Brennan Frank R, Polli J Ryan, Sathish Jean, Ramones Melissa, Wolf Babette, Schlothauer Tilman, Peters Shirley J, Maier Curtis C, Ji Changhua, Wensel David L, Witcher Derrick, Ryan Patricia C, Manetz T Scott, Flora Adriano, Soper Brian, Fogal Birgit, Dzielak Lindsey, Wang Xiaoting, Shastri Prathap Nagaraja, Price Karen, Doyle Michael, Sharda Nidhi, Struthers Mary, Brinkhaus Maximilian, Balbino Bianca, Stefanich Eric, Honda Masaki, Andersen Jan Terje, Mitchell-Ryan Shermaine, Humphreys David P
Discovery Research, UCB Pharma, Slough, UK.
Pharmacokinetic Sciences, Translational Medicine, Novartis Biomedical Research, Cambridge, MA, USA.
MAbs. 2025 Dec;17(1):2505092. doi: 10.1080/19420862.2025.2505092. Epub 2025 Jul 7.
Therapeutic monoclonal antibodies (mAbs) are often designed to not only bind targets via their antigen-binding domains (Fabs) but to also engage with cell surface receptors, FcγRs and FcRn, through their Fc regions, which may result in a variety of functional outcomes, including antibody- dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC) and alteration of circulating half-lives. Engineering the Fc regions to achieve desirable pharmacology and pharmacokinetics is a widely adopted strategy in drug development. Fc regions can be modified through amino acid substitutions and glycoengineering, resulting in enhanced or reduced effector functions, preferential binding to FcR subtypes, or pH-dependent binding to FcRns. These alterations in binding and effector activities of mAbs may potentially also be accompanied by undesirable effects or safety concerns. Critical assessment of pharmacology and safety in the nonclinical setting is essential before exposing humans to the engineered mAb. For Fc-modified mAbs, the choice of in vitro and in vivo nonclinical pharmacology and safety models need to account for species differences in FcR expression and function, potentially divergent effects of Fc modifications in humans versus nonclinical species, impact of target and cognate ligand expression patterns, and potential impact of emergent anti-drug antibodies directed against the mAb. Using a variety of industry case studies, we highlight key aspects of nonclinical pharmacology and toxicology testing strategies, factors that influence choice of nonclinical models, translatability of findings, input from health authorities and suggest best practice approaches for nonclinical testing of Fc modified mAbs.
治疗性单克隆抗体（mAb）的设计通常不仅要通过其抗原结合域（Fab）结合靶标，还要通过其Fc区域与细胞表面受体FcγR和FcRn相互作用，这可能导致多种功能结果，包括抗体依赖性细胞毒性（ADCC）、抗体依赖性细胞吞噬作用（ADCP）、补体依赖性细胞毒性（CDC）以及循环半衰期的改变。在药物开发中，对Fc区域进行工程改造以实现理想的药理学和药代动力学是一种广泛采用的策略。Fc区域可以通过氨基酸替换和糖基工程进行修饰，从而增强或降低效应器功能、优先结合FcR亚型或实现pH依赖性结合FcRn。mAb结合和效应器活性的这些改变也可能伴随着不良影响或安全问题。在将工程化mAb应用于人体之前，在非临床环境中对药理学和安全性进行严格评估至关重要。对于Fc修饰的mAb，体外和体内非临床药理学和安全性模型的选择需要考虑FcR表达和功能的物种差异、Fc修饰在人类与非临床物种中可能存在的不同效应、靶标和同源配体表达模式的影响以及针对mAb产生的抗药物抗体的潜在影响。通过各种行业案例研究，我们强调了非临床药理学和毒理学测试策略的关键方面、影响非临床模型选择的因素、研究结果的可转化性、卫生当局的意见，并提出了Fc修饰mAb非临床测试的最佳实践方法。
