Your browser doesn't support javascript.
loading
Tumour inhibitory activity on pancreatic cancer by bispecific nanobody targeting PD-L1 and CXCR4.
Hao, Shuai; Xu, Shuyi; Li, Liangzhu; Li, Yaxian; Zhao, Meiqi; Chen, Junsheng; Zhu, Shunying; Xie, Yueqing; Jiang, Hua; Zhu, Jianwei; Wu, Mingyuan.
Afiliación
  • Hao S; Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, 200240, Shanghai, People's Republic of China.
  • Xu S; Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, 200240, Shanghai, People's Republic of China.
  • Li L; Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, 200240, Shanghai, People's Republic of China.
  • Li Y; Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, 200240, Shanghai, People's Republic of China.
  • Zhao M; Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, 200240, Shanghai, People's Republic of China.
  • Chen J; Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, 200240, Shanghai, People's Republic of China.
  • Zhu S; Institute of Translational Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, 200240, Shanghai, People's Republic of China.
  • Xie Y; Jecho Laboratories, Inc, 7320 Executive Way, 21704, Frederick, MD, USA.
  • Jiang H; Jecho Laboratories, Inc, 7320 Executive Way, 21704, Frederick, MD, USA.
  • Zhu J; Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, 200240, Shanghai, People's Republic of China. jianweiz@sjtu.edu.cn.
  • Wu M; Jecho Laboratories, Inc, 7320 Executive Way, 21704, Frederick, MD, USA. jianweiz@sjtu.edu.cn.
BMC Cancer ; 22(1): 1092, 2022 Oct 25.
Article en En | MEDLINE | ID: mdl-36284271
ABSTRACT

BACKGROUND:

Antibodies and derivative drugs targeting immune checkpoints have been approved for the treatment of several malignancies, but there are fewer responses in patients with pancreatic cancer. Here, we designed a nanobody molecule with bi-targeting on PD-L1 and CXCR4, as both targets are overexpressed in many cancer cells and play important roles in tumorigenesis. We characterized the biochemical and anti-tumour activities of the bispecific nanobodies in vitro and in vivo.

METHODS:

A nanobody molecule was designed and constructed. The nanobody sequences targeting PD-L1 and CXCR4 were linked by the (G4S)3 flexible peptide to construct the anti-PD-L1/CXCR4 bispecific nanobody. The bispecific nanobody was expressed in E. coli cells and purified by affinity chromatography. The purified nanobody was biochemically characterized by mass spectrometry, Western blotting and flow cytometry to confirm the molecule and its association with both PD-L1 and CXCR4. The biological function of the nanobody and its anti-tumour effects were examined by an in vitro tumour cell-killing assay and in vivo tumour inhibition in mouse xenograft models.

RESULTS:

A novel anti-PD-L1/CXCR4 bispecific nanobody was designed, constructed and characterized. The molecule specifically bound to two targets on the surface of human cancer cells and inhibited CXCL12-induced Jurkat cell migration. The bispecific nanobody increased the level of IFN-γ secreted by T-cell activation. The cytotoxicity of human peripheral blood mononuclear cells (hPBMCs) against pancreatic cancer cells was enhanced by the molecule in combination with IL-2. In a human pancreatic cancer xenograft model, the anti-PD-L1/CXCR4 nanobody markedly inhibited tumour growth and was superior to the combo-treatment by anti-PD-L1 nanobody and anti-CXCR4 nanobody or treatment with atezolizumab as a positive control. Immunofluorescence and immunohistochemical staining of xenograft tumours showed that the anti-tumour effects were associated with the inhibition of angiogenesis and the infiltration of immune cells.

CONCLUSION:

These results clearly revealed that the anti-PD-L1/CXCR4 bispecific nanobody exerted anti-tumour efficacy in vitro and inhibited tumour growth in vivo. This agent can be further developed as a therapeutic reagent to treat human pancreatic cancer by simultaneously blocking two critical targets.
Asunto(s)
Palabras clave

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Anticuerpos Biespecíficos / Anticuerpos de Dominio Único Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: BMC Cancer Asunto de la revista: NEOPLASIAS Año: 2022 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Anticuerpos Biespecíficos / Anticuerpos de Dominio Único Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: BMC Cancer Asunto de la revista: NEOPLASIAS Año: 2022 Tipo del documento: Article