anti-PD-1/anti-CTLA-4/anti-VEGF trispecific antibody HC010

A trispecific antibody directed against the negative immunoregulatory human cell receptor programmed cell death protein 1 (PD-1; PDCD1; CD279), the cytotoxic T-lymphocyte-associated antigen 4 (CTLA4; CTLA-4), and the human vascular endothelial growth factor (VEGF), with potential immune checkpoint inhibitory, anti-angiogenic and antineoplastic activities. Upon administration, anti-PD-1/anti-CTLA-4/anti-VEGF trispecific antibody HC010 simultaneously targets, binds to and blocks PD-1 and CTLA-4 expressed on tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment (TME), thereby inhibiting the PD-1- and CTLA-4-mediated downregulation of T-cell activation and proliferation. This restores immune function and enhances cytotoxic T-lymphocyte (CTL)-mediated tumor cell lysis, which may lead to a reduction in tumor growth. The binding of HC010 to VEGF prevents binding of VEGF to its receptor VEGFR, abrogates VEGF/VEGFR-mediated signaling and may lead to the inhibition of vascular endothelial cell proliferation. The inhibition of tumor angiogenesis may further decrease tumor cell proliferation and prevent metastasis. Both PD-1 and CTLA-4 negatively regulate the activation and effector functions of T cells. They play key roles in the downregulation of the immune system and tumor evasion from host immunity. Dual checkpoint blockade of PD-1 and CTLA-4 enhances T-cell activation and proliferation more than the blockade of either immune checkpoint receptor alone. VEGF is overexpressed in a variety of cancers and is associated with increased invasiveness and decreased survival.