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Chimeric and humanized antibodies

The use of murine mAbs in immunotherapy is impaired by their limited half-life in the circulation because patients raise human anti-mouse antibodies, which precludes long-term treatments. To circumvent the problem of immunogenicity, some chimeric antibodies were genetically engineered that combine the V regions of the mouse antibody, responsible for the binding of the Ag, with the human antibody C regions [1,2]. These chimeric antibodies are expected to be less immunogenic than their murine counterpart, avoiding anti-isotypic antibodies [3,4]. Moreover, the presence of human C regions lead to molecules with efficient effector functions such as complement and cell mediated lysis [5].

It is possible to reduce further the murine part of the chimeric antibody, decreasing therefore immunogenicity, without affecting specificity and affinity for the antigen. The strategy is to identify the amino acids present at the binding site that correspond to the CDRs and those responsible for the conformation of the binding site. On the basis of correlations between antibody structure and amino acid primary sequence, Chothia et al. [6,7] proposed that there is a small repertoire of main chain conformations called canonical structures for at lease five of the six hypervariable loops (L1, L2, L3, H1 and H2) and that the particular conformation adopted is determined by a few conserved key residues.

Winter's group has genetically engineered humanized or reshaped Abs which are human Abs in which the only murine amino acids present are those of the CDR and those necessary for the conservation of the conformation of the binding site [8-10].

The IMGT unique numbering for V-DOMAIN and V-LIKE-DOMAIN [11] has allowed to propose a standardized delimitation of the FR-IMGT and CDR-IMGT based on structural data, which are particularly important to be considered for antibody humanization.

[1] Bouliane, G. L. et al., Nature, 312, 643-646 (1984).
[2] Neuberger, M. S. et al., Nature, 314, 268-270 (1985).
[3] Bruggemann, M. et al., J. Exp. Med., 170, 2153-2157 (1989).
[4] LoBuglio, A. F. et al., Proc. Natl. Acad. Sci. USA, 86, 4220-4224 (1989).
[5] Bruggemann, M. et al., J. Exp. Med., 166, 1351-1361 (1987).
[6] Chothia, C. and Lesk, A. M., J. Mol. Biol., 196, 901-917 (1987).
[7] Chothia, C. et al., Nature, 342, 877-883 (1989).
[8] Jones, P. T. et al., Nature, 321, 522-525 (1986).
[9] Riechmann, L. et al., Nature, 332, 323-327 (1988).
[10] Verhoeyen, M. et al., Science, 239, 1534-1536 (1988).
[11] Lefranc, M.-P. et al., Dev. Comp. Immunol., 27, 55-77 (2003) PMID: 12477501 pdf with permission form Elsevier
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