 kDa, compared to the molecular weight of antibodies, which is 150 kDa. In spite of its small size, the binding site of Affibody@ molecules is 5 similar to that of an antibody. (v) Anticalins - Pieris Anticalins@ are products developed by the company Pieris ProteoLab AG. They are derived from lipocalins, a widespread group of small and robust proteins that are usually 10 involved in the physiological transport or storage of chemically sensitive or insoluble compounds. Several natural lipocalins occur in human tissues or body liquids. The protein architecture is reminiscent of immunoglobulins, with hypervariable loops on top of a rigid framework. However, in contrast with antibodies or their recombinant 15 fragments, lipocalins are composed of a single polypeptide chain with 160 to 180 amino acid residues, being just marginally bigger than a single immunoglobulin domain. The set of four loops, which makes up the binding pocket, shows pronounced structural plasticity and tolerates a variety of side chains. The binding site can thus be 20 reshaped in a proprietary process in order to recognize prescribed target molecules of different shape with high affinity and specificity. One protein of lipocalin family, the bilin-binding protein (BBP) of Pieris Brassicae has been used to develop anticalins by mutagenizing the set of four loops. One example of a 25 patent application describing "anticalins" is PCT WO 199916873. (vi) Affilin - Scil Proteins AffilinTM molecules are small non-immunoglobulin proteins which are designed for specific affinities towards proteins and small molecules. New Affilin TM molecules can be 30 very quickly selected from two libraries, each of which is based on a different human derived scaffold protein. AffilinTM molecules do not show any structural homology to immunoglobulin proteins. Scil Proteins employs two AffilinTM scaffolds, one of which is gamma crystalline, a human structural eye lens protein and the other is "ubiquitin" superfamily proteins. Both 45 WO 2007/096149 PCT/EP2007/001506 human scaffolds are very small, show high temperature stability and are almost resistant to pH changes and denaturing agents. This high stability is mainly due to the expanded beta sheet structure of the proteins. Examples of gamma crystalline derived proteins are described in W0200104144 and examples of "ubiquitin-like" proteins are described in 5 W02004106368. Pharmaceutical compositions In another aspect, the present invention provides a composition, e.g., a pharmaceutical composition, containing one or a combination of monoclonal antibodies, or antigen-binding 10 portion(s) thereof, of the present invention, formulated together with a pharmaceutically acceptable carrier. Such compositions may include one or a combination of (e.g., two or more different) antibodies, or immunoconjugates or bispecific molecules of the invention. For example, a pharmaceutical composition of the invention can comprise a combination of antibodies (or immunoconjugates or bispecifics) that bind to different epitopes on the target 15 antigen or that have complementary activities. Pharmaceutical compositions of the invention also can be administered in combination therapy, i.e., combined with other agents. For example, the combination therapy can include an anti- hTSLP antibody of the present invention combined with at least one other anti-inflammatory agent. Examples of therapeutic agents that can be used in 20 combination therapy are described in greater detail below in the section on uses of the antibodies of the invention. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. The carrier should be 25 suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion). Depending on the route of administration, the active compound, i.e., antibody, immunoconjuage, or bispecific molecule, may be coated in a material to protect the compound from the action of acids and other natural conditions that may inactivate the compound. 30 The pharmaceutical compounds of the invention may include one or more pharmaceutically acceptable salts. A "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects (see e.g., Berge, S.M., et al., 1977 J. Pharm. Sci. 66:1-19). Examples of such salts include acid addition salts and base addition salts. Acid addition salts 46 WO 2007/096149 PCT/EP2007/001506 include those derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like, as well as from nontoxic organic acids such as aliphatic mono- and di-carboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the 5 like. Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium and the like, as well as from nontoxic organic amines, such as NN'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine and the like. A pharmaceutical composition of the invention also may include a pharmaceutically 10 acceptable anti-oxidant. Examples of pharmaceutically acceptable antioxidants include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and metal chelating agents, such as citric acid, 15 ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper 20 fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of presence of microorganisms may be 25 ensured both by sterilization procedures, supra, and by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as, 30 aluminum monostearate and gelatin. Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the 47 WO 2007/096149 PCT/EP2007/001506 active compound, use thereof in the pharmaceutical compositions of the invention is contemplated. Supplementary active compounds can also be incorporated into the compositions. Therapeutic compositions typically must be sterile and stable under the conditions of 5 manufacture and storage. The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating 10 such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, one can include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption for example, monostearate salts and gelatin. 15 Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by sterilization microfiltration. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated 20 above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation are vacuum drying and freeze-drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. The amount of active ingredient which can be combined with a carrier material to 25 produce a single dosage form will vary depending upon the subject being treated, and the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the composition which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.01 per cent to about ninety-nine percent of active ingredient, 30 from about 0.1 per cent to about 70 per cent, or from about 1 percent to about 30 percent of active ingredient in combination with a pharmaceutically acceptable carrier. Dosage regimens are adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased 48 WO 2007/096149 PCT/EP2007/001506 as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined 5 quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity 10 in individuals. For administration of the antibody, the dosage ranges from about 0.000 1 to 100 mg/kg, and more usually 0.01 to 5 mg/kg, of the host body weight. For example dosages can be 0.3 mg/kg body weight, 1 mg/kg body weight, 3 mg/kg body weight, 5 mg/kg body weight or 10 mg/kg body weight or within the range of 1-10 mg/kg. An exemplary treatment regime 15 entails administration once per week, once every two weeks, once every three weeks, once every four weeks, once a month, once every 3 months or once every three to 6 months. Dosage regimens for an anti- hTSLP antibody of the invention include 1 mg/kg body weight or 3 mg/kg body weight by intravenous administration, with the antibody being given using one of the following dosing schedules: every four weeks for six dosages, then every three 20 months; every three weeks; 3 mg/kg body weight once followed by 1 mg/kg body weight every three weeks. In some methods, two or more monoclonal antibodies with different binding specificities are administered simultaneously, in which case the dosage of each antibody administered falls within the ranges indicated. Antibody is usually administered on multiple 25 occasions. Intervals between single dosages can be, for example, weekly, monthly, every three months or yearly. Intervals can also be irregular as indicated by measuring blood levels of antibody to the target antigen in the patient. In some methods, dosage is adjusted to achieve a plasma antibody concentration of about 1-1000 pg/mi and in some methods about 25-300 pg/ml. 30 Alternatively, antibody can be administered as a sustained release formulation, in which case less frequent administration is required. Dosage and frequency vary depending on the half-life of the antibody in the patient. In general, human antibodies show the longest half-life, followed by humanized antibodies, chimeric antibodies, and nonhuman antibodies. The dosage and frequency of administration can vary depending on whether the treatment is 49 WO 2007/096149 PCT/EP2007/001506 prophylactic or therapeutic. In prophylactic applications, a relatively low dosage is administered at relatively infrequent intervals over a long period of time. Some patients continue to receive treatment for the rest of their lives. In therapeutic applications, a relatively high dosage at relatively short intervals is sometimes required until progression of the disease 5 is reduced or terminated or until the patient shows partial or complete amelioration of symptoms of disease. Thereafter, the patient can be administered a prophylactic regime. Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, 10 and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used 15 in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. A therapeuticallyy effective dosage" of an anti- hTSLP antibody of the invention can results in a decrease in severity of disease symptoms, an increase in frequency and duration 20 of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction. A composition of the present invention can be administered by one or more routes of administration using one or more of a variety of methods known in the art. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary 25 depending upon the desired results. Routes of administration for antibodies of the invention include intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal or other parenteral routes of administration, for example by injection or infusion. The phrase "parenteral administration" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, 30 intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrastemal injection and infusion. 50 WO 2007/096149 PCT/EP2007/001506 Alternatively, an antibody of the invention can be administered by a nonparenteral route, such as a topical, epidermal or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually or topically. The active compounds can be prepared with carriers that will protect the compound 5 against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are patented or generally known to those skilled in the art. See, e.g., Sustained 10 and Controlled Release Drug Delivery Systems, J.R. Robinson, ed., Marcel Dekker, Inc., New York, 1978. Therapeutic compositions can be administered with medical devices known in the art. For example, in one embodiment, a therapeutic composition of the invention can be administered with a needleless hypodermic injection device, such as the devices shown in 15 U.S. Patent Nos. 5,399,163; 5,383,851; 5,312,335; 5,064,413; 4,941,880; 4,790,824 or 4,596,556. Examples of well known implants and modules useful in the present invention include: U.S. Patent No. 4,487,603, which shows an implantable micro-infusion pump for dispensing medication at a controlled rate; U.S. Patent No. 4,486,194, which shows a therapeutic device for administering medicants through the skin; U.S. Patent No. 4,447,233, 20 which shows a medication infusion pump for delivering medication at a precise infusion rate; U.S. Patent No. 4,447,224, which shows a variable flow implantable infusion apparatus for continuous drug delivery; U.S. Patent No. 4,439,196, which shows an osmotic drug delivery system having multi-chamber compartments; and U.S. Patent No. 4,475,196, which shows an osmotic drug delivery system. These patents are incorporated herein by reference. Many 25 other such implants, delivery systems, and modules are known to those skilled in the art. In certain embodiments, the human monoclonal antibodies of the invention can be formulated to ensure proper distribution in vivo. For example, the blood-brain barrier (BBB) excludes many highly hydrophilic compounds. To ensure that the therapeutic compounds of the invention cross the BBB (if desired), they can be formulated, for example, in liposomes. 30 For methods of manufacturing liposomes, see, e.g., U.S. Patents 4,522,811; 5,374,548; and 5,399,331. The liposomes may comprise one or more moieties which are selectively transported into specific cells or organs, thus enhance targeted drug delivery (see, e.g., V.V. Ranade, 1989 J. Cline Pharmacol. 29:685). Exemplary targeting moieties include folate or biotin (see, e.g., U.S. Patent 5,416,016 to Low et al.); mannosides (Umezawa et al., 1988 51 WO 2007/096149 PCT/EP2007/001506 Biochem. Biophys. Res. Commun. 153:1038); antibodies (P.G. Bloeman et al., 1995 FEBS Lett. 357:140; M. Owais et al., 1995 Antimicrob. Agents Chernother. 39:180); surfactant protein A receptor (Briscoe et al., 1995 Am. J. Physiol.1233:134); p120 (Schreier et al., 1994 J. Biol. Chem. 269:9090); see also K. Keinanen; M.L. Laukkanen, 1994 FEBSLett. 346:123; 5 J.J. Killion; I.J. Fidler, 1994 Immunomethods 4:273. Uses and methods of the invention The antibodies (and immunoconjugates and bispecific molecules) of the present invention have in vitro and in vivo diagnostic and therapeutic utilities. For example, these 10 molecules can be administered to cells in culture, e.g. in vitro or in vivo, or in a subject, e.g., in vivo, to treat, prevent or diagnose a variety of disorders. The term "subject" as used herein in intended to include human and non-human animals. Non-human animals includes all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cats, cows, horses, chickens, amphibians, and reptiles. The methods are particularly suitable 15 for treating human patients having a disorder associated with aberrant hTSLP expression. When antibodies to hTSLP are administered together with another agent, the two can be administered in either order or simultaneously. In one embodiment, the antibodies (and immunoconjugates and bispecific molecules) of the invention can be used to detect levels of hTSLP, or levels of cells that contain hTSLP. 20 This can be achieved, for example, by contacting a sample (such as an in vitro sample) and a control sample with the anti- hTSLP antibody under conditions that allow for the formation of a complex between the antibody and hTSLP. Any complexes formed between the antibody and hTSLP are detected and compared in the sample and the control. For example, standard detection methods, well known in the art, such as ELISA and flow cytometic assays, can be 25 performed using the compositions of the invention. Accordingly, in one aspect, the invention further provides methods for detecting the presence of hTSLP (e.g., hTSLP antigen) in a sample, or measuring the amount of hTSLP, comprising contacting the sample, and a control sample, with an antibody of the invention, or an antigen binding portion thereof, which specifically binds to hTSLP, under conditions that 30 allow for formation of a complex between the antibody or portion thereof and hTSLP. The formation of a complex is then detected, wherein a difference in complex formation between the sample compared to the control sample is indicative of the presence of hTSLP in the sample. 52 WO 2007/096149 PCT/EP2007/001506 Also within the scope of the invention are kits consisting of the compositions (e.g., antibodies, human antibodies, immunoconjugates and bispecific molecules) of the invention and instructions for use. The kit can further contain a least one additional reagent, or one or more additional antibodies of the invention (e.g., an antibody having a complementary 5 activity which binds to an epitope on the target antigen distinct from the first antibody). Kits typically include a label indicating the intended use of the contents of the kit. The term label includes any writing, or recorded material supplied on or with the kit, or which otherwise accompanies the kit. The invention having been fully described, it is further illustrated by the following 10 examples and claims, which are illustrative and are not meant to be further limiting. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are within the scope of the present invention and claims. The contents of all references, including issued patents and published patent applications, cited throughout this 15 application are hereby incorporated by reference. The following examples describe monoclonal, in particular human monoclonal, anti human TSLP antibody that specifically binds to human TSLP and neutralized its biological activity in different cell based assays, including primary human cell assays. The developed 20 antibodies showed extremely high affinity in the low pM range. EXAMPLES For the generation of therapeutic antibodies against human TSLP protein, selections with the MorphoSys HuCAL GOLD* phage display library were carried out. HuCAL 25 GOLD* is a Fab library based on the HuCAL* concept6-s 9, in which all six CDRs are diversified, and which employs the CysDisplay" technology for linking Fab fragments to the phage surface'. Example 1: Generation of human TSLP-specific antibodies from the HuCAL 30 GOLD@ Library Phagemid rescue, phage amplification, and purification The HuCAL GOLD* library was amplified in 2xYT medium containing 34 pg/ml chloramphenicol and 1% glucose (2xYT-CG). After infection with VCSM 13 helper phages at 53 WO 2007/096149 PCT/EP2007/001506 an OD 600 nm of 0.5 (30 min at 37'C without shaking; 30 min at 37*C shaking at 250 rpm), cells were spun down (4120 g; 5 min; 4"C), resuspended in 2xYT/ 34 pg/ml chloramphenicol/ 50 pg/ml kanamycin/ 0.25 mM IPTG and grown overnight at 22*C. Phages were PEG-precipitated twice from the supernatant, resuspended in PBS/ 20% 5 glycerol and stored at -80*C. Phage amplification between two panning rounds was conducted as follows: mid-log phase E. coli TG1 cells were infected with eluted phages and plated onto LB-agar supplemented with 1% of glucose and 34 pg/ml of chloramphenicol (LB-CG plates). After overnight incubation at 30*C, the TG1 colonies were scraped off the agar plates and used to 10 inoculate 2xYT-CG until an 0D 600 nm of 0.5 was reached and VCSM13 helper phages added for infection as described above. Pannings with HuCAL GOLD* For the selection of antibodies recognizing human TSLP two different panning 15 strategies were applied. In summary, HuCAL GOLD* phage-antibodies were divided into four pools comprising different combinations of VH master genes (pool 1: VH1/5 X,, pool 2: VH3 ,Kc, pool 3: VH2/4/6 XK, pool 4: VH1-6 XK). These pools were individually subjected to three rounds of solid phase panning on human TSLP directly coated to Maxisorp plates and in addition three of solution pannings on biotinylated TSLP. 20 The first panning variant was solid phase panning against human TSLP: 2 wells on a Maxisorp plate (F96 Nunc-Immunoplate) were coated with 300 p1 of 5pg/ml TSLP- each o/n at 4*C. The coated wells were washed 2x with 350pl PBS and blocked with 350pl 5% MPBS for 2h at RT on a microtiter plate shaker. For each panning about 10"3 HuCAL GOLD* phage-antibodies were blocked with equal volume of PBST/5% 25 MP for 2h at room temperature. The coated wells were washed 2x with 350lp PBS after the blocking. 300pi of pre-blocked HuCAL GOLD* phage-antibodies were added to each coated well and incubated for 2h at RT on a shaker. Washing was performed by adding five times 350pi PBS/0.05% Tween, followed by washing another four times with PBS. Elution of phage from the plate was performed with 300 pl 20mM DTT in 10mM Tris/HCI pH8 per 30 well for 10 min. The DTT phage eluate was added to 14 ml of Ecoli TG1, which were grown to an OD 6 00 of 0.6-0.8 at 37*C in 2YT medium and incubated in 50ml plastic tubes for 45min at 37 0 C without shaking for phage infection. After centrifugation for 10 min at 5000rpm, the bacterial pellets were each resuspended in 500p 2xYT medium, plated on 2xYT-CG agar plates and incubated overnight at 30 0 C. Colonies were then scraped from the plates and 54 WO 2007/096149 PCT/EP2007/001506 phages were rescued and amplified as described above. The second and third rounds of the solid phase panning on directly coated TSLP was performed according to the protocol of the first round except for increasing the stringency of the washing procedure. The second panning variant was solution panning against biotinylated human TSLP: 5 For the solution panning, using biotinylated TSLP coupled to Dynabeads M-280 (Dynal), the following protocol was applied: 1.5 ml Eppendorf tubes were blocked with 1.5 ml 2xChemiblocker diluted 1:1 with PBS over night at 4*C. 2 00pi streptavidin coated magnetic Dynabeads M-280 (Dynal) were washed lx with 200 jl PBS and resuspended in 200 il lxChemiblocker (diluted in lx PBS). Blocking of beads was performed in pre-blocked 10 tubes over night at 4*C. Phages diluted in 500p1l PBS for each panning condition were mixed with 500pl 2xChemiblocker / 0.1% Tween 1 h at RT (rotator). Pre-adsorption of phages was performed twice: 50 pl of blocked Streptavidin magnetic beads were added to the blocked phages and incubated for 30 min at RT on a rotator. After separation of beads via a magnetic device (Dynal MPC-E) the phage supernatant (-iml) was transferred to a new blocked tube 15 and pre-adsorption was repeated on 50 pl blocked beads for 30 min. Then, 200 nM biotinylated hTSLP was added to blocked phages in a new blocked 1.5 ml tube and incubated for 1 h at RT on a rotator. 100 pl of blocked streptavidin magnetic beads were added to each panning phage pool and incubated 10 min at RT on a rotator. Phages bound to biotinylated TSLP were immobilized to the magnetic beads and collected with a magnetic particle 20 separator (Dynal MPC-E). Beads were then washed 7x in PBS/0.05% Tween using a rotator, followed by washing another three times with PBS. Elution of phage from the Dynabeads was performed adding 300 pl 20 mM DTT in 10 mM Tris/HCI pH 8 to each tube for 10 min. Dynabeads were removed by the magnetic particle separator and the supernatant was added to 14ml of an E.coli TG-1 culture grown to OD 600 n of 0.6-0.8. Beads were then washed once 25 with 200pl PBS and together with additionally removed phages the PBS was added to the 14 ml E.coli TG-I culture. For phage infection, the culture was incubated in 50 ml plastic tubes for 45 min at 37*C without shaking. After centrifugation for 10 min at 5000 rpm, the bacterial pellets were each resuspended in 500 pl 2xYT medium, plated on 2xYT-CG agar plates and incubated overnight at 30 *C. Colonies were then scraped from the plates and 30 phages were rescued and amplified as described above. The second and third rounds of the solution panning on biotinylated TSLP was performed according to the protocol of the first round except for increasing the stringency of the washing procedure. 55 WO 2007/096149 PCT/EP2007/001506 Subeloning and expression of soluble Fab fragments The Fab-encoding inserts of the selected HuCAL GOLD* phagemids were sub-cloned into the expression vector pMORPH*X9_FabFH (Fig 1) in order to facilitate rapid and 5 efficient expression of soluble Fabs. For this purpose, the plasmid DNA of the selected clones was digested with Xbal and EcoRI, thereby excising the Fab-encoding insert (ompA-VLCL and phoA-Fd), and cloned into the Xbal/EcoRI-digested expression vector pMORPH*X9_FabFH. Fabs expressed from this vector carry two C-terminal tags (FLAG TM and 6xHis, respectively) for both, detection and purification. 10 Microexpression of HuCAL GOLD* Fab antibodies in E. coli Chloramphenicol-resistant single colonies obtained after subcloning of the selected Fabs into the pMORPH*X9_FabFH expression vector were used to inoculate the wells of a sterile 96-well microtiter plate containing 100 pd 2xYT-CG medium per well and grown 15 overnight at 37 0 C. 5 pl of each E. coli TG-1 culture was transferred to a fresh, sterile 96-well microtiter plate pre-filled with 100 pl 2xYT medium supplemented with 34 pg/ml chloramphenicol and 0.1% glucose per well. The microtiter plates were incubated at 30"C shaking at 400 rpm on a microplate shaker until the cultures were slightly turbid (-2-4 hrs) with an 0D 6 00 nm of -0.5. 20 To these expression plates, 20 pl 2xYT medium supplemented with 34 pg/ml chloramphenicol and 3 mM IPTG (isopropyl-B-D-thiogalactopyranoside) was added per well (end concentration 0.5 mM IPTG), the microtiter plates sealed with a gas-permeable tape, and incubated overnight at 30*C shaking at 400 rpm. Generation of whole cell lysates (BEL extracts): To each well of the expression 25 plates, 40 pl BEL buffer (2xBBS/ EDTA: 24.7 g/l boric acid, 18.7 g NaCl, 1.49 g EDTA/1, pH 8.0) was added containing 2.5 mg/ml lysozyme and incubated for I h at 22*C on a microtiter plate shaker (400 rpm). The BEL extracts were used for binding analysis by ELISA or a BioVeris M-series* 384 analyzer (see Example 2). 30 Enzyme Linked Immunosorbent Assay (ELISA) Techniques 5 pg/ml of human recombinant TSLP (R&D Systems) in PBS was coated onto 384 well Maxisorp plates (Nunc-Immunoplate) o/n at 4*C. After coating the wells were washed once with PBS / 0.05 % Tween (PBS-T) and 2x with PBS. Then the wells were blocked with 56 WO 2007/096149 PCT/EP2007/001506 PBS-T with 2% BSA for 2 h at RT. In parallel 15 pl BEL extract and 15 pl PBS-T with 2% BSA were incubated for 2 h at RT. The blocked Maxisorp plated were washed 3x with PBS T before 10 pl of the blocked BEL extracts were added to the wells and incubated for I h at RT. For detection of the primary Fab antibodies, the following secondary antibodies were 5 applied: alkaline phospatase (AP)-conjugated AffiniPure F(ab') 2 fragment, goat anti-human, anti-mouse or -anti-sheep IgG (Jackson Immuno Research). For the detection of AP conjugates fluorogenic substrates like AttoPhos (Roche) were used according to the instructions by the manufacturer. Between all incubation steps, the wells of the microtiter plate were washed with PBS-T three times and three times after the final incubation with 10 secondary antibody. Fluorescence was measured in a TECAN Spectrafluor plate reader. Expression of HuCAL GOLD* Fab antibodies in E. coli and purification Expression of Fab fragments encoded by pMORPH*X9_FabFH in TG- 1 cells was carried out in shaker flask cultures using 750 ml of 2xYT medium supplemented with 15 34 pg/ml chloramphenicol. Cultures were shaken at 30*C until the OD 60 0 nm reached 0.5. Expression was induced by addition of 0.75 mM IPTG for 20 h at 30*C. Cells were disrupted using lysozyme and Fab fragments isolated by Ni-NTA chromatography (Qiagen, Hilden, Germany). Protein concentrations were determined by UV-spectrophotometry ". 20 Example 2: Identification of neutralizing anti-human TSLP Fab candidates that inhibit TSLP induced signaling of the TSLP receptor 22 different human TSLP specific antibodies, which were selected from the HuCAL GOLD* library, were tested for the potency to neutralize human TSLP. 25 A. Blocking of TSLP binding to the TSLP receptor by anti-human TSLP Fabs in FACS assay Binding inhibition of biotinylated TSLP to Ba/F3 cells, expressing hTSLPR, hIL7Ra was analyzed by FACS. The Fab antibodies were diluted in FACS buffer (cellwash (B&D) / 3%FCS). 50 pl biotinylated TSLP at 100 ng/ml was incubated with 50 pl of 100 pg/ml Fab 30 for I h at RT. To avoid internalization of the TSLP receptor all further steps with cells were carried out at 4 *C or on ice. 100 pl Ba/F3 cells at 2x 106 cells/ml were transferred to each well of a 96 well plate (NUNC) and centrifuged at 2000 rpm; 4 *C. Cells were washed 2x with 150 pl cold FACS buffer, resuspended with the Fab / biotinylated TSLP mix and 57 WO 2007/096149 PCT/EP2007/001506 incubated for 1 h at 4*C on a shaker. Streptavidin PE 1:400 in FACS-buffer was added for detection. After 30 min incubation, cells were centrifuged as mentioned above and washed 2x with 150pI cold FACS buffer. 5000 cells were analyzed in FACS. MOR04494, MOR04496, MOR04497 and MOR04609 showed inhibition of cell binding. 5 Inhibition of TSLP dependent STAT5 activation Ba/F3 cells, expressing hTSLPR, hIL7Ra and a Stat5-Luc reporter gene, were grown in the presence of 5 ng/ml TSLP. 10 Pl of 1x10 6 cells/ml in assay buffer (RPMI-1640 w/o phenol red, 10 % FCS, penicillin 10 Uml'/streptomycin 10 pgmi-', 1 % puromycin) were 10 added to Costar 96-well white plate (Coming). 70 p1 of assay buffer and 10 pl of anti-TSLP antibody (10x) in assay buffer was added and incubated for 20 min at 37 *C. 10 pl of 5 ng/ml TSLP (R&D Systems; 0.5 ng/ml final concentration) in assay buffer was added to give a final assay volume of 100 pl. The plate was covered and left for 5-6 h at 37 "C in a humidified incubator. To the wells 100 pd (1:1 with assay volume) of Bright-GloTM luciferase (Promega) 15 were added and incubated for 5 min at RT. The plate was sealed with TopSealTM before recording luminescence. MOR04493, MOR04494, MOR04496, MOR04497 and MOR04609 neutralized TSLP in this assay. Determination of Neutralizing Activity in Primary Monocyte Isolation of human blood moncytes - 150 mL of blood was collected from healthy 20 adult volunteers on the NHRC donor panel. Blood was collected with tubes containing ImL of anti-coagulant (20 mg/mL EDTA in PBS) per 10 mL blood and then diluted with 12.5 mL PBS per 20 mL blood. Red blood cells were then sedimented by mixing the diluted blood with 12.5 mL 4 % Dextran (in PBS) per tube and incubating for 40 minutes on ice. PBMCs were isolated by density centrifugation using Ficoll and the 'buffy coat' containing PBMCs 25 was recovered using a plastic pastete. The cells were washed once (300xg for 7 minutes) in PBS and counted. MACS isolation of cells was carried out according to the manufacturers instructions using the Monocyte Isolation kit II (Miltenyi Biotec). All buffer additions and washes were with MACS buffer at 4*C (PBS, 0.5 % BSA, 2mM EDTA, pH 7.2) unless otherwise stated. Briefly, to 107 cells, 30 pL of buffer and 10 pL each of FcR Blocking 30 Reagent and Biotin-Antibody Cocktail were added, mixed well and incubated for 10 minutes. A further 30 ttL of buffer and 20 pL of Anti-Biotin Microbeads were then added to the cells and incubated for 15 minutes. Cells were washed (300xg for 10 minutes), resuspended at 108 cells per 500 pL buffer and applied to the 'primed' LS column. The 'untouched' monocyte 58 WO 2007/096149 PCT/EP2007/001506 fraction was collected by retaining all other cell types on the column. During the isolation procedure samples were collected for later analysis by flow cytometry. TARC production by monocytes treated with TSLP and blocking the response with anti TSLP antibodies - Freshly isolated monocytes were resuspended at I x 106 cells per mL of 5 assay buffer (RPMI 1640, 10 % FCS, penicillin 10 U/nL / streptomycin 10 ptg/mL). 100 pL of cells were added to each well of a 96-well flat-bottomed plate to give a concentration of 100,000 cells per well. 80 pL of assay buffer was added to wells that were used for the TSLP dose response curve and 60 iL was added to wells in which anti-TSLP antibodies were to be tested. For the anti-TSLP antibody testing, 20 iL of a 1Ox stock solution of each anti-TSLP 10 antibody was added to the cells and incubated at 37*C, 5 % CO 2 for 20 minutes. rhTSLP was then added at 0.5 ng/mL to each well (20 pL of lOx stock solution per well) containing anti TSLP antibody. A TSLP dose response curve was included on each plate. Plates were incubated for 24 hours at 37*C, 5 % CO 2 after which supernatants were harvested and stored at -20"C for future analysis. 15 ELISA of monocyte supernatants to measure TARC - Measurements of TARC production in culture supernatants was carried out using a human TARC duoset ELISA kit (R+D Systems) according to manufacturer's instructions. Briefly monocyte supernatants were diluted 1:2 in assay buffer (RPMI 1640, 10 % FCS, penicillin 10 U/mL / streptomycin 10 pg/mL) and added in triplicate to 96-well half-area plates previously coated with TARC 20 capture antibody. Plates were incubated for 2 hours at RT then washed again. 50 pL of biotinylated detection mAb was then added to each well and incubated for a further 2 hours at RT. Plates were washed and horseradish peroxidase was added at 50 pL per well and incubated for 20 minutes at RT in the dark. A final wash was carried out and 100 pL of TMB substrate was added per well and plates were incubated at RT in the dark. Colour 25 development was stopped after 20 minutes incubation by addition of 50 piL 1 M sodium hydroxide. Plates were read immediately on a Spectramax microplate reader set at 450nm (Molecular Devices). Data was analysed using SoftmaxPro software and percentage inhibition of maximal absorbance response by anti-TSLP antibodies was calculated using an Excel spreadsheet. 30 Neutralization of Natural Human TSLP in Receptor Gene Assay Human natural TSLP was generated by treating primary human fibroblast cells (Clonetics), with a cytokine cocktail containing IL-1P (I ng/ml), TNF-a (1 ng/ml) and IL-13 (10 ng/ml) 59 WO 2007/096149 PCT/EP2007/001506 for 24 hours at 37*C in phenol-red free RPMI containing 10% FBS. The cell culture supernatant containing induced natural TSLP was shown to be active in the RGA described above. A I in 10 dilution of the natural TSLP containing TSLP corresponded to 5 approximately the same level of activity in the RGA as 0.5 ng/ml of rhTSLP and hence was used as the final dilution when testing the activity of candidate antibodies. TSLP / TSLP receptor binding inhibition BioVeris assay For the TSLP binding inhibition assay, recombinant human TSLP (R&D Systems) 10 was directly coupled (NHS/EDC coupling) to carboxylic acid M-270 Dynal magnetic beads. 50 pl Fab antibodies per well (10 pM stock, 1:5 dilution steps) were incubated for 2 h with 25 pl TSLP coated beads in 96 well plates (Nunc). 50 p1 of 100 pM TSLP-receptor/Fc fusion and 1:1000 diluted anti-human Fc detection antibody labeled with BV-tag m according to instructions of supplier (BioVeris, Europe, Witney, Oxforfshire, UK) were added to each well 15 and incubated for I h. (Final Fab concentration: 32 nM - 4 pM, final TSLP conc: 40 pM). Detection was performed by BioVeris M-384 SERIES@ Workstation (BioVeris Europe, Witney, Oxforfshire, UK). MOR04493, MOR04494, MOR04496, MOR04497, MOR04609, and MOR04832 showed inhibition of TSLP receptor binding in this assay. 20 Determination of nanomolar affinities using surface plasmon resonance (Biacore) Kinetic SPR analysis was performed on a SA-chip (Biacore, Sweden) which had been coated with a density of -400 RU biotinylated recombinant human TSLP i. A respective amount of biotinylated human serum albumin (HSA) was immobilized on the reference flow 25 cell. PBS (136 mM NaCl, 2.7 mM KCI, 10 mM Na2HPO4, 1.76 mM KH2PO4 pH 7.4) was used as the running buffer. The Fabs were applied in concentration series of 16 - 500 nM at a flow rate of 20 pl/min. Association phase was set to 60 s and dissociation phase to 120 s. The summarized affinities of the parental Fab antibodies 4493, 4494, 4496, 4497, 4832 and 4609 to human TSLP determined by that method are in the range of 8 - 1400 nM. 60 WO 2007/096149 PCT/EP2007/001506 Example 3: Affinity maturation of selected anti-TSLP Fabs by parallel exchange of LCDR3 and HCDR2 cassettes B. Generation of Fab libraries for affinity maturation 5 In order to increase the affinity and inhibitory activity of the identified anti-TSLP antibodies, 6 Fab clones MOR04493, MOR04494, MOR04496, MOR04497, MOR04609, and MOR04832 were subjected to affinity maturation. For this purpose, CDR regions were optimized by cassette mutagenesis using trinucleotide directed mutagenesis 2
"
3 . The following paragraph briefly describes the protocol used for cloning of the 10 maturation libraries and Fab optimization. Fab fragments from expression vector pMORPH*X9_FabFH were cloned into the phagemid vector pMORPH*25 (US 6,753,136). Two different strategies were applied in parallel to optimize both, the affinity and the efficacy of the parental Fabs. Six phage antibody Fab libraries were generated where the LCDR3 of six parental 15 clones was replaced by a repertoire of individual light chain CDR3 sequences. In parallel, the HCDR2 region of each parental clone was replaced by a repertoire of individual heavy chain CDR2 sequences. Affinity maturation libraries were generated by standard cloning procedures and transformation of the diversified clones into electro-competent E. coli TOP OF' cells (Invitrogen). Fab-presenting phages were prepared as described in Example 20 1A. Four maturation pools were built and kept separate during the subsequent selection process: e pool 1: LCDR3 libraries of MOR04493 and MOR04832 * pool 2: HCDR2 libraries of MOR04493 and MOR04832 e pool 3: LCDR3 libraries of MOR04494; MOR04496; MOR04497; 25 MOR04609 * pool 4: HCDR2 libraries of MOR04494; MOR04496; MOR04497; MOR04609 Maturation panning strategies 30 Pannings using the four antibody pools were performed on biotinylated recombinant human TSLP (R&D Systems) in solution for three rounds, respectively as described in Example 1 B, solution panning against biotinylated human TSLP. The selection stringency 61 WO 2007/096149 PCT/EP2007/001506 was increased by reduction of biotinylated antigen from panning round to panning round, by prolonged washing steps and by addition of non-biotinylated antigen for off-rate selection. Electrochemiluminescene (BioVeris) based binding analysis for detection of 5 TSLP binding Fab in bacterial lysates Binding of optimized Fab antibodies in E. coli lysates (BEL extracts) to TSLP was analyzed in BioVeris M-SERIES* 384 AnalyzerBioVeris, Europe, Witney, Oxforfshire, UK). BEL extracts were diluted in assay buffer (PBS/0,05%Tween20/0.5%BSA) for use in BioVeris screening. Biotinylated TSLP (R&D Systems) was coupled to streptavidin coated 10 paramagnetic beads, Anti-human (Fab)' 2 (Dianova) was ruthenium labeled using the BV tag*m (BioVeris Europe, Witney, Oxfordshire, UK). This secondary antibody was added to the TSLP coupled beads before measuring in the BioVeris M-SERIES* 384 Analyzer. After sequence analysis of hits from the BioVeris screening, 20 unique Fab clones were identified: MOR05008; MOR05009; MOR05010; MOR0501 1; MOR05012; MOR05013; MOR05014; 15 MOR05015; MOR05016; MOR05017; MOR05018; MOR05019; MOR05020; MOR05021; MOR05022; MOR05023; MOR05024; MOR05025; MOR05026; MOR05027. IgG conversion and cross-transfection of two independently optimized variable chains in order to further improve the affinities of the antibodies All 20 optimized Fab antibodies were sub-cloned into IgGI format. Affinity of all 20 20 IgGI of MOR05008; MOR05009; MOR05010; MOR05011; MOR05012; MOR05013; MOR05014; MOR05015; MOR05016; MOR05017; MOR05018; MOR05019; MOR05020; MOR0502 1; MOR05022; MOR05023; MOR05024; MOR05025; MOR05026; MOR05027 was measured in solution equilibrium titration from tissue culture supernatant. For a further improvement of affinity the independently optimized H-CDR2 and L 25 CDR3 from matured IgGIs, which were derived from the same parental clone, were combined, because there was a high probability that this combination would lead to a further gain of affinity 1416. The heavy and the light chain of the IgGI were on separate vectors and therefore by cross-transfection it was possible to combine the two different optimized chains which were then co-expressed in one cell and assemble to IgG antibodies. This method was 30 applied for binders that were derived from the parental clone MOR04494 and MOR04497, where from both the H-CDR2 and the L-CDR3 library optimized chains were identified in parallel. For MOR04494 all six optimized heavy chains from MOR05010 - MOR05015 were combined one by one with the three optimized light chains of MOR05016 - MOR05018 resulting in 18 new antibodies. For MOR04497 the one optimized H-CDR2 of MOR5019 62 WO 2007/096149 PCT/EP2007/001506 was combined with the three optimized light chains of MOR05020 - MOR05022 resulting in 3 new antibodies. Determination of picomolar affinities using Solution Equilibrium Titration (SET) 5 For KD determination, monomer fractions (at least 90% monomer content, analyzed by analytical SEC; Superdex75, Amersham Pharmacia) of Fab were used. In addition it was possible to determine the affinities of IgG 1, as the antigen TSLP is supposed to be a monomer in solution. Electrochemiluminescence (ECL) based affinity determination in solution and data evaluation were basically performed as described by Haenel et al., 2005. A 10 constant amount of Fab or IgGI was equilibrated with different concentrations (serial 3" dilutions) of recombinant human TSLP (R&D Systems) in solution. Biotinylated human TSLP coupled to paramagnetic beads (M-280 Streptavidin, Dynal), and BV-tagm (BioVeris Europe, Witney, Oxfordshire, UK) labeled anti-human (Fab)' 2 (Dianova) was added and the mixture incubated for 30 min. Subsequently, the concentration of unbound Fab was 15 quantified via ECL detection using the M-SERIES* 384 analyzer (BioVeris Europe). Affinity determination to cynomolgus TSLP (mammalian expression and purification at NVS) in solution was done essentially as described above replacing the human TSLP by the cynomolgus TSLP. For detection of free Fab, biotinylated human TSLP coupled to paramagnetic beads was used. Affinities were calculated according to Haenel et al. (2005)"7. 20 Using the assay conditions described above (monomeric) affinities for the affinity-optimized anti-TSLP IgGs were determined in solution. The affinities to human and cynomolgus TSLP are summarized in Table 5. Table 5: Affinities of optimized IgGI. 63 WO 2007/096149 PCT/EP2007/001506 VH- /VL pairs for lgG rh TSLP cyno TSLP- Parental IgG APP binder VH VL MORO# KD [M] KD [M] 1 5008 10 1438 MOR04493 2 5009 5 10861 3 4494 .>200 20857 4 5010 2 1099 5 5011 31 4951 6 5012 25 1535 7 5013 34 1367 8 5014 8 3711 9 5015 26 2959 10 5016 7 98 11 5017 4 111 12 5018 14 358 13 5010 5016 5154 13 18 14 5010 5017 5155 1 9 15 5010 5018 5156 16 58 16 5011 5016 5157 1 34MR04494 17 5011 5017 5158 9 21 18 5011 5018 5159 12 87 19 5012 5016 5160 27 28 20 5012 5017 5161 11 11 21 5012 5018 $162 21 81 22 5013 5016 5163 22 17 23 5013 5017 5164 14 8 24 5013 5018 5165 19 45 25 5014 5016 5166 22 27 26 5014 5017 5167 14 16 27 5014 5018 5168 <1 108 28 5015 5016 5169 1 53 29' 5015 5017 5170 11 25 30' 5015 5018 5171 29 71 31 4497 >200 >20nM 32 5019 36 3825 33 5020 13 103 34 5021 14 79 MOR04497 35 1 5022 7 79 36 5019 5020 5172 122 7540 37 5019 5021 5173 39 3377 38 5019 5022 5174 117 4763 39 5023 5 > 20 nM 40 5024 4 > 20 nM 41 5025 7 > 20 nM MOR04832 42 5026 12 >20nM 43 5027 7 > 20 nM parental W-clnes 64 WO 2007/096149 PCT/EP2007/001506 Thus, as a further aspect of the present invention, there is presented the use of an isolated hTSLP-binding region of an antibody or functional fragment thereof having an KD of less than 100 pM, suitably less than 50pM, preferably less than 30pM, in the treatment of a disease associated with the presence of cell receptor target hTSLP, such as asthma or atopic 5 dermatitis. Reference List 1. Reche,P.A. et al. Human thymic stromal lymphopoietin preferentially stimulates myeloid cells. JImmunol 167, 336-343 (200 1). 10 2. Soumelis,V. et aL. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol 3, 673-680 (2002). 3. Levin,S.D. et al. Thymic stromal lymphopoietin: a cytokine that promotes the development of IgM+ B cells in vitro and signals via a novel mechanism. JImmunol 162, 677-683 (1999). 15 4. Novak,N. & Bieber,T. The role of dendritic cell subtypes in the pathophysiology of atopic dermatitis. JAm Acad. Dermatol. 53, S171-S 176 (2005). 5. Quentmeier,H. et aL. Cloning of human thymic stromal lymphopoietin (TSLP) and signaling mechanisms leading to proliferation. Leukemia 15, 1286-1292 (2001). 20 6. Knappik,A. et aL Fully synthetic human combinatorial antibody libraries (HuCAL) based on modular consensus frameworks and CDRs randomized with trinucleotides. JMol Biol 296, 57-86 (2000). 7. Krebs,B. et aL. High-throughput generation and engineering of recombinant human antibodies. J Immunol Methods 254, 67-84 (200 1). 25 8. Rauchenberger,R. et al. Human combinatorial Fab library yielding specific and functional antibodies against the human fibroblast growth factor receptor 3. JBiol Chem 278, 38194-38205 (2003). 65 WO 2007/096149 PCT/EP2007/001506 9. Knappik,A. et al. Fully synthetic human combinatorial antibody libraries (HuCAL) based on modular consensus frameworks and CDRs randomized with trinucleotides. JMol Biol 296, 57-86 (2000). 10. L6hning,C. Novel methods for displaying (poly)peptides/proteins on 5 bacteriophage particles via disulfide bonds. (WO 01/05950). 2001. Ref Type: Patent 11. Krebs,B. et al. High-throughput generation and engineering of recombinant human antibodies. J Immunol Methods 254, 67-84 (2001). 12. Nagy,Z.A. et al. Fully human, HLA-DR-specific monoclonal 10 antibodies efficiently induce programmed death of malignant lymphoid cells. Nat Med 8, 801-807 (2002). 13. Virnekas,B. et al. Trinucleotide phosphoramidites: ideal reagents for the synthesis of mixed oligonucleotides for random mutagenesis. Nucleic Acids Res 22, 5600-5607 (1994). 15 14. Chen,Y. et al. Selection and analysis of an optimized anti-VEGF antibody: crystal structure of an affinity-matured Fab in complex with antigen. JMol Biol 293, 865-881 (1999). 15. Schier,R. et al. Isolation of picomolar affinity anti-c-erbB-2 single chain Fv by molecular evolution of the complementarity determining regions in the 20 center of the antibody binding site. JMol Biol 263, 551-567 (1996). 16. Yang,W.P. et al. CDR walking mutagenesis for the affinity maturation of a potent human anti-HIV- 1 antibody into the picomolar range. J Mol Biol 254, 392 403 (1995). 17. Haenel,C., Satzger,M., Ducata,D.D., Ostendorp,R. & Brocks,B. 25 Characterization of high-affinity antibodies by electrochemiluminescence-based equilibrium titration. Anal Biochem 339, 182-184 (2005). 66 WO 2007/096149 PCT/EP2007/001506 * . 0 0 0 0 0 0 LL- t t LLI U- U- 0 0 0 0 0 L - L U 000 000000 00000i00~004a Cl) U) Cl) >-- >- >- - a__ OO a0,0 a olo 10 0.4 Wq wl 14 fl .4 N 0 000 000U00 0 00D00 00 LU L- L ILLU ILLLL LLL.-U-U > > >> >> > >>> > v ev . 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L I I- F- F- I -- L I L F- I- F- U - 0' I-- 0 - I I--) - U) U) (D 00 0(D (99(9-000000(!)(9 (D~~j C (9> 9((9 > (D0000 9 0 COC COC COCCto 1- 0 0) 0 - 04 qlCt CO -0 C)C t M C CCO C C4 CclC 0 (9 -)t )V )L ot o w w w w w w r - o - i- r C C5 0 Cl0 ) C C C, , 5,C 40 C.. . . . . . . C C C .. . . .C0 CD w~~~~~~~~ ~ ~ ~ ~ wZ ww i Y I 0 0 0 0 0 0C0 0 0 0 0 0 0 0 00 0 0 0 0 0C 0 0Z0Z0Z0Z0CO C COC CO OC COC CO OC COC CO OC)CO OC C CO OC CO OCO OC C6C WO 2007/096149 PCT/EP2007/001506 m0 ~4It nD N -JJ < o> > >> -J >- >- mIw mw w 00C30 U-LLL LL~f z zz 3: 0; aa a~ a co U) c)o co w D C wo wwwwZ co coC O co U-LL LLwLL U- co Z < (D~ 000(DOC 0 0 co >--> z z - - - - c- - -co Co ) oU co Zo Z----------------o co m V. . .w co o Co C--> C CC0 C>CoCo C 14 ) w w- t 0 00 40 00 00 Ci) C CoC Co 1 0 000 000000 0i 0 Co4 U)o~ Coooz~ Co m ~<<~<< < . 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(D101o(D0o0 00 Ulu)U010 Ulu 0 0 0 0 o (D (9 0 0Q 0 0 0 o 0 0 0 0 0 -: 01F1 , F F F Fl FQ!F F 04 C0 WO 2007/096149 PCT/EP2007/001506 '10 O o %o o %D ID D 0 % % 7Ii > - i .r. . 0000 000z0 0 coM U) ) Q 0 w w c oc a a , o.n lwwa Lflcn~ zzzzzmzlzi in j 0n L0 fn M M aZ M Z ~I mYN m'mC IM 0 0000 0 000000 0000 000000000> > - I - > >- >- > >- - > >- - >->71 WO 2007/096149 PCT/EP2007/001506 Annex 2 HuCAL GOLD® anti-TSLP antibody amino acid sequences MOR04493 VH, SEQ ID NO: 67: QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGII 5 PDFGWANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARSGMFYSILFDY WGQGTLVTVSS MOR04493 VL, SEQ ID NO: 68: DIQMTQSPSSLSASVGDRVTITCRASQDIYNYLNWYQQKPGKAPKLLIYGASS LQSGVPSRFSGSGSGTDFTLTISSLQPEDFAVYYCQQQNDYPLTFGQGTKVEIKRT 10 MOR04494 VH, SEQ ID NO: 69: QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSNIS YDSSDTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQQYFDHIDIW GQGTLVTVSS 15 MOR04494 VL, SEQ ID NO: 70: DIELTQPPSVSVAPGQTARISCGGDSLGGKYVYWYQQKPGQAPVLVIYGDSK RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYTNALSTVFGGGTKLTVLGQ MOR04496 VH, SEQ ID NO: 71: 20 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAISWVRQAPGKGLEWVSSISY SGSSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARMEYWYHLLYM DYWGQGTLVTVSS MOR04496 VL, SEQ ID NO: 72: DIVLTQSPATLSLSPGERATLSCRASQSIGDNYLAWYQQKPGQAPRLLIYDAN 25 NRATGVPARFSGSGSGTDFTLTISSLEPEDFATYYCQQYDDHPLTFGQGTKVEIKRT MOR04497 VH, SEQ ID NO: 73: QVQLVESGGGLVQPGGSLRLSCAASGFTFSNHALSWVRQAPGKGLEWVSGI QYDGSNTGYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARYYGYSYMD 30 YWGQGTLVTVSS MOR04497 VL, SEQ ID NO: 74: DIELTQPPSVSVAPGQTARISCSGDNLGSKYVHWYQQKPGQAPVLVIYADNN RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYDHMLQVFGGGTKLTVLGQ 72 WO 2007/096149 PCT/EP2007/001506 MOR04609 VH, SEQ ID NO: 75: QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWGWIRQSPGRGLEWLGRI YYRSKWLNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCARDGGWYIDV WGQGTLVTVSS 5 MOR04609 VL, SEQ ID NO: 76: DIELTQPPSVSVAPGQTARISCSGDNLGSYYANWYQQKPGQAPVLVIYEDKRP SGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSFDSYHSDYVFGGGTKLTVLGQ MOR04832 VH, SEQ ID NO: 77: 10 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGNI YPIFGYANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARYGQYGQHFSH GGMDVWGQGTLVTVSS MOR04832 VL, SEQ ID NO: 78: DIQMTQSPSSLSASVGDRVTITCRASQDISISLTWYQQKPGKAPKLLIYGAFSL 15 QSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYGTSATFGQGTKVEIKRT MOR05008 VH, SEQ ID NO: 79: QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGII PEFGFTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARSGMFYSILFDY 20 WGQGTLVTVSS MOR05008 VL, SEQ ID NO: 68: DIQMTQSPSSLSASVGDRVTITCRASQDIYNYLNWYQQKPGKAPKLLIYGASS LQSGVPSRFSGSGSGTDFTLTISSLQPEDFAVYYCQQQNDYPLTFGQGTKVEIKRT 25 MOR05009 VH, SEQ ID NO: 80: QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGHI SPEFGFTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARSGMFYSILFDY WGQGTLVTVSS MOR05009 VL, SEQ ID NO: 68: 30 DIQMTQSPSSLSASVGDRVTITCRASQDIYNYLNWYQQKPGKAPKLLIYGASS LQSGVPSRFSGSGSGTDFTLTISSLQPEDFAVYYCQQQNDYPLTFGQGTKVEIKRT MOR05010 VH, SEQ ID NO: 81: 73 WO 2007/096149 PCT/EP2007/001506 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSGIF FDGETYYAGSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQQYFDHIDIWG QGTLVTVSS MOR05010 VL, SEQ ID NO: 70: 5 DIELTQPPSVSVAPGQTARISCGGDSLGGKYVYWYQQKPGQAPVLVIYGDSK RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYTNALSTVFGGGTKLTVLGQ MOR05011 VH, SEQ ID NO: 82: QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSGIF 10 YDGSTYYPDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQQYFDHIDIWG QGTLVTVSS MOR05011 VL, SEQ ID NO: 70: DIELTQPPSVSVAPGQTARISCGGDSLGGKYVYWYQQKPGQAPVLVIYGDSK RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYTNALSTVFGGGTKLTVLGQ 15 MOR05012 VH, SEQ ID NO: 83: QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSGIF FTGETYYPDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQQYFDHIDIWG QGTLVTVSS 20 MOR05012 VL, SEQ ID NO: 70: DIELTQPPSVSVAPGQTARISCGGDSLGGKYVYWYQQKPGQAPVLVIYGDSK RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYTNALSTVFGGGTKLTVLGQ MOR05013 VH, SEQ ID NO: 84: 25 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSGIF FDGETYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQQYFDHIDIWG QGTLVTVSS MOR05013 VL, SEQ ID NO: 70: DIELTQPPSVSVAPGQTARISCGGDSLGGKYVYWYQQKPGQAPVLVIYGDSK 30 RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYTNALSTVFGGGTKLTVLGQ MOR05014 VH, SEQ ID NO: 85: 74 WO 2007/096149 PCT/EP2007/001506 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSGIF FDGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQQYFDHIDIWG QGTLVTVSS MOR05014 VL, SEQ ID NO: 70: 5 DIELTQPPSVSVAPGQTARISCGGDSLGGKYVYWYQQKPGQAPVLVIYGDSK RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYTNALSTVFGGGTKLTVLGQ MOR05015 VH, SEQ ID NO: 86: QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSGT 10 FFDGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQQYFDHIDIW GQGTLVTVSS MOR05015 VL, SEQ ID NO: 70: DIELTQPPSVSVAPGQTARISCGGDSLGGKYVYWYQQKPGQAPVLVIYGDSK RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYTNALSTVFGGGTKLTVLGQ 15 MOR05016 VH, SEQ ID NO: 69: QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSNIS YDSSDTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQQYFDHIDIW GQGTLVTVSS 20 MOR05016 VL, SEQ ID NO: 87: DIELTQPPSVSVAPGQTARISCGGDSLGGKYVYWYQQKPGQAPVLVIYGDSK RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYDLQSLNIVFGGGTKLTVLGQ MOR05017 VH, SEQ ID NO: 69: 25 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSNIS YDSSDTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQQYFDHIDIW GQGTLVTVSS MOR05017 VL, SEQ ID NO: 88: DIELTQPPSVSVAPGQTARISCGGDSLGGKYVYWYQQKPGQAPVLVIYGDSK 30 RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYDLKSLNVVFGGGTKLTVLGQ MOR05018 VH, SEQ ID NO: 69: 75 WO 2007/096149 PCT/EP2007/001506 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSNIS YDSSDTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQQYFDHIDIW GQGTLVTVSS MOR05018 VL, SEQ ID NO: 89: 5 DIELTQPPSVSVAPGQTARISCGGDSLGGKYVYWYQQKPGQAPVLVIYGDSK RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYDLGSLNLVFGGGTKLTVLGQ MOR05019 VH, SEQ ID NO: 90: QVQLVESGGGLVQPGGSLRLSCAASGFTFSNHALSWVRQAPGKGLEWVSVIS 10 FDGVKFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARYYGYSYMDYW GQGTLVTVSS MOR05019 VL, SEQ ID NO: 74: DIELTQPPSVSVAPGQTARISCSGDNLGSKYVHWYQQKPGQAPVLVIYADNN RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYDHMLQVFGGGTKLTVLGQ 15 MOR05020 VH, SEQ ID NO: 73: QVQLVESGGGLVQPGGSLRLSCAASGFTFSNHALSWVRQAPGKGLEWVSGI QYDGSNTGYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARYYGYSYMD YWGQGTLVTVSS 20 MOR05020 VL, SEQ ID NO: 91: DIELTQPPSVSVAPGQTARISCSGDNLGSKYVHWYQQKPGQAPVLVIYADNN RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCSSYDSNSIRVFGGGTKLTVLGQ MOR05021 VH, SEQ ID NO: 73: 25 QVQLVESGGGLVQPGGSLRLSCAASGFTFSNHALSWVRQAPGKGLEWVSGI QYDGSNTGYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARYYGYSYMD YWGQGTLVTVSS MOR05021 VL, SEQ ID NO: 92: DIELTQPPSVSVAPGQTARISCSGDNLGSKYVHWYQQKPGQAPVLVIYADNN 30 RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCSSYDLDGVRVFGGGTKLTVLGQ MOR05022 VH, SEQ ID NO: 73: 76 WO 2007/096149 PCT/EP2007/001506 QVQLVESGGGLVQPGGSLRLSCAASGFTFSNHALSWVRQAPGKGLEWVSGI QYDGSNTGYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARYYGYSYMD YWGQGTLVTVSS MOR05022 VL, SEQ ID NO: 93: 5 DIELTQPPSVSVAPGQTARISCSGDNLGSKYVHWYQQKPGQAPVLVIYADNN RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCSSYTTSGIRVFGGGTKLTVLGQ MOR05023 VH, SEQ ID NO: 77: QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGNI 10 YPIFGYANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARYGQYGQHFSH GGMDVWGQGTLVTVSS MOR05023 VL, SEQ ID NO: 94: DIQMTQSPSSLSASVGDRVTITCRASQDISISLTWYQQKPGKAPKLLIYGAFSL QSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFYFHSPTFGQGTKVEIKRT 15 MOR05024 VH, SEQ ID NO: 77: QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGNI YPIFGYANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARYGQYGQHFSH GGMDVWGQGTLVTVSS 20 MOR05024 VL, SEQ ID NO: 95: DIQMTQSPSSLSASVGDRVTITCRASQDISISLTWYQQKPGKAPKLLIYGAFSL QSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFWFEPVTFGQGTKVEIKRT MOR05025 VH, SEQ ID NO: 77: 25 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGNI YPIFGYANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARYGQYGQHFSH GGMDVWGQGTLVTVSS MOR05025 VL, SEQ ID NO: 96: DIQMTQSPSSLSASVGDRVTITCRASQDISISLTWYQQKPGKAPKLLIYGAFSL 30 QSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFWFHPVTFGQGTKVEIKRT MOR05026 VH, SEQ ID NO: 77: 77 WO 2007/096149 PCT/EP2007/001506 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGNI YPIFGYANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARYGQYGQHFSH GGMDVWGQGTLVTVSS MOR05026 VL, SEQ ID NO: 97: 5 DIQMTQSPSSLSASVGDRVTITCRASQDISISLTWYQQKPGKAPKLLIYGAFSL QSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFWSEPVTFGQGTKVEIKRT MOR05027 VH, SEQ ID NO: 77: QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGNI 10 YPIFGYANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARYGQYGQHFSH GGMDVWGQGTLVTVSS MOR05027 VL, SEQ ID NO: 98: DIQMTQSPSSLSASVGDRVTITCRASQDISISLTWYQQKPGKAPKLLIYGAFSL QSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFWTEPVTFGQGTKVEIKRT 15 MOR05154 VH, SEQ ID NO: 81: QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSGIF FDGETYYAGSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQQYFDHIDIWG QGTLVTVSS 20 MOR05154 VL, SEQ ID NO: 87: DIELTQPPSVSVAPGQTARISCGGDSLGGKYVYWYQQKPGQAPVLVIYGDSK RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYDLQSLNIVFGGGTKLTVLGQ MOR05155 VH, SEQ ID NO: 81: 25 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSGIF FDGETYYAGSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQQYFDHIDIWG QGTLVTVSS MOR05155 VL, SEQ ID NO: 88: DIELTQPPSVSVAPGQTARISCGGDSLGGKYVYWYQQKPGQAPVLVIYGDSK 30 RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYDLKSLNVVFGGGTKLTVLGQ MOR05156 VH, SEQ ID NO: 81: 78 WO 2007/096149 PCT/EP2007/001506 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSGIF FDGETYYAGSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQQYFDHIDIWG QGTLVTVSS MOR05156 VL, SEQ ID NO: 89: 5 DIELTQPPSVSVAPGQTARISCGGDSLGGKYVYWYQQKPGQAPVLVIYGDSK RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYDLGSLNLVFGGGTKLTVLGQ MOR05157 VH, SEQ ID NO: 82: QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSGIF 10 YDGSTYYPDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQQYFDHIDIWG QGTLVTVSS MOR05157 VL, SEQ ID NO: 87: DIELTQPPSVSVAPGQTARISCGGDSLGGKYVYWYQQKPGQAPVLVIYGDSK RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYDLQSLNIVFGGGTKLTVLGQ 15 MOR05158 VH, SEQ ID NO: 82: QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSGIF YDGSTYYPDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQQYFDHIDIWG QGTLVTVSS 20 MOR05158 VL, SEQ ID NO: 88: DIELTQPPSVSVAPGQTARISCGGDSLGGKYVYWYQQKPGQAPVLVIYGDSK RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYDLKSLNVVFGGGTKLTVLGQ MOR05159 VH, SEQ ID NO: 82: 25 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSGIF YDGSTYYPDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQQYFDHIDIWG QGTLVTVSS MOR05159 VL, SEQ ID NO: 89: DIELTQPPSVSVAPGQTARISCGGDSLGGKYVYWYQQKPGQAPVLVIYGDSK 30 RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYDLGSLNLVFGGGTKLTVLGQ MOR05160 VH, SEQ ID NO: 83: 79 WO 2007/096149 PCT/EP2007/001506 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSGIF FTGETYYPDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQQYFDHIDIWG QGTLVTVSS MOR05160 VL, SEQ ID NO: 87: 5 DIELTQPPSVSVAPGQTARISCGGDSLGGKYVYWYQQKPGQAPVLVIYGDSK RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYDLQSLNIVFGGGTKLTVLGQ MOR05161 VH, SEQ ID NO: 83: QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSGIF 10 FTGETYYPDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQQYFDHIDIWG QGTLVTVSS MOR05161 VL, SEQ ID NO: 88: DIELTQPPSVSVAPGQTARISCGGDSLGGKYVYWYQQKPGQAPVLVIYGDSK RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYDLKSLNVVFGGGTKLTVLGQ 15 MOR05162 VH, SEQ ID NO: 83: QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSGIF FTGETYYPDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQQYFDHIDIWG QGTLVTVSS 20 MOR05162 VL, SEQ ID NO: 89: DIELTQPPSVSVAPGQTARISCGGDSLGGKYVYWYQQKPGQAPVLVIYGDSK RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYDLGSLNLVFGGGTKLTVLGQ MOR05163 VH, SEQ ID NO: 84: 25 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSGIF FDGETYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQQYFDHIDIWG QGTLVTVSS MOR05163 VL, SEQ ID NO: 87: DIELTQPPSVSVAPGQTARISCGGDSLGGKYVYWYQQKPGQAPVLVIYGDSK 30 RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYDLQSLNIVFGGGTKLTVLGQ MOR05164 VH, SEQ ID NO: 84: 80 WO 2007/096149 PCT/EP2007/001506 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSGIF FDGETYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQQYFDHIDIWG QGTLVTVSS MOR05164 VL, SEQ ID NO: 88: 5 DIELTQPPSVSVAPGQTARISCGGDSLGGKYVYWYQQKPGQAPVLVIYGDSK RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYDLKSLNVVFGGGTKLTVLGQ MOR05165 VH, SEQ ID NO: 84: QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSGIF 10 FDGETYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQQYFDHIDIWG QGTLVTVSS MOR05165 VL, SEQ ID NO: 89: DIELTQPPSVSVAPGQTARISCGGDSLGGKYVYWYQQKPGQAPVLVIYGDSK RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYDLGSLNLVFGGGTKLTVLGQ 15 MOR05166 VH, SEQ ID NO: 85: QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSGIF FDGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQQYFDHIDIWG QGTLVTVSS 20 MOR05166 VL, SEQ ID NO: 87: DIELTQPPSVSVAPGQTARISCGGDSLGGKYVYWYQQKPGQAPVLVIYGDSK RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYDLQSLNIVFGGGTKLTVLGQ MOR05167 VH, SEQ ID NO: 85: 25 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSGIF FDGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQQYFDHIDIWG QGTLVTVSS MOR05167 VL, SEQ ID NO: 88: DIELTQPPSVSVAPGQTARISCGGDSLGGKYVYWYQQKPGQAPVLVIYGDSK 30 RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYDLKSLNVVFGGGTKLTVLGQ MOR05168 VH, SEQ ID NO: 85: 81 WO 2007/096149 PCT/EP2007/001506 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSGIF FDGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQQYFDHIDIWG QGTLVTVSS MOR05168 VL, SEQ ID NO: 89: 5 DIELTQPPSVSVAPGQTARISCGGDSLGGKYVYWYQQKPGQAPVLVIYGDSK RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYDLGSLNLVFGGGTKLTVLGQ MOR05169 VH, SEQ ID NO: 86: QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSGT 10 FFDGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQQYFDHIDIW GQGTLVTVSS MOR05169 VL, SEQ ID NO: 87: DIELTQPPSVSVAPGQTARISCGGDSLGGKYVYWYQQKPGQAPVLVIYGDSK RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYDLQSLNIVFGGGTKLTVLGQ 15 MOR05170 VH, SEQ ID NO: 86: QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSGT FFDGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQQYFDHIDIW GQGTLVTVSS 20 MOR05170 VL, SEQ ID NO: 88: DIELTQPPSVSVAPGQTARISCGGDSLGGKYVYWYQQKPGQAPVLVIYGDSK RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYDLKSLNVVFGGGTKLTVLGQ MOR05171 VH, SEQ ID NO: 86: 25 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMSWVRQAPGKGLEWVSGT FFDGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQQYFDHIDIW GQGTLVTVSS MOR05171 VL, SEQ ID NO: 89: DIELTQPPSVSVAPGQTARISCGGDSLGGKYVYWYQQKPGQAPVLVIYGDSK 30 RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYDLGSLNLVFGGGTKLTVLGQ MOR05172 VH, SEQ ID NO: 90: 82 WO 2007/096149 PCT/EP2007/001506 QVQLVESGGGLVQPGGSLRLSCAASGFTFSNHALSWVRQAPGKGLEWVSVIS FDGVKFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARYYGYSYMDYW GQGTLVTVSS MOR05172 VL, SEQ ID NO: 91: 5 DIELTQPPSVSVAPGQTARISCSGDNLGSKYVHWYQQKPGQAPVLVIYADNN RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCSSYDSNSIRVFGGGTKLTVLGQ MOR05173 VH, SEQ ID NO: 90: QVQLVESGGGLVQPGGSLRLSCAASGFTFSNHALSWVRQAPGKGLEWVSVIS 10 FDGVKFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARYYGYSYMDYW GQGTLVTVSS MOR05173 VL, SEQ ID NO: 92: DIELTQPPSVSVAPGQTARISCSGDNLGSKYVHWYQQKPGQAPVLVIYADNN RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCSSYDLDGVRVFGGGTKLTVLGQ 15 MOR05174 VH, SEQ ID NO: 90: QVQLVESGGGLVQPGGSLRLSCAASGFTFSNHALSWVRQAPGKGLEWVSVIS FDGVKFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARYYGYSYMDYW GQGTLVTVSS 20 MOR05174 VL, SEQ ID NO: 93: DIELTQPPSVSVAPGQTARISCSGDNLGSKYVHWYQQKPGQAPVLVIYADNN RPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCSSYTTSGIRVFGGGTKLTVLGQ MOR 5164,5167,5170 LIGHT CHAIN LAMBDA 25 The LC Lamda amino acid sequence is shown in SEQ ID NO: 99: and is encoded by the nucleotide sequence of SEQ ID NO: 100: MAWALLLLTLLTQGTGSWADIELTQPPSVSVAPGQTARISCGGDSLGGKYVY WYQQKPGQAPVLVIYGDSKRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSY 30 DLKSLNVVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVT VAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGST VEKTVAPTECS (SEQ ID NO: 99:) ATGGCCTGGGCTCTGCTGCTCCTCACCCTCCTCACTCAGGGCACAGGATCC 35 TGGGCTGATATCGAACTGACCCAGCCGCCTTCAGTGAGCGTTGCACCAGGTCAG ACCGCGCGTATCTCGTGTGGCGGCGATTCTCTTGGTGGTAAGTATGTTTATTGGT ACCAGCAGAAACCCGGGCAGGCGCCAGTTCTTGTGATTTATGGTGATTCTAAGCG TCCCTCAGGCATCCCGGAACGCTTTAGCGGATCCAACAGCGGCAACACCGCGAC CCTGACCATTAGCGGCACTCAGGCGGAAGACGAAGCGGATTATTATTGCCAGTC 83 WO 2007/096149 PCT/EP2007/001506 TTATGATCTTAAGTCTCTTAATGTTGTGTTTGGCGGCGGCACGAAGTTAACCGTCC TAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGA GCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGA CTTCTACCCGGGA GCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGA 5 GACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCT GAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCAC GCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA (SEQ ID NO: 100:) 10 MOR 5164, 5167, 5170 LIGHT CHAIN LAMBDA (OPTIMIZED) The LC Lamda amino acid sequence is shown in SEQ ID NO: 101: and is encoded by the nucleotide sequence of SEQ ID NO: 102: 15 MSVLTQVLALLLLWLTGTRCDIELTQPPSVSVAPGQTARISCGGDSLGGKYV YWYQQKPGQAPVLVIYGDSKRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQS YDLKSLNVVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAV TVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGS TVEKTVAPTECS (SEQ ID NO: 101:) 20 ATGAGTGTGCTCACTCAGGTCCTGGCGTTGCTGCTGCTGTGGCTTACAGGT ACGCGTTGCGACATCGAGCTGACCCAGCCCCCCAGCGTGTCTGTGGCCCCTGGCC AGACCGCCCGGATCAGCTGTGGCGGCGACAGCCTGGGCGGCAAGTACGTGTACT GGTATCAGCAGAAGCCCGGCCAGGCCCCCGTGCTGGTGATCTACGGCGACAGCA 25 AGCGGCCCAGCGGCATCCCCGAGCGGTTCAGCGGCAGCAACAGCGGCAACACCG CCACCCTGACCATCAGCGGCACCCAGGCCGAGGACGAGGCCGACTACTACTGCC AGAGCTACGACCTGAAGAGCCTGAACGTGGTGTTTGGCGGCGGAACAAAGCTTA CCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCT GAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACC 30 CGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGA GTGGAGACAACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAG CTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCA GGTCACGCATGAAGGGAGCACCGTGGAAAAGACAGTGGCCCCTACAGAATGTTC ATAG (SEQ ID NO: 102) 35 MOR5164 HEAVY CHAIN IgGl: The HC Lamda amino acid sequence is shown in SEQ ID NO: 103 and is encoded by the nucleotide sequence of SEQ ID NO: 104 40 MKHLWFFLLLVAAPRWVLSQVQLVESGGGLVQPGGSLRLSCAASGFTFSSY YMSWVRQAPGKGLEWVSGIFFDGETYYADSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCARQQYFDHIDIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVN HKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC 45 VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK (SEQ ID NO: 103) 50 84 WO 2007/096149 PCT/EP2007/001506 ATGAAACACCTGTGGTTCTTCCTCCTGCTGGTGGCAGCTCCCAGATGGGTCCTGT CCCAGGTGCAATTGGTGGAAAGCGGCGGCGGCCTGGTGCAACCGGGCGGCAGCC TGCGTCTGAGCTGCGCGGCCTCCGGATTTACCTTFTCTTCTTATTATATGTCTTGG GTGCGCCAAGCCCCTGGGAAGGGTCTCGAGTGGGTGAGCGGTATTTTTTTTGATG 5 GTGAGACTTATTATGCTGATTCTGTTAAGGGTCGTTTTACCATTTCACGTGATAAT TCGAAAAACACCCTGTATCTGCAAATGAACAGCCTGCGTGCGGAAGATACGGCC GTGTATTATTGCGCGCGTCAGCAGTATTTTGATCATATTGATATTTGGGGCCAAG GCACCCTGGTGACGGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCT GGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGT 10 CAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGAC CAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTC AGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGC AACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAA ATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGG 15 GGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCC GGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGG TCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGC CGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCC TGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAG 20 CCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAG AACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTG GGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA CTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGG 25 CAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACT ACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA (SEQ ID NO: 104) MOR5164 HEAVY CHAIN IgG1 (OPTIMIZED) 30 The HC Lamda amino acid sequence is shown in SEQ ID NO: 105 and is encoded by the nucleotide sequence of SEQ ID NO: 106 MAWVWTLPFLMAAAQSVQAQVQLVESGGGLVQPGGSLRLSCAASGFTFSSY YMSWVRQAPGKGLEWVSGIFFDGETYYADSVKGRFTISRDNSKNTLYLQMNSLRAE 35 DTAVYYCARQQYFDHIDIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVN HKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF 40 YPSDIAVEWESNGQPENNYKTITPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK (SEQ ID NO: 105) ATGGCTTGGGTGTGGACCTTGCCATTCCTGATGGCAGCTGCCCAAAGTGTC CAGGCCCAGGTGCAGCTGGTGGAATCTGGCGGCGGACTGGTGCAGCCTGGCGGC 45 AGCCTGAGACTGAGCTGCGCCGCCAGCGGCTTCACCTTCAGCAGCTACTACATGA GCTGGGTGCGGCAGGCCCCTGGCAAGGGCCTGGAATGGGTGTCCGGCATCTTCTT CGACGGCGAGACCTACTACGCCGACAGCGTGAAGGGCCGGTTCACCATCAGCCG GGACAACAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGCGGGCCGAGGA CACCGCCGTGTACTACTGCGCCAGGCAGCAGTACTTCGACCACATCGACATCTGG 50 GGCCAGGGCACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCT 85 WO 2007/096149 PCT/EP2007/001506 TCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGC CCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTAC TCCCTCAGCAGCGTCGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACA 5 TCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGC CCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCT GGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATC TCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCT GAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACA 10 AAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACC GT CCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAA AGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCG AGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCA 15 GGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTG GACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGT GGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACC ACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA (SEQ ID NO: 106) 20 MOR5167 HEAVY CHAIN IgGi: The HC Lamda amino acid sequence is shown in SEQ ID NO: 107 and is encoded by the nucleotide sequence of SEQ ID NO: 108 25 MKHLWFFLLLVAAPRWVLSQVQLVESGGGLVQPGGSLRLSCAASGFTFSSY YMSWVRQAPGKGLEWVSGIFFDGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCARQQYFDHIDIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVN 30 HKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK (SEQ ID NO: 107) 35 ATGAAACACCTGTGGTTCTTCCTCCTGCTGGTGGCAGCTCCCAGATGGGTC CTGTCCCAGGTGCAATTGGTGGAAAGCGGCGGCGGCCTGGTGCAACCGGGCGGC AGCCTGCGTCTGAGCTGCGCGGCCTCCGGATTTACCTTTTCTTCTTATTATATGTC 40 TTGGGTGCGCCAAGCCCCTGGGAAGGGTCTCGAGTGGGTGAGCGGTATTTTTTTT GATGGTACTACTTATTATGCTGATTCTGTTAAGGGTCGTTTFACCATT1TCACGTGA TAATTCGAAAAACACCCTGTATCTGCAAATGAACAGCCTGCGTGCGGAAGATAC GGCCGTGTATTATTGCGCGCGTCAGCAGTATTTTGATCATATTGATATTTGGGGC CAAGGCACCCTGGTGACGGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCC 45 CCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCT GACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCC CTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCT GCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCC 50 AAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGG 86 WO 2007/096149 PCT/EP2007/001506 GGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTC CCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGA GGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAA GCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGT 5 CCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAA AGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCG AGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCA GGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTG 10 GACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGT GGCAGCAGGGGAACGTCTTrCTCATGCTCCGTGATGCATGAGGCTCTGCACAACC ACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA (SEQ ID NO: 108) 15 MOR5167 HEAVY CHAIN IgG1 (OPTIMIZED): The HC Lamda amino acid sequence is shown in SEQ ID NO: 109 and is encoded by the nucleotide sequence of SEQ ID NO: 110 MAWVWTLPFLMAAAQSVQAQVQLVESGGGLVQPGGSLRLSCAASGFTFSSY 20 YMSWVRQAPGKGLEWVSGIFFDGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAE DTAVYYCARQQYFDHIDIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVN HKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN 25 GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF YPSDIAVEWESNGQPENNYKTrPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK (SEQ ID NO: 109) ATGGCTTGGGTGTGGACCTTGCCA-TCCTGATGGCAGCTGCCCAAAGTGTC 30 CAGGCCCAGGTGCAGCTGGTGGAATCTGGCGGCGGACTGGTGCAGCCTGGCGGC AGCCTGAGACTGAGCTGCGCCGCCAGCGGCTTCACCTTCAGCAGCTACTACATGA GCTGGGTGCGGCAGGCCCCTGGCAAGGGCCTGGAATGGGTGTCCGGCATCTTCTT CGACGGCACCACCTACTACGCCGACAGCGTGAAGGGCCGGTTCACCATCAGCCG GGACAACAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGCGGGCCGAGGA 35 CACCGCCGTGTACTACTGCGCCAGGCAGCAGTACTTCGACCACATCGACATCTGG GGCCAGGGCACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCT TCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGC CCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTAC 40 TCCCTCAGCAGCGTCGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACA TCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGC CCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCT GGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATC TCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCT 45 GAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACA AAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACC GTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAAC AAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAAC 50 CAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGG 87 WO 2007/096149 PCT/EP2007/001506 AGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA (SEQ ID NO: 110) 5 MOR5170 HEAVY CHAIN IgGl: The HC Lamda amino acid sequence is shown in SEQ ID NO: 111 and is encoded by the nucleotide sequence of SEQ ID NO: 112 10 MKHLWFFLLLVAAPRWVLSQVQLVESGGGLVQPGGSLRLSCAASGFTFSSY YMSWVRQAPGKGLEWVSGTFFDGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRA EDTAVYYCARQQYFDHIDIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGC LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV 15 NHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MH4EALHNHYTQKSLSLSPGK (SEQ ID NO: 111) 20 ATGAAACACCTGTGGTTCTTCCTCCTGCTGGTGGCAGCTCCCAGATGGGTC CTGTCCCAGGTGCAATTGGTGGAAAGCGGCGGCGGCCTGGTGCAACCGGGCGGC AGCCTGCGTCTGAGCTGCGCGGCCTCCGGATTTACCTTTTCTTCTTATTATATGTC TTGGGTGCGCCAAGCCCCTGGGAAGGGTCTCGAGTGGGTGAGCGGTACTTTTTTT 25 GATGGTTCTACTTATTATGCTGATTCTGTTAAGGGTCGTTTTACCATTTCACGTGA TAATTCGAAAAACACCCTGTATCTGCAAATGAACAGCCTGCGTGCGGAAGATAC GGCCGTGTA TTATTGCGCGCGTCAGCAGTATTTGATCATATTGATATTTGGGGC CAAGGCACCCTGGTGACGGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCC CCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT 30 GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCT GACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCC CTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCT GCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCC AAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGG 35 GGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTC CCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGA GGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAA GCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGT CCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAA 40 AGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCG AGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCA GGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTG GACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGT 45 GGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACC ACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA (SEQ ID NO: 112) 50 88 WO 2007/096149 PCT/EP2007/001506 MOR5170 HEAVY CHAIN IgGI (OPTIMIZED): The HC Lamda amino acid sequence is shown in SEQ ID NO: 113 and is encoded by the nucleotide sequence of SEQ ID NO: 114 5 MAWVWTLPFLMAAAQSVQAQVQLVESGGGLVQPGGSLRLSCAASGFTFSSY YMSWVRQAPGKGLEWVSGTFFDGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRA EDTAVYYCARQQYFDHIDIWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGC LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT 10 CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGK (SEQ ID NO: 113) 15 ATGGCTTGGGTGTGGACCTTGCCATTCCTGATGGCAGCTGCCCAAAGTGTC CAGGCCCAGGTGCAGCTGGTGGAATCTGGCGGCGGACTGGTGCAGCCTGGCGGC AGCCTGAGACTGAGCTGCGCCGCCAGCGGCTTCACCTTCAGCAGCTACTACATGA GCTGGGTGCGGCAGGCCCCTGGCAAGGGCCTGGAATGGGTGTCCGGCACCTTCT 20 TCGACGGCAGCACCTACTACGCCGACAGCGTGAAGGGCCGGTTCACCATCAGCC GGGACAACAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGCGGGCCGAGG ACACCGCCGTGTACTACTGCGCCAGGCAGCAGTACTTCGACCACATCGACATCTG GGGCCAGGGCACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTC TTrCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCT 25 GCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCG CCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTA CTCCCTCAGCAGCGTCGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC ATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAG CCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCC 30 TGGGGGGACCGTCAGTCTTCCTCTfCCCCCCAAAACCCAAGGACACCCTCATGAT CTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCC TGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGAC AAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCAC CGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAA 35 CAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCC CCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGT GCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGC 40 AGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC AACCACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAATGA (SEQ ID NO: 114) 45 89

权利要求:
Claims (41)
[1] 1. An isolated human or humanized antibody or functional fragment thereof comprising an antigen-binding region that is specific for TSLP, wherein the antibody or functional fragment thereof binds TSLP. 5
[2] 2, The antibody or functional fragment thereof according to claim 1, wherein the antibody or functional fragment thereof binds the TSLP with a KD of I x 10-9 M or less.
[3] 3. An isolated antigen-binding region of an antibody or functional fragment thereof, comprising an H-CDRI region depicted in the amino acid sequence of SEQ ID NO: 3, and conservative variants thereof. 10
[4] 4. An isolated antigen-binding region of an antibody or functional fragment thereof, comprising an H-CDR2 region depicted in an amino acid sequence selected from the group of SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20, and conservative variants thereof.
[5] 5. An isolated antigen-binding region of an antibody or functional fragment thereof, 15 comprising an H-CDR3 region depicted in the amino acid sequence SEQ ID NO: 28, and conservative variants thereof.
[6] 6. An isolated antigen-binding region of an antibody or functional fragment thereof, comprising an H-CDRI region depicted in the amino acid sequence of SEQ ID NO: 3, an H CDR2 region depicted in an amino acid sequence selected from the group of SEQ ID NO: 15, 20 SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20, and an H-CDR3 region depicted in the amino acid sequence SEQ ID NO: 28, and conservative variants thereof.
[7] 7. The isolated antigen-binding region of an antibody or functional fragment thereof, comprising an L-CDRl region depicted in the amino acid sequence of SEQ ID NO: 38, and 25 conservative variants thereof.
[8] 8. The isolated antigen-binding region of an antibody or functional fragment thereof, comprising an L-CDR2 region depicted in the amino acid sequence SEQ ID NO: 47, and conservative variants thereof.
[9] 9. The isolated antigen-binding region of an antibody or functional fragment thereof, 30 comprising an L-CDR3 region depicted in the amino acid sequence SEQ ID NO: 60, and conservative variants thereof.
[10] 10. The isolated antigen-binding region of an antibody or functional fragment thereof, comprising an L-CDRI region depicted in the amino acid sequence of SEQ ID NO: 38, an L-CDR2 region depicted in the amino acid sequence SEQ ID NO: 47, and an L 90 WO 2007/096149 PCT/EP2007/001506 CDR3 region depicted in the amino acid sequence SEQ ID NO: 60, and conservative variants thereof.
[11] 11. An isolated antigen-binding region of an antibody or functional fragment thereof, comprising an H-CDRI region depicted in the amino acid sequence of SEQ ID NO: 3, an H 5 CDR2 region depicted in an amino acid sequence selected from the group of SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20, an H-CDR3 region depicted in the amino acid sequence SEQ ID NO: 28, an L-CDR1 region depicted in the amino acid sequence of SEQ ID NO: 38, an L-CDR2 region depicted in the amino acid sequence SEQ ID NO: 47, and an L-CDR3 region depicted in the amino acid sequence SEQ 10 ID NO: 60, and conservative variants thereof.
[12] 12. The isolated antigen-binding region of an antibody or functional fragment thereof according to claim 11 where the H-CDR2 region is SEQ ID NO: 15, and conservative variants thereof.
[13] 13. The isolated antigen-binding region of an antibody or functional fragment thereof 15 according to claim 11 where the H-CDR2 region is SEQ ID NO: 17, and conservative variants thereof.
[14] 14. The isolated antigen-binding region of an antibody or functional fragment thereof according to claim 11 where the H-CDR2 region is SEQ ID NO: 18, and conservative variants thereof. 20
[15] 15. The isolated antigen-binding region of an antibody or functional fragment thereof according to claim 11 where the H-CDR2 region is SEQ ID NO: 19, and conservative variants thereof.
[16] 16. The isolated antigen-binding region of an antibody or functional fragment thereof according to claim 11 where the H-CDR2 region is SEQ ID NO: 20, and conservative 25 variants thereof.
[17] 17. The isolated antigen-binding region of an antibody or functional fragment thereof comprising a sequence having at least 60, 70, 80, 90 or 95 percent sequence identity in the CDR regions with the CDR regions described in any one of claims 1-16.
[18] 18. An isolated human or humanized TSLP antibody comprising an isolated antigen 30 binding region of an antibody or functional fragment thereof according to any one of claims 1-17.
[19] 19. The isolated antibody according to claim 18, which is an IgG I, IgG2 or an IgG4. 91 WO 2007/096149 PCT/EP2007/001506
[20] 20. The isolated antibody according to claim 18 or 19 comprising a heavy chain variable region selected from SEQ ID NO: 84, SEQ ID NO: 85 and SEQ ID NO: 86, and conservative variants thereof.
[21] 21. The isolated antibody according to any one of claims 18-20 comprising the light 5 chain variable region SEQ ID NO: 88.
[22] 22. The isolated antibody according to any one of claims 18-21 where the heavy chain variable region is SEQ ID NO: 84, and conservative variants thereof.
[23] 23. The isolated antibody according to any one of claims 18-21 where the heavy chain variable region is SEQ ID NO: 85, and conservative variants thereof. 10
[24] 24. The isolated antibody according to any one of claims 18-21 where the heavy chain variable region is SEQ ID NO: 86, and conservative variants thereof.
[25] 25. The isolated antibody according to any one of claims 18-21 which is an IgGI having a light chain lamda sequence selected from SEQ ID NO: 99 or SEQ ID NO: 101, and a heavy chain sequence selected from SEQ ID NO: 103, SEQ ID No: 105, SEQ ID NO: 107, 15 SEQ ID NO: 109, SEQ ID NO: 111 and SEQ ID NO: 113, and conservative variants thereof.
[26] 26. An isolated or recombinant polynucleotide which encodes a polypeptide comprising an antigen-binding region of an antibody or functional fragment thereof according to any one of claims 1-17 or an isolated antibody according to any one of claims 18-25. 20
[27] 27. The polynucleotide of claim 26, wherein the antibody is a human antibody.
[28] 28. The polynucleotide of claim 26 or claim 27, wherein the polynucleotide encodes am antibody comprising H-CDR1, H-CDR2, and H-CDR3 sequences, and L-CDRI, L CDR2, and L-CDR3 sequences, selected from: (a) H-CDR SEQ ID NO: 3, SEQ ID NO: 15, SEQ ID NO: 28; 25 L-CDR SEQ ID NO: 38, SEQ ID NO: 47, SEQ ID NO: 60. (b) H-CDR SEQ ID NO: 3, SEQ ID NO: 17, SEQ ID NO: 28; L-CDR SEQ ID NO: 38, SEQ ID NO: 47, SEQ ID NO: 60. (c) H-CDR SEQ ID NO: 3, SEQ ID NO: 18, SEQ ID NO: 28; L-CDR SEQ ID NO: 38, SEQ ID NO: 47, SEQ ID NO: 60. 30 (d) H-CDR SEQ ID NO: 3, SEQ ID NO: 19, SEQ ID NO: 28; L-CDR SEQ ID NO: 38, SEQ ID NO: 47, SEQ ID NO: 60. (e) H-CDRSEQ ID NO: 3, SEQ ID NO: 20, SEQ ID NO: 28; and L-CDR SEQ ID NO: 38, SEQ ID NO: 47, SEQ ID NO: 60. 92 WO 2007/096149 PCT/EP2007/001506
[29] 29. The polynucleotide of any one of claims 26-28, wherein the antibody comprises (i) a mature light chain variable region sequence and (ii) a mature heavy chain variable region sequence selected from: (a) (i) SEQ ID NO: 101, (ii) SEQ ID NO: 105; 5 (b) (i) SEQ ID NO: 101, (ii) SEQ ID NO: 107; and (c) (i) SEQ ID NO: 101, (ii) SEQ ID NO: 109; each of which is at least 80% identical to the mature region of said light and heavy chains sequences.
[30] 30. The polynucleotide of claim 29, wherein the antibody mature light chain variable 10 region sequence and a mature heavy chain variable region sequence are identical to said sequences.
[31] 31. The polynucleotide of any one of claims 26-30 which is a DNA.
[32] 32. An isolated host cell comprising (1) a recombinant DNA segment encoding a heavy chain of the antibody of any one of claims 18-25, and (2) a second recombinant DNA 15 segment encoding a light chain of the antibody; wherein said DNA segments are respectively operably linked to a first and a second promoter, and are capable of being expressed in said host cell.
[33] 33. The host cell of claim 32, wherein the monoclonal antibody is a human antibody.
[34] 34. The host cell of claim 32 or claim 33, wherein the monoclonal antibody comprises 20 a heavy and light chain sequence selected from: (a) H-CDR SEQ ID NO: 3, SEQ ID NO: 15, SEQ ID NO: 28; L-CDR SEQ ID NO: 38, SEQ ID NO: 47, SEQ ID NO: 60. (b) H-CDR SEQ ID NO: 3, SEQ ID NO: 17, SEQ ID NO: 28; L-CDR SEQ ID NO: 38, SEQ ID NO: 47, SEQ ID NO: 60. 25 (c) H-CDR SEQ ID NO: 3, SEQ ID NO: 18, SEQ ID NO: 28; L-CDR SEQ ID NO: 38, SEQ ID NO: 47, SEQ ID NO: 60. (d) H-CDR SEQ ID NO: 3, SEQ ID NO: 19, SEQ ID NO: 28; L-CDR SEQ ID NO: 38, SEQ ID NO: 47, SEQ ID NO: 60. (e) H-CDRSEQ ID NO: 3, SEQ ID NO: 20, SEQ ID NO: 28; and 30 L-CDR SEQ ID NO: 38, SEQ ID NO: 47, SEQ ID NO: 60.
[35] 35. The host cell of any one of claims 32-34, wherein the antibody comprises (i) a mature light chain variable region sequence and (ii) a mature heavy chain variable region sequence selected from: (a) (i) SEQ ID NO: 101, (ii) SEQ ID NO: 105; 93 WO 2007/096149 PCT/EP2007/001506 (b) (i) SEQ ID NO: 101, (ii) SEQ ID NO: 107; and (c) (i) SEQ ID NO: 101, (ii) SEQ ID NO: 109; each of which is at least 80% identical to the mature region of said light and heavy chains sequences. 5
[36] 36. The host cell of claim 35, wherein the monoclonal antibody mature light chain variable region sequence and a mature heavy chain variable region sequence are identical to said sequences.
[37] 37. The host cell of any one of claims 32-36 that is a non-human mammalian cell line.
[38] 38. A pharmaceutical composition comprising an antibody or functional fragment 10 according to any of claims 18-25 and a pharmaceutically acceptable carrier or excipient therefor.
[39] 39. A method for treating a disorder or condition associated with the presence of cell receptor target hTSLP, comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition according to claim 38. 15
[40] 40. The method according to claim 39, wherein the disorder or condition is asthma.
[41] 41. The method according to claim 39, wherein the disorder or condition is atopic dermatitis. 94

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公开号 | 公开日

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CL2007000478A1|2008-03-14|

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RU2008137531A|2010-03-27|

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EP1991583B1|2012-12-19|

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GB0603683D0|2006-04-05|

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US8420787B2|2013-04-16|

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BRPI0708145A2|2011-05-17|

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NO20083911L|2008-11-05|

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MX2008010807A|2008-09-01|

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CN101389657A|2009-03-18|

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EP2341076A2|2011-07-06|

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EP1991583A1|2008-11-19|

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TW200813089A|2008-03-16|

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ES2404058T3|2013-05-23|

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US20090186022A1|2009-07-23|

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CR10184A|2008-12-03|

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JP2009527235A|2009-07-30|

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法律状态:
2012-09-13| MK4| Application lapsed section 142(2)(d) - no continuation fee paid for the application|

优先权:

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申请号 | 申请日 | 专利标题

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GBGB0603683.4A|GB0603683D0|2006-02-23|2006-02-23|Organic compounds|

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GB0603683.4||2006-02-23||

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PCT/EP2007/001506|WO2007096149A1|2006-02-23|2007-02-21|Thymic stromal lympho po i et inantibodies and uses thereof|

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