Noncovalent PROTAC Antibody Drug Conjugates
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krum-dkrum-phd-cheme-2025-thesis.pdf
Description
Thesis PDF
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16.37 MB
Format
Adobe PDF
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645a79eadb79196b614addf6aed0495f
Author(s)
Krum, David
Advisor(s)
Wittrup, Karl Dane
Date Issued
February 2026
Publisher
Massachusetts Institute of Technology
Abstract
Proteolysis Targeting Chimeras (PROTACs) are a new class of heterobifunctional drugs that induce proximity between an E3 ligase and a given protein of interest (POI), causing the POI to be ubiquitinated and targeted for proteasomal degradation. While the event-driven, irreversible pharmacodynamics of PROTACs offer advantages over traditional occupancy-driven small molecule inhibitors, their large molecular weight and existence outside of Lipinski chemical space give rise to poor pharmacokinetic behavior. To ameliorate these issues, PROTACs can be conjugated to anti-tumor antibodies to improve circulation time in vivo and promote accumulation of the drug in the tumor. The conjugation chemistry and purification of antibody drug conjugates is time and labor intensive, and we therefore propose a facile, noncovalent, “plug-and-play” conjugation strategy whereby an anti-PROTAC antibody fragment is included in a bispecific antibody. In this work, we develop a pharmacokinetic model describing the kinetics of reversible, noncovalent antibody drug conjugates. We use yeast surface display to develop high-affinity antibodies that bind to the most common small molecules employed in Proteolysis Targeting Chimeras (PROTACs) guided by observations from our modelling. We test the binding and delivery kinetics of these non-covalent antibody drug conjugates in vitro and demonstrate that that the antibodies induce internalization of the drug, leading to target protein degradation and cytotoxicity in murine and human cell lines. Finally, we investigate the in vivo pharmacokinetics and anti-tumor efficacy of various PROTAC drugs, demonstrating an improvement relative to drugs without conjugation to an antibody.
MIT Department
Massachusetts Institute of Technology. Department of Chemical Engineering
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