Ligation of OX40 (CD134, TNFRSF4) on activated T cells by its natural ligand (OX40L, CD252, TNFSF4) enhances cellular survival, proliferation, and effector functions such as cytokine release and cellular cytotoxicity. We engineered a recombinant human OX40L IgG4P Fc fusion protein termed MEDI6383 that assembles into a hexameric structure and exerts potent agonist activity following engagement of OX40. MEDI6383 displayed solution-phase agonist activity that was enhanced when the fusion protein was clustered by Fc gamma receptors (FcγRs) on the surface of adjacent cells. The resulting costimulation of OX40 on T cells induced NFκB promoter activity in OX40-expressing T cells and induced Th1-type cytokine production, proliferation, and resistance to regulatory T cell (Treg)-mediated suppression. MEDI6383 enhanced the cytolytic activity of tumor-reactive T cells and reduced tumor growth in the context of an alloreactive human T cell:tumor cell admix model in immunocompromised mice. Consistent with the role of OX40 costimulation in the expansion of memory T cells, MEDI6383 administered to healthy nonhuman primates elicited peripheral blood CD4 and CD8 central and effector memory T-cell proliferation as well as B-cell proliferation. Together, these results suggest that OX40 agonism has the potential to enhance antitumor immunity in human malignancies. Mol Cancer Ther; 17(5); 1024–38. ©2018 AACR.

中文翻译：

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MEDI6383（一种工程化人 OX40 配体 IgG4P Fc 融合蛋白）的有效免疫调节

OX40（CD134、TNFRSF4）通过其天然配体（OX40L、CD252、TNFSF4）与活化的T细胞连接可增强细胞存活、增殖和效应子功能，例如细胞因子释放和细胞毒性。我们设计了一种称为 MEDI6383 的重组人 OX40L IgG4P Fc 融合蛋白，该蛋白组装成六聚体结构并在 OX40 结合后发挥有效的激动剂活性。MEDI6383 显示出溶液相激动剂活性，当融合蛋白被相邻细胞表面的 Fc γ 受体 (FcγR) 聚集时，该活性得到增强。由此产生的 OX40 对 T 细胞的共刺激诱导了表达 OX40 的 T 细胞中的 NFκB 启动子活性，并诱导了 Th1 型细胞因子的产生、增殖和对调节性 T 细胞 (Treg) 介导的抑制的抵抗。MEDI6383 在免疫功能低下小鼠的同种异体反应性人 T 细胞：肿瘤细胞混合模型的背景下，增强了肿瘤反应性 T 细胞的细胞溶解活性并减少了肿瘤生长。与 OX40 共刺激在记忆 T 细胞扩增中的作用一致，将 MEDI6383 施用于健康的非人类灵长类动物，引发外周血 CD4 和 CD8 中枢和效应记忆 T 细胞增殖以及 B 细胞增殖。总之，这些结果表明 OX40 激动具有增强人类恶性肿瘤抗肿瘤免疫力的潜力。摩尔癌症治疗; 17(5); 1024-38。©2018 AACR。对健康的非人类灵长类动物施用 MEDI6383 可引发外周血 CD4 和 CD8 中枢和效应记忆 T 细胞增殖以及 B 细胞增殖。总之，这些结果表明 OX40 激动具有增强人类恶性肿瘤抗肿瘤免疫力的潜力。摩尔癌症治疗; 17(5); 1024-38。©2018 AACR。对健康的非人类灵长类动物施用 MEDI6383 可引发外周血 CD4 和 CD8 中枢和效应记忆 T 细胞增殖以及 B 细胞增殖。总之，这些结果表明 OX40 激动具有增强人类恶性肿瘤抗肿瘤免疫力的潜力。摩尔癌症治疗; 17(5); 1024-38。©2018 AACR。