在肿瘤学领域，抗药物抗体（ADA）的发展会显着降低反应的持久性，但历史上并未达到令人担忧的程度。因此，ADA 在肿瘤学临床研究中的相关性和关注度有限，并且关于该主题的现有文献也很少。近年来，T 细胞接合剂在癌症免疫治疗的多产领域中取得了卓越的地位。这些药物的作用方式预计会有效刺激抗肿瘤免疫，但由于免疫反应的整体增强，可能会引发 ADA，这是一个意想不到的推论。因此，ADA 的形成正在成为此类生物制剂成功临床开发的重要决定因素。在这里，我们描述了帕索妥昔单抗 (AMG 212) 的免疫原性及其影响，帕索妥昔单抗是一种前列腺特异性膜抗原 (PSMA) 靶向双特异性 T 细胞接合剂（ NCT01723475 中的 BiTE®）分子，这是一项针对转移性去势抵抗性前列腺癌 (mCRPC) 患者的首次人体 (FIH) 多中心剂量递增研究。为了解释研究中 SC 组和 CIV 组之间观察到的 ADA 发生率差异，我们询问了其他患者和产品特定因素，这些因素可能解释了给药途径之外的差异。所有受试者均在皮下 (SC) 臂中接受至少 1 个周期的 AMG 212 治疗。这些 ADA 具有中和作用，并导致严重的暴露损失，这与初始前列腺表面抗原 (PSA) 反应的同时逆转有关，从而降低了患者 PSA 反应的持久性。从 SC 转向连续静脉 (CIV) 给药途径，显着没有受试者将 ADA 发展为 AMG 212。通过一系列逐步的功能测定，我们的研究表明，除了历史上更具免疫原性的给药途径外，体内的非耐受性 T 细胞表位AMG 212 氨基酸序列可能驱动了 SC 组中观察到的高滴度、持续的 ADA 反应。这些对 AMG 212 ADA 反应的机制见解强调了进行临床前免疫原性风险评估的重要性，并提倡不断迭代以更好地进行临床前免疫原性风险评估。我们的生物制品。版权所有 © 2023 Penny、Hainline、Theoharis、Wu、Brandl、Webhofer、McComb、Wittemer-Rump、Koca、Stienen、Bargou、Hummel、Loidl、Grüllich、Eggert、Tran 和 Mytych。

In oncology, anti-drug antibody (ADA) development that significantly curtails response durability has not historically risen to a level of concern. The relevance and attention ascribed to ADAs in oncology clinical studies have therefore been limited, and the extant literature on this subject scarce. In recent years, T cell engagers have gained preeminence within the prolific field of cancer immunotherapy. These drugs whose mode of action is expected to potently stimulate anti-tumor immunity, may potentially induce ADAs as an unintended corollary due to an overall augmentation of the immune response. ADA formation is therefore emerging as an important determinant in the successful clinical development of such biologics.Here we describe the immunogenicity and its impact observed to pasotuxizumab (AMG 212), a prostate-specific membrane antigen (PSMA)-targeting bispecific T cell engager (BiTE®) molecule in NCT01723475, a first-in-human (FIH), multicenter, dose-escalation study in patients with metastatic castration-resistant prostate cancer (mCRPC). To explain the disparity in ADA incidence observed between the SC and CIV arms of the study, we interrogated other patient and product-specific factors that may have explained the difference beyond the route of administration.Treatment-emergent ADAs (TE-ADA) developed in all subjects treated with at least 1 cycle of AMG 212 in the subcutaneous (SC) arm. These ADAs were neutralizing and resulted in profound exposure loss that was associated with contemporaneous reversal of initial Prostate Surface Antigen (PSA) responses, curtailing durability of PSA response in patients. Pivoting from SC to a continuous intravenous (CIV) administration route remarkably yielded no subjects developing ADA to AMG 212. Through a series of stepwise functional assays, our investigation revealed that alongside a more historically immunogenic route of administration, non-tolerant T cell epitopes within the AMG 212 amino acid sequence were likely driving the high-titer, sustained ADA response observed in the SC arm.These mechanistic insights into the AMG 212 ADA response underscore the importance of performing preclinical immunogenicity risk evaluation as well as advocate for continuous iteration to better our biologics.Copyright © 2023 Penny, Hainline, Theoharis, Wu, Brandl, Webhofer, McComb, Wittemer-Rump, Koca, Stienen, Bargou, Hummel, Loidl, Grüllich, Eggert, Tran and Mytych.