4UB0

New design for monovalent bispecific IgG through cysteine engineering of the CH1-CL interface

Summary for 4UB0

• Entry DOI: 10.2210/pdb4ub0/pdb
• Descriptor: IgG1, heavy chain, IgG1, light chain (3 entities in total)
• Functional Keywords: fab, knobs-into-holes, bispecific, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 2
• Total formula weight: 46847.18

Authors

Oganesyan, V.Y.,Dall'Acqua, W.F. (deposition date: 2014-08-11, release date: 2015-07-15, Last modification date: 2023-12-27)

Primary citation

Mazor, Y.,Oganesyan, V.,Yang, C.,Hansen, A.,Wang, J.,Liu, H.,Sachsenmeier, K.,Carlson, M.,Gadre, D.V.,Borrok, M.J.,Yu, X.Q.,Dall'Acqua, W.,Wu, H.,Chowdhury, P.S.
Improving target cell specificity using a novel monovalent bispecific IgG design.
Mabs, 7:377-389, 2015

PubMed Abstract: Monovalent bispecific IgGs cater to a distinct set of mechanisms of action but are difficult to engineer and manufacture because of complexities associated with correct heavy and light chain pairing. We have created a novel design, "DuetMab," for efficient production of these molecules. The platform uses knobs-into-holes (KIH) technology for heterodimerization of 2 distinct heavy chains and increases the efficiency of cognate heavy and light chain pairing by replacing the native disulfide bond in one of the CH1-CL interfaces with an engineered disulfide bond. Using two pairs of antibodies, cetuximab (anti-EGFR) and trastuzumab (anti-HER2), and anti-CD40 and anti-CD70 antibodies, we demonstrate that DuetMab antibodies can be produced in a highly purified and active form, and show for the first time that monovalent bispecific IgGs can concurrently bind both antigens on the same cell. This last property compensates for the loss of avidity brought about by monovalency and improves selectivity toward the target cell.

PubMed: 25621507
DOI: 10.1080/19420862.2015.1007816

Experimental method

X-RAY DIFFRACTION (2.2 Å)