Compositions and methods of treating cancer with glycomimetic peptides

Abstract

The present disclosure relates to pharmaceutical compositions comprising a peptide or multivalent polypeptide, and an anti-cancer agent. In some embodiments, the anti-cancer agent is conjugated to the peptide or multivalent polypeptide. The present disclosure also relates to a method of treating cancer or reducing cancer cell proliferation using the peptide or multivalent polypeptide. In some aspects, the peptide or multivalent polypeptide enhances the efficacy of the anti-cancer agent, the targeting of the anti-cancer agent to the cancer cells, or both.

What is claimed is: 
     
         1 . A pharmaceutical composition, comprising:
 a pharmaceutically acceptable carrier;   an anti-cancer agent; and   a therapeutic peptide, wherein the therapeutic peptide comprises:
 a sequence of X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 , or 
 a construct having a central framework, a linker sequence, and at least two arms, wherein each arm consists of a core sequence of X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 , and each arm is linked to the central framework via the linker sequence, 
   wherein
 X 1  is H or N, 
 X 2  is P or Q, 
 X 3  is S or H, 
 X 4  is H, T, or L, 
 X 5  is P, K, or is absent, 
 X 6  is R, L, S, or is absent, 
 X 7  is S, L, or is absent, and 
 X 8  is G or is absent. 
   
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein X 1  is N, X 2  is Q, X 3  is H, X 4  is T, X 5  is P, and/or X 6  is R. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein at least one core sequence comprises NQHTPR (SEQ ID NO: 1). 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the peptide and Ca 2+ -dependent lectin-type receptor family member 10A (CLEC10A) have a binding energy (ΔG′) of higher than −35 kJ/mol; f have an equilibrium dissociation constant (K D ) of 0.01-0.2 μM; or both. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the peptide is in an amount sufficient to trigger endocytosis of Ca 2+ -dependent lectin-type receptor family member 10A (CLEC10A) into a cell; increase a peritoneal immune cell population; or both. 
     
     
         6 . The pharmaceutical composition of  claim 5 , wherein the peritoneal immune cell is selected from the group consisting of: T cells expressing CD3; activated natural killer T (NKT) cells expressing CD3, NK1.1, and CD69; activated natural killer (NK) cells expressing CD3 − , NK1.1, and CD69; T cells expressing CD4; activated T cells expressing CD4 and CD69; cytotoxic T cells expressing CD8; activated cytotoxic T cells expressing CD8 and CD69; mature, active macrophages expressing CD11b, F4/80, and CD86; dendritic cells (DCs) expressing CD11c; activated DCs expressing CD11c and CD86; B cells expressing CD19; memory B cells expressing CD19, CD73, CD80, and CD273; and combinations thereof. 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the peptide is in an amount sufficient to induce release of IFN-γ; and the anti-cancer agent is selected from the group consisting of: a chemotherapy drug, a cancer immunotherapy drug, a photosensitizer, and combinations thereof. 
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein the chemotherapy drug is selected from the group consisting of: an alkylating agent, an antimetabolite, an anti-tumor antibiotic, an antiviral drug, a mitotic inhibitor, a topoisomerase inhibitor, and combinations thereof, wherein the alkylating agent is selected from the group consisting of: busulfan, carboplatin, cisplatin, cyclophosphamide, mitomycin C (MTC), and temozolamide; the antimetabolite is selected from the group consisting of: 5-Fluorouracil (5-FU, FU), 6-mercaptopurine (6-MP), capecitabine (Xeloda), cytosine arabinoside (AraC), gemcitabine (dFdC), hydroxyurea (HU), and methotrexate (MTX); the anti-tumor antibiotic is selected from the group consisting of: Bleomycin, dactinomycin (cosmegen), and daunorubicin (cerubidine, rubidomycin); the antiviral drug is selected from the group consisting of: acyclovir (Acy), foscarnet (FOS), and ganciclovir (gan); the mitotic inhibitor is selected from the group consisting of: demecolcine, docetaxel (taxotere), eribulin (halaven), ixabepilone (ixempra), paclitaxel (taxol), and vinblastine; and the topoisomerase inhibitor is selected from the group consisting of: camptothecin (CPT), etoposide (VP-16), irinotecan (camptosar), and topotecan (hycamtin); the cancer immunotherapy drug is selected from the group consisting of: a cellular immunotherapy drug, an antibody therapy drug, a cytokine therapy drug, and polysaccharide K; the cellular immunotherapy drug is selected from the group consisting of: sipuleucel-T (provenge), tisagenlecleucel (kymriah), and axicabtagene ciloleucel (yescarta); the antibody therapy drug is selected from the group consisting of: an anti-CD20 antibody, an anti-CD52 antibody, an anti-CTLA-4 antibody, an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-PD-L2 antibody; and the cytokine therapy drug is selected from the group consisting of: IFNα, IFNβ, IFNγ, IFNλ, and IL-2. 
     
     
         9 . The pharmaceutical composition of  claim 8 , wherein the anti-CD20 antibody is selected from the group consisting of: ofatumumab (arzerra), and rituximab (rituxan, mabthera); the anti-CD52 antibody is alemtuzumab (campath-1H); the anti-PD-1 antibody is selected from the group consisting of: nivolumab (opdivo), and pembrolizumab (keytruda); and the anti-PD-L1 antibody is selected from the group consisting of: atezolizumab (tecentriq), avelumab (bavencio), and durvalumab (imfinzi); and the anti-CTLA-4 antibody is ipilimumab (yervoy). 
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein the anti-cancer agent is selected from the group consisting of: a STING ligand, a chemotherapy drug, and a photodynamic therapy drug. 
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein the anti-cancer agent comprises cyclic dinucleotide (CDN), 5,6-dimethylxanthenone-acetic acid (DMXAA)), doxorubicin, chlorin p6, or combinations thereof. 
     
     
         12 . The pharmaceutical composition of  claim 1 , wherein the anti-cancer agent and the peptide have an average molar ratio of between 10:1 and 12:1. 
     
     
         13 . A method of reducing cancer cell progression, comprising contacting the cell with the pharmaceutical composition of  claim 1  in an amount sufficient to reduce cancer cell progression. 
     
     
         14 . The method of  claim 13 , wherein reducing cancer cell progression includes reducing cancer cell proliferation. 
     
     
         15 . The method of  claim 13 , wherein the cancer cell expresses CLEC10A, ASGPR-1, CLEC4F, or combinations thereof. 
     
     
         16 . The method of  claim 13 , wherein the cancer is selected from the group consisting of: bladder cancer, breast cancer, cervical cancer, hepatocellular carcinoma, Kaposi sarcoma, lung cancer, lymphoma, malignant melanoma, melanoma, mesothelioma, metastatic melanoma lung cancer, non-small cell lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cell cancer, small-cell lung cancer, peritoneal cancer, and squamous lung cancer. 
     
     
         17 . The method of  claim 13 , wherein the cancer is ovarian cancer and the administration of the anti-cancer agent proceeds the administration of the peptide by at least 1 day. 
     
     
         18 . The method of  claim 13 , wherein the administration of the anti-cancer agent proceeds the administration of the peptide by at least 30 days. 
     
     
         19 . The method of  claim 13 , wherein the amount of the peptide is within the range of 1 nmol to 1,000 nmol per kg of body weight of the subject, and the subject is a human. 
     
     
         20 . A pharmaceutical composition, comprising:
 a pharmaceutically acceptable carrier;   an anti-cancer agent; and   a therapeutic peptide, wherein the therapeutic peptide comprises: the sequence VQATQSNQHTPR (SEQ ID NO: 2) or a construct having a central framework, a linker sequence, and at least two arms, wherein at least one arm comprises VQATQSNQHTPR (SEQ ID NO: 2), and each arm is linked to the central framework via the linker sequence.