Tiwari Abhinav, Abraham Anson K, Harrold John M, Zutshi Anup, Singh Pratap
Pharmacokinetics, Dynamics and Metabolism, Pfizer, Cambridge, Massachusetts, USA.
Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck, West Point, Pennsylvania, USA.
AAPS J. 2017 Mar;19(2):510-519. doi: 10.1208/s12248-016-0004-1. Epub 2016 Dec 21.
Affinity optimization of monoclonal antibodies (mAbs) is essential for developing drug candidates with the highest likelihood of clinical success; however, a quantitative approach for setting affinity requirements is often lacking. In this study, we computationally analyzed the in vivo mAb-target binding kinetics to delineate general principles for defining optimal equilibrium dissociation constant ([Formula: see text]) of mAbs against soluble and membrane-bound targets. Our analysis shows that in general [Formula: see text] to achieve 90% coverage for a soluble target is one tenth of its baseline concentration ([Formula: see text]), and is independent of the dosing interval, target turnover rate or the presence of competing ligands. For membrane-bound internalizing targets, it is equal to the ratio of internalization rate of mAb-target complex and association rate constant ([Formula: see text]). In cases where soluble and membrane-bound forms of the target co-exist, [Formula: see text] lies within a range determined by the internalization rate ([Formula: see text]) of the mAb-membrane target complex and the ratio of baseline concentrations of soluble and membrane-bound forms ([Formula: see text]). Finally, to demonstrate practical application of these general rules, we collected target expression and turnover data to project [Formula: see text] for a number of marketed mAbs against soluble (TNFα, RANKL, and VEGF) and membrane-bound targets (CD20, EGFR, and HER2).
单克隆抗体（mAb）的亲和力优化对于开发具有临床成功最高可能性的候选药物至关重要；然而，通常缺乏一种设定亲和力要求的定量方法。在本研究中，我们通过计算分析了体内mAb与靶点的结合动力学，以阐明针对可溶性和膜结合靶点定义mAb最佳平衡解离常数（[公式：见原文]）的一般原则。我们的分析表明，一般来说，对于可溶性靶点，要达到90%的覆盖率，[公式：见原文]为其基线浓度（[公式：见原文]）的十分之一，且与给药间隔、靶点周转率或竞争性配体的存在无关。对于膜结合内化靶点，它等于mAb-靶点复合物的内化速率与结合速率常数（[公式：见原文]）的比值。在靶点的可溶性和膜结合形式共存的情况下，[公式：见原文]处于由mAb-膜靶点复合物的内化速率（[公式：见原文]）以及可溶性和膜结合形式的基线浓度比值（[公式：见原文]）所确定的范围内。最后，为了证明这些一般规则的实际应用，我们收集了靶点表达和周转率数据，以预测多种针对可溶性靶点（TNFα、RANKL和VEGF）和膜结合靶点（CD20、EGFR和HER2）的上市mAb的[公式：见原文]。
