A PSMA-targeted bispecific antibody for prostate cancer driven by a small-molecule targeting ligand.
Sci Adv
; 7(33)2021 08.
Article
en En
| MEDLINE
| ID: mdl-34380625
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).
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Anticuerpos Biespecíficos
/
Neoplasias de la Próstata Resistentes a la Castración
Límite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Sci Adv
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos