CDR grafted humanised chimeric T-cell antibodies

Details CDR grafted humanised chimeric T-cell antibodies CDR grafted humanised chimeric T-cell antibodies

1994-07-15

1996-03-26

Chan, Christina Y.

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...

435 691, 435 697, 435 911, 4352401, 43524027, 4352523, 4353201, 4352402, 5303871, 53038822, 53038875, 530867, 536 2353, A61K 3516, A61K 3900, A61K 39395, C07K 1600

Patent

active

055021670

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a humanized antibody which binds to resting and activated T cells, inhibits T cell proliferation and lyses T cells from mice transgenic for human CD2, to the preparation of such an antibody and to a pharmaceutical composition which contains the antibody.
Antibodies typically comprise two heavy chains linked together by disulphide bonds and two light chains. Each light chain is linked to a respective heavy chain by disulphide bonds. Each heavy chain has at one end a variable domain followed by a number of constant domains. Each light chain has a variable domain at one end and a constant domain at its other end. The light chain variable domain is aligned with the variable domain of the heavy chain. The light chain constant domain is aligned with the first constant domain of the heavy chain. The constant domains in the light and heavy chains are not involved directly in binding the antibody to antigen.
The variable domains of each pair of light and heavy chains form the antigen binding site. The domains on the light and heavy chains have the same general structure and each domain comprises a framework of four regions, whose sequences are relatively conserved, connected by three complementarity determining regions (CDRs). The four framework regions largely adopt a beta-sheet conformation and the CDRs form loops connecting, and in some cases forming part of, the beta-sheet structure. The CDRs are held in close proximity by the framework regions and, with the CDRs from the other domain, contribute to the formation of the antigen binding site. CDRs and framework regions of antibodies may be determined by reference to Kabat et al., ("Sequences of proteins of immunological interest" U.S. Dept. of Health and Human Services, U.S. Government Printing Office, 1987).
The preparation of an altered antibody in which the CDRs are derived from a different species than the framework of the antibody's variable domains is disclosed in EP-A-0239400. The CDRs may be derived from a rat or mouse monoclonal antibody. The framework of the variable domains, and the constant domains, of the altered antibody may be derived from a human antibody. Such a humanised antibody elicits a negligible immune response when administered to a human compared to the immune response mounted by a human against a rat or mouse antibody. Humanised CAMPATH-1 antibody (Campath is a Trademark of The Wellcome Foundation Ltd.) is disclosed in EP-A-0328404.
Human T cells play an important role in regulation of the immune response. Anti-T cell antibodies may therefore be immunosuppressive when administered in vivo. Such antibodies may be useful as a result in the treatment of for example, graft versus host disease, transplant rejection and autoimmune diseases such as rheumatoid arthritis.
Non-human monoclonal antibodies have been raised which are anti-T cell antibodies. However, non-human monoclonal antibodies do not fix human complement particularly well and are immunogenic when injected into a human patient. Chimaeric antibodies have been proposed in WO 89/09622 which are composed of a human constant region and a mouse variable region. However, a significant immunogenicity problem remains.
According to one aspect the present invention provides a humanised antibody in which the amino acid sequence of the CDRs is derived from the sequence of the CDRs of a monoclonal antibody having the specificity of binding to resting and activated T-cells, inhibiting T-cell proliferation and lysing T-cells from mice transgenic for human CD2 and in which sufficient of the amino acid sequence of each CDR has been retained to provide the same specificity for the humanised antibody.
According to another aspect of the present invention, there is provided a humanised antibody in which sufficient of the amino acid sequence of each CDR shown below is provided such that the antibody is capable of binding to a human T-cell antigen:
The antibody preferably has the structure of a natural antibody or a fragment thereof. The antibody may therefore comprise a

REFERENCES:
Uggla et al. Scand. J. Immunol. 29:507-515 (1989).
Yakida Hideo JP2097400 (1990) abstract only.
Chothia et al., J. Mol. Bio. 196:901-907 (1987).

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