anti-PD-1/anti-4-1BB bispecific antibody IBI-319

A bispecific antibody targeting both the human negative immunoregulatory checkpoint receptor programmed cell death protein 1 (PD-1; PDCD1; CD279) and 4-1BB (CD137; tumor necrosis factor receptor superfamily member 9; TNFRSF9), with potential checkpoint inhibitory, immunostimulating and antineoplastic activities. Upon administration, anti-PD-1/anti-4-1BB bispecific antibody IBI-319 simultaneously targets and binds to PD-1, which is expressed on a variety of leukocyte subsets including activated T lymphocytes in the tumor microenvironment (TME), and 4-1BB, which is expressed on activated T lymphocytes and natural killer (NK) cells. This crosslinks PD-1- and 4-1BB-expressing T cells. Through 4-1BB binding, IBI-319 acts as a conditional 4-1BB agonist, resulting in T-cell co-stimulation and enhances T-lymphocyte-mediated anti-tumor activity. At the same time, PD-1 binding prevents PD-L1 from binding to and activating its receptor PD-1 and inhibits the PD-L1/PD-1-mediated downregulation of T-cell activation and proliferation. This abrogates T-cell inhibition, activates antigen-specific T lymphocytes and enhances cytotoxic T-cell-mediated tumor cell lysis, which may lead to a reduction in tumor growth. PD-L1 binding to PD-1 on activated T cells inhibits the expansion and survival of CD8-positive T cells, suppresses the immune system and results in immune evasion. 4-1BB, a surface glycoprotein of the tumor necrosis factor receptor superfamily, is an inducible costimulatory receptor that plays a key role in T-cell proliferation, survival and cytolytic activity.