Christopher Ing
Chief Scientific Officer, ProteinQure Inc.
Structure-based Drug Design of a Novel Sortilin-Targeted Peptide Drug Conjugate with Efficacy in Preclinical Models of Breast Cancer
Abstract
Antibody drug conjugates (ADCs) have changed the clinical landscape for the treatment of advanced breast cancer. Despite their promise, ADCs face key limitations including
poor tumor penetration, a narrow therapeutic window, and challenges with linker and payload stability. Consequently, alternative targeted therapeutic modalities have emerged,
including peptide-conjugated drugs (PDCs) which can have dramatically different pharmacokinetic properties. The cell surface protein sortilin is a lysosomal trafficking
receptor that is overexpressed in a variety of cancers, including triple-negative breast cancer. We used computational methods to identify a targeting peptide for payload
delivery based on a fragment of the endogenous ligand progranulin. After verifying its binding, stability, and internalization properties, we discuss linker and conjugation
chemistry to support tumor-targeted delivery of a potent microtubule inhibitor, monomethyl auristatin E. We evaluate cytotoxicity of sortilin-targeting PDCs and their
efficacy in tumor growth inhibition in vivo. Structure-based design was employed to explore the importance of binding affinity and stability in a series of analogues. From
additional in vivo characterization, we identified a molecule (PQ203), with favorable potency, pharmacokinetics, and safety signals, which is undergoing IND-enabling studies
for a phase I clinical trial in 2025.
Bio
Chris is the co-founder and CSO of ProteinQure, a biotechnology company focused on the development of next-generation protein-based therapeutics. He received a PhD in Biochemistry at the University of Toronto focusing on structural biology and biophysics of ion channels, enzymes, and membrane receptors. Previously, he studied Theoretical Chemistry and Computational Physics at the University of Waterloo. He currently leads computational chemistry methods development and applications at ProteinQure, based in Toronto, Canada. He is passionate about cross-disciplinary collaboration to design novel synthetic protein libraries, new protein modalities, and better data-driven strategies for rational drug design.