PD-1 Peptide Inhibitors

Abstract

This disclosure provides peptides which have a strong affinity for the checkpoint receptor “programmed death 1” (PD-1). These peptides block the interaction of PD-1 with its ligand PD-L1 and can therefore be used for various therapeutic purposes, such as inhibiting the progression of a hyperproliferative disorder, including cancer; treating infectious diseases; enhancing a response to vaccination; treating sepsis; and promoting hair re-pigmentation or lightening of pigmented skin lesions.

1 . A method of inhibiting the progression of a hyperproliferative disorder, treating an infectious disease, enhancing a response to vaccination, treating sepsis, promoting hair re-pigmentation, or promoting lightening of a pigmented skin lesion, comprising administering to an individual in need thereof an effective amount of at least one peptide selected from the group consisting of (i) a peptide comprising the amino acid sequence SEQ ID NO:1; (ii) a peptide comprising the amino acid sequence SEQ ID NO:2; (iii) a peptide comprising the amino acid sequence SEQ ID NO:3; and (iv) a peptide comprising the amino acid sequence SEQ ID NO:4, wherein the administration comprises:
 (a) administration of a nucleic acid encoding the at least one peptide;   (b) administration of a peptide carrier system comprising the at least one peptide; or   (c) administration of a CAR-T cell that expresses the at least one peptide.   
     
     
         2 . The method of  claim 1 , which comprises administration of the nucleic acid encoding the at least one peptide, wherein the nucleic acid is selected from the group consisting of DNA, cDNA, PNA, and RNA. 
     
     
         3 . The method of  claim 1 , which comprises the administration of the peptide carrier system comprising the at least one peptide, wherein the peptide carrier system is selected from the group consisting of a microparticle, a polymeric nanoparticle, a liposome, a solid lipid nanoparticle, a hydrophilic mucoadhesive polymer, a thiolated polymer, a polymer matrix, a nanoemulsion, and a hydrogel. 
     
     
         4 . The method of  claim 1 , wherein the at least one peptide is administered to inhibit progression of the hyperproliferative disorder. 
     
     
         5 . The method of  claim 4 , wherein the hyperproliferative disorder is a cancer. 
     
     
         6 . The method of  claim 5 , wherein the cancer is a melanoma. 
     
     
         7 . The method of  claim 5 , further comprising administering a second therapy to the patient. 
     
     
         8 . The method of  claim 7 , wherein the second therapy comprises a cancer vaccine. 
     
     
         9 . The method of  claim 7 , wherein the second therapy comprises a chimeric antigen receptor (CAR) T cell therapy. 
     
     
         10 . The method of  claim 7 , wherein the second therapy comprises reducing or blocking activity of a molecule selected from the group consisting of PD-1, PD-L1, lymphocyte-activation gene-3 (LAG-3), cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), V-domain Immunoglobulin Suppressor of T cell Activation (VISTA), T-cell Immunoglobulin domain and Mucin domain 3 (TIM-3), a killer immunoglobulin-like receptor (KIR), indoleamine (2,3)-dioxygenase (IDO), B and T Lymphocyte Attenuator (BTLA), A2A adenosine receptor (A2AR). 
     
     
         11 . The method of  claim 7 , wherein the second therapy comprises a cytokine. 
     
     
         12 . The method of  claim 7 , wherein the second therapy comprises an agonist of a molecule selected from the group consisting of CD40, OX40, glucocorticoid-induced tumor necrosis factor-related protein (GITR), and Inducible T-cell COStimulator (ICOS). 
     
     
         13 . The method of  claim 7 , wherein the second therapy comprises a therapeutic agent selected from the group consisting of a 4-1BB agonist, a 4-1BB antagonist, an inhibitor of anaplastic lymphoma kinase (ALK), an inhibitor of histone deacetylase (HDAC), and an inhibitor of VEGFR. 
     
     
         14 . The method of  claim 1 , wherein the at least one peptide is administered to treat an infectious disease. 
     
     
         15 . The method of  claim 14 , wherein the infectious disease is malaria or hepatitis B. 
     
     
         16 . The method of  claim 14 , wherein the at least one peptide is administered as a vaccine adjuvant to a vaccine against the infectious disease. 
     
     
         17 . The method of  claim 1 , wherein the at least one peptide is administered to treat sepsis. 
     
     
         18 . The method of  claim 1 , wherein the at least one peptide is administered to promote hair re-pigmentation or to promote lightening of a pigmented skin lesion.