A PSMA-targeted bispecific antibody for prostate cancer driven by a small-molecule targeting ligand
| Autor: | Christina Jamieson, Sung Chang Lee, Jennifer Ma, Sean B. Joseph, Minsoo Kim, Anna A. Kulidjian, Peter G. Schultz, Ashley K. Woods, Wenxue Ma, Mike Petrassi, Michelle Muldong, Travis S. Young, Hwayoung Yun, Christopher J. Kane, Eric N. Hampton, Chan Hyuk Kim, Jing Li, Vanessa Núñez, Eduardo Laborda, Klyushnichenko Vadim, Sei-hyun Choi, John Wisler, Christina C. N. Wu |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Urologic Diseases
Male CD3 Complex medicine.drug_class T-Lymphocytes Castration-Resistant Monoclonal antibody Ligands Antibodies Cell Line Prostate cancer Mice Clinical Research In vivo Cell Line Tumor Antibodies Bispecific medicine Potency Animals Humans Research Articles Cancer Clinical Trials as Topic Tumor Multidisciplinary biology business.industry Prostate Cancer Prevention Prostatic Neoplasms SciAdv r-articles medicine.disease Ligand (biochemistry) Small molecule Prostatic Neoplasms Castration-Resistant 5.1 Pharmaceuticals biology.protein Cancer research Bispecific Blinatumomab Development of treatments and therapeutic interventions Antibody business Biotechnology medicine.drug Research Article |
| Zdroj: | Science Advances Science advances, vol 7, iss 33 |
| ISSN: | 2375-2548 |
| Popis: | CCW702 is a bispecific antibody that combines the specificity of an imaging ligand with the potency of a T cell immunotherapy. 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). |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|