前苏联专利SU1329604A3 Method of producing conjugated compound specific relative to melanoma cells

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专利摘要:
The invention relates to the field of medicine and may find application in the preparation of compounds that inhibit growth and developed melanomas. The aim of the invention is to increase the therapeutic activity of the drug. To obtain the conjugated compound, ricin A chain (p) is complexed with an antibody to human melanoma (AT). P has cytotoxic activity, and AT is capable of selectively recognizing the antigen of cancer cells. Before conjugation, AT is treated with 3- (2-pyridyl disulfanyl) - propionic acid in a buffer solution in the presence of carbodiimide. The treatment is carried out for 20 hours at a temperature. Modified in this way AT conjugated with P for 20 hours at a temperature. The resulting compound is purified from impurities in the traditional way. The compound possesses significant specificity of action with respect to melanoma cells and is harmless to healthy cells. The cytotoxic activity of the compound is 400 times higher than the cytotoxic activity of P. with S CO with sD with a cm
公开号:SU1329604A3
申请号:SU823427002
申请日:1982-04-14
公开日:1987-08-07
发明作者:Клаус Янсен Франц；Грос Пьер
申请人:Санофи (Фирма)；
IPC主号:

专利说明:

The use of medicine relates to medicine, in particular, to a method for the preparation of antitumor preparations, and can be used in the preparation of compounds that inhibit the development of melanomas.
The aim of the invention is to increase the therapeutic activity of the drug due to the specificity of the delivery of the antitumor substance to the tumor cells.
To obtain a conjugated compound, ricin A chain of A, possessing a cytotoxic ak-15, is modified with a reagent entering into
activity, and combining the disulfide type with a covalet-type bond with a human antimelanoma antibody, which is capable of selectively recognizing anti-cancer cells.
Ll create a dsulfide bond between the antibody and the chain A Ritzi N Ac .-- H2 + HOC-CH2CH2 S-S-r.
ABOUT
Ac-l H-C-CH CH2
O (P
CC chain A SH- Н-С-Ш-СН-З-З-chain А +
0
(horse number 10)
where AJ itn gel antnmelanom; chain A - chain A. Ricin;
(|) is a modified antibody that carries an activated disulfide group.
The reaction of the reagent compound with immunoglobulin is performed in a homogeneous liquid medium, usually in water or in a buffer solution. The dissolution of the reagents, if necessary, is introduced into a reactive medium up to 20% by volume of an organic solvent that is miscible with water, such as alcohol, and more specifically, tertiary butanol.
The reaction is carried out at ambient temperature for a period of several hours up to 24 hours. After: -1-pgo using dialysis, the removal of goat,:; and 1 epi, has a low molecular weight and, in particular, an excess of reagents .
The connection with the ricin chain A of osuttdest is prepared in an aqueous solution of two proteins with a temperature not exceeding, for a time equal to from several to a whole day. The resulting solution is dialyzed.
It is not necessary that each of these proteins have either a thiol group or an activated disulfide group.
Chain A ricin has a thiol group capable of reacting.
The animelanom antibody contains neither the function of free thiol nor other sulfur atoms suitable for the coupling reaction. For the administration of activated disulfide groups, the antibody
the reaction with a chemical group existing in the molecule, namely: with the rpynnoii NHj side chains of lysine amino acids present in the molecule.
Schematically, these reactions can be expressed as follows:
Ac-l H-C-CH CH2-S-S
TSl
O (P
t)
B
QSH
five
0
five
0
five
to remove low molecular weight compounds, after which the conjugated compound is purified by any known method.
Example 1 Antibody antimelanoma antibody directed against human melanoma P 97 antigen is obtained in the traditional way. The final purification is carried out by dialysis against PBS buffer solution (UcM phosphate, 140 mM sodium chloride, pH 7.4.
In order to obtain Ricia's A chain from pre-crushed Ricunus communis grains, the oil is extracted by repeatedly treating the grains with ethyl ether at a temperature not exceeding 4 ° C. After distilling off the ether and suction, the resulting powder is suspended in sodium chloride solution acidified to pH 4. stirring with a solution of sodium chloride, the extract is dialyzed first with water, then with a buffer with a low ionic strength TRIS-HCl, 10 mM, pH 7.7. The dialysis precipitate is separated by filtration.
Get the raw solution containing proteins. The solution obtained is purified by absorption chromatography on a column of Sepharose equilibrated with TRIS-HCl buffer, 10 mM, pH 7.7, cooled to. Eluents: TRIS-HC1 buffer, 10 mM pp 7.7, and the same buffer mixed with galactose.
The purified ricin solution is concentrated by ultrafiltration on a porous membrane. Get a clean solution of ricin in the buffer.
The ricin chain A isolation of the purified solution is treated with a reducing agent, for example, 2-mercaptoethanol on a column with an ion-exchange poly saccharide matrix, for example DEAE Sepharose 6B, equilibrated with TRIS-HC1 buffer, 0.1 M, pH 8.4, containing the said reducing agent. Two chains A and B of ricin are fixed on the column due to on-line communication with the DAEA groups, and the chain B is also fixed due to the affinity for the Sepharose matrix.
Elution of chain A was performed with TRIS-HCl, 0.1 M, pH 8.4, containing 0.1 M NaCl and 2-mercapto-ethanol with a concentration of 2.5%. Get the fraction containing the chain And ricin identified by electrophoresis. This fraction is dialyzed on a column with carboxymethyl cellulose, equilibrated in phosphate buffer 10 mM, pH 6.5, mol. M. ricin obtained chain A 30,000 3000; iso-electric point: 7.5.
To modify the antibody antimela nome to 0.5 ml of a solution containing
20MG / III 1- (2-pyridshdisulfanyl) - propionic acid in tertiary butanol, 0.2 ml of a solution containing 60 mg / ml 1-methyl-3- (3-dimethylaminpropyl) -carbodiimide was added and the mixture is stirred for 3 minutes at ambient temperature.
30 ml of the solution thus obtained was added to 1.66 ml of the antimelanoma antibody solution containing 2.4 mg / ml in PBS buffer solution. The incubation period is 20 hours at 30 ° C.
The solution is then continuously dialyzed for 3 hours against
21l PBS buffer solution at temperature. In this way, 4 mg of activated antibody is obtained at a concentration of 2.3 mg / ml.
-
ten
15
20
2Ч604
Using a spectro-Lottometric analysis at a wavelength of 343, he released 2-thionpyridine using. By identifying the reduced glutathione, it is determined that an antibody has been obtained that carries 2.6 activator groups per mole of antibody.
For profit; conjugated compound to 1.3 ml of the solution of activated antibody in PBS buffer solution (concentration of 2.3 mg / ml or 3 mg of activated antibody was added 0.52 ml of ricin chain A solution, taken in the same buffer solution (concentration 5, 8 mg / ml.) Incubate for 20 hours at 25 C.
The reaction mixture is subjected to chromatography on a Sepacdex C 100 gel column. In each fraction, the antibody concentration is determined by spectrophotometry at 280 nm and chain A concentration by its inhibitory ability with respect to proteosynthesis measured on a cell system. Identical fractions containing the conjugated compound are combined and approximately 1 mg of the compound is thus obtained with a concentration of 0.2 ml / mg.
The analysis performed showed that the solution contains 50 mg / ml of biologically active chain A or about 1.4 moles of chain A per mole of antibody.
In addition, an investigation carried out using cytofluorometry made it possible to find out that the antimelano antibody used, the corresponding activated antibody, and the conjugated connection of this antibody with the ricin chain A are 5 very similar fluorescence histograms. This suggests that the antibody does not undergo any significant changes during the activation and coupling reactions.
thirty
35
40
it has been able to, in particular, that it remains capable, even in a common connection, to recognize the antigen P 97, against which it is directed.
PRI and MERP 2. The compound obtained is examined for its anti-cancer effect.
Determination of proteosynthesis inhibition.
The main biological property of ricin chain A is the inhibition (inhibition) of cellular proteosynthesis by altering the ribosomal subunit 60 S.
Using a cell model, determine the effect of the test substances on the introduction of C-leupine into the cells affected by the cancer culture.
The cells used belong to the cell progeny 1-1.1477, obtained from human melanoma, which has the P 97 antigen. These cells after trypsination are preincubated for at least 24 hours in order to allow the new appearance of surface antigens, which possibly changed. After addition of the material under study, a new incubation is carried out. At the end of the incubation, the measurement of the degree of incorporation of the C-leuppma thus treated with the cells is started.
This change is carried out in accordance with the traditional method, using the C-leucine indicator to determine the degree of proteosynthesis. The determination of the radioactivity obtained in this case is carried out on 1.11x isolated f; 1 cells.
At the end of these definitions, the effect of dose dependence is constructed on the basis of the concentration of the studied substances, and on the ordinate the use of C-leucine, expressed as a percentage, is postponed.
to the introduction in comparison of the absence of the studied
la ratio: Mi: ie glue K1g with a hundred more S),
From the graph, the concentration at which the 50% of the C-Lyceum and the inhibitory concentration 50 (C 50) occur is determined for the cal- ient study of the substance.
As a result of the determination, it was established that the resulting conjugated compound is iinbHofi cytotoxic
active activity .C / i 50 - 5 -10 M), i.e. about 400 times more significant than the cytoxic activity of the егicin ц flake.
Inhibition of the formation of colonies.
Cells with a melanoma culture M 1477 are peeled off from their substrate using Versene solution (PBS buffer solution containing ethylenediamine
five
0
five
0
five
0
five
0
five
heteroacetic acid) or by trypsinization. These cells are seeded (on the basis of 210 cells per Petri dish, having a diameter of 5 cm) medium of the following composition: medium PPM1 1640 (Mericux) with glutamine added 2 mM, sodium bicarbonate 2 g / l, 15% inactivated calf seed droplet (Seromed) and the antibiotic penicillin, streptomycin and amphotericin R).
After 24 hours, the cells are treated with various concentrations of the compound prepared in Example 1.
For comparison, a similar series of experiments was carried out with ricin, with the ricin L chain and with a non-specific conjugated compound of this cell progeny (in common with ricin chain A and anti-DNP / PS 10 antibody).
After 24 hours the culture medium is removed and replaced with the same fresh medium without any cytotoxic substance.
After 10-15 days, the number of developing colonies is determined by coloration using a purple crystal solution and an automatic colony counter (Artek system 880).
This method allows to detect such low quantities as 10 viable cells per dish, and also to carry out a check using control cultures. Thus, it was found that the formation of colonies is strictly proportional to the initial concentration of cells, but at least in the range from 10 to 10 cells per ml.
As a result of the experiment, it was established that the obtained conjugated compound has a high activity, since the last melanoma cell was killed at a concentration approximately equal to the total compound. This concentration is perfectly comparable to that of ricin (1), whereas for ricin's chain A, a concentration of 10 M is necessary to achieve a similar effect.
The conjugated compound is completely inactive at a concentration below 2-10 M.
The results of this experiment fully confirm the results obtained in the study of inhibition of proteosynthesis.
Thus, the compounds obtained according to the invention have significant specificity of action with respect to the cellular progeny of human melanoma. These compounds may be used in the treatment of human melanomas and possibly other cancers that are exposed to the antibody used.
These conjugated compounds are defined for use as an injection. They can be used either alone or in combination with other drugs shown for cancer diseases, and in particular, in combination with other immuno-suppressant drugs to slow and weaken the patient's natural immune response to persistent HrfHX substances in his body. which are conjugated compounds.
In order to completely remove the rapeseed cells, the treatment must be carried out using a sufficient dose of the conjugated substance, and the duration of treatment must be determined in each individual case depending on the cause and nature of the disease being recovered.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining a conjugated compound specific for melanoma cells, characterized in that, in order to increase the therapeutic activity of the preparation, antibodies to melanoma, treated in the presence of a water-soluble carbodiimide compound of the formula
ABOUT,
/ s- (CIS) g-5-zones
25 interact with the ricin chain A.

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FR2437213B1|1978-09-28|1983-05-06|Cm Ind|

US4315851A|1978-12-29|1982-02-16|Kureha Kagaku Kogyo Kabushiki Kaisha|Pharmaceutical composition having antitumor activity|

FR2466252B2|1979-10-03|1983-08-12|Clin Midy|JPH0259128B2|1981-09-08|1990-12-11|Suntory Ltd|

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EP2599793A1|2008-05-29|2013-06-05|Nuclea Biotechnologies, Inc.|Anti-phospho-akt antibodies|

ES2654387T3|2008-07-23|2018-02-13|Ambrx, Inc.|Modified bovine G-CSF polypeptides and their uses|

PT2337846T|2008-09-26|2018-04-05|Ambrx Inc|Non-natural amino acid replication-dependent microorganisms and vaccines|

AU2009296397B2|2008-09-26|2012-11-08|Ambrx Inc.|Modified animal erythropoietin polypeptides and their uses|

CN104922655A|2009-02-06|2015-09-23|加利福尼亚大学董事会|Calcium-binding agents induce hair growth and/or nail growth|

WO2011087810A1|2009-12-21|2011-07-21|Ambrx, Inc.|Modified porcine somatotropin polypeptides and their uses|

MX349301B|2009-12-21|2017-07-21|Ambrx Inc|Modified bovine somatotropin polypeptides and their uses.|

WO2011133948A2|2010-04-22|2011-10-27|Longevity Biotech, Inc.|Highly active polypeptides and methods of making and using the same|

US9567386B2|2010-08-17|2017-02-14|Ambrx, Inc.|Therapeutic uses of modified relaxin polypeptides|

US11246915B2|2010-09-15|2022-02-15|Applied Molecular Transport Inc.|Cholix toxin-derived fusion molecules for oral delivery of biologically active cargo|

MX354016B|2010-09-15|2018-02-07|J Mrsny Randall|Systems and methods of delivery of bioactive agents using bacterial toxin-derived transport sequences.|

ES2644865T3|2010-09-29|2017-11-30|Uti Limited Partnership|Methods for the treatment of autoimmune diseases using bioabsorbent and biocompatible nanospheres|

US9511151B2|2010-11-12|2016-12-06|Uti Limited Partnership|Compositions and methods for the prevention and treatment of cancer|

CN103518135B|2011-03-11|2016-08-17|内布拉斯加大学董事委员会|The biomarker of coronary artery disease|

US9790262B2|2011-04-05|2017-10-17|Longevity Biotech, Inc.|Compositions comprising glucagon analogs and methods of making and using the same|

US9796754B2|2011-05-27|2017-10-24|Ambrx, Inc.|Compositions containing, methods involving, and uses of non-natural amino acid linked dolastatin derivatives|

DK3170821T3|2011-05-27|2021-10-11|Ambrx Inc|COMPOSITIONS CONTAINING, INVOLVING PROCEDURES, AND USES OF NON-NATURAL AMINO ACID-BINDED DOLASTATIN DERIVATIVES|

DK2822575T3|2012-03-03|2020-06-15|Immungene Inc|MANIPULATED, MUTERATED ANTIBODY-INTERFERON FUSION MOLECULES|

US10988516B2|2012-03-26|2021-04-27|Uti Limited Partnership|Methods and compositions for treating inflammation|

EP3536700A1|2012-06-07|2019-09-11|Ambrx, Inc.|Prostate-specific membrane antigen antibody drug conjugates|

US20150152187A1|2012-06-14|2015-06-04|Ambrx, Inc.|Anti-PSMA Antibodies Conjugated to Nuclear Receptor Ligand Polypeptides|

EP2861262B1|2012-06-19|2018-11-28|Ambrx, Inc.|Anti-cd70 antibody drug conjugates|

US9603948B2|2012-10-11|2017-03-28|Uti Limited Partnership|Methods and compositions for treating multiple sclerosis and related disorders|

WO2014145718A2|2013-03-15|2014-09-18|Longevity Biotech, Inc.|Peptides comprising non-natural amino acids and methods of making and using the same|

US10519247B2|2013-11-01|2019-12-31|Board Of Regents,The University Of Texas System|Targeting HER2 and HER3 with bispecific antibodies in cancerous cells|

CA2929700A1|2013-11-04|2015-05-07|Uti Limited Partnership|Methods and compositions for sustained immunotherapy|

FR3018526B1|2014-03-14|2021-06-11|Herakles|CVI DENSIFICATION INSTALLATION INCLUDING A HIGH-CAPACITY PREHEATING ZONE|

EP3139965B1|2014-05-07|2021-09-29|Applied Molecular Transport Inc.|Cholix toxin-derived fusion molecules for oral delivery of biologically active cargo|

KR20170070227A|2014-10-24|2017-06-21|브리스톨-마이어스 스큅 컴퍼니|Modified fgf-21 polypeptides and uses thereof|

MX2017014199A|2015-05-06|2018-03-28|Uti Lp|Nanoparticle compositions for sustained therapy.|

CA3006759A1|2015-11-30|2017-06-08|The Regents Of The University Of California|Tumor-specific payload delivery and immune activation using a human antibody targeting a highly specific tumor cell surface antigen|

CA3020601A1|2016-04-12|2017-10-19|Blaze Bioscience, Inc.|Methods of treatment using chlorotoxin conjugates|

WO2018089807A2|2016-11-11|2018-05-17|The Regents Of The University Of California|Anti-cd46 antibodies and methods of use|

CN110291205A|2016-12-12|2019-09-27|塞弗德公司|The immuno-PCR and foranalysis of nucleic acids of integration in automatic reaction box|

JP2020503367A|2017-01-05|2020-01-30|ザリージェンツオブザユニバーシティオブカリフォルニア|PAC1 receptor agonistand use thereof|

CN110637027A|2017-02-08|2019-12-31|百时美施贵宝公司|Modified relaxin polypeptides comprising pharmacokinetic enhancers and uses thereof|

EP3762009A1|2018-03-08|2021-01-13|Applied Molecular Transport Inc.|Toxin-derived delivery constructs for oral delivery|

JP2021519076A|2018-03-29|2021-08-10|アンブルックス，インコーポレイテッドＡｍｂｒｘ，Ｉｎｃ．|Humanized anti-prostate specific membrane antigenantibody drug conjugate|

WO2020047176A1|2018-08-28|2020-03-05|Ambrx, Inc.|Anti-cd3 antibody folate bioconjugates and their uses|

BR112021004488A2|2018-09-11|2021-06-01|Ambrx, Inc.|interleukin-2 polypeptide conjugates and their uses|

JP2022512746A|2018-10-19|2022-02-07|アンブルックス，インコーポレイテッド|Interleukin-10 polypeptide complex, its dimer, and their use|

EP3844169A4|2019-08-16|2021-12-15|Applied Molecular Transport Inc.|Compositions, formulations, and interleukin production and purification|

BR112021015832A2|2019-02-12|2022-01-18|Ambrx Inc|Compositions containing antibody-tlr agonist conjugates, methods and uses thereof|

WO2021173889A1|2020-02-26|2021-09-02|Ambrx, Inc.|Uses of anti-cd3 antibody folate bioconjugates|

WO2021183832A1|2020-03-11|2021-09-16|Ambrx, Inc.|Interleukin-2 polypeptide conjugates and methods of use thereof|

WO2022040596A1|2020-08-20|2022-02-24|Ambrx, Inc.|Antibody-tlr agonist conjugates, methods and uses thereof|

法律状态:

优先权:

申请号 | 申请日 | 专利标题

FR8107596A|FR2504010B1|1981-04-15|1981-04-15|ANTI-CANCER MEDICINAL PRODUCTS CONTAINING THE RICIN-ASSOCIATED CHAIN ASSOCIATED WITH ANTIMELANOMA ANTIBODY AND PROCESS FOR THEIR PREPARATION|

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