双特异性抗体
单克隆抗体
蛋白质工程
计算生物学
抗原
化学
抗体
计算机科学
生物
生物化学
免疫学
酶
作者
Gregory L. Moore,Matthew J. Bernett,Rumana Rashid,Erik Pong,Duc-Hanh T. Nguyen,Jonathan Jacinto,Araz Eivazi,Alex Nisthal,Juan E. Diaz,Seung Y. Chu,Umesh Muchhal,John R. Desjarlais
出处
期刊:Methods
[Elsevier]
日期:2019-02-01
卷期号:154: 38-50
被引量:37
标识
DOI:10.1016/j.ymeth.2018.10.006
摘要
Bispecific monoclonal antibodies can bind two protein targets simultaneously and enable therapeutic modalities inaccessible by traditional mAbs. Bispecific formats containing a heterodimeric Fc region are of particular interest, as a heterodimeric Fc empowers both bispecificity and altered valencies while retaining the developability and druggability of a monoclonal antibody. We present a robust heterodimeric Fc platform, called the XmAb® bispecific platform, engineered for efficient development of bispecific antibodies and Fc fusions of multiple formats. First, we engineer a purification solution for proteins containing a heterodimeric Fc using engineered isoelectric point differences in the Fc region that enable straightforward purification of the heterodimeric species. Then, we combine this purification solution with a novel set of Fc substitutions capable of achieving heterodimer yields over 95% with little change in thermostability. Next, we illustrate the flexibility of our heterodimeric Fc with a case study in which a wide range of tumor-associated antigen × CD3 bispecifics are generated, differing in choice of tumor antigen, affinities for both tumor antigen and CD3, and tumor antigen valency. Finally, we present manufacturing data reinforcing the robustness of the heterodimeric Fc platform at scale.
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