A novel 4-1BB/HER2 bispecific antibody shows potent antitumor activities by increasing and activating tumor-infiltrating T cells.
Am J Cancer Res
; 13(7): 3246-3256, 2023.
Article
en En
| MEDLINE
| ID: mdl-37559991
Resistance to HER2-targeted therapy narrows the efficacy of cancer immunotherapy. Although 4-1BB/CD137 is a promising drug target as a costimulatory molecule of immune cells, no therapeutic drug has been approved in the clinic because of systemic toxicity or limited efficacy. Previously, we developed a humanized anti-HER2 monoclonal antibody (mAb) HuA21 and anti-4-1BB mAb HuB6 with distinct antigen epitopes for cancer therapy. Here, we generated an Fc-muted IgG4 HER2/4-1BB bispecific antibody (BsAb) HK006 by the fusion of HuB6 scFv and HuA21 Fab. HK006 exhibited synergistic antitumor activity by blocking HER2 signal transduction and stimulating the 4-1BB signaling pathway simultaneously and strictly dependent on HER2 expression in vitro and in vivo. Strikingly, HK006 treatment enhanced antitumor immunity by increasing and activating tumor-infiltrating T cells. Moreover, HK006 did not induce nonspecific production of proinflammatory cytokines and had no obvious toxicity in mice. Overall, these data demonstrated that HK006 should be a promising candidate for HER2-positive cancer immunotherapy.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
Am J Cancer Res
Año:
2023
Tipo del documento:
Article
País de afiliación:
China
Pais de publicación:
Estados Unidos