Logic-gated antibody pairs that selectively act on cells co-expressing two antigens

Authors

Simone C. Oostindie, Genmab, Utrecht, the Netherlands,Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands
Derek A. Rinaldi, Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM, USA
Gijs G. Zom, Genmab, Utrecht, the Netherlands
Michael J. Wester, Department of Physics and Astronomy, University of New Mexico, Albuquerque, NM, USA
Desiree Paulet, 1 Genmab, Utrecht, the Netherlands
Kusai Al-Tamimi, 1 Genmab, Utrecht, the Netherlands
Els van der Meijden, 1 Genmab, Utrecht, the Netherlands
Jennifer R. Scheick, 1 Genmab, Utrecht, the Netherlands
Tessa Wilpshaar, 1 Genmab, Utrecht, the Netherlands
Bart de Jong, 1 Genmab, Utrecht, the Netherlands
Marloes Hoff-van den Broek, 1 Genmab, Utrecht, the Netherlands
Rachel M. Grattan, Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM, USA
Janita J. Oosterhoff, Genmab, Utrecht, the Netherlands
Julie Vignau, Genmab, Utrecht, the Netherlands
Sandra Verploegen, Genmab, Utrecht, the Netherlands
Peter Boross, Genmab, Utrecht, the Netherlands
Frank J. Beurskens, Genmab, Utrecht, the Netherlands
Diane S. Lidke, Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM, USA, Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
Janine Schuurman, Genmab, Utrecht, the Netherlands
Rob N. de Jong, Genmab, Utrecht, the Netherlands

Document Type

Article

Publication Date

10-1-2022

Abstract

The use of therapeutic monoclonal antibodies is constrained because single antigen targets often do not provide sufficient selectivity to distinguish diseased from healthy tissues. We present HexElect, an approach to enhance the functional selectivity of therapeutic antibodies by making their activity dependent on clustering after binding to two different antigens expressed on the same target cell. lmmunoglobulin G (lgG)-mediated clustering of membrane receptors naturally occurs on cell surfaces to trigger complement- or cell-mediated effector functions or to initiate intracellular signaling. We engineer the Fc domains of two different lgG antibodies to suppress their individual homo-oligomerization while promoting their pairwise hetero-oligomerization after binding co-expressed antigens. We show that recruitment of complement component C1q to these hetero-oligomers leads to clustering-dependent activation of effector functions such as complement mediated killing of target cells or activation of cell surface receptors. HexElect allows selective antibody activity on target cells expressing unique, potentially unexplored combinations of surface antigens.

Recommended Citation

Oostindie SC, Rinaldi DA, Zom GG, Wester MJ, Paulet D, Al-Tamimi K, van der Meijden E, Scheick JR, Wilpshaar T, de Jong B, Hoff-van den Broek M, Grattan RM, Oosterhoff JJ, Vignau J, Verploegen S, Boross P, Beurskens FJ, Lidke DS, Schuurman J, de Jong RN. Logic-gated antibody pairs that selectively act on cells co-expressing two antigens. Nat Biotechnol. 2022 Oct;40(10):1509-1519. doi: 10.1038/s41587-022-01384-1. Epub 2022 Jul 25. PMID: 35879362; PMCID: PMC9546771.