Humanization and molecular modeling of the anti-CD4 monoclonal antibody, OKT4A.
Humanization and molecular modeling of the anti-CD4 monoclonal antibody, OKT4A.
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DOI：
10.4049/jimmunol.156.8.2840
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发表时间：
1996-04
影响因子：
4.4
通讯作者：
Virginia Pulito;Victoria A. Roberts;J. Adair;Annette L. Rothermel;Alexander M. Collins;Sally S. Varga;Cathy Martocello;M. W. Bodmer;L. Jolliffe;R. Zivin
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文献类型：
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作者：
Virginia Pulito;Victoria A. Roberts;J. Adair;Annette L. Rothermel;Alexander M. Collins;Sally S. Varga;Cathy Martocello;M. W. Bodmer;L. Jolliffe;R. Zivin
OKT4A是一种识别CD4受体表位的小鼠单抗，在体外和多种移植排斥和自身免疫性疾病的非人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不会引起细胞因子释放综合征或CD4+细胞耗竭，但尽管同时存在强烈的免疫抑制，但确实会诱导人抗小鼠Ab （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，我们开发了这种Ab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）之外仅保留了三个小鼠序列衍生的氨基酸残基。对OKT4A和gOKT4A-4的详细计算机模拟为人性化后恢复活动所需的变化提供了计算基础。这也为银结合位点提供了一个合理的表示。gOKT4A-4的初步临床结果表明，我们已经消除了在亲本小鼠Ab中观察到的免疫原性。
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.