PD-1 (programmed cell death 1) is an important immune checkpoint receptor expressed by activated T cell and B cells. It functions to mediate immunosuppression. PD-1 is expressed on activated T cells, B cells, and natural killer (NK) cells. The ligands for PD-1 are PD-L1 and PD-L2, which are expressed on many tumor cells and antigen-presenting cells, such as monocytes, dendritic cells (DC) and macrophages.
PD-1 is a member of the immunoglobulin (Ig) superfamily that contains a single Ig V-like domain in its extracellular region. The PD-1 cytoplasmic domain contains two tyrosines, with the most membrane-proximal tyrosine located within an immuno-receptor tyrosine-based inhibitory motif (ITIM). PD-1 attenuates antigen receptor signaling by recruiting cytoplasmic phosphatases via its cytoplasmic domain. Human and murine PD-1 proteins share about 60% amino acid identity with conservation of four potential N-glycosylation sites, and residues that define the Ig-V domain.
PD-1 acts to deliver a negative immune response signal when induced in T cells. Activation of PD-1 via selective binding to one of its ligands activates an inhibitory immune response that decreases T cell proliferation and/or the intensity and/or duration of a T cell response. PD-1 also regulates effector T cell activity in peripheral tissues in response to infection or tumor progression (Pardoll, Nat Rev Cancer, 2012, 12(4):252-264).
Endogenous immune checkpoints, such as the PD-1 signaling pathway, that normally terminate immune responses to mitigate collateral tissue damage can be co-opted by tumors to evade immune destruction. The interaction between PD-L1 and PD-1 in cancers can decrease the number of tumor-infiltrating immune cells, and inhibit an immune response to the cancer cells. Downregulation of T cell activation and cytokine secretion upon binding to PD-1 has been observed in several human cancers (Freeman et al., J Exp Med, 2000, 192(7):1027-34; Latchman et al., Nat Immunol, 2001, 2(3):261-8). In addition, the PD-1 ligand PD-L1 is overexpressed in many cancers, including breast cancer, colon cancer, esophageal cancer, gastric cancer, glioma, leukemia, lung cancer, melanoma, multiple myeloma, ovarian cancer, pancreatic cancer, renal cell carcinoma, and urothelial cancer. It has also been shown that patients with cancer have a limited or reduced adaptive immune response due to increased PD-1/PD-L1 interactions by immune cells. This increase in activated PD-1 signaling has also been seen in patients with viral infections. For instance, hepatitis B and C viruses can induce overexpression of PD-1 ligands on hepatocytes and activate PD-1 signaling in effector T-cells. This, in turn, leads to T-cell exhaustion and immune tolerance to the viral infection (Boni et al., J Virol, 2007, 81:4215-4225; Golden-Mason et al., J Immunol, 2008, 180:3637-3641).
Current PD-1 antagonists, such as pidilizumab, pembrolizumab (Keytruda®) and nivolumab (Opdivo®) are antibodies that target PD-1 on all lymphatic cells of the body. These antibodies have nanomolar affinities to PD-1, which is weaker than the interaction between PD-1 and its ligands within the immune synapse, e.g., the interface between an antigen-presenting cell and a lymphocyte.
There is a need in the art for effective protein-based therapeutic treatment that can reverse the inhibition of adaptive immunity in patients with cancer or chronic infection. The present invention satisfies this and other needs.
USPTO Backgrounds
USPTO Backgrounds