Targeting Tumor-Specific 4-1BB Activation with Claudin 18.2 X 4-1BB Bispecific Antibody for Potent Tumor Suppression

The abstract focuses on the development of a bispecific antibody, TJ-CD4B, targeting Claudin 18.2 (CLDN18.2), a protein overexpressed in various solid tumors, making it a promising target for cancer immunotherapy. TJ-CD4B is designed to engage the 4-1BB antigen, redirecting and activating T cells to target CLDN18.2 positive tumor cells.

The antibody's binding capability was assessed through protein and cell-based assays, demonstrating a stronger affinity for CLDN18.2 compared to a benchmark monoclonal antibody (IMAB362). TJ-CD4B's functionality was evaluated using a 4-1BB signaling reporter assay and primary human T cell assay, showing activation of 4-1BB signaling dependent on CLDN18.2 expression.

In a humanized 4-1BB mouse model with CLDN18.2 overexpressing colon cancer cells, TJ-CD4B exhibited robust tumor growth inhibition (TGI) and increased tumor infiltrating lymphocytes without affecting peripheral lymphocytes, suggesting a minimized risk of peripheral toxicity.

The study concludes that TJ-CD4B has shown potent anti-tumor activity specifically in the tumor microenvironment, supporting its further development. The antibody is considered reasonably developable and is expected to enter clinical trials in early 2021.

The research was presented at the Annual Meeting of the American Association for Cancer Research in 2020, highlighting its significance in the field of cancer therapy.