6GHG

Variable heavy - variable light domain and Fab-arm CrossMabs with charged residue exchanges

Summary for 6GHG

• Entry DOI: 10.2210/pdb6ghg/pdb
• Descriptor: Fab heavy chain, Fab light chain, SODIUM ION, ... (5 entities in total)
• Functional Keywords: antibody, fab fragment, dp47, ang2, vegf, crossmab, charge variants, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 4
• Total formula weight: 93011.25

Authors

Regula, J.,Imhof-Jung, S.,Molhoj, M.,Benz, J.,Ehler, A.,Bujotzek, A.,Schaefer, W.,Klein, C. (deposition date: 2018-05-07, release date: 2018-09-12, Last modification date: 2024-10-16)

Primary citation

Regula, J.T.,Imhof-Jung, S.,Molhoj, M.,Benz, J.,Ehler, A.,Bujotzek, A.,Schaefer, W.,Klein, C.
Variable heavy-variable light domain and Fab-arm CrossMabs with charged residue exchanges to enforce correct light chain assembly.
Protein Eng. Des. Sel., 31:289-299, 2018

PubMed Abstract: 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 CrossMabCH1-CL exchange does not lead to the formation of unexpected side products, whereas the CrossMabFab and the CrossMabVH-VL formats result in the formation of typical side products. Thus, CrossMabCH1-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 CrossMabVH-VL and improvements for the CrossMabFab design.

PubMed: 30169707
DOI: 10.1093/protein/gzy021

Experimental method

X-RAY DIFFRACTION (1.88 Å)