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  • Title: Humanization and molecular modeling of the anti-CD4 monoclonal antibody, OKT4A.
    Author: Pulito VL, Roberts VA, Adair JR, Rothermel AL, Collins AM, Varga SS, Martocello C, Bodmer M, Jolliffe LK, Zivin RA.
    Journal: J Immunol; 1996 Apr 15; 156(8):2840-50. PubMed ID: 8609403.
    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.
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