Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Patent
1988-04-27
1991-07-09
Doll, John
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
530389, 530402, 530409, 530410, 424 8591, C07K 1706, A61K 3944
Patent
active
050307193
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE ART
The present invention relates to cytotoxic antibody conjugates.
Particularly, the present invention relates to cytotoxic antibody conjugates in which a folic acid-antagonistic folic acid analogue is conjugated with an antibody selectively binding to a specific antigen in the cells to be killed or its fragment including the antigen-binding site through an oligopeptide, and a process for preparation thereof.
BACKGROUND OF THE ART
A folic acid-antagonistic folic acid analogue means a substance which has a chemical structure similar to folic acid, but inhibits partially or totally the actions of folic acid or its derivatives. A variety of such substances have been synthesized and some of them have been applied to the chemotherapy for cancers such as leukemia or malignant tumors.
It has been known that a cytotoxic conjugate of a folic acid-antagonistic folic acid analogue with an antibody is formed by linking methotrexate with the antibody using a water-soluble carbodiimide as a condensation agent or using an active ester of methotrexate (see P. N. Kulkarni et al.: Cancer Research 41, 2700-2706, 1981). Further, M. C. Garnet disclosed a method of conjugating methotrexate with an antibody via serum albumin as an intermediary (Int. J. Cancer, 31, 661-670, 1983). Neither, however, the process for conjugation of a folic acid-antagonistic folic acid analogue with an antibody or its fragment via an oligopeptide nor such a cytotoxic antibody conjugate have been known. Conventional conjugates resulting from direct conjugation of methotrexate with an antibody is unsatisfactory in potency and selectivity of cytotoxicity and antitumor activity, while oligopeptide-mediated conjugates seem to meet the expectation of resolving these problems.
DISCLOSURE OF THE INVENTION
The present inventors have made intense study on the development of procedures for conjugating a folic acid-antagonistic folic acid analogue with an antibody or its fragment via an oligopeptide and of useful cytotoxic antibody conjugates through the processes. The intermediate obtained by linking a folic acid-antagonistic folic acid analogue to an oligopeptide at the N-terminal has carboxyl groups on the folic acid analogue as well as on the C-terminal of the oligopeptide. Therefore, it cannot be bonded to an antibody or its fragment selectively only through the latter carboxyl. The development of a new type of reaction of the intermediate with an antibody or its fragment is required including the derivation of a suitably reactive compound from the intermediate.
The present inventors have reached this invention by finding that a halogenated (especially iodinated or brominated) acetyl hydrazide is high reactive with an antibody or its fragment and the folic acid-antagonistic folic acid analogue can be led to a halogenated acetyl hydrazide derivative through the oligopeptide moiety.
Namely, the present invention relates to cytotoxic antibody conjugates in which a folic acid-antagonistic folic acid analogue is bonded through an oligopeptide and preferably relates to cytotoxic antibody conjugates with excellent cytotoxicity and antitumor properties having a general formula [I] acid-antagonistic folic acid analogue, --NH--Y--CO-- represents the residual group of an oligopeptide containing L-leucyl-L-alanyl-L-leucine, Ab represents an antibody or its fragment, the N-atom adjacent to Ab is the nitrogen atom originating from the antibody or its fragment, and n is an integer of from 1 to 30.
The present invention also relates to a general process for preparation of cytotoxic antibody conjugates including the conjugates stated above, in other words, a process for preparation of cytotoxic antibody conjugates of general formula [II] originating from the cytotoxic substance, the N-atom linking with Ab originates from the anti-body or its fragment, and n is an integer of from 1 to 30,
characterized by reaction of an ahtibody or its fragment with a halogenated acetyl hydrazide derivative of a cytotoxic substance having a general formula [III] a haloge
REFERENCES:
patent: 4203898 (1980-05-01), Cullinan et al.
patent: 4376765 (1983-03-01), Trouet et al.
patent: 4671958 (1987-06-01), Rodwell et al.
Aboud-Pirak et al. (1989) Biochem. Pharmacol. 38(4)-641-648.
Baurain et al., Drugs Exptl. Clin. Res. IX, 4:303-311 (1983).
Kulkarni et al., (1981), Cancer Res. 41:2700-2706.
Trouet et al., (1982), Proc. Natl. Acas. Sci. 79:626-629.
Umemoto et al., (1989) Cancer Immunol. Immunother. 28:9-16.
Umemoto et al., (1989) Int. J. Cancer 43:677-684.
Hara Takeshi
Kato Yoshinori
Umemoto Naoji
Doll John
Kim Kay
Teijin Limited
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