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

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

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2840-2850
Number of pages11
JournalJournal of Immunology
Volume156
Issue number8
StatePublished - Apr 15 1996

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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