A PSMA-targeted bispecific antibody for prostate cancer driven by a small-molecule targeting ligand

Sci Adv. 2021 Aug 11;7(33):eabi8193. doi: 10.1126/sciadv.abi8193. Print 2021 Aug.


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).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Bispecific* / pharmacology
  • Antibodies, Bispecific* / therapeutic use
  • CD3 Complex / therapeutic use
  • Cell Line, Tumor
  • Clinical Trials as Topic
  • Humans
  • Ligands
  • Male
  • Mice
  • Prostatic Neoplasms, Castration-Resistant* / drug therapy
  • Prostatic Neoplasms, Castration-Resistant* / metabolism
  • Prostatic Neoplasms, Castration-Resistant* / pathology
  • T-Lymphocytes


  • Antibodies, Bispecific
  • CD3 Complex
  • Ligands

Associated data

  • ClinicalTrials.gov/NCT04077021