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Figure S1 from PF-06804103, A Site-specific Anti-HER2 Antibody–Drug Conjugate for the Treatment of HER2-expressing Breast, Gastric, and Lung Cancers

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posted on 2023-04-03, 18:23 authored by Edmund I. Graziani, Matthew Sung, Dangshe Ma, Bitha Narayanan, Kimberly Marquette, Sujiet Puthenveetil, L. Nathan Tumey, Jack Bikker, Jeffrey Casavant, Eric M. Bennett, Manoj B. Charati, Jonathon Golas, Christine Hosselet, Cynthia M. Rohde, George Hu, Magali Guffroy, Hadi Falahatpisheh, Martin Finkelstein, Tracey Clark, Frank Barletta, Lioudmila Tchistiakova, Judy Lucas, Edward Rosfjord, Frank Loganzo, Christopher J. O'Donnell, Hans-Peter Gerber, Puja Sapra

In vivo efficacy of site-specific anti-HER2 vc0101 4 DAR ADCs in N87 xenograft tumor model.

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PF-06804103 Project Team

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ARTICLE ABSTRACT

The 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: (i) a new auristatin payload with optimized pharmacodynamic properties, (ii) a cleavable linker for optimized payload release and enhanced antitumor efficacy, and (iii) 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 (i) an enhanced efficacy against low HER2-expressing breast, gastric, and lung tumor models, (ii) overcomes in vitro- and in vivo–acquired T-DM1 resistance, and (iii) 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.

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