Anti-Human PD-1 (Pembrolizumab) (IVMB0395)

PD-1 is a transmembrane protein in the CD28/CTLA-4 subfamily of the Ig superfamily^{1, 2}. When stimulated via the T cell receptor (TCR), Tregs translocate PD-1 to the cell surface³. Programmed cell death 1 ligand 1 (PD-L1; CD274; B7H1) and programmed cell death 1 ligand 2 (PD-L2; CD273; B7DC) have been identified as PD-1 ligands¹. PD-1 is co-expressed with PD-L1 on tumor cells and tumor-infiltrating antigen-presenting cells (APCs)². Additionally, PD-1 is co-expressed with IL2RA on activated CD4⁺ T cells³.

PD-1 is an immune checkpoint receptor that suppresses cancer-specific immune responses⁴. Additionally, PD-1 acts as a T cell inhibitory receptor and plays a critical role in peripheral tolerance induction and autoimmune disease prevention as well as important roles in the survival of dendritic cells, macrophage phagocytosis, and tumor cell glycolysis². 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.

Pembrolizumab was generated as a humanized monoclonal antibody by grafting the variable region sequences of a mouse anti-human PD-1 antibody onto a human IgG4-κ isotype framework containing a stabilizing S228P Fc mutation^{5, 6}. Pembrolizumab shows high affinity for the PD-1 receptor and prevents PD-1 binding to ligands PD-L1 and PD-L2. Additionally, pembrolizumab strongly inhibits PD-L1 and PD-L2 and has robust activity in a functional ex vivo T cell modulation assay using human donor blood cells.

Pembrolizumab is used in adult and pediatric patients to treat unresectable or metastatic solid tumors with certain genetic abnormalities⁷. Binding of pembrolizumab to PD-1 does not engage Fc receptors or activate complement and therefore is devoid of cytotoxic activity⁸.