This program aims to develop an antagonist antibody targeting BTLA for immuno-oncology. By blocking this new checkpoint of the B7/CD28 family, the anti-BTLA should unleash the anti-tumor immune response in a wide range of cancers.
BTLA (B and T lymphocyte attenuator) is an inhibitory receptor of the B7/CD28 immunoglobulin superfamily and as such shares structural similarities with PD-1 and CTLA-4. Its ligand is HVEM (herpes virus entry mediator), a member of the tumor necrosis factor receptor (TNFR) family whose expression is associated with poor prognosis in multiple cancer types. Interaction with HVEM leads to phosphorylation of the two cytoplasmic ITIM motifs of BTLA and recruitment of protein tyrosine phosphatases SHP-1 and SHP-2, which in turn inhibit the signaling cascades downstream of the TCR or BCR complexes. BTLA is expressed on most immune cells, with the exception of NK cells, and its inhibitor function is well documented across B, T and γδT cells. Importantly, BTLA displays a unique expression pattern during differentiation of T cells that distinguishes this receptor from other inhibitory receptors of the B7/CD28 family: its expression is high in naïve cells and progressively decreases upon T cell activation. BTLA is therefore a target of choice in naïve effector T cells where inhibitory receptors PD-1 and CTLA-4 are absent.
ImCheck Therapeutics’ has identified a lead anti-BTLA antibody that efficiently promotes the proliferation and activation of T and γδT cells, enhances the anti-tumor activity of anti-PD1 and anti-TIM3 antibodies, and suppresses tumor growth in preclinical studies.