1] Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. [2].
1] Eli Lilly Biotechnology Center, San Diego, California, USA. [2].
Nat Biotechnol. 2014 Feb;32(2):191-8. doi: 10.1038/nbt.2797. Epub 2014 Jan 26.
Robust generation of IgG bispecific antibodies has been a long-standing challenge. Existing methods require extensive engineering of each individual antibody, discovery of common light chains, or complex and laborious biochemical processing. Here we combine computational and rational design approaches with experimental structural validation to generate antibody heavy and light chains with orthogonal Fab interfaces. Parental monoclonal antibodies incorporating these interfaces, when simultaneously co-expressed, assemble into bispecific IgG with improved heavy chain-light chain pairing. Bispecific IgGs generated with this approach exhibit pharmacokinetic and other desirable properties of native IgG, but bind target antigens monovalently. As such, these bispecific reagents may be useful in many biotechnological applications.
生成 IgG 双特异性抗体一直是一个长期存在的挑战。现有的方法需要对每个抗体进行广泛的工程改造，或者需要发现共同的轻链，或者需要进行复杂而费力的生化处理。在这里，我们将计算和合理的设计方法与实验结构验证相结合，生成具有正交 Fab 界面的抗体重链和轻链。包含这些界面的亲本单克隆抗体，当同时共表达时，会组装成双特异性 IgG，从而改善重链-轻链配对。使用这种方法产生的双特异性 IgG 表现出天然 IgG 的药代动力学和其他理想特性，但仅结合单价靶抗原。因此，这些双特异性试剂可能在许多生物技术应用中有用。
