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Humanization and molecular modeling of the anti-CD4 monoclonal antibody, OKT4A.

1996; American Association of Immunologists; Volume: 156; Issue: 8 Linguagem: Inglês

10.4049/jimmunol.156.8.2840

1550-6606

Virginia Pulito, Victoria Roberts, John R. Adair, Annette L. Rothermel, Amélie Collins, Sally Varga, C Martocello, Mark Bodmer, Linda K. Jolliffe, Robert A. Zivin,

T-cell and B-cell Immunology

Abstract OKT4A, a murine mAb that recognizes an epitope on the CD4 receptor, is a potent immunosuppressive agent in vitro and in a variety of nonhuman primate models of graft rejection and autoimmune disease. Initial human cardiac transplant trials suggest that OKT4A does not cause either cytokine release syndrome or CD4+ cell depletion, but does induce a human anti-mouse Ab (HAMA) response despite strong concurrent immunosuppression. To further investigate the potential of OKT4A as an immunomodulator, it was necessary to decrease its immunogenicity. Therefore, we developed a humanized version of this Ab (gOKT4A-4), which has the same binding affinity and in vitro immunosuppressive properties of OKT4A, but retains only three murine sequence-derived amino acid residues outside of the complementarity-determining regions (CDRs). Detailed computer modeling of both OKT4A and gOKT4A-4 provided a computational rationale for the changes necessary to regain activity after humanization. This has also provided a plausible representation of the Ag binding site. Preliminary clinical results with gOKT4A-4 suggest that we have eliminated the immunogenicity observed in the parent murine Ab.