Pulito V L, Roberts V A, Adair J R, Rothermel A L, Collins A M, Varga S S, Martocello C, Bodmer M, Jolliffe L K, Zivin R A
Drug Discovery, R.W. Johnson Pharmaceutical Research Institute, Raritan, NJ 08869, USA.
J Immunol. 1996 Apr 15;156(8):2840-50.
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.
OKT4A是一种识别CD4受体上一个表位的鼠单克隆抗体，在体外以及多种移植物排斥和自身免疫性疾病的非人类灵长类动物模型中是一种有效的免疫抑制剂。最初的人类心脏移植试验表明，OKT4A既不会引起细胞因子释放综合征，也不会导致CD4+细胞耗竭，但尽管同时进行了强效免疫抑制，它仍会诱导人抗鼠抗体（HAMA）反应。为了进一步研究OKT4A作为免疫调节剂的潜力，有必要降低其免疫原性。因此，我们开发了该抗体的人源化版本（gOKT4A-4），它具有与OKT4A相同的结合亲和力和体外免疫抑制特性，但在互补决定区（CDR）之外仅保留三个源自鼠序列的氨基酸残基。对OKT4A和gOKT4A-4进行的详细计算机建模为人类化后恢复活性所需的变化提供了计算依据。这也为抗原结合位点提供了一个合理的表征。gOKT4A-4的初步临床结果表明，我们已经消除了在亲本鼠抗体中观察到的免疫原性。
