World’s first anti-BTLA monoclonal antibody for injection approved for clinical trials
BTLA is an immunoglobulin (Ig) receptor family member identified in 2003. It has a single IgV extracellular domain with sequence similarities with PD-1 and CTLA-4. BTLA is
expressed on activated T and B lymphocytes, and subsets of DCs.
HVEM, a TNF receptor widely expressed in hematopoietic system, was identified as a counter receptor for BTLA in 2005. HVEM is expressed on T, B, NK, myeloid and dendric
cells, and a variety of tumor cells including NSCLC, melanoma, colorectal cancer and lymphomas. Tumor expression of HVEM has been associated with poor prognosis and
BTLA contains two ITIM domains in its cytoplasmic region, which recruit SHP-1 and SHP-2 phosphatases upon receptor activation by mAb crosslinking or ligand engagement. BTLAdeficient mice are viable and fertile but show enhanced T cell activation in animal models of autoimmunity and inflammation, indicating an inhibitory function of BTLA to control T cell activation in vivo. Study of peripheral blood mononuclear cells (PBMC) from melanoma and NSCLC patients revealed that BTLA is expressed at high levels on tumor
specific CTLs and inhibits T cell function upon engagement by tumor expressed HVEM, suggesting BTLA blockade might potentially improve T cell function and anti-tumor
immunity. BTLA also co-expressed with PD-1 on tumor specific CTLs in melanoma and NSCLC patients.
Importantly, co-blockade of BTLA and PD-1 pathways increased the frequency and effector cytokine production of melanoma specific CTLs, whereas either BTLA or PD-1 blockade alone had limited effect, suggesting BTLA pathway is a potential resistance mechanism for patients refractory to anti-PD-1 monotherapy.
In vitro and in vivo studies have shown TAB004 or JS004 can promote antigen specific T cell proliferation and effector function, reduce tumor burden and improve survival in
human BTLA knock-in tumor models.
The Company plans to initiate fist-in-human (FIH) dose escalation study of TAB004 in advance solid tumors refractory to prior immunotherapy and explore combination use of
TAB004 with toripalimab, its marketed anti-PD-1 antibody, in the dose expansion phase of the trial.