A CLDN18.2-Targeting Bispecific T Cell Co-Stimulatory Activator for Cancer Immunotherapy

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Co-stimulatory receptor agonist antibodies show antitumor potential but face clinical hurdles due to T cell activation side effects.
• Bispecific antibody formats are being explored to mitigate off-tumor immune activation and improve safety.
• Targeting CLDN18.2 is a strategy for specific tumor treatment.

Purpose of the Study:

• To develop and evaluate a bispecific antibody combining anti-CLDN18.2 and anti-CD28 functionalities.
• To assess the T cell co-stimulation, safety, and antitumor efficacy of this novel bispecific antibody.
• To provide proof-of-concept for a new therapeutic strategy against CLDN18.2-positive tumors.

Main Methods:

• Production of a bispecific antibody with anti-CLDN18.2 and anti-CD28 binding domains.
• In vitro evaluation of T cell co-stimulation and effector cytokine production using coculture assays.
• In vivo assessment of antitumor efficacy and safety in preclinical mouse tumor models.

Main Results:

• The bispecific antibody effectively co-stimulated T cells in a CLDN18.2-dependent manner, increasing effector cytokines.
• Treatment reduced tumor burden and enhanced T cell infiltration into tumors.
• A decrease in immunosuppressive cells, including tumor-associated macrophages and myeloid-derived suppressor cells, was observed without systemic adverse effects.

Conclusions:

• The developed anti-CLDN18.2-anti-CD28 bispecific antibody demonstrates potent antitumor activity and favorable safety profile.
• This study provides proof-of-concept for a bispecific co-stimulatory activator strategy for CLDN18.2-positive malignancies.
• The findings support further development of this bispecific antibody for cancer immunotherapy.