Jain Tushar, Sun Tingwan, Durand Stéphanie, Hall Amy, Houston Nga Rewa, Nett Juergen H, Sharkey Beth, Bobrowicz Beata, Caffry Isabelle, Yu Yao, Cao Yuan, Lynaugh Heather, Brown Michael, Baruah Hemanta, Gray Laura T, Krauland Eric M, Xu Yingda, Vásquez Maximiliano, Wittrup K Dane
Department of Computational Biology, Adimab LLC, Lebanon, NH 03766.
Department of Protein Analytics, Adimab LLC, Lebanon, NH 03766.
Proc Natl Acad Sci U S A. 2017 Jan 31;114(5):944-949. doi: 10.1073/pnas.1616408114. Epub 2017 Jan 17.
Antibodies are a highly successful class of biological drugs, with over 50 such molecules approved for therapeutic use and hundreds more currently in clinical development. Improvements in technology for the discovery and optimization of high-potency antibodies have greatly increased the chances for finding binding molecules with desired biological properties; however, achieving drug-like properties at the same time is an additional requirement that is receiving increased attention. In this work, we attempt to quantify the historical limits of acceptability for multiple biophysical metrics of "developability." Amino acid sequences from 137 antibodies in advanced clinical stages, including 48 approved for therapeutic use, were collected and used to construct isotype-matched IgG1 antibodies, which were then expressed in mammalian cells. The resulting material for each source antibody was evaluated in a dozen biophysical property assays. The distributions of the observed metrics are used to empirically define boundaries of drug-like behavior that can represent practical guidelines for future antibody drug candidates.
抗体是一类非常成功的生物药物，有50多种此类分子已获批用于治疗，目前还有数百种正处于临床开发阶段。用于发现和优化高效抗体的技术改进极大地增加了找到具有所需生物学特性的结合分子的机会；然而，同时实现类药物特性是一项越来越受关注的额外要求。在这项工作中，我们试图量化“可开发性”的多个生物物理指标在历史上的可接受限度。我们收集了处于临床后期的137种抗体的氨基酸序列，其中包括48种已获批用于治疗的抗体，并用于构建同型匹配的IgG1抗体，然后在哺乳动物细胞中进行表达。对每种来源抗体产生的材料进行了十几种生物物理性质测定。观察到的指标分布用于凭经验定义类药物行为的界限，这可为未来的抗体药物候选物提供实际指导。
