The world's first! Junshi Biological BTLA monoclonal antibody was accepted for clinical trial in the US

On March 25th, Junshi Biotech announced the development of the world's first (First in human, FIH) recombinant humanized IgG4κ single for B- and T-lymphocyte attenuating factor (BTLA). Cloned antibody (TAB004, or JS004). The New Drug Clinical Trial Application (IND) was accepted by the US Food and Drug Administration (FDA) on March 22 and is intended for the treatment of advanced unresectable or metastatic solid tumors, including patients with PD-1 antibody resistance.

BTLA is an important immunological checkpoint molecule expressed in activated T and B lymphocytes found in 2003. It has a similar structure to other immunological checkpoint molecules such as PD-1 and CTLA-4 (single immunoglobulin variable region). IgV extracellular domain) and similar intracellular signaling mechanisms (two cytoplasmic ITIM domains recruit to activate SHP-1 and SHP-2 phosphatase to inhibit lymphocyte function).

HVEM (Herpesvirus entry mediator, herpesvirus entry mediator) was identified as a ligand for BTLA in 2005 and is widely expressed in human immune cells such as T cells, B cells, NK cells, myeloid cells, and Dendritic cells, as well as a variety of tumor cells (including non-small cell lung cancer, melanoma, colorectal cancer, and lymphoma).

Under normal physiological conditions, BTLA binds to its ligand HVEM, which can inhibit the excessive activation of lymphocytes in the body and prevent the immune system from damaging itself. In tumor cells such as lung cancer, melanoma, colorectal cancer and lymphoma, by binding to HVEM and binding to BTLA expressed by tumor-specific killer lymphocytes, the immune function of lymphocytes can be inhibited. High tumor expression of HVEM is associated with poor prognosis.

In vitro experiments with melanoma-derived cells found that co-blocking of BTLA and PD-1 pathways significantly increased the number and function of tumor-specific killer lymphocytes, far superior to PD-1 blocking alone, indicating BTLA Activation of the pathway in the tumor microenvironment is one of the potential resistance mechanisms of PD-1 antibodies.

These results show that the blockade of BTLA immune checkpoint molecules can further improve lymphocyte function, especially when combined with anti-PD-1 monoclonal antibody, it is possible to further improve the efficacy of immunological checkpoint blockade therapy, expand immunotherapy Local beneficiaries.

The world's first recombinant humanized monoclonal antibody, JS004, specifically developed against BTLA, is intended for the treatment of advanced unresectable or metastatic solid tumors, including lymphoma. In vitro and in vivo studies have shown that JS004 can promote tumor-specific T lymphocyte proliferation and enhance lymphocyte function, reducing tumor burden and improving survival rate in a tumor model of BTLA humanized mice.

Junshi Biotech plans to carry out the JS004 Phase I climbing test in patients with PD-1 antibody-resistant solid tumors, and in the Phase I expansion group for combination therapy with Treiprilizumab (anti-PD-1 mAb) try.