Immunomodulatory compounds

Abstract

The present disclosure provides a peptide conjugate useful for inhibiting the progression of hyperproliferative disorders, inhibiting the progression of sepsis, inhibiting the progression of infectious diseases, enhancing responses to vaccines, or inhibiting the progression of synucleinopathy. The peptide conjugate can inhibit the function of PD1 and / or block the interaction of LAG3 with MHC-II. The peptide conjugate can include two peptides separated by a polyethylene glycol (PEG) linker.

Description

[Technical Field]

[0001] This application incorporates by reference the contents of the 2.65kb of text filed which is the Sequence Listing for this application, filed on June 1, 2020, entitled "00047900275sequencelisting.txt."

[0002] Each scientific article, patent, and published patent application cited in this disclosure is incorporated herein by reference in its entirety.

[0003] Technical Field The present disclosure relates generally to immunomodulatory peptides. [Background technology]

[0004] background There is a continuing need for useful regulators of immune checkpoint pathways. For example, programmed cell death-1 (PD1) and its ligands, PD-L1 and PD-L2, are widely expressed and exert numerous immunoregulatory roles in T cell activation, including attenuating immunity to tumor cells and infectious agents. PD1 is therefore an attractive target for various therapeutic applications. Cytotoxic T lymphocyte-associated antigen (CTLA-4), which provides negative signals to T cells, is also an attractive therapeutic target.

[0005] Lymphocyte activation gene 3 (LAG3 (also known as LAG-3, LAG 3, Lag3, CD223, and FDC protein)) is a member of the immunoglobulin superfamily of receptors. LAG3 is expressed on immune cells (activated T cells, Huard et al., 1994; natural killer cells, Triebel et al., 1990; B cells, Kisielow et al., 2005; plasmacytoid dendritic cells, Workman et al., 2009), where it binds to MHC class II (MHC-II) and acts as an immune checkpoint receptor. LAG3 also binds to fibronectin-like protein (FGL1), and disrupting this binding can enhance antitumor immunity (Wang et al., 2019). LAG3 is also expressed on neurons, where it acts as a receptor for α-synuclein aggregates characteristic of synucleinopathies (Mao et al., 2016), disorders characterized by the abnormal accumulation of α-synuclein protein aggregates in neurons, nerve fibers, or glial cells. Synucleinopathies include idiopathic and hereditary forms of Parkinson's disease (PD); diffuse Lewy body (DLB) disease (also known as Dementia with Lewy Bodies or Lewy body dementia); incidental Lewy body disease; Lewy body variant of Alzheimer's disease (LBV); Combined Alzheimer's and Parkinson's disease (CAPD); pure autonomic failure (PAF); multiple system atrophy (MSA) (e.g., olivopontocerebellar atrophy, striatonigral degeneration, and Shy-Drager syndrome); pantothenate kinase-associated neurodegeneration; Down's syndrome; Gaucher-related synucleinopathies; and neurodegenerative diseases involving brain iron deposition. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Huard et al., "Cellular expression and tissue distribution of the human LAG-3-encoded protein, an MHC class II ligand," Immunogenetics 39 (3): 213-7, 1994 [Non-patent document 2] Triebel et al., “LAG3, a novel lymphocyte activation gene closely related to CD4,” J. Exp. Med. 171, 1393-405, 1990 [Non-patent document 3] Kisielow et al., "Expression of lymphocyte activation gene 3 (LAG-3) on B cells is induced by T cells". European Journal of Immunology 35 (7): 2081-8, 2005 [Non-patent document 4] Workman et al., "LAG-3 regulates plasmacytoid dendritic cell homeostasis," Journal of Immunology 182 (4): 1885-91, 2009 [Non-patent document 5] Wang et al., “Anaplastic lymphoma kinase (ALK) inhibitors: a review of design and discovery,” Med. Chem. Commun. 5, 1266-79, 2014 [Brief explanation of the drawings]

[0007] [Figure 1]Figure 1 is a graph reporting the results of a TR-FRET assay testing the ability of peptide conjugates and individual peptides to affect the interaction between LAG3 and MHC-II. * indicates precipitation when diluted in assay buffer at 1 mM (100 μM final).

[0008] [Figure 2] Figure 2A is a graph showing the results of a TR-FRET assay testing peptide LG42 (SEQ ID NO: 6) and Figure 2B is a graph showing the results of a TR-FRET assay testing peptide LD10da (SEQ ID NO: 8).

[0009] [Figure 3] FIG. 3 is a graph showing the results of a TR-FRET assay testing peptide LG11 (SEQ ID NO: 3).

[0010] [Figure 4] Figure 4A is a graph showing the results of a TR-FRET assay testing peptide conjugate BT1. Figure 4B is a graph showing the results of a TR-FRET assay testing peptide conjugate BT2.

[0011] [Figure 5] FIG. 5 is a graph showing the results of a TR-FRET assay testing the peptide conjugate BT3.

[0012] [Figure 6] Figure 6A is a graph showing the results of a TR-FRET assay testing peptide conjugate BT4, and Figure 6B is a graph showing the results of a TR-FRET assay testing peptide conjugate BT5.

[0013] [Figure 7] Figure 7A is a graph showing the results of a TR-FRET assay testing peptide conjugate BT6 and Figure 7B is a graph showing the results of a TR-FRET assay testing peptide conjugate BT7.

[0014] [Figure 8] Figure 8A is a graph showing the results of a TR-FRET assay testing peptide conjugate BT8, and Figure 8B is a graph showing the results of a TR-FRET assay testing peptide conjugate BT9.

[0015] [Figure 9] Figure 9A is a graph showing the results of a TR-FRET assay testing peptide conjugate BT10 and Figure 9B is a graph showing the results of a TR-FRET assay testing peptide conjugate BT11.

[0016] [Figure 10] FIG. 10 is a graph showing the results of a PD1-PDL1 cell reporter assay testing various peptide conjugates and peptides. DETAILED DESCRIPTION OF THE INVENTION

[0017] Detailed Description The present disclosure provides peptide conjugates that inhibit the function of PD1 and / or block the interaction of LAG3 with MHC-II. The peptide conjugates of the present disclosure comprise two peptides separated by a polyethylene glycol (PEG) linker. Each of the peptide conjugates disclosed herein comprises two of four peptides having the sequences and orientations as shown in Table 1. [Table 1]

[0018] "LD10" (SEQ ID NO: 1) is a peptide that inhibits the function of the checkpoint receptor "programmed death 1" (PD1). "LG11" (also known as "LAG3-11") (SEQ ID NO: 3) is a peptide that binds to LAG3 and blocks its interaction with MHC-II.

[0019] Examples of peptide conjugates are shown in Table 2, in which lowercase letters indicate D-form amino acids; "PEG4" is a PEG linker of four PEG units, and "Ac" is C-terminal acetylation. [Table 2]

[0020] As illustrated in Table 2, in some embodiments, the peptides of the peptide conjugates are modified using chemical or recombinant methods to enhance stability or other pharmacokinetic properties. See, e.g., US 2017 / 0020956. Modifications include, but are not limited to, substitution of one or more L-amino acids with their corresponding D-forms, acetylation on the C-terminal and / or N-terminal residues, and amidation on the C-terminal and / or N-terminal residues.

[0021] As shown in the examples below, in some cases peptide conjugates have more potent activity than their corresponding single peptides.

[0022] In some embodiments, the peptide conjugate inhibits the function of PD1. Examples of such peptide conjugates are BT7, BT9, BT10, and BT11.

[0023] In some embodiments, the peptide conjugate inhibits the interaction between LAG3 and MHC-II. Examples of such peptide conjugates are BT1, BT2, BT3, BT4, BT5, BT6, and BT7.

[0024] In some embodiments, the peptide conjugate inhibits the function of PD1 and the interaction of LAG3 with MHC-II. BT7 is an example of such a peptide conjugate.

[0025] The peptides of the peptide conjugates can be produced by any method known in the art, including synthetic methods, recombinant methods, or both. Synthetic methods include solid-phase or liquid-phase methods and can include the use of protecting groups. See, for example, Bodanszky et al. (1976), McOmie (1973), Merrifield (1963), Neurath et al. (1976), and Stuart & Young (1984).

[0026] Recombinant production of peptides used in peptide conjugates can be carried out using any nucleotide sequence(s) encoding the peptide in any suitable expression system. Nucleic acid molecules encoding one or more of the disclosed peptides can be incorporated into expression cassettes containing control elements operably linked to the coding sequence. Control elements include, but are not limited to, initiators, promoters (including inducible, repressible, and constitutive promoters), enhancers, and polyadenylation signals. A signal sequence can be included. The expression cassette can be provided in a vector that can be introduced into a suitable host cell for production of the peptide(s). Methods for constructing expression cassettes and expression vectors are well known. An expression vector can contain one or more expression cassettes encoding one or more peptides (comprising, consisting essentially of, or consisting of any of SEQ ID NOS: 1-4).

[0027] The PEG linker can be incorporated by any suitable method known in the art. In some embodiments, the linker is incorporated using Fmoc chemistry. For example, the 4-mer PEG linkers BT1-BT11 were incorporated using Fmoc-N-amido-dPEG® 4-acid (Quanta BioDesign).

[0028] The PEG linker can vary in length (e.g., 2, 3, 4, 5, 6).

[0029] In some embodiments, the peptide conjugates can be labeled (eg, with biotin or a fluorescent label) and used, for example, as diagnostic reagents.

[0030] therapeutic use The peptide conjugates disclosed herein have many therapeutic applications. "Treat," as used herein, includes reducing or inhibiting the progression of one or more symptoms of the condition for which the peptide conjugate is administered.

[0031] Peptide conjugates that inhibit the interaction between PD1 and PDL1 can be used to treat hyperproliferative disorders (including cancer), treat infectious diseases, enhance responses to vaccinations, treat sepsis, promote hair re-pigmentation, and promote lightening of pigmented skin lesions.

[0032] Peptide conjugates that inhibit the interaction between LAG3 and MHC-II may also be used to treat hyperproliferative disorders (including cancer), may be useful for reducing or treating one or more symptoms of synucleinopathies, infectious diseases, and sepsis, and may be useful for enhancing responses to vaccinations.

[0033] In some embodiments, administration is in conjunction with one or more other therapies. "In conjunction with" includes administration along with, before, or after the administration of the one or more other therapies.

[0034] Pharmaceutical compositions, routes of administration, and devices One or more peptide conjugates (as discussed above) are typically administered in a pharmaceutical composition comprising a pharmaceutically acceptable vehicle. A "pharmaceutically acceptable vehicle" may include one or more substances that do not affect the biological activity of the peptide or modified versions thereof and that do not cause adverse reactions when administered to a patient. The pharmaceutical composition may be liquid or lyophilized. A lyophilized composition may be provided in a kit with an appropriate liquid, typically water for injection (WFI) for use in reconstituting the composition. Other suitable forms of pharmaceutical compositions include suspensions, emulsions, and tablets.

[0035] In some embodiments, the pharmaceutical composition comprises a plurality of only one type of peptide conjugate (e.g., BT1, BT2, BT4, BT5, BT6, BT7, BT9, BT10, BT11). In other embodiments, the pharmaceutical composition comprises a plurality of more than one type of peptide conjugate (e.g., any one of BT1, BT2, BT4, BT5, BT6, BT7, BT9, BT10, BT11 and one or more of BT1, BT2, BT4, BT5, BT6, BT7, BT9, BT10, BT11).

[0036] The pharmaceutical compositions can be administered by any suitable route, including, but not limited to, intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, epidural, intratumoral, transdermal (e.g., US 2017 / 0281672), mucosal (e.g., intranasal or oral), pulmonary, and topical (e.g., US 2017 / 0274010) routes. See, e.g., US 2017 / 0101474.

[0037] Administration can be systemic or local. In addition to local infusion and injection, implants can be used to achieve local administration. Examples of suitable materials include, but are not limited to, sialastic membranes, polymers, fibrous matrices, and collagen matrices.

[0038] Topical administration may be by cream, ointment, lotion, transdermal patch (eg, a microneedle patch), or other suitable form well known in the art.

[0039] Administration can also be by controlled release, for example, using a microneedle patch, a pump, and / or suitable polymeric materials. Examples of suitable materials include, but are not limited to, poly(2-hydroxyethyl methacrylate), poly(methyl methacrylate), poly(acrylic acid), poly(ethylene-co-vinyl acetate), poly(methacrylic acid), polyglycolide (PLG), polyanhydrides, poly(N-vinylpyrrolidone), poly(vinyl alcohol), polyacrylamide, poly(ethylene glycol), polylactide (PLA), poly(lactide-co-glycolide) (PLGA), and polyorthoesters.

[0040] Devices that contain any of the above peptide conjugates include, but are not limited to, syringes, pumps, transdermal patches, spray devices, vaginal rings, and pessaries.

[0041] Treatment of hyperproliferative disorders (including cancer) In some embodiments, one or more of the peptide conjugates described above are administered to a patient to inhibit the progression of a hyperproliferative disorder (including cancer). Such inhibition can include, for example, reducing the proliferation of neoplastic or preneoplastic cells; destroying neoplastic or preneoplastic cells; and inhibiting tumor metastasis or reducing tumor size.

[0042] Examples of cancer include, but are not limited to, melanoma (including cutaneous or intraocular malignant melanoma), kidney cancer, prostate cancer, breast cancer, colon cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, cancer of the fallopian tubes, cancer of the endometrium, cancer of the cervix, cancer of the vagina, cancer of the vulva, Hodgkin's disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, Cancers of the endocrine system, thyroid cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia (including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, and lymphocytic lymphoma), bladder cancer, kidney or ureter cancer, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, and T-cell lymphoma.

[0043] Cancer Combination Therapy In some embodiments, one or more of the peptide conjugates described above are administered along with one or more other cancer therapies or immunotherapies (e.g., those described below).

[0044] In some embodiments, the second treatment includes a second agent that reduces or blocks the activity of PD1 (e.g., nivolumab, pembrolizumab, durvalumab) or reduces or blocks the activity of CTLA-4 (e.g., ipilimumab, tremelimumab).

[0045] In some embodiments, the second treatment comprises an agent that reduces or blocks the activity of PD-L1 (e.g., atezolizumab).

[0046] In some embodiments, the second treatment comprises another agent that reduces or blocks the activity of LAG3 or other inhibitory checkpoint molecules and / or molecules that suppress the immune system. These molecules include, but are not limited to: 1. V-domain Immunoglobulin Suppressor of T cell Activation (VISTA (also known as c10orf54, PD1H, DD1α, Gi24, Dies1, and SISP1); see US 2017 / 0334990, US 2017 / 0112929, Gao et al., 2017, Wang et al., 2011; Liu et al., 2015); 2. T-cell immunoglobulin domain and mucin domain 3 (TIM-3; see US 2017 / 0198041, US 2017 / 0029485, US 2014 / 0348842, Sakuishi et al, 2010); 3. Killer immunoglobulin-like receptors (KIRs; see US 2015 / 0290316); 4. Drugs that inhibit indoleamine(2,3)-dioxygenase (IDO; see Mellemgaard et al., 2017); 5. B and T Lymphocyte Attenuator (BTLA; see US 2016 / 09222114); and 6. A2A adenosine receptor (A2AR; see Beavis et al, 2015; US 2013 / 0267515; US 2017 / 0166878; Leone et al, 2015; Mediavilla-Varela et al, 2017; Young et al, 2016).

[0047] Agents that reduce or block the activity of LAG3 include, but are not limited to, BMS-986016, IMP321, and GSK2831781 (He et al., 2016).

[0048] Agents that reduce or block the activity of VISTA include, but are not limited to, small molecules (e.g., CA-170) and antibodies (e.g., Le Mercier et al., 2014).

[0049] Agents that reduce or block the activity of TIM-3 include, but are not limited to, antibodies (e.g., MBG453 and TSR-022; see Dempke et al., 2017).

[0050] Agents that reduce or block the activity of KIR include, but are not limited to, monoclonal antibodies (e.g., IPH2101 and lirilumab (BMS-986015, formerly IPH2102); see Benson & Caligiuri, 2014).

[0051] Agents that reduce or block the activity of IDO include, but are not limited to, epacadostat and agents disclosed in US 2017 / 0037125.

[0052] Agents that reduce or block the activity of BTLA include, but are not limited to, peptides (e.g., Spodzieja et al., 2017).

[0053] Agents that reduce or block the activity of A2AR include, but are not limited to, small molecules (eg, CPI-444 and bipadenant).

[0054] In some embodiments, the second treatment comprises a cytokine (eg, interleukin 7).

[0055] In some embodiments, the second treatment comprises an agonist of a stimulatory checkpoint molecule. These molecules include, but are not limited to: 1.CD40; 2.OX40; 3. Glucocorticoid-induced tumor necrosis factor-related protein (GITR); and 4. Inducible T cell costimulatory factor (ICOS).

[0056] CD40 agonists include, but are not limited to, CD40 agonist monoclonal antibodies (e.g., cp-870,893, ChiLob7 / 4, dacetuzumab, and lucatumumab).See, for example, Vonderheide et al., 2007; Khubchandani et al., 2009; Johnson et al., 2010; Bensinger et al., 2012; Vonderheide and Glennie, 2013; Johnson et al., 2015.

[0057] OX40 agonists include, but are not limited to, OX40 agonist antibodies (e.g., MOXR0916, MED16469, MED10562, PF-045618600, GSK3174998, and INCCAGN01949) and OX40L-Fc fusion proteins (e.g., MEDI6383). See, for example, Huseni et al., 2014; Linch et al., 2015; Messenheimer et al., 2017. See also, Shrimali et al., 2017.

[0058] Agonists of GITR include, but are not limited to, MEDI1873. See, e.g., Schaer et al., 2012; Tigue et al., 2017.

[0059] ICOS agonists include, but are not limited to, ICOS agonist antibodies JTX-2011 and GSK3359609.See, for example, Harvey et al., 2015;Michaelson et al., 2016.

[0060] In other embodiments, the second treatment is a 4-1BB agonist (Shindo et al., 2015) (e.g., urelumab); a 4-1BB antagonist (see US 2017 / 0174773); an inhibitor of anaplastic lymphoma kinase (ALK; Wang et al., 2014; US 2017 / 0274074) (e.g., crizotinib, ceritinib, alectinib, PF-06463922, NVP-TAE684, AP26113, TSR-011, X-396, CEP-37440, RXDX-101); an inhibitor of histone deacetylase (HDAC; US See 2017 / 0327582); VEGFR inhibitors (e.g., axitinib, sunitinib, sorafenib, tivozanib, bevacizumab); and / or anti-CD27 antibodies (e.g., varlilumab).

[0061] In some embodiments, the second treatment comprises a cancer vaccine (e.g., Duraiswamy et al., 2013). A "cancer vaccine" is an immunogenic composition intended to elicit an immune response against a specific antigen in an individual to whom the cancer vaccine is administered. Cancer vaccines typically contain a tumor antigen that can induce or stimulate an immune response against the tumor antigen. A "tumor antigen" is an antigen present on the surface of a target tumor. A tumor antigen may be a molecule not expressed by non-tumor cells or may be, for example, an altered version of a molecule expressed by non-tumor cells (e.g., a misfolded, truncated, or otherwise mutated protein).

[0062] In some embodiments, the second treatment comprises chimeric antigen receptor (CAR) T-cell therapy. See, e.g., John et al., 2013; Chong et al., 2016.

[0063] In some embodiments, one or more of the peptide conjugates described above are administered along with a CAR-T cell cancer therapy to increase the efficacy of the CAR-T cell cancer therapy.

[0064] In some embodiments, one or more of the peptide conjugates described above are administered with an oncolytic virus, for example, as disclosed in US 2017 / 0143780. Non-limiting examples of oncolytic viruses are described above.

[0065] Further therapeutic uses Synucleinopathy In some embodiments, one or more of the above peptide conjugates (e.g., BT1, BT2, BT4, BT5, BT6, BT7) may be useful for reducing symptoms of synucleinopathy, either alone or in combination with other therapeutic interventions (e.g., L-DOPA, dopamine agonists (e.g., ropinirole, pramipexole), dopamine reuptake inhibitors (e.g., amantadine), and cholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine)). Examples of synucleinopathies include idiopathic and hereditary forms of Parkinson's disease (PD); diffuse Lewy body (DLB) disease (also known as Dementia with Lewy Bodies or Lewy body dementia); incident Lewy body disease; Lewy body variant of Alzheimer's disease (LBV); combined Alzheimer's and Parkinson's disease (CAPD); pure autonomic failure (PAF); multiple system atrophy (MSA) (e.g., olivopontocerebellar atrophy, striatonigral degeneration, and Shy-Drager syndrome); pantothenate kinase-associated neurodegeneration; Down's syndrome; Gaucher-related synucleinopathies; and neurodegenerative diseases involving brain iron deposition.

[0066] sepsis LAG3 expression is upregulated in sepsis (Patil et al., 2017). Thus, one or more of the above peptide conjugates (e.g., BT1, BT2, BT4, BT5, BT6, BT7) may be useful for treating sepsis, either alone or in combination with other therapeutic interventions (e.g., antibiotics, intravenous fluids, and vasopressors).

[0067] infectious disease In some embodiments, one or more of the above peptide conjugates may be administered to treat infectious diseases, including, for example, chronic infections caused by viruses, fungi, bacteria, and protozoa, as well as helminths, either alone or in combination with other therapeutic interventions.

[0068] Examples of viral agents include human immunodeficiency virus (HIV), Epstein-Barr virus (EBV), herpes simplex virus (HSV) (including HSV1 and HSV2), human papillomavirus (HPV), varicella-zoster virus (VSV), cytomegalovirus (CMV), hepatitis A virus, hepatitis B virus, and hepatitis C virus.

[0069] Examples of fungal agents include Aspergillus, Candida, Coccidioides, Cryptococcus, and Histoplasma capsulatum.

[0070] Examples of bacterial agents include streptococci (eg, pyogenes, agalactiae, pneumoniae), Chlamydia pneumoniae, Listeria monocytogenes, and Mycobacterium tuberculosis.

[0071] Examples of protozoa include Sarcodina (eg, Entamoeba), Mastigophora (eg, Giardia), Ciliophora (eg, Balantidium), and Sporozoa (eg, Plasmodium falciparum, Cryptosporidium).

[0072] Examples of helminths include Platyhelminths (eg, flukes, cestodes), Acanthocephalins, and Nematodes.

[0073] Vaccine adjuvants In some embodiments, one or more of the peptide conjugates can be administered as a vaccine adjuvant with a vaccine to enhance the response to vaccination (e.g., by increasing effector T cells and / or reducing T cell exhaustion). The vaccine can be, for example, an RNA vaccine (e.g., US 2016 / 0130345, US 2017 / 0182150), a DNA vaccine, a recombinant vector, a protein vaccine, or a peptide vaccine. Such vaccines can be delivered, for example, using virus-like particles, as is well known in the art. In certain embodiments, for example, the following are provided: (Item 1) 1. A compound comprising: (a) a first peptide; (b) a PEG linker covalently attached to the C-terminus of said first peptide; and (c) a second peptide covalently attached to said PEG linker at the N-terminus of said second peptide, wherein: (i) the first peptide has the amino acid sequence of SEQ ID NO:1 and the second peptide has an amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4; (ii) the first peptide has the amino acid sequence of SEQ ID NO:2 and the second peptide has an amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3; (iii) the first peptide has the amino acid sequence of SEQ ID NO:3 and the second peptide has an amino acid sequence selected from the group consisting of SEQ ID NO:1 and SEQ ID NO:2; or (iv) the first peptide has the amino acid sequence of SEQ ID NO: 4, and the second peptide has an amino acid sequence selected from the group consisting of SEQ ID NO: 1 and SEQ ID NO: 2; compound. (Item 2) 2. The compound according to item 1, wherein the first peptide comprises an N-terminal modification. (Item 3) 3. The compound according to item 1 or 2, wherein the second peptide comprises a C-terminal modification. (Item 4) 4. The compound according to any one of items 1 to 3, wherein the first peptide has the amino acid sequence of SEQ ID NO: 1, and the first peptide contains D-serine at its N-terminus. (Item 5) 5. The compound according to any one of items 1 to 4, wherein the second peptide has the amino acid sequence of SEQ ID NO: 1, and the second peptide contains D-serine at its N-terminus. (Item 6) (i) the first peptide has the amino acid sequence of SEQ ID NO: 1 and the second peptide has the amino acid sequence of SEQ ID NO: 3; (ii) the first peptide has the amino acid sequence of SEQ ID NO:3 and the second peptide has an amino acid sequence selected from the group consisting of SEQ ID NO:1 and SEQ ID NO:2; (iii) the first peptide has the amino acid sequence of SEQ ID NO:4 and the second peptide has the amino acid sequence of SEQ ID NO:2; or (iv) the first peptide has the amino acid sequence of SEQ ID NO:2, and the second peptide has an amino acid sequence selected from the group consisting of SEQ ID NO:3 and SEQ ID NO:4; The compound according to any one of items 1 to 5. (Item 7) (i) the first peptide has the amino acid sequence of SEQ ID NO:2 and the second peptide has the amino acid sequence of SEQ ID NO:3; (ii) the first peptide has the amino acid sequence of SEQ ID NO:1 and the second peptide has an amino acid sequence selected from the group consisting of SEQ ID NO:1 and SEQ ID NO:2; or (iii) the first peptide has the amino acid sequence of SEQ ID NO: 2 and the second peptide has the amino acid sequence of SEQ ID NO: 1; The compound according to any one of items 1 to 5. (Item 8) (a) a compound according to any one of items 1 to 7; and (b) a pharmaceutically acceptable carrier; 10. A pharmaceutical composition comprising: (Item 9) 10. A method of inhibiting the progression of a hyperproliferative disorder, inhibiting the progression of sepsis, inhibiting the progression of an infectious disease, enhancing response to a vaccine, or inhibiting the progression of a synucleinopathy, said method comprising administering to an individual in need thereof an effective amount of a compound according to any one of paragraphs 1 to 7. (Item 10) 10. The method of claim 9, wherein the pharmaceutical composition is administered to inhibit the progression of a hyperproliferative disorder. (Item 11) 11. The method of claim 10, wherein the hyperproliferative disorder is cancer. (Item 12) 10. The method of claim 9, wherein the compound is administered to inhibit the progression of sepsis. (Item 13) 10. The method of claim 9, wherein the compound is administered to inhibit the progression of an infectious disease. (Item 14) 10. The method of claim 9, wherein the compound is administered to enhance the response to a vaccine. (Item 15) Item 10. The method of item 9, wherein the compound is administered to inhibit the progression of a synucleinopathy, and the compound is the compound of item 6. (Item 16) Item 16. The method of item 15, wherein the synucleinopathy is selected from the group consisting of Parkinson's disease (PD), dementia with Lewy bodies (DLB), pure autonomic failure (PAF), and multiple system atrophy (MSA). [Example]

[0074] Example 1. Disruption of LAG3-MHC-II interactions A homogeneous time-resolved fluorescence (HTRF) LAG3 / MHC-II binding assay (Cisbio US Inc.) was used to measure the interaction between MHC-II and LAG3 in the presence of various peptides and peptide conjugates. In this assay, the interaction between Tag1-LAG3 and Tag2-MHC-II is detected using anti-Tag1-Terbium (HTRF donor) and anti-Tag2-XL665 (HTRF acceptor). When the donor and acceptor antibodies are brought into close proximity due to the binding of LAG3 to MHC-II, excitation of the donor antibody induces fluorescence resonance energy transfer (FRET) toward the acceptor antibody, which then specifically emits light at 665 nm. This specific signal is directly proportional to the degree of LAG3 / MHC-II interaction. Therefore, agents that block the interaction between LAG3 and MHC-II cause a decrease in the HTRF ratio.

[0075] Peptide conjugates BT1, BT2, BT3, BT4, BT5, BT6, BT7, BT8, BT9, and peptides LG11 (LAG3-11), LAG3-56 (SEQ ID NO:5), and LAG3-42 (SEQ ID NO:6) were each tested at three concentrations: 100 μM, 10 μM, and 1 μM. The results are shown in Figure 1. The dashed lines represent the HTRF ratio readings of the control ovalbumin peptide (OVA, SEQ ID NO:7) (baseline) at each concentration.

[0076] Each concentration of peptide conjugates BT1, BT2, BT4, BT5, BT6, BT7, and two concentrations of BT8 reduced the HTRF signal in this assay. BT9, which contains two LD10 (SEQ ID NO: 1) peptides, behaved like a LAG3 agonist in this assay. BT3 had a similar agonist response.

[0077] Example 2. Disruption of LAG3-MHC-II interactions; dilution curves The peptide conjugate and LG peptide were treated with IC 50To estimate the β-actin activity, a full dilution curve was tested in the LAG3:MHCII TR-FRET assay described above. Peptide conjugates were tested starting at 100 μM or 10 μM. The LG peptide was tested starting at 100 μM. The results are shown in Figures 2-9.

[0078] Peptides LG42 (LAG3-42; SEQ ID NO: 6) and LD10da (SEQ ID NO: 8) showed no response in this assay, confirming previous observations (Figures 2A and 2B).

[0079] Peptide LG11 (LAG3-11) was found to be a soluble peptide in the IC 50 = 1.156e-005, showing a dose-response (Figure 3).

[0080] Peptide conjugates BT1 and BT2 were tested in 10-fold dilutions starting at 10 μM, as precipitation occurred at 100 μM. BT1 and BT2 (IC 50 =8.44e-006) reduced the HTRF signal at 10 μM (Figure 4A, Figure 4B).

[0081] The peptide conjugate BT3 was tested in 10-fold dilutions starting at 100 μM. BT3 showed agonist activity at 100 μM and 10 μM (FIG. 5).

[0082] Peptide conjugates BT4 and BT5 were tested in 10-fold dilutions starting at 10 μM, as precipitation occurred at 100 μM. BT4 and BT5 reduced the HTRF signal at 10 μM (FIGS. 6A and 6B).

[0083] Peptide conjugates BT6 and BT7 were tested in 10-fold dilutions starting at 100 μM. BT4 (IC 50 =1.4565e-007) and BT5(IC 50 = approximately 1.285e-008) reduced the HTRF signal (Figures 7A and 7B). 50 is an estimate due to the nature of the dose curve.

[0084] The peptide conjugates BT8 and BT9 were tested in 10-fold dilutions starting at 100 μM. BT8 showed agonist activity at 100 μM (FIG. 8A), but no equivalent response was observed. BT9 showed no real effect (FIG. 8B).

[0085] Peptide conjugates BT10 and BT11 were tested in 10-fold dilutions starting at 100 μM. BT10 and BT11 showed activity at 100 μM; however, no dose response was observed (FIGS. 9A and 9B).

[0086] In summary, peptide conjugates BT1, BT2, and BT4-7 all exhibited some level of antagonist activity. 50 Values ​​were obtained for BT2, BT6 and BT7; these values ​​were obtained for the IC of LG11. 50 See Table 3. [Table 3]

[0087] Peptide conjugates BT9, B10, and B11 (which only contain the LD10 sequence) showed no activity or activity only at 100 μM. The lack of a dose curve suggests that the response at 100 μM may not accurately reflect the response at 100 μM.

[0088] BT8 exhibited agonist activity, but only at 100 μM, suggesting that this concentration may not accurately reflect the activity of BT8.

[0089] Example 3. Effect of peptide conjugates in PD1 / PDL1 cell reporter assay Jurkat cells expressing PD1 and SHP1 proteins (each fused to a fragment of the enzyme fragment complementation (EFC) system) were co-incubated with PDL1-presenting U2OS cells. This resulted in PD1 activation and SHP1 recruitment to the PD1 receptor, bringing the two EFC fragments together and generating a light signal. The cells in the co-culture were incubated at room temperature (RT) for 2 hours (PD1 assay). The assay signal was generated using a PathHunter Bioassay Detection kit. The microplate was equipped with a PerkinElmer ENVISION Fluorescence Imaging System (FILM) for chemiluminescent signal detection. TM The instrument was used to read the signal after generation. Inhibitory peptides or antibodies added to the cultures result in a reduction in the light signal. The degree of inhibition was calculated using the following formula: Percent inhibition = 100% x [1 - (mean RLU of test sample - mean RLU of vehicle control) / mean RLU of EC80 control - mean RLU of vehicle control)].

[0090] Peptide conjugates BT1-BT11 were tested in triplicate wells at three concentrations: 3.6 μM, 10.8 μM, and 32.5 μM. Peptide conjugates were dissolved in DMSO and serially diluted in assay buffer. The highest concentration that could be tested in this assay was 32.5 μM peptide conjugate (1% DMSO).

[0091] Peptides LD12 (SEQ ID NO: 9), LD10 (SEQ ID NO: 1), and LD16 (SEQ ID NO: 10) were tested in triplicate at three concentrations: 11 μM, 33 μM, and 100 μM. LD peptides were dissolved in water and serially diluted in assay buffer. RLU was measured at the end of the assay, and % inhibition (% efficacy) was calculated using the formula above.

[0092] The results are shown in Figure 10.

[0093] The results showed that peptide conjugates BT7, BT9, BT10, and BT11 reduced the activity of PD1 at one or two of the concentrations tested. BT9, BT10, and BT11 each contain two LD10 peptides in different orientations, while peptide conjugate BT7 contains LD10 and LG11 sequences; see Table 2.

[0094] Peptide conjugates BT1, BT2, BT3, BT4, BT5, BT6, and BT8 showed no inhibition at any of the concentrations tested.

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Claims

1. 1. A compound comprising: (a) a first peptide; (b) a PEG linker covalently attached to the C-terminus of said first peptide; and (c) a second peptide covalently attached to said PEG linker at the N-terminus of said second peptide, wherein: (i) the first peptide has the amino acid sequence of SEQ ID NO:1 and the second peptide has an amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4; (ii) the first peptide has the amino acid sequence of SEQ ID NO:2 and the second peptide has an amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3; (iii) the first peptide has the amino acid sequence of SEQ ID NO:3 and the second peptide has an amino acid sequence selected from the group consisting of SEQ ID NO:1 and SEQ ID NO:2; or (iv) the first peptide has the amino acid sequence of SEQ ID NO:4, and the second peptide has an amino acid sequence selected from the group consisting of SEQ ID NO:1 and SEQ ID NO:2; compound.

2. The compound of claim 1 , wherein the first peptide comprises an N-terminal modification.

3. 3. The compound of claim 1 or claim 2, wherein the second peptide comprises a C-terminal modification.

4. The compound according to any one of claims 1 to 3, wherein the first peptide has the amino acid sequence of SEQ ID NO: 1, and the first peptide contains D-serine at its N-terminus.

5. The compound according to any one of claims 1 to 4, wherein the second peptide has the amino acid sequence of SEQ ID NO: 1, and the second peptide includes D-serine at its N-terminus.

6. (i) the first peptide has the amino acid sequence of SEQ ID NO: 1 and the second peptide has the amino acid sequence of SEQ ID NO: 3; (ii) the first peptide has the amino acid sequence of SEQ ID NO:3 and the second peptide has an amino acid sequence selected from the group consisting of SEQ ID NO:1 and SEQ ID NO:2; (iii) the first peptide has the amino acid sequence of SEQ ID NO:4 and the second peptide has the amino acid sequence of SEQ ID NO:2; or (iv) the first peptide has the amino acid sequence of SEQ ID NO:2, and the second peptide has an amino acid sequence selected from the group consisting of SEQ ID NO:3 and SEQ ID NO:4; The compound according to any one of claims 1 to 5.

7. (i) the first peptide has the amino acid sequence of SEQ ID NO:2 and the second peptide has the amino acid sequence of SEQ ID NO:3; (ii) the first peptide has the amino acid sequence of SEQ ID NO:1 and the second peptide has an amino acid sequence selected from the group consisting of SEQ ID NO:1 and SEQ ID NO:2; or (iii) the first peptide has the amino acid sequence of SEQ ID NO: 2 and the second peptide has the amino acid sequence of SEQ ID NO: 1; The compound according to any one of claims 1 to 5.

8. (a) a compound according to any one of claims 1 to 7; and (b) a pharmaceutically acceptable carrier; 10. A pharmaceutical composition comprising:

9. 10. A composition for inhibiting the progression of a hyperproliferative disorder, inhibiting the progression of sepsis, inhibiting the progression of an infectious disease, enhancing response to a vaccine, or inhibiting the progression of a synucleinopathy, comprising a compound according to any one of claims 1 to 7.

10. 10. The composition of claim 9, wherein the composition is administered to inhibit the progression of the hyperproliferative disorder.

11. The composition of claim 10, wherein the hyperproliferative disorder is cancer.

12. 10. The composition of claim 9, wherein the composition is administered to inhibit the progression of sepsis.

13. 10. The composition of claim 9, wherein the composition is administered to inhibit the progression of an infectious disease.

14. 10. The composition of claim 9, wherein the composition is administered to enhance a response to a vaccine.

15. The composition of claim 9, wherein the composition is administered to inhibit the progression of a synucleinopathy, and the compound is a compound of claim 6.

16. 16. The composition of claim 15, wherein the synucleinopathy is selected from the group consisting of Parkinson's disease (PD), dementia with Lewy bodies (DLB), pure autonomic failure (PAF), and multiple system atrophy (MSA).

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