Antibody-proteolysis targeting chimera conjugate enables selective degradation of receptor-interacting serine/threonine-protein kinase 2 in HER2+ cell lines

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Chan, Karina and Sathyamurthi, Preethi Soundarya and Queisser, Markus A. and Mullin, Michael and Shrives, Harry and Coe, Diane M. and Burley, Glenn A. (2023) Antibody-proteolysis targeting chimera conjugate enables selective degradation of receptor-interacting serine/threonine-protein kinase 2 in HER2+ cell lines. Bioconjugate Chemistry, 34 (11). pp. 2049-2054. ISSN 1520-4812 (https://doi.org/10.1021/acs.bioconjchem.3c00366)

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Abstract

Proteolysis targeting chimeras (PROTACs) are a family of heterobifunctional molecules that are now realizing their promise as a therapeutic strategy for targeted protein degradation. However, one limitation of existing designs is the lack of cell-selective targeting of the protein degrading payload. This manuscript reports a cell-targeted approach to degrade receptor-interacting serine/threonine-protein kinase 2 (RIPK2) in HER2+ cell lines. An antibody-PROTAC conjugate is prepared containing a protease-cleavable linkage between the antibody and the corresponding degrader. Potent RIPK2 degradation is observed in HER2+ cell lines, whereas an equivalent anti-IL4 antibody-PROTAC conjugate shows no degradation at therapeutically relevant concentrations. No RIPK2 degradation was observed in HER2- cell lines for both bioconjugates. This work demonstrates the potential for the cell-selective delivery of PROTAC scaffolds by engaging with signature extracellular proteins expressed on the surface of particular cell types.

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