Preclinical Efficacy and Immunological Safety of FR104, an Antagonist Anti-CD28 Monovalent Fab' Antibody
Preclinical Efficacy and Immunological Safety of FR104, an Antagonist Anti-CD28 Monovalent Fab' Antibody
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DOI：
10.1111/j.1600-6143.2012.04164.x
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发表时间：
2012-10-01
影响因子：
8.8
通讯作者：
Vanhove, B.
中科院分区：
文献类型：
--
作者：
Poirier, N.;Mary, C.;Vanhove, B.
拮抗性抗 CD28 抗体可阻止 T 细胞共刺激并与 CTLA4Ig 区分开，因为它们不能阻断 CTLA-4 和 PDL-1 共抑制信号。他们证明了在抑制效应 T 细胞同时增强调节性 T 细胞功能和免疫耐受方面的功效。然而，尚未开发出没有免疫毒性且具有良好药代动力学特征的抗CD28抗体。在这里，我们描述了 FR104，一种新型人源化聚乙二醇化抗 CD28 Fab' 抗体片段，在猴子中具有较长的消除半衰期。在体外，即使存在抗 CD3 抗体或与二抗交联，FR104 也无法诱导人 T 细胞增殖和细胞因子分泌。此外，在人源化 NOD/SCID 小鼠中过继转移人 PBMC，而超级激动剂和二价抗体引发快速细胞因子分泌和人 T 细胞激活，而 FR104 则不然。这些人源化小鼠出现了严重的移植物抗宿主病，通过以 CTLA4 依赖性方式施用 FR104 可以预防这种疾病。有趣的是，给予高剂量的CTLA4-Ig对于预防GVHD无效，而给予低剂量则部分有效。总之，我们证明 FR104 对人类 T 细胞缺乏激动剂活性，因此与 CD80/CD86 拮抗剂相比，通过保留 CTLA-4，与可能导致更高治疗指数的临床开发相容。
Antagonist anti-CD28 antibodies prevent T cell costimulation and differentiate from CTLA4Ig since they cannot block CTLA-4 and PDL-1 coinhibitory signals. They demonstrated efficacy in suppressing effector T cells while enhancing regulatory T cells function and immune tolerance. However, anti-CD28 antibodies devoid of immunotoxicity and with a good pharmacokinetic profile have not yet been developed. Here, we describe FR104, a novel humanized pegylated anti-CD28 Fab' antibody fragment presenting a long elimination half-life in monkeys. In vitro, FR104 failed to induce human T cell proliferation and cytokines secretion, even in the presence of anti-CD3 antibodies or when cross-linked with secondary antibodies. Furthermore, in humanized NOD/SCID mice adoptively transferred with human PBMC, whereas superagonist and divalent antibodies elicited rapid cytokines secretion and human T cell activation, FR104 did not. These humanized mice developed a florid graft-versus-host disease, which was prevented by administration of FR104 in a CTLA4-dependent manner. Interestingly, administration of high doses of CTLA4-Ig was ineffective to prevent GVHD, whereas administration of low doses was partially effective. In conclusion, we demonstrated that FR104 is devoid of agonist activity on human T cells and thus compatible with a clinical development that might lead to higher therapeutic indexes, by sparing CTLA-4, as compared to CD80/CD86 antagonists.