Antibody Development and Protein Engineering, BioPharmaceuticals R&D, AstraZeneca , Cambridge, UK.
Discovery Biosciences, Oncology R&D, AstraZeneca , Gaithersburg, MD, USA.
MAbs. 2021 Jan-Dec;13(1):1857100. doi: 10.1080/19420862.2020.1857100.
Preclinical studies of PD-L1 and CTLA-4 blockade have relied heavily on mouse syngeneic tumor models with intact immune systems, which facilitate dissection of immunosuppressive mechanisms in the tumor microenvironment. Commercially developed monoclonal antibodies (mAbs) targeting human PD-L1, PD-1, and CTLA-4 may not demonstrate cross-reactive binding to their mouse orthologs, and surrogate anti-mouse antibodies are often used in their place to inhibit these immune checkpoints. In each case, multiple choices exist for surrogate antibodies, which differ with respect to species of origin, affinity, and effector function. To develop relevant murine surrogate antibodies for the anti-human PD-L1 mAb durvalumab and the anti-human CTLA-4 mAb tremelimumab, rat/mouse chimeric or fully murine mAbs engineered for reduced effector function were developed and compared with durvalumab and tremelimumab. Characterization included determination of target affinity, in vivo effector function, pharmacokinetic profile, and anti-tumor efficacy in mouse syngeneic tumor models. Results showed that anti-PD-L1 and anti-CTLA-4 murine surrogates with pharmacologic properties similar to those of durvalumab and tremelimumab demonstrated anti-tumor activity in a subset of commonly used mouse syngeneic tumor models. This activity was not entirely dependent on antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis effector function, or regulatory T-cell depletion, as antibodies engineered to lack these features showed activity in models historically sensitive to checkpoint inhibition, albeit at a significantly lower level than antibodies with intact effector function.
临床前研究的 PD-L1 和 CTLA-4 封锁严重依赖于具有完整免疫系统的小鼠同基因肿瘤模型，这有利于剖析肿瘤微环境中的免疫抑制机制。商业化开发的针对人 PD-L1、PD-1 和 CTLA-4 的单克隆抗体（mAb）可能不会与人源 PD-L1、PD-1 和 CTLA-4 的鼠源同源物发生交叉反应性结合，并且通常使用替代的抗鼠抗体来抑制这些免疫检查点。在每种情况下，都存在用于替代抗体的多种选择，这些选择在来源物种、亲和力和效应功能方面存在差异。为了开发用于抗人 PD-L1 mAb 度伐鲁单抗和抗人 CTLA-4 mAb 替西木单抗的相关鼠源替代抗体，开发了针对降低效应功能的鼠/人嵌合或完全人源 mAb，并将其与度伐鲁单抗和替西木单抗进行了比较。表征包括测定靶标亲和力、体内效应功能、药代动力学特征以及在小鼠同基因肿瘤模型中的抗肿瘤功效。结果表明，具有与度伐鲁单抗和替西木单抗相似的药效学特性的抗 PD-L1 和抗 CTLA-4 鼠源替代物在一组常用的小鼠同基因肿瘤模型中显示出抗肿瘤活性。这种活性不完全依赖于抗体依赖性细胞毒性、抗体依赖性细胞吞噬作用效应功能或调节性 T 细胞耗竭，因为设计缺乏这些特征的抗体在以前对检查点抑制敏感的模型中显示出活性，尽管其活性水平明显低于具有完整效应功能的抗体。
