VivoGenie Anti-Human PD-1 (Tislelizumab) – Fc Reduced Biosimilar (IVMB0543)

Programmed cell death 1 (PD-1) is a transmembrane protein in the Ig superfamily^1,2 that acts as an immune checkpoint receptor³, a T cell inhibitory receptor, plays critical roles in peripheral tolerance induction, autoimmune disease prevention, macrophage phagocytosis, tumor cell glycolysis, and dendritic cell survival². PD-1 prevents uncontrolled T cell activity, leading to attenuation of T cell proliferation, cytokine production, and cytolytic activities. Additionally, the PD-1 pathway is a major mechanism of tumor immune evasion, and, as such, PD-1 is a target of cancer immunotherapy². Programmed cell death 1 ligand 1 (PD-L1; CD274; B7H1) and programmed cell death 1 ligand 2 (PD-L2; CD273; B7DC) are ligands¹.

Tislelizumab was developed by BeiGene as an immunotherapeutic for hematological cancers and advanced solid tumors⁴. Tislelizumab is a humanized mouse monoclonal antibody designed as a synthetic protein fusion of the 317-4B6 heavy chain VH fragment with human γ4 chain clone mut10 effector/constant domain fragment (disulfide with anti-human PD-1) and synthetic clone 317-4B6 light chain VL fragment with human κ chain constant region fragment, dimer^4,5.

Tislelizumab binds to PD-1 with high specificity and affinity using the critical epitopes Gln75, Thr76, Asp77 and Arg86, blocking PD-1 and preventing ligand binding⁴. The epitope is located on the CC’ loop of the front β sheet face of PD-1 and causes stereospecific hindrance to PD-L1 binding⁶. Unlike other IgG4 anti-PD-1 blocking antibodies, the S228P mutation known to bind to Fc-γ receptor 1 (FcγRI) and induce antibody-dependent cellular phagocytosis of T cells is not present⁴ and several mutations in the Fc-hinge region render tislelizumab unable to bind to FcγRs generally⁶. Consequently, tislelizumab has low affinity for FcγRI and baseline antibody-dependent cellular phagocytosis relative to control antibodies⁴. Additionally, FcR-mediated effects such as antibody-dependent cell-mediated cytotoxicity or compliment-dependent cytotoxicity are not observed^4,6.