anti-GARP/PD-L1 bispecific antibody BPB-101

An immunoglobulin G1 (IgG1) humanized bispecific antibody directed against the transforming growth factor beta (TGFbeta) activator glycoprotein A repetitions predominant (GARP; leucine-rich repeat-containing protein 32; LRRC32) and the immunosuppressive ligand programmed cell death-1 ligand 1 (PD-L1; PDL1; cluster of differentiation 274; CD274), with potential immune checkpoint inhibitory, immunomodulating and antineoplastic activities. Upon administration, anti-GARP/PD-L1 bispecific antibody BPB-101 selectively targets and binds to GARP. This specifically blocks the GARP-mediated release of the cytokine transforming growth factor-beta 1 (TGF-b1) from the GARP-TGFbeta complex (small latent complex; SLC) and neutralizes free/mature TGF-beta, thereby relieving the immunosuppression caused by TGF-b1 and reversing the immunosuppressive nature in the tumor microenvironment (TME). This improves anti-tumor immune responses. BPB-101 simultaneously targets, binds to, and inhibits the activity of PD-L1 on tumor cells, blocking its binding to and activation of its receptor programmed cell death 1 (PD-1; cluster of differentiation 279; CD279). This reverses T-cell inactivation caused by PD-1/PD-L1 signaling and enhances the cytotoxic T-lymphocyte (CTL)-mediated anti-tumor immune response against PD-L1-expressing tumor cells. This prevents both TGF-beta- and PD-L1-mediated immuno-suppressive pathways signaling, inhibits the negative regulatory function of regulatory T cells (Tregs) and increases natural killer (NK) cell and cytotoxic T-lymphocyte (CTL) activities. This restores and enhances anti-tumor responses and inhibits tumor cell proliferation in susceptible tumor cells. GARP, a transmembrane protein highly expressed on activated, immunosuppressive Tregs in the TME, is essential for the expression of TGF-b1 on the cell surface of activated Tregs; it plays an important role in regulation of the immune cell function and the immunosuppressive nature of Tregs. TGF-b1 stimulates stromal cell proliferation, neovascularization, cancer cell metastasis, and inhibits immune cell infiltration. PD-L1 is overexpressed by many human cancer cell types. PD-L1 binding to PD-1 on T cells suppresses the immune system and results in immune evasion. PD-1, a transmembrane protein belonging to the immunoglobulin superfamily (IgSF) expressed on activated T cells, is a negative regulator of the immune system that limits the expansion and survival of CD8-positive T cells.