HUMANIZATION AND MOLECULAR MODELING OF THE ANTI-CD4 MONOCLONAL-ANTIBODY, OKT4A

OKT4A, a murine mAb that recognizes an epitope on the CD4 receptor, is a potent immunosuppressive agent in vitro and in a variety of nonhuma n primate models of graft rejection and autoimmune disease. Initial hu man 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 immunos uppression. To further investigate the potential of OKT4A as an immuno modulator, 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 OK T4A, but retains only three murine sequence-derived amino acid residue s 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 humanizat ion, This has also provided a plausible representation of the Ag bindi ng site. Preliminary clinical results with gOKT4A-4 suggest that we ha ve eliminated the immunogenicity observed in the parent murine Ab.