A PSMA-targeted bispecific antibody for prostate cancer driven by a small-molecule targeting ligand
Sung Chang Lee, S. Y. Jennifer, Min Soo Kim, Eduardo Laborda, Seihyun Choi, Eric Hampton, Hwayoung Yun, Vanessa Núñez, Michelle Muldong, Christina Wu, Wenxue Ma, Anna Kulidjian, Christopher J. Kane, Vadim Klyushnichenko, Ashley K. Woods, Sean B. Joseph, Mike Petrassi, John Wisler, Jing Li, Christina 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).