Development of antagonistic mAbs that specifically target the immune checkpoint receptor, programmed cell death protein-1 (PD-1), is of great interest for cancer immunotherapy. Here, we report the biophysical characteristics and nonclinical antagonistic activities of sasanlimab (PF-06801591), a humanized anti-PD-1 antibody of IgG4 isotype. We show that sasanlimab binds selectively and with similar high potency to human and cynomolgus monkey PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, with no detectable Fc-dependent effector function. The binding of sasanlimab to human and cynomolgus PD-1 is associated with the formation of a stable complex, which is likely to be the main driver of this high-affinity interaction. In vitro, sasanlimab significantly augmented T-cell proliferation and cytokine production in mixed lymphocyte reaction and superantigen stimulation assays. In vivo, sasanlimab accelerated the incidence of GvHD by enhancing T-cell proliferation and cytokine secretion in a xenogeneic model of acute GvHD and halted the growth of MC-38 colon adenocarcinoma tumors in human PD-1 knock-in mice. Pharmacokinetic and toxicokinetic findings from cynomolgus monkey showed that sasanlimab was active and well-tolerated. Taken together, the data presented here support the clinical development of sasanlimab for the treatment of patients with advanced cancers as a single agent or in combination with other immunotherapies.

中文翻译：

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Sasanlimab 的药理特性和临床前活性，一种高亲和力的工程抗人 PD-1 抗体

开发特异性靶向免疫检查点受体程序性细胞死亡蛋白-1 (PD-1) 的拮抗性 mAb 对癌症免疫治疗具有重要意义。在这里，我们报告了 sasanlimab (PF-06801591) 的生物物理特征和非临床拮抗活性，这是一种 IgG4 同种型的人源化抗 PD-1 抗体。我们表明 sasanlimab 与人类和食蟹猴 PD-1 受体选择性结合并具有相似的高效能，并阻断其与 PD-L1 和 PD-L2 的相互作用，没有可检测到的 Fc 依赖性效应子功能。sasanlimab 与人和食蟹猴 PD-1 的结合与稳定复合物的形成有关，这可能是这种高亲和力相互作用的主要驱动因素。体外，sasanlimab 在混合淋巴细胞反应和超抗原刺激试验中显着增强了 T 细胞增殖和细胞因子的产生。在体内，sasanlimab 通过在急性 GvHD 异种模型中增强 T 细胞增殖和细胞因子分泌来加速 GvHD 的发生，并在人 PD-1 敲入小鼠中阻止 MC-38 结肠腺癌肿瘤的生长。食蟹猴的药代动力学和毒代动力学结果表明 sasanlimab 具有活性且耐受性良好。总之，此处提供的数据支持 sasanlimab 作为单一药物或与其他免疫疗法联合治疗晚期癌症患者的临床开发。sasanlimab 通过增强急性 GvHD 异种模型中的 T 细胞增殖和细胞因子分泌来加速 GvHD 的发生，并在人 PD-1 敲入小鼠中阻止 MC-38 结肠腺癌肿瘤的生长。食蟹猴的药代动力学和毒代动力学结果表明 sasanlimab 具有活性且耐受性良好。总之，此处提供的数据支持 sasanlimab 作为单一药物或与其他免疫疗法联合治疗晚期癌症患者的临床开发。sasanlimab 通过增强急性 GvHD 异种模型中的 T 细胞增殖和细胞因子分泌来加速 GvHD 的发生，并在人 PD-1 敲入小鼠中阻止 MC-38 结肠腺癌肿瘤的生长。食蟹猴的药代动力学和毒代动力学结果表明 sasanlimab 具有活性且耐受性良好。总之，此处提供的数据支持 sasanlimab 作为单一药物或与其他免疫疗法联合治疗晚期癌症患者的临床开发。