Improving target cell specificity using a novel monovalent bispecific IgG design

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. Th...

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Bibliographic Details
Published in:	mAbs Vol. 7; no. 2; pp. 377 - 389
Main Authors:	Mazor, Yariv, Oganesyan, Vaheh, Yang, Chunning, Hansen, Anna, Wang, Jihong, Liu, Hongji, Sachsenmeier, Kris, Carlson, Marcia, Gadre, Dhanesh V, Borrok, Martin Jack, Yu, Xiang-Qing, Dall'Acqua, William, Wu, Herren, Chowdhury, Partha Sarathi
Format:	Journal Article
Language:	English
Published:	United States Taylor & Francis 04-03-2015
Subjects:	Antibodies, Bispecific - biosynthesis Antibodies, Bispecific - chemistry Antibodies, Bispecific - genetics Antibody Affinity - genetics antibody engineering Biotechnology bispecific antibody cancer Cetuximab - biosynthesis Cetuximab - chemistry Cetuximab - genetics disulfide EGFR HEK293 Cells HER2 Humans Immunoglobulin G - biosynthesis Immunoglobulin G - chemistry Immunoglobulin G - genetics multi-targeting Trastuzumab - biosynthesis Trastuzumab - chemistry Trastuzumab - genetics Biotechnology RAGE, receptor for advanced glycosylation CH1, 2 and 3-heavy chain constant domain 1, 2 and 3 disulfide mAbs, monoclonal antibodies FcRn, neonatal Fc receptor IL-6, interleukin 6 EGFR, epidermal growth factor receptor EGFR IGFR, insulin like growth factor receptor antibody engineering CL-, light chain constant domain DSC-differential scanning calorimetry PNGase, protein N-glycanase CDR, complementarity determining region multi-targeting FcγR, receptor for IgG Fc E:T, ratio of effector to target cells Q1q, first component of complement 1 bispecific antibody cancer ADCC, antibody-dependent cell-mediated cytotoxicity HER2 IgG, Immunoglobulin G
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Summary:	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 C H 1-C L 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1942-0862 1942-0870
DOI:	10.1080/19420862.2015.1007816