A PSMA-targeted bispecific antibody for prostate cancer driven by a small-molecule targeting ligand
Sung Chang Lee, Jennifer S Y Ma, Min Soo Kim, Eduardo Laborda, Sei-Hyun Choi, Eric N Hampton, Hwayoung Yun, Vanessa Nunez, Michelle T Muldong, Christina N Wu, Wenxue Ma, Anna A Kulidjian, Christopher J Kane, Vadim Klyushnichenko, Ashley K Woods, Sean B Joseph, Mike Petrassi, John Wisler, Jing Li, Christina A M Jamieson, Peter G Schultz, Chan Hyuk Kim, Travis S Young, Sung Chang Lee, Jennifer S Y Ma, Min Soo Kim, Eduardo Laborda, Sei-Hyun Choi, Eric N Hampton, Hwayoung Yun, Vanessa Nunez, Michelle T Muldong, Christina N Wu, Wenxue Ma, Anna A Kulidjian, Christopher J Kane, Vadim Klyushnichenko, Ashley K Woods, Sean B Joseph, Mike Petrassi, John Wisler, Jing Li, Christina A M Jamieson, Peter G Schultz, Chan Hyuk Kim, Travis S Young
Abstract
Despite the development of next-generation antiandrogens, metastatic castration-resistant prostate cancer (mCRPC) remains incurable. Here, we describe a unique semisynthetic bispecific antibody that uses site-specific unnatural amino acid conjugation to combine the potency of a T cell-recruiting anti-CD3 antibody with the specificity of an imaging ligand (DUPA) for prostate-specific membrane antigen. This format enabled optimization of structure and function to produce a candidate (CCW702) with specific, potent in vitro cytotoxicity and improved stability compared with a bispecific single-chain variable fragment format. In vivo, CCW702 eliminated C4-2 xenografts with as few as three weekly subcutaneous doses and prevented growth of PCSD1 patient-derived xenograft tumors in mice. In cynomolgus monkeys, CCW702 was well tolerated up to 34.1 mg/kg per dose, with near-complete subcutaneous bioavailability and a PK profile supporting testing of a weekly dosing regimen in patients. CCW702 is being evaluated in a first in-human clinical trial for men with mCRPC who had progressed on prior therapies (NCT04077021).
Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
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References
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