Production of chimeric antibodies - a combinatorial approach

Details Production of chimeric antibodies - a combinatorial approach Production of chimeric antibodies - a combinatorial approach

1994-06-24

1996-10-15

Adams, Donald E.

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Recombinant dna technique included in method of making a...

435 5, 435 697, 435 698, 435 911, 4352351, 4352523, 43525233, 4353201, 5303871, 5303873, 530867, 536 231, 536 234, 536 2333, A61K 3516, A61K 3900, C07K 1600

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active

055653324

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to the production of antibodies. More particularly, it relates to the production of antibodies with increased human characteristics over a parent antibody specific for the same antigen.
Many rodent monoclonal antibodies have been isolated using hybridoma technology and utilised for in vivo therapeutic and diagnostic purposes in humans. For example, an early application of these mouse monoclonal antibodies was as targeting agents to kill or image tumours (F. H. Deland and D. M. Goldenberg 1982 in `Radionuclide Imaging` ed. D. E. Kuhl pp289-297, Pergamon, Paris; R. Levy and R. A. Miller Ann. Rev. Med. 1983, 34 pp107-116). However, the use of such antibodies in vivo can lead to problems. The foreign immunoglobulins can elicit an anti-globulin response (known as a human anti-mouse antibody (HAMA) response) Which can interfere with therapy (R. A. Miller et al, 1983 Blood 62 988-995) or cause allergic or immune complex hypersensitivity (B. Ratner, 1943, Allergy, Anaphylaxis and Immunotherapy Williams and Wilkins, Baltimore).
To overcome these problems, Winter and colleagues (GB2188638B) developed a method of humanising or "reshaping` such antibodies. The complementarity determining regions (CDRs) of the mouse antibody, which comprise the antigen combining site, are inserted into human framework regions thereby generating antibodies in which only the CDR sequences are derived from the original mouse antibody. This is the technique known as "CDR-grafting" or "CDR-imprinting". One such reshaped antibody CAMPATH-1 (L. Riechmann et al, 1988 Nature 332, pp323-327 has been used successfully in the treatment of B cell lymphoma (G. Hale et al, 1988 Lancet 2, pp1394-1399) and vasculitis (P. W. Mathieson et al New Engl. J. Med. 1990 323, pp250-254) and rheumatoid arthritis (V. Kyle et at 1991 J. Rheumatol. 18, pp1737-1738). This has prompted the humanisation of a large number of antibodies for therapeutic purposes directed against cancer markers, for example the interleukin 2 receptor (C. Queen et al, 1989 Proc. Natl. Acad. Sci. USA, 86, pp10029-10033); epidermal growth factor receptor (C. A. Kettleborough et al 1991 Protein Eng. 4, pp773-783; P. Carter et al 1992 Proc. Natl. Acad. Sci. USA 89, pp4285-4289) and carcinoembryonic antigen (K. Bosslet et al. Brit. J. Cancer 65, pp234-238, 1992). A number of antibodies directed against infectious viruses have also been humanised, for instance antibodies directed against respiratory syncytial virus (P. R. Tempest et al, 1991 Bio/Technology 9, pp266-271); herpes simplex virus (M. S. Co et al 1991 Proc. Natl. Acad. Sci. USA 88, pp2869-2873) and human immunodeficiency virus (H. Maeda et al 1991 Human Antibodies and Hybridomas 2, pp124-134). Humanised antibodies have also been used for imaging tumours after labelling with radioisotopes (V. Hird et al, 1991 Brit. J. Cancer 64 911-914).
Successful reshaping depends on the rodent and human framework regions being structurally conserved both in the orientation of the beta-sheets of each domain and in the packing of the heavy and light chains together; the hypervariable loops making the majority of contacts with antigen and the loops being supported in a similar way by the underlying beta-sheet framework. Although these conditions are likely to be true for some antibodies, the restitution of key contacts between the loops and the framework has proved necessary in others, and has been assisted by molecular modelling (Riechmann et al, 1988 supra; Tempest et al, 1991 supra) and systematic matching of rodent and human framework regions to minimise differences in primary sequences (Queen et al, 1989 supra; Gorman et al, 1991 supra; Maeda et al supra). Studies have shown that there are a number of residues in the `Vernier` zone underlying the CDRs of both heavy and light chain variable domains which may adjust CDR structure and fine tune to fit the antigen and thus have a strong effect on affinity and specificity (J. Foote and G. Winter 1992 J. Mol. Biol. 224 487-499).A variation of this approach is to transfer th

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