Proteolysis targeting chimera (PROTAC)-driven antibody internalization of oncogenic cell surface receptors.

Antibody-drug conjugates (ADCs) are increasingly used in clinic for multiple indications and may improve upon the activity of parental antibodies by delivering cytotoxic payloads into target cells. This activity is predicated upon internalization to release the cytotoxic payloads intracellularly. Since binding of ADCs to their cell surface targets does not guarantee their internalization, we hypothesize that proteolysis targeting chimeras (PROTACs) could improve the activity of ADCs through forced internalization. We show that PROTACs improve internalization of antibodies or their derivative antibody drug conjugates when both agents target the same oncogenic cell surface proteins (EGFR, HER2 or MET) by 1.4-1.9 fold in most models. PROTACs also significantly enhance cytotoxicity with HER2-targeting ADCs. These effects depend on dynamin and proteolysis. This application of PROTACs may impact the use of ADCs and provides a rationale to combine these agents in clinical trials.
Competing Interests: Competing interests: Mayo Clinic submitted patent 63/560,270 related to this work for the institution on 01 March 2024 listing the inventors Aaron S. Mansfield M.D., Ezequiel J. Tolosa Ph.D., Jennifer R. Ayers-Ringler Ph.D., Lin Yang Ph.D., and Farhad Kosari Ph.D. that is under review at the time of publication. Mitesh Borad reports grants to Mayo Clinic from Senhwa Pharmaceuticals, Adaptimmune, Agios Pharmaceuticals, Halozyme Pharmaceuticals, Celgene Pharmaceuticals, EMD Merck Serono, Toray, Dicerna, Taiho Pharmaceuticals, Sun Biopharma, Isis Pharmaceuticals, Redhill Pharmaceuticals, Boston Biomed, Basilea, Incyte Pharmaceuticals, Mirna Pharmaceuticals, Medimmune, Bioline, Sillajen, ARIAD Pharmaceuticals, PUMA Pharmaceuticals, Novartis Pharmaceuticals, QED Pharmaceuticals, Pieris Pharmaceuticals; and consulting to self from ADC Therapeutics, Exelixis Pharmaceuticals, Inspyr Therapeutics, G1 Therapeutics, Immunovative Therapies, OncBioMune Pharmaceuticals, Western Oncolytics, Lynx Group, Genentech, Merck, and Huya. Aaron Mansfield reports consulting fees to his institution from Genentech, Bristol Myers Squibb, AbbVie, AstraZeneca, Janssen, BeiGene, Takeda, Genzyme, Gilead Sciences, and Johnson & Johnson Global Services.
(© 2024. The Author(s).)