Data from PF-06804103, A Site-specific Anti-HER2 Antibody–Drug Conjugate for the Treatment of HER2-expressing Breast, Gastric, and Lung Cancers

Jeffrey Casavant,Matthew Sung,Dangshe Ma,Puja Sapra,Edmund I Graziani,L Nathan Tumey,Sujiet Puthenveetil,Jack Bikker,Christine Hosselet,Cynthia M Rohde,Judy Lucas,Hadi Falahatpisheh,Magali Guffroy,George Hu,Edward Rosfjord,Kimberly Marquette,Bitha Narayanan,Lioudmila Tchistiakova,Manoj B Charati,Eric M Bennett,Tracey Clark,Frank Loganzo,Frank Barletta,Hans‐Peter Gerber ,Martín Finkelstein ,Jonathan Golas ,Christopher J O’donnell

doi:10.1158/1535-7163.c.6542832

Abstract

<div>AbstractThe approval of ado-trastuzumab emtansine (T-DM1) in HER2+ metastatic breast cancer validated HER2 as a target for HER2-specific antibody–drug conjugates (ADC). Despite its demonstrated clinical efficacy, certain inherent properties within T-DM1 hamper this compound from achieving the full potential of targeting HER2-expressing solid tumors with ADCs. Here, we detail the discovery of PF-06804103, an anti-HER2 ADC designed to have a widened therapeutic window compared with T-DM1. We utilized an empirical conjugation site screening campaign to identify the engineered ĸkK183C and K290C residues as those that maximized in vivo ADC stability, efficacy, and safety for a four drug–antibody ratio (DAR) ADC with this linker–payload combination. PF-06804103 incorporates the following novel design elements: (<a href="#bib1" target="_blank">i</a>) a new auristatin payload with optimized pharmacodynamic properties, (<a href="#bib2" target="_blank">ii</a>) a cleavable linker for optimized payload release and enhanced antitumor efficacy, and (<a href="#bib3" target="_blank">iii</a>) an engineered cysteine site–specific conjugation approach that overcomes the traditional safety liabilities of conventional conjugates and generates a homogenous drug product with a DAR of 4. PF-06804103 shows (<a href="#bib1" target="_blank">i</a>) an enhanced efficacy against low HER2-expressing breast, gastric, and lung tumor models, (<a href="#bib2" target="_blank">ii</a>) overcomes in vitro- and in vivo–acquired T-DM1 resistance, and (<a href="#bib3" target="_blank">iii</a>) an improved safety profile by enhancing ADC stability, pharmacokinetic parameters, and reducing off-target toxicities. Herein, we showcase our platform approach in optimizing ADC design, resulting in the generation of the anti-HER2 ADC, PF-06804103. The design elements of identifying novel sites of conjugation employed in this study serve as a platform for developing optimized ADCs against other tumor-specific targets.</div>

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