PD-1 / CTLA-4 / VEGF-A

Class

trispecific antibody (hexavalent, Fc-silenced)

Pathway

dual immune checkpoint blockade + anti-angiogenesis

This molecule is a trispecific antibody engineered to simultaneously block two immune checkpoints (PD-1 and CTLA-4) and neutralize VEGF-A, a growth factor that drives new blood vessel formation (angiogenesis). PD-1 and CTLA-4 are receptors that normally restrain T cells, the immune system's cytotoxic effector cells, to prevent excessive immune activation; tumors exploit these checkpoints to evade immune attack. Blocking both pathways removes restraints at different stages of the T cell response, since PD-1 mainly limits T cells already engaged with target cells while CTLA-4 limits their initial activation. VEGF-A, beyond promoting vessel growth, also fosters an immunosuppressive tumor environment and abnormal vasculature that impedes immune cell entry into tumors. By combining checkpoint blockade with VEGF-A neutralization in one molecule, the approach aims to both unleash antitumor immunity and improve the physical and immunological conditions of the tumor for that immunity to act. This multi-target strategy is broadly relevant across solid tumors where combination therapies targeting immune evasion and abnormal vasculature have shown biological rationale for improving responses beyond what single-pathway blockade achieves. The hexavalent, Fc-silenced antibody design is intended to engage all three targets while minimizing unwanted immune effector functions.