---

Presenter: Sunny Periyasamy

Faculty Sponsor: S. Thai Thayumanavan

School: UMass Amherst

Research Area: Cancer Studies

Session: Poster Session 6, 4:15 PM - 5:00 PM, Auditorium, A36

ABSTRACT

Targeted protein degraders have unique advantages over traditional occupancy-based inhibitors. Among these, a PROTAC-based protein degradation approach has been identified as one of the most promising pathways to combat drug resistance in cancer therapy. While the high potency of PROTACs offers clear advantages, that same feature also presents dose-limiting toxicity in other tissues. Additionally, their bivalent features and the associated high molecular weight limit the bioavailability of PROTACs. Although antibody drug conjugates (ADCs) have emerged as a potential solution for targeted delivery of therapeutics, the inherent challenges of low drug to antibody ratio (DAR) and complex synthetic requirements are yet to be overcome. Polymers provide distinct advantages over small linker molecules as they can significantly change their physical attributes upon minutely altering their chemical structures. Moreover, they can overcome the challenge of low DAR by incorporating multiple drug copies. By utilizing rational polymer design, we have developed robust antibody-nanogel conjugates which can covalently/non-covalently carry a wide variety of drug molecules. Further, we introduce chemical triggers to the polymer structure for ensuring efficient release of the therapeutics inside cells, as well as antibody-based targeting for achieving tissue specificity. Altogether, we are able to generate a universal platform for efficient delivery of PROTACs in a cell-specific manner, thereby mitigating toxicity. We envision this work to provide a generalizable platform towards a broader range of various disease models and an opportunity to harness full potential of the PROTAC technology.