Nagaraja Shastri Prathap, Shah Nirav, Lechmann Martin, Mody Hardik, Retter Marc W, Zhu Min, Li Tommy, Wang Jun, Shaik Naveed, Zheng Xirong, Ovacik Meric, Hua Fei, Jawa Vibha, Boetsch Christophe, Cao Yanguang, Burke John, Datta Kaushik, Gadkar Kapil, Upreti Vijay, Betts Alison
Clinical Pharmacology and Pharmacometrics, Johnson and Johnson Innovative Medicine, Spring House, Pennsylvania, USA.
Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Munich, Penzberg, Germany.
Clin Pharmacol Ther. 2025 Jan;117(1):34-55. doi: 10.1002/cpt.3439. Epub 2024 Sep 19.
T-cell-engaging bispecific antibodies (TCEs) that target tumor antigens and T cells have shown great promise in treating cancer, particularly in hematological indications. The clinical development of TCEs often involves a lengthy first-in-human (FIH) trial with many dose-escalation cohorts leading up to an early proof of concept (POC), enabling either a no-go decision or dose selection for further clinical development. Multiple factors related to the target, product, disease, and patient population influence the efficacy and safety of TCEs. The intricate mechanism of action limits the translatability of preclinical models to the clinic, thereby posing challenges to streamline clinical development. In addition, unlike traditional chemotherapy, the top dose and recommended phase II doses (RP2Ds) for TCEs in the clinic are often not guided by the maximum tolerated dose (MTD), but rather based on the integrated dose-response assessment of the benefit/risk profile. These uncertainties pose complex challenges for translational and clinical pharmacologists (PK/PD scientists), as well as clinicians, to design an efficient clinical study that guides development. To that end, experts in the field, under the umbrella of the American Association of Pharmaceutical Scientists, have reviewed learnings from published literature and currently marketed products to share perspectives on the FIH and clinical pharmacology strategies to support early clinical development of TCEs.
靶向肿瘤抗原和T细胞的T细胞接合双特异性抗体（TCE）在癌症治疗中显示出巨大前景，尤其是在血液学适应症方面。TCE的临床开发通常涉及一项漫长的首次人体试验（FIH），其中有许多剂量递增队列，直至早期概念验证（POC），从而能够做出终止决定或选择剂量以进行进一步的临床开发。与靶点、产品、疾病和患者群体相关的多个因素会影响TCE的疗效和安全性。其复杂的作用机制限制了临床前模型向临床的转化能力，从而给简化临床开发带来挑战。此外，与传统化疗不同，TCE在临床中的最高剂量和推荐的II期剂量（RP2D）通常不是由最大耐受剂量（MTD）指导，而是基于对获益/风险概况的综合剂量反应评估。这些不确定性给转化和临床药理学家（PK/PD科学家）以及临床医生设计指导开发的高效临床研究带来了复杂挑战。为此，美国药学科学家协会旗下的该领域专家回顾了已发表文献和当前上市产品的经验教训，以分享关于FIH和临床药理学策略的观点，以支持TCE的早期临床开发。
