Department of Therapeutics Discovery, Amgen Research, Amgen Inc ., Thousand Oaks, CA USA.
Department of Therapeutics Discovery, Amgen Research, Amgen Inc ., San Francisco, CA USA.
MAbs. 2021 Jan-Dec;13(1):1870058. doi: 10.1080/19420862.2020.1870058.
Bispecific antibodies, engineered to recognize two targets simultaneously, demonstrate exceptional clinical potential for the therapeutic intervention of complex diseases. However, these molecules are often composed of multiple polypeptide chains of differing sequences. To meet industrial scale productivity, enforcing the correct quaternary assembly of these chains is critical. Here, we describe Chain Selectivity Assessment (CSA), a high-throughput method to rationally select parental monoclonal antibodies (mAbs) to make bispecific antibodies requiring correct heavy/light chain pairing. By deploying CSA, we have successfully identified mAbs that exhibit a native preference toward cognate chain pairing that enables the production of hetero-IgGs without additional engineering. Furthermore, CSA also identified rare light chains (LCs) that permit positive binding of the non-cognate arm in the common LC hetero-IgGs, also without engineering. This rational selection of parental mAbs with favorable developability characteristics is critical to the successful development of bispecific molecules with optimal manufacturability properties.
双特异性抗体，设计用于同时识别两个靶点，为复杂疾病的治疗干预提供了卓越的临床潜力。然而，这些分子通常由多个不同序列的多肽链组成。为了满足工业规模的生产能力，强制这些链的正确四级组装至关重要。在这里，我们描述了链选择性评估（CSA），这是一种高通量方法，可以合理选择亲本单克隆抗体（mAb）来制造需要正确重链/轻链配对的双特异性抗体。通过部署 CSA，我们已经成功地鉴定出 mAb，它们表现出对同源链配对的天然偏好，从而能够在无需额外工程的情况下生产异源 IgG。此外，CSA 还鉴定出了稀有轻链（LC），它们允许在常见的 LC 异源 IgG 中与非同源臂进行阳性结合，同样无需工程。这种对具有良好可开发性特征的亲本 mAb 的理性选择对于成功开发具有最佳制造性能的双特异性分子至关重要。
