4.1 Article

Variable heavy-variable light domain and Fab-arm CrossMabs with charged residue exchanges to enforce correct light chain assembly

期刊

PROTEIN ENGINEERING DESIGN & SELECTION
卷 31, 期 7-8, 页码 289-299

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OXFORD UNIV PRESS
DOI: 10.1093/protein/gzy021

关键词

Angiopoietin-2; bispecific antibody; CrossMab; VEGF

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Technologies for the production of bispecific antibodies need to overcome two major challenges. The first one is correct heavy chain assembly, which was solved by knobs-into-holes technology or charge interactions in the CH3 domains. The second challenge is correct light chain assembly. This can be solved by engineering the Fab-arm interfaces or applying the immunoglobulin domain crossover approach. There are three different crossovers possible, namely Fab-arm, constant domain and variable domain crossovers. The CrossMab(CH1-CL) exchange does not lead to the formation of unexpected side products, whereas the CrossMab(Fab) and the CrossMab(VH-VL) formats result in the formation of typical side products. Thus, CrossMab(CH1-CL) was initially favored for therapeutic antibody development. Here, we report a novel improved CrossMab design principle making use of site-specific positional exchanges of charged amino acid pairs in the constant domain of these CrossMabs to enable the correct light chain assembly in the CrossMab(VH-VL) and improvements for the CrossMab(Fab) design.

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