Bispecific antibody targeting both B7-H3 and PD-L1 exhibits superior antitumor activities

Area of Science:

• Immunology and Cancer Therapy

Background:

• Current PD-1/PD-L1 monoclonal antibodies (mAbs) have limited response rates and face drug resistance challenges in cancer treatment.
• Co-expression of B7-H3 and PD-L1 is observed in various solid tumors, suggesting a potential for combination therapies targeting both pathways.
• No bispecific antibodies targeting both PD-1 and B7-H3 have advanced to clinical development.

Purpose of the Study:

• To generate and evaluate a novel bispecific antibody (BsAb) targeting both B7-H3 and PD-L1.
• To assess the therapeutic potential of the B7-H3×PD-L1 BsAb in preclinical cancer models.

Main Methods:

• A stable B7-H3×PD-L1 bispecific antibody (BsAb) was engineered in an IgG1-VHH format.
• The BsAb was characterized for thermostability, T cell activation, IFN-γ production, and antibody-dependent cell-mediated cytotoxicity (ADCC).
• Antitumor efficacy was evaluated in a PBMC humanized A375 xenogeneic tumor model.

Main Results:

• The B7-H3×PD-L1 BsAb demonstrated favorable thermostability and enhanced immune cell activation, including T cell activation, IFN-γ production, and ADCC.
• In vivo studies showed superior antitumor activity of the BsAb compared to monotherapies and combination therapies in a humanized tumor model.
• The BsAb exhibited increased specificity for tumors co-expressing B7-H3 and PD-L1, inducing a synergistic therapeutic effect.

Conclusions:

• The developed B7-H3×PD-L1 BsAb offers a promising therapeutic strategy for B7-H3 and PD-L1 double-positive tumors.
• This BsAb demonstrates potential advantages over individual monoclonal antibodies and combination therapies, warranting further clinical investigation.