Abstract

<div>Abstract<p>The approval of ado-trastuzumab emtansine (T-DM1) in HER2<sup>+</sup> 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 <i>in vivo</i> 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 <i>in vitro</i>- and <i>in vivo</i>–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.</p></div>

Full Text

Published Version

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.