Identification and Characterization of MEDI4736, an Antagonistic Anti-PD-L1 Monoclonal Antibody
Identification and Characterization of MEDI4736, an Antagonistic Anti-PD-L1 Monoclonal Antibody
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DOI：
10.1158/2326-6066.cir-14-0191
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发表时间：
2015-09-01
影响因子：
10.1
通讯作者：
McCourt, Matthew
中科院分区：
文献类型：
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作者：
Stewart, Ross;Morrow, Michelle;McCourt, Matthew
程序性细胞死亡1配体1 （PD-L1）是控制t细胞活化的B7/CD28蛋白家族的成员。许多肿瘤可以上调PD-L1的表达，抑制抗肿瘤t细胞反应，避免免疫监视和消除。我们已经鉴定并鉴定了MEDI4736，这是一种人IgG1单克隆抗体，具有高亲和力和特异性与PD-L1结合，并且被独特地设计用于防止抗体依赖性细胞介导的细胞毒性。体外实验表明，MEDI4736是PD-L1功能的有效拮抗剂，可阻断PD-1和CD80的相互作用，克服原代人t细胞活化的抑制。在体内，在含有共植入的人T细胞的新型异种移植模型中，MEDI4736显著抑制人肿瘤的生长。这种活性完全依赖于移植T细胞的存在，支持了MEDI4736的免疫作用机制。为了进一步确定PD-L1阻断的效用，在免疫功能正常的小鼠中研究了一种抗小鼠PD-L1抗体。在这里，抗小鼠PD-L1显著提高了CT26结肠直肠癌细胞植入小鼠的存活率。与奥沙利铂联合可增强抗pd - l1的抗肿瘤活性，导致CT26肿瘤内HMGB1释放增加。综上所述，我们的研究结果表明，在临床前模型中，PD-L1功能的抑制在单独治疗或联合使用时具有强大的抗肿瘤活性，并表明它可能是治疗癌症的一种有前景的治疗方法。MEDI4736目前正在进行一些单独或与其他药物联合的临床试验，包括抗ctla -4、抗pd -1和IDO、MEK、BRAF和EGFR抑制剂。(c) 2015年aacr。
Programmed cell-death 1 ligand 1 (PD-L1) is a member of the B7/CD28 family of proteins that control T-cell activation. Many tumors can upregulate expression of PD-L1, inhibiting antitumor T-cell responses and avoiding immune surveillance and elimination. We have identified and characterized MEDI4736, a human IgG1 monoclonal antibody that binds with high affinity and specificity to PD-L1 and is uniquely engineered to prevent antibody-dependent cell-mediated cytotoxicity. In vitro assays demonstrate that MEDI4736 is a potent antagonist of PD-L1 function, blocking interaction with PD-1 and CD80 to overcome inhibition of primary human T-cell activation. In vivo MEDI4736 significantly inhibits the growth of human tumors in a novel xenograft model containing coimplanted human T cells. This activity is entirely dependent on the presence of transplanted T cells, supporting the immunological mechanism of action for MEDI4736. To further determine the utility of PD-L1 blockade, an anti-mouse PD-L1 antibody was investigated in immunocompetent mice. Here, anti-mouse PD-L1 significantly improved survival of mice implanted with CT26 colorectal cancer cells. The antitumor activity of anti-PD-L1 was enhanced by combination with oxaliplatin, which resulted in increased release of HMGB1 within CT26 tumors. Taken together, our results demonstrate that inhibition of PD-L1 function can have potent antitumor activity when used as monotherapy or in combination in preclinical models, and suggest it may be a promising therapeutic approach for the treatment of cancer. MEDI4736 is currently in several clinical trials both alone and in combination with other agents, including anti-CTLA-4, anti-PD-1, and inhibitors of IDO, MEK, BRAF, and EGFR. (C) 2015 AACR.