Boesch Austin W, Miles Adam R, Chan Ying N, Osei-Owusu Nana Y, Ackerman Margaret E
a Thayer School of Engineering, Dartmouth College , Hanover , NH , USA.
b Wasatch Microfluidics , Salt Lake City , UT , USA.
MAbs. 2017 Apr;9(3):455-465. doi: 10.1080/19420862.2016.1274845. Epub 2017 Jan 5.
Non-human primate (NHP) studies are often an essential component of antibody development efforts before human trials. Because the efficacy or toxicity of candidate antibodies may depend on their interactions with Fcγ receptors (FcγR) and their resulting ability to induce FcγR-mediated effector functions such as antibody-dependent cell-meditated cytotoxicity and phagocytosis (ADCP), the evaluation of human IgG variants with modulated affinity toward human FcγR is becoming more prevalent in both infectious disease and oncology studies in NHP. Reliable translation of these results necessitates analysis of the cross-reactivity of these human Fc variants with NHP FcγR. We report evaluation of the binding affinities of a panel of human IgG subclasses, Fc amino acid point mutants and Fc glycosylation variants against the common allotypes of human and rhesus macaque FcγR by applying a high-throughput array-based surface plasmon resonance platform. The resulting data indicate that amino acid variation present in rhesus FcγRs can result in disrupted, matched, or even increased affinity of IgG Fc variants compared with human FcγR orthologs. These observations emphasize the importance of evaluating species cross-reactivity and developing an understanding of the potential limitations or suitability of representative in vitro and in vivo models before human clinical studies when either efficacy or toxicity may be associated with FcγR engagement.
在进行人体试验之前，非人灵长类动物（NHP）研究通常是抗体开发工作的重要组成部分。由于候选抗体的疗效或毒性可能取决于它们与Fcγ受体（FcγR）的相互作用以及由此诱导FcγR介导的效应功能（如抗体依赖性细胞介导的细胞毒性和吞噬作用（ADCP））的能力，因此在NHP的传染病和肿瘤学研究中，对与人类FcγR具有调节亲和力的人IgG变体的评估越来越普遍。要可靠地转化这些结果，就需要分析这些人类Fc变体与NHP FcγR的交叉反应性。我们报告了通过应用基于高通量阵列的表面等离子体共振平台，对一组人IgG亚类、Fc氨基酸点突变体和Fc糖基化变体与人及恒河猴FcγR常见同种异型的结合亲和力进行评估的结果。所得数据表明，与人类FcγR直系同源物相比，恒河猴FcγR中存在的氨基酸变异可导致IgG Fc变体的亲和力受到破坏、匹配甚至增加。这些观察结果强调了在人体临床研究之前评估物种交叉反应性以及了解代表性体外和体内模型的潜在局限性或适用性的重要性，因为疗效或毒性可能与FcγR参与有关。
