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.

ORCID iDs

Chan, Karina, Sathyamurthi, Preethi Soundarya, Queisser, Markus A., Mullin, Michael, Shrives, Harry, Coe, Diane M. and Burley, Glenn A. ORCID logoORCID: https://orcid.org/0000-0002-4896-113X;
CORE (COnnecting REpositories)