PDF(Pubmed)
Abstract：
The ability to leverage antibodies to agonize disease relevant biological pathways has tremendous potential for clinical investigation. Yet while antibodies have been successful as antagonists, immune mediators, and targeting agents, they are not readily effective at recapitulating the biology of natural ligands. Among the important determinants of antibody agonist activity is the geometry of target receptor engagement. Here, we describe an engineering approach inspired by a naturally occurring Fab-Fab homotypic interaction that constrains IgG in a unique i-shaped conformation. i-shaped antibody (iAb) engineering enables potent intrinsic agonism of five tumor necrosis factor receptor superfamily (TNFRSF) targets. When applied to bispecific antibodies against the heterodimeric IL-2 receptor pair, constrained bispecific IgG formats recapitulate IL-2 agonist activity. iAb engineering provides a tool to tune agonist antibody function and this work provides a framework for the development of intrinsic antibody agonists with the potential for generalization across broad receptor classes.
摘要：
利用抗体激动疾病相关生物学途径的能力具有巨大的临床研究潜力。然而，虽然抗体已经成功地作为拮抗剂，免疫介质，和靶向剂，它们不容易有效地概括天然配体的生物学。抗体激动剂活性的重要决定因素是靶受体接合的几何结构。这里,我们描述了一种工程方法，其灵感来自天然存在的Fab-Fab同型相互作用，该相互作用将IgG限制在独特的i形构象中。i形抗体（iAb）工程能够有效地内在激动五个肿瘤坏死因子受体超家族（TNFRSF）靶标。当应用于针对异二聚体IL-2受体对的双特异性抗体时，限制性双特异性IgG形式重现IL-2激动剂活性。iAb工程提供了调节激动剂抗体功能的工具，这项工作为开发内在抗体激动剂提供了框架，具有跨广泛受体类别的推广潜力。
