WO2020036987A1 - Peptides et compositions pour traitement et imagerie ciblés - Google Patents

Peptides et compositions pour traitement et imagerie ciblés Download PDF

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WO2020036987A1
WO2020036987A1 PCT/US2019/046392 US2019046392W WO2020036987A1 WO 2020036987 A1 WO2020036987 A1 WO 2020036987A1 US 2019046392 W US2019046392 W US 2019046392W WO 2020036987 A1 WO2020036987 A1 WO 2020036987A1
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trem
cancer
inhibitor
group
iii
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PCT/US2019/046392
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English (en)
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Alexander B. Sigalov
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Signablok, Inc.
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Priority to CA3109702A priority Critical patent/CA3109702A1/fr
Priority to EP19769270.0A priority patent/EP3836951A1/fr
Priority to US17/268,046 priority patent/US20210322508A1/en
Publication of WO2020036987A1 publication Critical patent/WO2020036987A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1774—Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/001102—Receptors, cell surface antigens or cell surface determinants
    • A61K39/001111—Immunoglobulin superfamily
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55516—Proteins; Peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • compositions and methods of treating cancer and other diseases related to activated immune cells using modulators of the TREM-1/DAP-12 signaling pathway modulate TREM- 1 -mediated immunological response as standalone and combination-therapy treatment regimen. Further, methods are provided for predicting the efficacy of TREM-l modulatory therapies in patients.
  • the present invention relates to targeted treatment, prevention and/or detection of cancer including but not limited to lung cancer including non-small cell lung cancer, pancreatic cancer, giant cell tumor of the tendon sheath, tenosynovial giant cell tumor, pigmented villonodular synovitis, cancer cachexia, etc., and other cancers associated with myeloid cell activation and recruitment. Additionally, the present invention relates to the targeted treatment, prevention and/or detection of scleroderma including but not limited to calcinosis, Raynaud’s phenomenon, esophageal dysmotility, scleroderma, or telangiectasia syndrome (CREST). The invention further relates to personalized medical treatments.
  • lung cancer including non-small cell lung cancer, pancreatic cancer, giant cell tumor of the tendon sheath, tenosynovial giant cell tumor, pigmented villonodular synovitis, cancer cachexia, etc.
  • scleroderma including but not limited to calcino
  • therapeutic peptides often causes activation of nontarget cells and leads to undesired side effects and increases risk of undesired immunogenic effects.
  • Limitations generally attributed to therapeutic peptides are: a short half-life in the circulation because of their rapid degradation by proteolytic enzymes of the digestive system and blood plasma; rapid removal from the circulation by the liver (hepatic clearance) and kidneys (renal clearance); poor ability to cross physiological barriers, such as the blood-brain barrier.
  • therapeutic peptides having general hydrophilicity; high conformational flexibility, and use resulting sometimes in a lack of selectivity involving interactions with different receptors/targets (poor specific biodistribution), described in part in Vlieghe, et al. Drug Discov Today 2010, 15:40-56.
  • compositions and methods of treating cancer and other diseases related to activated immune cells using modulators of the TREM-1/DAP-12 signaling pathway modulate TREM- 1 -mediated immunological response as standalone and combination-therapy treatment regimen. Further, methods are provided for predicting the efficacy of TREM-l modulatory therapies in patients.
  • the present invention relates to targeted treatment, prevention and/or detection of cancer including but not limited to lung cancer including non-small cell lung cancer, pancreatic cancer, giant cell tumor of the tendon sheath, tenosynovial giant cell tumor, pigmented villonodular synovitis, cancer cachexia, etc., and other cancers associated with myeloid cell activation and recruitment. Additionally, the present invention relates to the targeted treatment, prevention and/or detection of scleroderma including but not limited to calcinosis, Raynaud’s phenomenon, esophageal dysmotility, scleroderma, or telangiectasia syndrome (CREST). The invention further relates to personalized medical treatments.
  • lung cancer including non-small cell lung cancer, pancreatic cancer, giant cell tumor of the tendon sheath, tenosynovial giant cell tumor, pigmented villonodular synovitis, cancer cachexia, etc.
  • scleroderma including but not limited to calcino
  • each trifunctional peptide is capable of at least three functions: 1) mediating formation of naturally long half-life lipopeptide/lipoprotein particles upon interaction with lipoproteins, 2) facilitation of the targeted delivery to cells of interest and/or sites of disease, and 3) treatment, prevention, and/or detection of a disease or condition.
  • each trifunctional peptide is capable of at least three functions: 1) mediating the self-assembly of naturally long half-life lipopeptide particles upon binding to lipid or lipid mixtures, 2) facilitation of the targeted delivery to cells of interest and/or sites of disease, and 3) treatment, prevention, and/or detection of a disease or condition.
  • the present invention relates to amphipathic trifunctional peptides consisting of two amino acid domains, wherein upon interaction with plasma lipoproteins, one amino acid domain mediates formation of naturally long half-life lipopeptide/lipoprotein particles and targets these particles to macrophages, whereas the other amino acid domain inhibits the TREM- 1/DAP-12 receptor signaling complex expressed on macrophages.
  • the invention further relates to personalized medical treatments for cancer that involve targeting specific cancers by their tumor environment.
  • the invention further relates to personalized medical treatments for scleroderma (systemic sclerosis, SSc). More specifically, the invention provides for treatment of scleroderma or a related autoimmune or a fibrotic condition by using modulators of the TREM-1/DAP-12 pathway standalone or together with other antifibrotic therapies and the use of such combinations in the treatment of scleroderma.
  • the invention provides a method for treating cancer in a patient in need thereof, said method comprising administering to said patient a therapeutically effective amount of at least one modulator that is effective for modulating the TREM-1/DAP-12 signaling pathway together with a therapeutically amount of an anticancer vaccine, an anticancer immunotherapy agent, anti-cancer immunomodulatory agent, an additional anticancer therapeutic, radiation therapy, surgery or a combination thereof.
  • said method further comprises administering said modulator together with a pharmaceutically acceptable excipient, carrier, diluents, or a combination thereof.
  • said carrier is selected from the group consisting of lipids, proteins or polypeptides, and mixtures thereof.
  • said method further comprises prior to administering the first dose of said modulator, the subject received a prior therapy selected from the group consising of an anticancer vaccine, an anticancer immunotherapy agent, anti-cancer immunomodulatory agent, an additional anticancer therapeutic, radiation therapy, surgery or a combination thereof.
  • a prior therapy selected from the group consising of an anticancer vaccine, an anticancer immunotherapy agent, anti-cancer immunomodulatory agent, an additional anticancer therapeutic, radiation therapy, surgery or a combination thereof.
  • said cancer recurred or progressed after the prior therapy.
  • said administration of said modulator to said patient is continued as a long-term maintenance treatment for duration between about two weeks to about five years, preferably said administration is continued for duration of up to one year.
  • said anticancer vaccine is selected from the group consisting of Gardasil, Cervarix, Sipuleucel-T/Provenge, and the like.
  • said anticancer immunotherapy agent is selected from the group consisting of Alemtuzumab, Ipilimumab, Ofatumumab, Nivolumab, Pembrolizumab, Rituximab, Blinatumomab, Daratumumab, Trastuzumab, Cetuximab, Elotuzumab, adoptive T-cell therapy, T-Vec, Interferon, Interleukin, and a combination thereof.
  • said anticancer immunomodulatory agent is selected from the group consisting of thalidomide, lenolidomide, pomalidomide, and a combination thereof.
  • said additional anticancer therapeutic is selected from the group consisting of an alkylating agent, a tubulin inhibitor, a topoisom erase inhibitor, proteasome inhibitor, a CHK1 inhibitor, a CHK2 inhibitor, a PARP inhibitor, a tyrosine kinase inhibitor, CSF-1/CSF-1R inhibitor, doxorubicin, gemcitabine, entrectinib, epirubicin, vinblastine, etoposide, topotecan, bleomycin, mytomycin c, and the like.
  • said alkylating agent is selected from the group consisting of dacarbazine, Procarbazine, Carmustine, Lomustine, Uramustine, BuSulfan, Streptozocin, Altreamine, Ifosfamine, Chrormethine, Cyclophasphamide, Cyclophosphamide, Chlorambucil, Fluorouracil (5-Fu), Melphalan, Triplatin tetranitrate, Satraplatin, Nedaplatin, Cisplatin, Carboplatin, Oxaliplatin, and the like.
  • said tubulin inhibitor is selected from the group consisting of Taxol, Docetaxel, Abraxane, Vinblastin, Epothilone, Colchicine, Cryptophycin, BMS 347550, Rhizoxin, Ecteinascidin, Dolastin 10, Cryptophycin 52, IDN-5109, and the like.
  • said topoisomerase inhibitor is a topoisomerase I inhibitor selected from the group consisting of Irinotecan, Topotecan, Camptothecins (CPT), and the like.
  • said topoisomerase inhibitor is a topoisomerase II inhibitor selected from the group consisting of Amsacrine, Etoposide, Teniposide, Epipodophyllotoxins, ellipticine, and the like.
  • said proteasome inhibitor is selected from the group consisting of Velcade (bortezomib), and Kyprolis (carfilzomib), and the like.
  • said CHK1 inhibitor is selected from the group consisting of TCS2312, PF-0047736, AZ07762, A- 69002, and A-641397, and the like.
  • said PARP inhibitor is selected from the group consisting of Olaparib, Talazoparib, ABT-888, (veliparib), KEG-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231, and the like.
  • said tyrosine kinase inhibitor is selected from the group consisting of pexidartinib, entrectinib, matinib mesylate (STI571; Gleevec), gefitinib (Iressa), erlotinib (OSI-1774; Tarceva), lapatinib (GW-572016), canertinib (CI-1033), semaxinib (SU5416), vatalanib (PTK787/ZK222584), sorafenib (BAY 43-9006), sutent (SET11248), and leflunomide (SU101), and the like.
  • said CSF-1/CSF-1R inhibitor is selected from the group consisting of CSF-1R kinase inhibitor, an antibody that binds CSF-1R and is capable of blocking binding of CSF-l and/or IL-34 to CSF-1R, and the like.
  • said CSF-1R kinase inhibitor is imatinib, nilotinib or PLX3397.
  • said radiation therapy is selected from the group consisting of X-rays, ion beams, electron beams, gamma-rays, UV-rays, and decay of a radioactive isotope, or a combination thereof.
  • said surgery is surgical tumor resection.
  • said cancer is lung cancer including non-small cell lung cancer, pancreatic cancer, breast cancer, liver cancer, multiple myeloma, melanoma, leukemia, central nervous system cancer, stomach cancer, prostate, colon cancer, colorectal cancer, brain cancer, gastrointestinal cancer, gastric cancer, ovarian cancer, renal cancer, skin cancer, osteosarcoma, endometrial cancer, esophageal cancer, kidney cancer, prostate cancer, thyroid cancer, neuroblastoma, neurofibroma, glioma, glioblastoma, glioblastoma multiforme, stomach cancer, bladder cancer, head and neck cancer, cervical cancer, giant cell tumor of the tendon sheath, tenosynovial giant cell tumor, pigmented villonodular synovitis and other cancers in which myeloid cells are involved or recruited and cancer cachexia.
  • lung cancer including non-small cell lung cancer, pancreatic cancer, breast cancer, liver cancer, multiple myeloma, melanoma,
  • said at least one said modulator comprises a variant peptide sequence that is capable of binding TREM- 1/DAP-12 and reducing or blocking TREM-1/DAP-12 activity (signaling and/or activation).
  • said variant peptide sequence comprises at least one D-amino acid.
  • said variant peptide sequence is a cyclic peptide.
  • said variant peptide sequence is derived from transmembrane domain sequences of human or animal TREM-l and/or its signaling subunit, DAP-12, or a combination thereof.
  • said variant peptide sequence comprises LR12 and/or LP17 peptide variants and the like or a combination thereof.
  • said modulator comprises at least one isolated antibody or fragment thereof, that is capable of specifically binding TREM-1/DAP-12 and which is capable of reducing or blocking TREM-1/DAP-12 activity (signaling and/or activation).
  • said method further comprises a diagnostic method. In one embodiment, said diagnostic method is performed prior to administering the first dose of said modulator to predict response of said patient to a therapy of the method of claim 1.
  • said diagnostic method comprises isolating a biological sample from said patient and determining in said sample the expression of CSF-l, CSF-1R, IL-6, TREM-l and/or number of CD68-positive cells or a combination thereof, wherein the higher is the expression level of CSF-l, CSF-1R, IL- 6, TREM-l or the higher is number of CD68-positive cells or a combination thereof, the better the patient is predicted to respond to a therapy of the method of claim 1.
  • said method comprises: (a) administering to said patient an amount of at least one said modulator of the method of claim 1 that is capable of binding TREM-l and is conjugated to at least one imaging probe, or a combination thereof, in a detectably effective amount; (b) imaging at least a portion of the patient; (c) detecting the labeled probe, wherein the location and amount of the labeled probe corresponds to at least one symptom of the myeloid cell-related cancer condition and correlates with the TREM-l expression levels and the higher the levels are, the better the patient is predicted to respond to a therapy of the method of claim 1.
  • said an imaging probe is selected from the group comprising Gd(III), Mn(II), Mn(III), Cr(II), Cr(III), Cu(II), Fe (III), Pr(III), Nd(III) Sm(III), Tb(III), Yb(III) Dy(III), Ho(III), Eu(II), Eu(III), and Er(III), Tl 201 , K 42 , In 111 , Fe.
  • the present invention encompasses the discovery that it is possible to combine multiple functions in one amphipathic polypeptide amino acid sequence to confer a variety of properties on the resulting peptide and provides novel peptides and compounds, which are capable of executing at least, three functions: 1) mediation of formation of naturally long half-life lipopeptide/lipoprotein particles (LP) upon interaction with native lipoproteins, 2) facilitation of the targeted delivery to cells of interest and/or sites of disease, and 3) treatment, prevention, and/or detection of a disease or condition.
  • said peptides and compounds of the present invention are used in combinations thereof.
  • the peptides and compounds of the present invention and combinations thereof have a wide variety of uses, particularly in the areas of oncology, transplantology, dermatology, hepatology, ophthalmology, cardiovascular diseases, sepsis, autoimmune diseases, neurodegenerative diseases and other diseases and conditions. They also are useful in the production of medical devices (for example, medical implants and implantable devices).
  • the invention provides a synthetic trifunctional peptide comprising: (a) a first amino acid domain that does not interact with native lipoproteins in isolated form, wherein said first amino acid domain is at least 3 amino acids in length and is capable of treating, preventing and/or detecting an immune-related disease or condition; and (b) a second amino acid domain that mediates formation of lipopeptide/lipoprotein particles upon interaction of the peptide with native lipoproteins and targets these particles to cells of interest and/or sites of disease or condition, which second amino acid domain is at least 6 amino acids in length and has an amphipathic alpha helical amino acid sequence.
  • said first amino acid domain comprises amino acid sequence Gly-Phe-Leu-Ser-Lys-Ser-Leu-Val-Phe, wherein Gly is glycine, Phe is phenylalanine, Leu is leucine, Ser is serine, Lys is lysine, and Val is valine.
  • said first amino acid domain comprises amino acid sequence Met-Trp-Lys-Thr-Pro-Thr-Leu-Lys-Tyr-Phe, wherein Met is methionine, Trp is tryptophan, Lys is lysine, Thr is threonine, Pro is proline, Leu is leucine, Tyr is tyrosine, and Phe is phenylalanine.
  • said second amino acid domain comprises amino acid sequence Trp-Gln-Glu-Glu-Met-Glu-Leu-Tyr-Arg-Gln-Lys-Val, wherein Tyr is tyrosine, Leu is leucine, Gln is glutamine, Lys is lysine, Trp is tryptophan, Glu is glutamic acid, Met is methionine, Arg is arginine, and Val is valine.
  • said second amino acid domain comprises amino acid sequence Gly-Glu-Glu-Met-Arg-Asp-Arg-Ala-Arg-Ala-His-Val, wherein Gly is glycine, Glu is glutamic acid, Met is methionine, Arg is arginine, Asp, asparagine, Ala is alanine, His is histidine, and Val is valine.
  • said first amino acid domain and/or said second amino acid domain are conjugated to at least one imaging probe.
  • the invention provides a method of imaging an immune-related disease or condition, comprising a) providing; i) a patient having at least one symptom of a disease or condition in which immune cells are involved or recruited, and ii) a compound of claim 8, wherein the composition has an affinity for immune receptors; b) administering said composition to said patient in a detectably effective amount, c) imaging at least a portion of the patient; and d) detecting the labeled probe, wherein the location of the labeled probe corresponds to at least one symptom of the immune-related disease or condition.
  • the invention provides a method of treating an immune-related disease or condition, comprising: a) providing; i) a patient having at least one symptom of a disease or condition in which immune cells are involved or recruited, and ii) the composition of claim 1 capable of modulating immune receptors; b) administering said composition to said patient under conditions such that said at least one symptom is reduced.
  • said immune-related disease or condition is selected from the group comprising cancer including but not limited to lung, pancreatic, breast, stomach, prostate, colon, brain and skin cancers, cancer cachexia, heart disease, atherosclerosis, peripheral artery disease, restenosis, stroke, bacterial infectious diseases, acquired immune deficiency syndrome (AIDS), allergic diseases, acute radiation syndrome, empyema, acute mesenteric ischemia, hemorrhagic shock, multiple sclerosis, autoimmune diseases (e.g., rheumatoid arthritis, psoriatic arthritis, Sjogrens, scleroderma, systemic lupus erythematosus, non-specific vasculitis, Kawasaki's disease, psoriasis, type I diabetes, pemphigus vulgaris), granulomatous diseases (e.g., tuberculosis, sarcoidosis, lymphomatoid granulomatosis, Wegener's granulomatosus), Gaucher
  • inflammatory bowel disease Crohn’s disease, celiac disease
  • Guillain-Barre syndrome Hashimoto's disease
  • pernicious anemia primary biliary cirrhosis, chronic active hepatitis, alcohol-induced liver disease, nonalcoholic fatty liver disease and non-alcoholic steatohepatitis
  • skin problems e.g. atopic dermatitis, psoriasis, pemphigus vulgaris
  • cardiovascular problems e.g. autoimmune pericarditis
  • allergic diathesis e.g. delayed type hypersensitivity
  • contact dermatitis herpes simplex/zoster
  • respiratory conditions e.g. allergic alveolitis
  • inflammatory conditions e.g. myositis
  • ankylosing spondylitis tissue/organ transplant (e.g., heart/lung transplants) rejection reactions, brain and spinal cord injuries, and other diseases and conditions where immune cells are involved or recruited.
  • the invention provides a synthetic trifunctional peptide comprising: (a) a first amino acid domain that does not interact with native lipoproteins in isolated form, which first amino acid domain is at least 3 amino acids in length and is capable of treating, preventing and/or detecting an immune-related disease or condition; and (b) a second amino acid domain that mediates formation of lipopeptide/lipoprotein particles upon interaction of the peptide with native lipoproteins and targets these particles to cells of interest and/or sites of disease or condition, which second amino acid domain is at least 6 amino acids in length and has an amphipathic alpha helical amino acid sequence.
  • said first amino acid domain comprises amino acid sequence Gly-Phe-Leu-Ser-Lys-Ser-Leu-Val-Phe, wherein Gly is glycine, Phe is phenylalanine, Leu is leucine, Ser is serine, Lys is lysine, and Val is valine.
  • said first amino acid domain comprises amino acid sequence Met-Trp- Lys-Thr-Pro-Thr-Leu-Lys-Tyr-Phe, wherein Met is methionine, Trp is tryptophan, Lys is lysine, Thr is threonine, Pro is proline, Leu is leucine, Tyr is tyrosine, and Phe is phenylalanine.
  • said second amino acid domain comprises amino acid sequence Trp-Gln-Glu-Glu- Met-Glu-Leu-Tyr-Arg-Gln-Lys-Val, wherein Tyr is tyrosine, Leu is leucine, Gln is glutamine, Lys is lysine, Trp is tryptophan, Glu is glutamic acid, Met is methionine, Arg is arginine, and Val is valine.
  • said the second amino acid domain comprises amino acid sequence Gly-Glu-Glu-Met-Arg-Asp-Arg-Ala-Arg-Ala-His-Val, wherein Gly is glycine, Glu is glutamic acid, Met is methionine, Arg is arginine, Asp, asparagine, Ala is alanine, His is histidine, and Val is valine.
  • said the first amino acid domain and/or the second amino acid domain are conjugated to at least one imaging probe.
  • the invention provides a method of imaging an immune-related disease or condition, comprising a) providing; i) a patient having at least one symptom of a disease or condition in which immune cells are involved or recruited, and ii) a compound of claim 8, wherein the composition has an affinity for immune receptors; b) administering said composition to said patient in a detectably effective amount c) imaging at least a portion of the patient; and d) detecting the labeled probe, wherein the location of the labeled probe corresponds to at least one symptom of the immune-related disease or condition.
  • the invention provides a method of treating an immune-related disease or condition, comprising: a) providing; i) a patient having at least one symptom of a disease or condition in which immune cells are involved or recruited, and ii) the composition of claim 1 capable of modulating immune receptors; b) administering said composition to said patient under conditions such that said at least one symptom is reduced.
  • said immune-related disease or condition is selected from the group comprising cancer including but not limited to lung, pancreatic, breast, stomach, prostate, colon, brain and skin cancers, cancer cachexia, heart disease, atherosclerosis, peripheral artery disease, restenosis, stroke, bacterial infectious diseases, acquired immune deficiency syndrome (AIDS), allergic diseases, acute radiation syndrome, empyema, acute mesenteric ischemia, hemorrhagic shock, multiple sclerosis, autoimmune diseases (e.g., rheumatoid arthritis, psoriatic arthritis, Sjogrens, scleroderma, systemic lupus erythematosus, non-specific vasculitis, Kawasaki's disease, psoriasis, type I diabetes, pemphigus vulgaris), granulomatous diseases (e.g., tuberculosis, sarcoidosis, lymphomatoid granulomatosis, Wegener's granulomatosus), Gaucher
  • inflammatory bowel disease Crohn’s disease, celiac disease
  • Guillain-Barre syndrome Hashimoto's disease
  • pernicious anemia primary biliary cirrhosis
  • chronic active hepatitis alcohol-induced liver disease
  • nonalcoholic fatty liver disease and non-alcoholic steatohepatitis skin problems (e.g. atopic dermatitis, psoriasis, pemphigus vulgaris), cardiovascular problems (e.g. autoimmune pericarditis), allergic diathesis (e.g. delayed type hypersensitivity), contact dermatitis, herpes simplex/zoster, respiratory conditions (e.g. allergic alveolitis), inflammatory conditions (e.g. myositis), ankylosing spondylitis, tissue/organ transplant (e.g., heart/lung transplants) rejection reactions, and other diseases and conditions where immune cells are involved or recruited.
  • tissue/organ transplant e.g., heart/lung transplants
  • the present disclosure provides novel peptides and compounds, which are capable of executing three functions: 1) assistance in the self-assembly of naturally long half-life lipopeptide particles upon interaction with lipoproteins, 2) facilitation of the targeted delivery to cells of interest and/or sites of disease, and 3) treatment, prevention, and/or detection of a disease or condition.
  • said peptides and compounds of the present invention form synthetic lipopeptide particles upon binding to lipid or lipid mixtures.
  • the invention provides a synthetic trifunctional polypeptide comprising at least one peptide domain of 3 to 35 amino acids in length having a C-terminal amino acid and at least one amphipathic domain of 6 to 45 to amino acids in length comprising an amphipathic lipopeptide having an N-terminal amino acid, wherein said first domain's C- terminal amino acid is attached to said second domain's N-terminal amino acid.
  • said synthetic trifunctional polypeptide further comprises an imaging agent.
  • said synthetic trifunctional polypeptide further comprises a therapeutic agent.
  • said synthetic trifunctional polypeptide further comprises a targeting agent.
  • said synthetic trifunctional polypeptide further comprises a lipopeptide nanoparticle.
  • the invention provides a population of spherical lipopeptide nanoparticles or discoidal lipopeptide nanoparticles comprising a plurality of synthetic trifunctional polypeptides, wherein said synthetic trifunctional polypeptide comprising at least one peptide domain of 3 to 35 amino acids in length having a C-terminal amino acid and at least one amphipathic domain of 6 to 45 to amino acids in length comprising an amphipathic lipopeptide having an N-terminal amino acid, wherein said first domain's C-terminal amino acid is attached to said second domain's N-terminal amino acid.
  • the invention provides a method of treating an immune-related disease or condition, comprising: a) providing; i) a patient having at least one symptom of a disease or condition in which immune cells are involved or recruited, and ii) a synthetic trifunctional polypeptide comprising at least one peptide domain of 3 to 35 amino acids in length having a C-terminal amino acid and at least one amphipathic domain of 6 to 45 to amino acids in length comprising an amphipathic lipopeptide having an N-terminal amino acid, wherein said first domain's C-terminal amino acid is attached to said second domain's N-terminal amino acid, wherein said trifunctional polypeptide is capable of modulating immune receptors; b) administering said synthetic trifunctional polypeptide to said patient under conditions such that said at least one symptom is reduced.
  • the invention relates to personalized medical treatments for cancer that involve targeting specific cancers by their tumor environment. More specifically, the invention provides for treatment of various cancers by using inhibitors of the TREM-1/DAP-12 pathway. These inhibitors include peptide variants and compositions that modulate the TREM-l -mediated immunological responses beneficial for the treatment of cancer. In addition, the invention provides for predicting the efficacy of TREM-l -targeted therapies in various cancers by analyzing biological samples for the presence of myeloid cells and for the TREM-l expression levels. In one embodiment, the peptides and compositions of the present invention modulate TREM-1/DAP-12 receptor complex expressed on macrophages. In one embodiment, the peptides and compositions of the invention are conjugated to an imaging probe.
  • the invention provides for detecting the TREM-l -expressing cells and tissues in an individual with cancer using imaging techniques and the peptides and compositions of the invention containing an imaging probe.
  • the peptides and compositions of the invention are used in combinations thereof.
  • the peptides and compositions of the invention are used in combinations with other anticancer therapeutic agents.
  • the present invention relates to the targeted treatment, prevention and/or detection of cancer including but not limited to pancreatic cancer, breast cancer, liver cancer, multiple myeloma, leukemia, bladder cancer, CNS cancer, stomach cancer, prostate, colorectal cancer, brain cancer, ovarian cancer, renal cancer, skin cancer, osteosarcoma and other cancers and cancer cachexia.
  • the invention provides for a method of treating cancer in an individual in need thereof by administering to the individual an effective amount of an inhibitor of the TREM-1/DAP-12 pathway.
  • the inhibitors are selected from peptide variants and compositions that suppress tumor growth by modulating the TREM-1/DAP-12 signaling pathway.
  • any or both the domains comprise minimal biologically active amino acid sequence.
  • the peptide variant comprises a cyclic peptide sequence.
  • the peptide variant comprises a disulfide-linked dimer.
  • the peptide variant includes amino acids selected from the group of natural and unnatural amino acids including, but not limited to, L-amino acids, or D-amino acids.
  • an imaging probe and/or an additional therapeutic agent is conjugated to the peptide variants and compositions of the invention.
  • the imaging agent is a Gd-based contrast agent (GBCA) for magnetic resonance imaging (MRI).
  • the imaging agent is a [ 64 Cu] -containing imaging probe for imaging systems such as a positron emission tomography (PET) imaging systems (and combined PET/computer tomography (CT) and PET/MRI systems).
  • PET positron emission tomography
  • CT computer tomography
  • the peptides and compositions of the invention are used in combinations thereof.
  • the peptides and compositions of the invention are used in combinations with other anticancer therapeutic agents.
  • the peptide variants and compositions of the present invention are incorporated into long half-life synthetic lipopeptide particles (SLP).
  • the peptide variants and compositions of the invention may incorporate into lipopeptide particles (LP) in vivo upon administration to the individual.
  • the peptides and compositions of the invention can cross the blood-brain barrier (BBB), blood-retinal barrier (BRB) and blood-tumor barrier (BTB).
  • BBB blood-brain barrier
  • BRBB blood-retinal barrier
  • BTB blood-tumor barrier
  • the invention provides for a method for suppressing tumor growth in an individual in need thereof by administering to the individual an amount of a TREM-l inhibitor that is effective for suppressing tumor growth.
  • methods of treating a proliferative disorder involving a synovial joint and/or tendon sheath in a subject comprising administering to the subject an effective amount of a compound or composition that modulates TREM-1/DAP-12 activity.
  • the proliferative disorder is selected from pigmented villonodular synovitis (PVNS), giant cell tumor of the tendon sheath (GCTTS), and tenosynovial giant cell tumor (TGCT) such as diffuse type tenosynovial gian cell tumor (dtTGCT).
  • the disorder is pigmented villonodular synovitis/diffuse type tenosynovial gian cell tumor (PVNS/dtTGCT).
  • the PVNS tumor volume is reduced by at least 30% or at least 40% or at least 50% or at least 60% or at least 70% after administration of at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten doses of the compound or composition that modulates TREM-1/DAP-12 activity.
  • the tumor volume is tumor volume in a single joint.
  • the single join is selected from a hip joint and a knee joint.
  • the tumor volume is total tumor volume in all joints affected by PVNS.
  • the subject experiences one or more than one of the following improvements in symptoms: (a) a reduction in joint pain, (b) an increase range of motion in a joint, and (c) an increase in functional capacity of a joint, following at least one dose of the compound or composition.
  • the compounds or compositions of the present invention are selected peptide variants and compositions (see, e.g., US 9,981,004; US 8,513,185; US 9,815,883; US 9,273,111; US 8,013,116) that modulate the TREM-1/DAP-12 signaling pathway.
  • the present invention relates to amphipathic trifunctional peptides consisting of two amino acid domains, wherein upon interaction with plasma lipoproteins, one amino acid domain mediates formation of naturally long half-life lipopeptide/lipoprotein complexes and targets these complexes to macrophages, whereas the other amino acid domain inhibits the TREM4/DAP-12 receptor signaling complex expressed on macrophages.
  • the peptide variant comprises a cyclic peptide sequence. In one embodiment, the peptide variant comprises a disulfide-linked dimer. In one embodiment, the peptide variant includes amino acids selected from the group of natural and unnatural amino acids including, but not limited to, L-amino acids, or D-amino acids. In one embodiment, an imaging probe and/or an additional therapeutic agent is conjugated to the compounds and compositions of the invention.
  • the compounds and compositions of the present invention are incorporated into long half-life synthetic lipopeptide complexes (LPC).
  • the compounds and compositions of the invention may incorporate into natural lipoprotein particles (LP) in vivo upon administration to the individual. See, e.g., US 20110256224 and (Sigalov 2014, Shen and Sigalov 2017, Shen et al. 2017, Rojas et al. 2018, Tornai et al. 2019).
  • the preferred TREM-l modulatory compounds and compositions are TREM-l inhibitory peptide sequences such e.g., as GF9 described in (described in (Sigalov 2014, Rojas et al. 2017, Shen and Sigalov 2017, Shen and Sigalov 2017) and disclosed in (US 8,513,185 and US 9,981,004) or LRU and LP17 (described in Gibot, et al. Infect Immun 2006, 74:2823-2830; Gibot, et al. Shock 2009, 32:633-637; Gibot, et al. Eur J Immunol 2007, 37:456- 466; Joffre, et al.
  • TREM-l inhibitory peptide sequences such e.g., as GF9 described in (described in (Sigalov 2014, Rojas et al. 2017, Shen and Sigalov 2017, Shen and Sigalov 2017) and disclosed in (US 8,513,185 and US 9,981,004) or LRU and
  • the preferred TREM-l modulatory compounds and compositions are antibodies that bind and block TREM-l such e.g., as those disclosed in US 10,189,902. In some embodiments, combinations of different TREM-l modulatory compounds and compositions of the invention is used.
  • the invention provides for a method of predicting the efficacy of TREM-l targeted therapies in an individual with the proliferative disorder by: (a) obtaining a biological sample from the individual; (b) determining the number of myeloid cells in the biological sample; (c) determining the expression levels of TREM-l in the cells contained within the biological sample; (d) measuring the level of soluble form of the human TREM-l receptor in the biological sample. See, e.g., US 8,021,836.
  • the subject prior to administering the first dose of the compound or composition that modulates the TREM-1/DAP-12 receptor complex signaling, the subject receives a first therapy selected from surgical synovectomy, radiation beam therapy, radio isotope synovectomy, and joint replacement.
  • a first therapy selected from surgical synovectomy, radiation beam therapy, radio isotope synovectomy, and joint replacement.
  • the PVNS recurred or progressed after the first therapy.
  • the compound or composition of the present invention is administered prior to a therapy selected from surgical synovectomy, radiation beam therapy, radio isotope synovectomy, and joint replacement.
  • the tumor is unresectable.
  • the subject has not received prior therapy with imatinib, nilotinib or a CSF1/CSF1R inhibitor, while in other embodiments the subject has received prior treatment with imatinib, nilotinib or a CSF1/CSF1R inhibitor. In some embodiments, the subject has not received prior treatment with a CSF1/CSF1R inhibitor, while in other embodiments the subject has received prior treatment with a CSF1/CSF1R inhibitor.
  • the compound or composition that modulates the TREM-1/DAP-12 receptor complex signaling is administered with imatinib, nilotinib, a CSF1/CSF1R inhibitor, anti programmed cell death protein 1 (anti -PD 1) or anti-programmed cell death ligand 1 (PDL1) antibodies.
  • the compound or composition of the present invention is provided as a pharmaceutical composition for intravenous administration. In one embodiment, the compound or composition of the present invention is provided as a pharmaceutical composition for oral administration. In one embodiment, the compound is administered once a day. In one embodiment, the compound is administered twice a day. In one embodiment, the method includes administering to the patient one or more additional therapeutic compounds.
  • the one or more additional therapeutic compound is selected from one or more of a Btk tyrosine kinase inhibitor, an Erbb2 tyrosine kinase receptor inhibitor; an Erbb4 tyrosine kinase receptor inhibitor, an mTOR inhibitor, a thymidylate synthase inhibitor, an EGFR tyrosine kinase receptor inhibitor, an epidermal growth factor antagonist, a Fyn tyrosine kinase inhibitor, a kit tyrosine kinase inhibitor, a Lyn tyrosine kinase inhibitor, a NK cell receptor modulator, a PDGF receptor antagonist, a PARP inhibitor, a poly ADP ribose polymerase inhibitor, a poly ADP ribose polymerase 1 inhibitor, a poly ADP ribose polymerase 2 inhibitor, a poly ADP ribose polymerase 3 inhibitor, a galacto
  • the one or more additional therapeutic compounds is selected from one or more of bavituximab, IMM-101, CAP1-6D, Rexin-G, genistein, CVac, MM-D37K, PCI-27483, TG-01, mocetinostat, LOAd-703, CPI-613, upamostat, CRS-207, NovaCaps, trametinib, Atu-027, sonidegib, GRASP A, trabedersen, nastorazepide, Vaccell, oregovomab, istiratumab, refametinib, regorafenib, lapatinib, selumetinib, rucaparib, pelareorep, tarextumab, PEGylated hyaluronidase, varlitinib, aglatimagene besadenovec, GBS-01, GI-4000, WF-10, galuniserti
  • the one or more additional therapeutic compound is FOLFIRINOX. In one embodiment, the one or more additional therapeutic compounds are gemcitabine and paclitaxel. In one embodiment, the one or more additional therapeutic compounds are gemcitabine and nab- paclitaxel.
  • the invention provides diagnostic markers to prognose the response to TREM-l therapy. In some embodiments, the invention provides prognostic markers to prognose the response to TREM-l therapy. It is not meant to limit the markers to those described herein.
  • the invention provides for a method of treating cancer in an individual in need thereof by administering to the individual a therapeutically effective amount of at least one modulator which affects myeloid cells by action on the TREM-1/DAP-12 signaling pathway together with a therapeutically effective amount of an anticancer vaccine, an anticancer immunotherapy agent, anti-cancer immunomodulatory agent, an additional anticancer therapeutic, radiation therapy, surgery or a combination thereof.
  • the subject of the present invention includes any human subject who has been diagnosed with, has symptoms of, or is at risk of developing a cancer or a pre- or post-cancerous condition.
  • the invention relates to personalized combination-therapy treatments for cancer that involve targeting specific cancers by their tumor environment. More specifically, the invention provides a method for treating various cancers by using modulators of the TREM-1/DAP-12 pathway together with other cancer therapies and the use of such combinations in the treatment of cancer.
  • these modulators may possess the antitumor activity. In some embodiments, these modulators may not possess the antitumor activity.
  • these modulators include peptide variants and compositions that are capable of binding TREM-l and reducing or blocking TREM-l activity (signaling and/or activation). In one embodiment these peptide variants and compositions modulate the TREM-l -mediated immunological responses beneficial for the treatment of cancer.
  • the peptides and compositions of the present invention modulate TREM-1/DAP-12 receptor complex expressed on monocytes, macrophages and neutrophils. In one embodiment, the peptides and compositions of the present invention modulate TREM-1/DAP-12 receptor complex expressed on tumor- associated macrophages. In one embodiment, the invention provides a method for predicting the efficacy of standalone or combination-therapy treatment that involve TREM-l -targeting therapies in various cancers by analyzing biological samples from cancer patients for the presence of myeloid cells and for the expression levels of TREM-l, CSF-l, CSF-1R, IL-6 and other markers. In one embodiment, the peptides and compositions of the invention are conjugated to an imaging probe.
  • the invention provides for detecting the TREM-l -expressing cells and tissues in an individual with cancer using imaging techniques and the peptides and compositions of the invention containing an imaging probe.
  • the peptides and compositions of the invention are used in combinations thereof.
  • the peptides and compositions of the invention are used in combinations with other anticancer therapeutic agents.
  • the present invention relates to the targeted treatment, prevention and/or detection of cancer including but not limited to lung cancer including non-small cell lung cancer (NSCLC), pancreatic cancer, breast cancer, liver cancer, multiple myeloma, melanoma, leukemia, bladder cancer, central nervous system (CNS) cancer, stomach cancer, prostate cancer, colorectal cancer, colon cancer, brain cancer, gastrointestinal cancer, gastric cancer, ovarian cancer, renal cancer, skin cancer, osteosarcoma, endometrial cancer, esophageal cancer, kidney cancer, thyroid cancer, neuroblastoma, neurofibroma, glioma, glioblastoma, glioblastoma multiforme, head and neck cancer, cervical cancer, pigmented villonodular synovitis (PVNS) and other cancers in which myeloid cells are involved or recruited and cancer cachexia.
  • NSCLC non-small cell lung cancer
  • pancreatic cancer breast cancer
  • liver cancer multiple myeloma
  • cancer is selected from the list including but not limited to lung cancer including NSCLC, pancreatic cancer, breast cancer, liver cancer, multiple myeloma, melanoma, leukemia, bladder cancer, central nervous system (CNS) cancer, stomach cancer, prostate cancer, colorectal cancer, colon cancer, brain cancer, gastrointestinal cancer, gastric cancer, ovarian cancer, renal cancer, skin cancer, osteosarcoma, endometrial cancer, esophageal cancer, kidney cancer, thyroid cancer, neuroblastoma, neurofibroma, glioma, glioblastoma, glioblastoma multiforme, head and neck cancer, cervical cancer, giant cell tumor of the tendon sheath (GCTTS), tenosynovial giant cell tumor (TGCT; also referred to in the art as TSGCT), PVNS and other cancers in which myeloid cells are involved or recruited and cancer cachexia.
  • lung cancer including NSCLC, pancreatic cancer, breast cancer, liver cancer, multiple myelo
  • the modulators of the TREM-1/DAP-12 signaling pathway are capable of suppressing tumor growth in the subject. In another aspect, the modulators are capable of delaying the development of cancer in the subject. In another aspect, the modulators are capable of reducing tumor size in the subject. In another aspect, the modulators are capable of treating cancer in the subject. In another aspect, the modulators are capable of treating cancer in the subject. In another aspect, the modulators are capable of increasing survival of the subject.
  • the modulators are capable of binding TREM-l and reducing or blocking TREM-l activity (signaling and/or activation).
  • the modulators comprise peptide variants and compositions that are capable of binding TREM-l and reducing or blocking TREM-l activity (signaling and/or activation) together with a pharmaceutically acceptable excipient, carrier, diluent, salt or a combination thereof.
  • the modulators comprise antibodies or fragments thereof that are capable of binding TREM-l and reducing or blocking TREM-l activity (signaling and/or activation) together with a pharmaceutically acceptable excipient, carrier, diluent, salt or a combination thereof.
  • the methods of combination therapy featured in the present invention may result in a synergistic effect, wherein the effect of a combination of compounds or other therapeutic agents is greater than the sum of the effects resulting from administration of any of the compounds or other therapeutic agents as single agents.
  • a synergistic effect may also be an effect that cannot be achieved by administration of any of the compounds or other therapeutic agents as single agents.
  • the synergistic effect may include, but is not limited to, an effect of treating cancer by reducing tumor size, inhibiting tumor growth, or increasing survival of the subject.
  • the synergistic effect may also include reducing cancer cell viability, inducing cancer cell death, and inhibiting or delaying cancer cell growth.
  • the invention provides for a method of predicting the efficacy of TREM-l targeted therapies in an individual with cancer by: (a) obtaining a biological sample from the individual; (b) determining the number of myeloid cells in the biological sample; (c) determining the expression levels of TREM-l in the cells contained within the biological sample.
  • the invention provides for a method of detecting TREM-l expression levels in an individual with cancer by: (a) administering to the individual the peptide variants and composition of the present invention having an affinity for TREM-l and an imaging probe in a detectably effective amount; (b) imaging at least a portion of the patient; (c) detecting the labeled probe, wherein the location of the labeled probe corresponds to at least one symptom of the myeloid cell-related condition.
  • the invention provides for a diagnostic method of detecting TREM-l expression levels in an individual with cancer by: (a) administering to the individual the modulators of TREM-l transmembrane signaling having an affinity for TREM-l and an imaging probe in a detectably effective amount; (b) imaging at least a portion of the patient; (c) detecting the labeled probe, wherein the location of the labeled probe corresponds to at least one symptom of the myeloid cell-related cancer condition and correlates with the TREM-l expression levels and the higher the levels are, the better the patient is predicted to respond to a TREM-l inhibitory therapy using the modulators of the TREM-1/DAP-12 signaling pathway as standalone therapy or in combinations with other anticancer treatments.
  • the invention provides a method for treating cancer in a patient in need thereof by modulating immune system activity, said method comprising administering to said patient an amount of a TREM-l inhibitor that is effective for inhibiting the TREM-l/DAP- 12 signaling pathway and suppressing tumor growth, or a combination thereof.
  • said method further comprises administering the amount of the TREM-l inhibitor together with a pharmaceutically acceptable excipient, carrier, diluents, or a combination thereof.
  • said method further comprises administering to said patient an anticancer vaccine, an anticancer immunotherapy agent, anti-cancer immunomodulatory agent, an additional anticancer therapeutic, radiation therapy or a combination thereof.
  • said anticancer vaccine is selected from the group consisting of Gardasil, Cervarix, and Sipuleucel-T/Provenge.
  • said anticancer immunotherapy agent is selected from the group consisting of Alemtuzumab, Ipilimumab, Nivolumab, Pembrolizumab, Rituximab, Interferon, Interleukin, and a combination thereof.
  • said anti-cancer immunomodulatory agent is selected from the group consisting of thalidomide, lenolidomide, pomalidomide, and a combination thereof.
  • said additional anti-cancer therapeutic is selected from the group consisting of an alkylating agent, a tubulin inhibitor, a topoisom erase inhibitor, proteasome inhibitor, a CHK1 inhibitor, a CHK2 inhibitor, PARP inhibitor, doxorubicin, epirubicin, vinblastine, etoposide, topotecan, bleomycin, and mytomycin c..
  • said alkylating agent is selected from the group consisting of dacarbazine, Procarbazine, Carmustine, Lomustine, Uramustine, BuSulfan, Streptozocin, Altreamine, Ifosfamine, Chrormethine, Cyclophasphamide, Cyclophosphamide, Chlorambucil, Fluorouracil (5-Fu), Melphalan, Triplatin tetranitrate, Satraplatin, Nedaplatin, Cisplatin, Carboplatin, and Oxaliplatin.
  • said tubulin inhibitor is selected from the group consisting of Taxol, Docetaxel, Vinblastin, Epothilone, Colchicine, Cryptophycin, BMS 347550, Rhizoxin, Ecteinascidin, Dolastin 10, Cryptophycin 52, and IDN- 5109.
  • said topoisomerase inhibitor is a topoisomerase I inhibitor selected from the group consisting of Irinotecan, Topotecan, and Camptothecins (CPT).
  • said topoisomerase inhibitor is a topoisomerase II inhibitor selected from the group consisting of Amsacrine, Etoposide, Teniposide, Epipodophyllotoxins, and ellipticine.
  • said proteasome inhibitor is selected from the group consisting of Velcade (bortezomib), and Kyprolis (carfilzomib).
  • said CHK1 inhibitor is selected from the group consisting of TCS2312, PF-0047736, AZ07762, A-69002, and A-64 1397.
  • said PARP inhibitor is selected from the group consisting of Olaparib, ABT-888, (veliparib), KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO- 1001, ONO-2231 and the like.
  • said radiation therapy is administered to said patient..
  • said at least one said TREM-l inhibitor comprises a variant TREM-l inhibitory peptide sequence derived from transmembrane domain sequences of human or animal TREM-l and/or its signaling subunit, DAP-12, thereof. In some embodiments, said at least one said TREM-l inhibitor comprises LR12 and/or LP17 peptide variants and the like.
  • the invention provides a method for detecting TREM-1/DAP-12 expression levels in a patient with cancer in need thereof, said method comprising administering to said patient an amount of a TREM-l inhibitor that is conjugated to at least one imaging probe, or a combination thereof.
  • said imaging probe is selected from the group comprising Gd(III), Mn(II), Mn(III), Cr(II), Cr(III), Cu(II), Fe (III), Pr(III), Nd(III) Sm(III), Tb(III), Yb(III) Dy(III), Ho(III), Eu(II), Eu(III), and Er(III), Tl 201 , K 42 , In 111 , Fe.
  • said at least one said TREM-l inhibitor comprises a variant TREM-l inhibitory peptide sequence derived from transmembrane domain sequences of human or animal TREM-l and/or its signaling subunit, DAP-12, thereof. In some embodiments, said at least one said TREM-l inhibitor comprises LR12 and/or LP17 peptide variants and the like.
  • the invention provides a method for treating cancer in a patient in need thereof by modulating immune system activity, said method comprising administering to said patient an amount of a TREM-l inhibitor that is effective for inhibiting the TREM-l/DAP- 12 signaling pathway and suppressing tumor growth, or a combination thereof.
  • said TREM-l inhibitor comprises a variant TREM-l inhibitory peptide sequence derived from transmembrane domain sequences of human or animal TREM-l and/or its signaling subunit, DAP- 12, thereof.
  • said a variant TREM-l inhibitory peptide sequence comprises amino acid sequence Gly-Phe-Leu-Ser-Lys-Ser-Leu-Val-Phe, wherein Gly is glycine, Phe is phenylalanine, Leu is leucine, Ser is serine, Lys is lysine, and Val is valine.
  • said variant TREM-l inhibitory peptide sequence is conjugated to at least one unmodified or modified amphipathic peptide sequence.
  • said an unmodified or modified amphipathic peptide sequence is derived from amino acid sequences of apolipoproteins selected from the group consisting of A-I, A-II, A-IV, B, C-I, C-II, C-III, and E, and any combination thereof.
  • said a modified amphipathic peptide sequence derived from amino acid sequences of apolipoproteins selected from the group consisting of A-I, A-II, A-IV, B, C-I, C-II, C-III, and E, and any combination thereof contains at least one amino acid residue which is chemically or enzymatically modified.
  • said a chemically or enzymatically modified amino acid residue is oxidized, halogenated or nitrated.
  • said an oxidized amino acid residue is the methionine residue.
  • said an unmodified amphipathic peptide sequence is derived from an apolipoprotein A-I amino acid sequence and comprises amino acid sequence Pro-Tyr-Leu-Asp-Asp-Phe-Gln-Lys-Lys-Trp-Gln-Glu-Glu-Met-Glu-Leu-Tyr-Arg-Gln-Lys-Val- Glu, wherein Pro is proline, Tyr is tyrosine, Leu is leucine, Asp, asparagine, Phe is phenylalanine, Gln is glutamine, Lys is lysine, Trp is tryptophan, Glu is glutamic acid, Met is methionine, Arg is arginine, and Val is
  • said an unmodified amphipathic peptide sequence is derived from an apolipoprotein A-I amino acid sequence and comprises amino acid sequence Pro-Leu-Gly-Glu-Glu-Met-Arg-Asp-Arg-Ala-Arg-Ala-His-Val- Asp-Ala-Leu-Arg-Thr-His-Leu-Ala, wherein Pro is proline, Leu is leucine, Gly is glycine, Glu is glutamic acid, Met is methionine, Arg is arginine, Asp, asparagine, Ala is alanine, His is histidine, Val is valine, and Thr is threonine.
  • said a modified amphipathic peptide sequence is derived from an apolipoprotein A-I amino acid sequence and comprises amino acid sequence Pro-Tyr-Leu-Asp-Asp-Phe-Gln-Lys-Lys-Trp-Gln-Glu-Glu-Met(0)-Glu- Leu-Tyr-Arg-Gln-Lys-Val-Glu, wherein Pro is proline, Tyr is tyrosine, Leu is leucine, Asp, asparagine, Phe is phenylalanine, Gln is glutamine, Lys is lysine, Trp is tryptophan, Glu is glutamic acid, Met(O) is methionine sulfoxide, Arg is arginine, and Val is valine.
  • said a modified amphipathic peptide sequence is derived from an apolipoprotein A-I amino acid sequence and comprises amino acid sequence Pro-Leu-Gly-Glu-Glu-Met(O)- Arg-Asp-Arg-Ala-Arg-Ala-His-Val-Asp-Ala-Leu-Arg-Thr-His-Leu-Ala, wherein Pro is proline, Leu is leucine, Gly is glycine, Glu is glutamic acid, Met is methionine sulfoxide, Arg is arginine, Asp, asparagine, Ala is alanine, His is histidine, Val is valine, and Thr is threonine.
  • said B is conjugated to an additional peptide sequence to enhance the targeting efficacy.
  • said an additional peptide sequence comprises amino acid sequence Arg-Gly-Asp (RGD), wherein Arg is arginine; Gly is glycine; and Asp is asparagine.
  • said A is conjugated to at least one additional therapeutic agent to enhance the therapeutic efficacy.
  • said an additional therapeutic agent is selected from the group of anticancer, antibacterial, antiviral, autoimmune, anti-inflammatory and cardiovascular agents, antioxidants, therapeutic peptides, and any combination thereof.
  • said anticancer therapeutic agent is selected from the group comprising paclitaxel, valrubicin, doxorubicin, taxotere, campotechin, etoposide, and any combination thereof.
  • said A and/or B are conjugated to at least one imaging probe.
  • said an imaging probe is selected from the group comprising Gd(III), Mn(II), Mn(III), Cr(II), Cr(III), Cu(II), Fe (III), Pr(III), Nd(III) Sm(III), Tb(III), Yb(III) Dy(III), Ho(III), Eu(II), Eu(III), and Er(III), Tl 201 , K 42 , In 111 , Fe.
  • the invention provides a method of making a synthetic lipopeptide nanoparticle, said method comprising: a) co-dissolving a predetermined amount of a mixture of neutral and/or charged lipids with: i. a predetermined amount of cholesterol; and ii. a predetermined amount of triglycerides and/or cholesteryl ester; b) drying the mixture of step (a) under nitrogen; c) co-dissolving the dried mixture of step (b) with: i. a predetermined amount of sodium cholate; and ii.
  • lipid is conjugated to at least one imaging probe.
  • said an imaging probe is selected from the group comprising Gd(III), Mn(II), Mn(III), Cr(II), Cr(III), Cu(II), Fe (III), Pr(III), Nd(III) Sm(III), Tb(III), Yb(III) Dy(III), Ho(III), Eu(II), Eu(III), and Er(III), Tl 201 , K 42 , In 111 , Fe.
  • said lipid is selected from the group comprising cholesterol, a cholesteryl ester, a phospholipid, a glycolipid, a sphingolipid, a cationic lipid, a diacylglycerol, and a triacyl glycerol.
  • said phospholipid is selected from the group comprising phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidyl serine (PS), phosphatidylinositol (PI), phosphatidylglycerol (PG), cardiolipin (CL), sphingomyelin (SM), phosphatidic acid (PA), and any combination thereof.
  • said lipid is polyethylene glycol(PEG)ylated.
  • the invention provides a method of imaging a myeloid cell-related condition, comprising a) providing; i) a patient having at least one symptom of a disease or condition in which myeloid cells are involved or recruited, and ii) a labeled probe, wherein the labeled probe includes the compositions of claims 1, 3, 4, and 21-25 having an affinity for TREM-l and an imaging probe; b) administering said composition to said patient in a detectably effective amount c) imaging at least a portion of the patient; and d) detecting the labeled probe, wherein the location of the labeled probe corresponds to at least one symptom of the myeloid cell-related condition.
  • said a myeloid cell-related condition is selected from the group comprising cancer including but not limited to lung, pancreatic, breast, stomach, prostate, colon, brain and skin cancers, cancer cachexia, heart disease, atherosclerosis, peripheral artery disease, restenosis, stroke, bacterial infectious diseases, acquired immune deficiency syndrome (AIDS), allergic diseases, acute radiation syndrome, inflammatory bowel disease, empyema, acute mesenteric ischemia, hemorrhagic shock, multiple sclerosis, autoimmune diseases (e.g., rheumatoid arthritis, Sjogrens, scleroderma, systemic lupus erythematosus, non specific vasculitis, Kawasaki's disease, psoriasis, type I diabetes, pemphigus vulgaris), granulomatous diseases (e.g., tuberculosis, sarcoidosis, lymphomatoid granulomatosis, Wegener's granulomatosus), Gau
  • the invention provides a method of treating a myeloid cell-related condition, comprising: a) providing; i) a patient having at least one symptom of a disease or condition in which myeloid cells are involved or recruited, and ii) the compositions of claims 1, 3, 4, and 23 capable of inhibiting TREM-l; b) administering said composition to said patient under conditions such that said at least one symptom is reduced.
  • said a myeloid cell-related condition is selected from the group comprising cancer including but not limited to lung, pancreatic, breast, stomach, prostate, colon, brain and skin cancers, cancer cachexia, heart disease, atherosclerosis, peripheral artery disease, restenosis, stroke, bacterial infectious diseases, acquired immune deficiency syndrome (AIDS), allergic diseases, acute radiation syndrome, inflammatory bowel disease, empyema, acute mesenteric ischemia, hemorrhagic shock, multiple sclerosis, autoimmune diseases (e.g., rheumatoid arthritis, Sjogrens, scleroderma, systemic lupus erythematosus, non-specific vasculitis, Kawasaki's disease, psoriasis, type I diabetes, pemphigus vulgaris), granulomatous diseases (e.g., tuberculosis, sarcoidosis, lymphomatoid granulomatosis, Wegener's granulomatosus),
  • cancer including
  • the invention provides a method of imaging a T cell-related condition, comprising a) providing; i) a patient having at least one symptom of a disease or condition in which T cells are involved or recruited, and ii) a labeled probe, wherein the labeled probe includes the compositions of claims 1, 5, 6, and 21-25 having an affinity for TCR and an imaging probe; b) administering said composition to said patient in a detectably effective amount c) imaging at least a portion of the patient; and d) detecting the labeled probe, wherein the location of the labeled probe corresponds to at least one symptom of the T cell-related condition.
  • said T cell-related condition is selected from the group including but not limited to include, but are not limited to, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, scleroderma, type I diabetes, gastroenterological conditions e.g. inflammatory bowel disease, Crohn’s disease, celiac disease, Guillain-Barre syndrome, Hashimoto's disease, pernicious anaemia, primary biliary cirrhosis, chronic active hepatitis; skin problems e.g. atopic dermatitis, psoriasis, pemphigus vulgaris; cardiovascular problems e.g.
  • autoimmune pericarditis e.g. delayed type hypersensitivity, contact dermatitis, AIDS virus, herpes simplex/zoster, respiratory conditions e.g. allergic alveolitis, inflammatory conditions e.g. myositis, ankylosing spondylitis, tissue/organ rejection, and other diseases and conditions where T cells are involved or recruited.
  • allergic diathesis e.g. delayed type hypersensitivity
  • contact dermatitis e.g. delayed type hypersensitivity
  • contact dermatitis e.g. delayed type hypersensitivity
  • contact dermatitis e.g. delayed type hypersensitivity
  • contact dermatitis e.g. delayed type hypersensitivity
  • contact dermatitis e.g. delayed type hypersensitivity
  • contact dermatitis e.g. delayed type hypersensitivity
  • contact dermatitis e.g. delayed type hypersensitivity
  • contact dermatitis e.g. delayed type hypersensitivity
  • contact dermatitis e.g. delayed type hypersensitivity
  • the invention provides a method of treating a T cell-related condition, comprising: a) providing; i) a patient having at least one symptom of a disease or condition in which T cells are involved or recruited, and ii) the compositions of claims 1, 5, 6, and 23 capable of inhibiting TCR; b) administering said composition to said patient under conditions such that said at least one symptom is reduced.
  • said a T cell- related condition is selected from the group including but not limited to include, but are not limited to, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, scleroderma, type I diabetes, gastroenterological conditions e.g.
  • inflammatory bowel disease Crohn’s disease, celiac disease, Guillain-Barre syndrome, Hashimoto's disease, pernicious anaemia, primary biliary cirrhosis, chronic active hepatitis; skin problems e.g. atopic dermatitis, psoriasis, pemphigus vulgaris; cardiovascular problems e.g. autoimmune pericarditis, allergic diathesis e.g. delayed type hypersensitivity, contact dermatitis, AIDS virus, herpes simplex/zoster, respiratory conditions e.g. allergic alveolitis, inflammatory conditions e.g. myositis, ankylosing spondylitis, tissue/organ rejection, and other diseases and conditions where T cells are involved or recruited.
  • skin problems e.g. atopic dermatitis, psoriasis, pemphigus vulgaris
  • cardiovascular problems e.g. autoimmune pericarditis, allergic diathesis e.g. delayed type
  • the invention provides a method of reducing pain in a subject with pigmented villonodular synovitis (PVNS) tumor, comprising administering to the subject an amount of a TREM-l modulator that is effective for inhibiting the TREM-1/DAP-12 signaling pathway and capable of reducing pain in PVNS subjects independently of tumor response.
  • PVNS tumor has a tumor volume.
  • said inhibition reduces said PVNS tumor volume by at least 30% after administration of at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten doses of the modulator that inhibits the TREM-1/DAP-12 signaling pathway.
  • said tumor volume is tumor volume in a single joint.
  • said single joint is selected from a hip joint and a knee joint.
  • said tumor volume is total tumor volume in all joints affected by PVNS.
  • said modulator is an antibody.
  • the subject prior to administering the first dose of said antibody, the subject received a prior therapy selected from surgical synovectomy, radiation beam therapy, radio isotope synovectomy, joint replacement and CSF1/CSF1R inhibitor.
  • said PVNS recurred or progressed after the prior therapy.
  • said antibody is administered prior to a therapy selected from surgical synovectomy, radiation beam therapy, radio isotope synovectomy, and joint replacement, or wherein the subject has a tumor that is unresectable. In some embodiments, said subject has not received prior treatment with a CSF1R inhibitor. In one embodiment, said method further comprises administering the amount of the TREM-l modulator together with a pharmaceutically acceptable excipient, carrier, diluents, or a combination thereof. In one embodiment, said method further comprises administering the amount of the TREM-l modulator together with an amount of an anticancer vaccine, an anticancer immunotherapy agent, anti-cancer immunomodulatory agent, an additional anticancer therapeutic, radiation therapy, or a combination thereof.
  • said anticancer vaccine is selected from the group consisting of Gardasil, Cervarix, and Sipuleucel-T/Provenge.
  • said anticancer immunotherapy agent is selected from the group consisting of Alemtuzumab, Ipilimumab, Nivolumab, Pembrolizumab, Rituximab, Interferon, Interleukin, and a combination thereof.
  • said anti-cancer immunomodulatory agent is selected from the group consisting of thalidomide, lenolidomide, pomalidomide, and a combination thereof.
  • said additional anti-cancer therapeutic is selected from the group consisting of an alkylating agent, a tubulin inhibitor, a topoisom erase inhibitor, proteasome inhibitor, a CHK1 inhibitor, a CHK2 inhibitor, PARP inhibitor, CSF1/CSF1R inhibitor, doxorubicin, epirubicin, vinblastine, etoposide, topotecan, bleomycin, and mytomycin c.
  • said alkylating agent is selected from the group consisting of dacarbazine, Procarbazine, Carmustine, Lomustine, Uramustine, BuSulfan, Streptozocin, Altreamine, Ifosfamine, Chrormethine, Cyclophasphamide, Cyclophosphamide, Chlorambucil, Fluorouracil (5-Fu), Melphalan, Triplatin tetranitrate, Satraplatin, Nedaplatin, Cisplatin, Carboplatin, and Oxaliplatin.
  • said tubulin inhibitor is selected from the group consisting of Taxol, Docetaxel, Vinblastin, Epothilone, Colchicine, Cryptophycin, BMS 347550, Rhizoxin, Ecteinascidin, Dolastin 10, Cryptophycin 52, and IDN-5109.
  • said topoisomerase inhibitor is a topoisomerase I inhibitor selected from the group consisting of Irinotecan, Topotecan, and Camptothecins (CPT).
  • said topoisomerase inhibitor is a topoisomerase II inhibitor selected from the group consisting of Amsacrine, Etoposide, Teniposide, Epipodophyllotoxins, and ellipticine.
  • said proteasome inhibitor is selected from the group consisting of Velcade (bortezomib), and Kyprolis (carfilzomib).
  • said CHK1 inhibitor is selected from the group consisting of TCS2312, PF- 0047736, AZ07762, A-69002, and A-64 1397.
  • said PARP inhibitor is selected from the group consisting of Olaparib, ABT-888, (veliparib), KEG-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the like.
  • said CSF1/CSF1R inhibitor is selected from the group consisting of CSF1R kinase inhibitor, an antibody that binds CSF1R and the like.
  • said CSF1R kinase inhibitor is imatinib or nilotinib.
  • said CSF1R kinase inhibitor is PLX3397.
  • said anti-CSFlR antibody blocks binding of CSF1 and/or IL-34 to CSF1R.
  • said anti-CSFlR antibody inhibits ligand-induced CSF1R phosphorylation in vitro.
  • said antibody is a humanized antibody.
  • a radiation therapy is administered to said patient.
  • said at least one said TREM-l inhibitor comprises a variant TREM-l inhibitory peptide sequence derived from transmembrane domain sequences of human or animal TREM-l and/or its signaling subunit, DAP-12, thereof.
  • said at least one said TREM-l inhibitor comprises LR12 and/or LP17 peptide variants and the like.
  • the invention provides a method for detecting TREM-1/DAP-12 expression levels in a patient with cancer in need thereof, said method comprising administering to said patient an amount of a TREM-l inhibitor that is conjugated to at least one imaging probe, or a combination thereof.
  • the invention provides a method of predicting the efficacy of TREM-l targeted therapies in an individual with the proliferative disorder by: (a) obtaining a biological sample from the individual; (b) determining the number of myeloid cells in the biological sample; (c) determining the expression levels of TREM-l in the cells contained within the biological sample; (d) measuring the level of soluble form of the human TREM-l receptor in the biological sample.
  • the invention provides a method of diagnosing disease of the proliferative disorder in a subject, wherein said disease is PVNS or TGCT, which method comprises the steps of (a) measuring a level of the soluble form of the human TREM-l receptor in a biological sample obtained from said subject; (b) comparing the measured level of the soluble form of the human TREM-l receptor in the sample with a mean level in a control population of individuals not PVNS or TGCT; (c) correlating elevated levels of the soluble form of the human TREM-l receptor with the presence or extent of said proliferative disease.
  • said step of measuring the level of the soluble form of the human TREM-l receptor comprises the steps of: (a) contacting said biological sample with a compound capable of binding the soluble form of the human TREM-l receptor; (b) detecting the level of the soluble form of the human TREM-l receptor present in the sample by observing the level of binding between said compound and the soluble form of the human TREM-l receptor.
  • said method further comprises comprising the steps of measuring the level of the soluble form of the human TREM-l receptor in a second or further sample from said subject, the first and second or further samples being obtained at different times; and comparing the levels in the samples to indicate the progression or remission of the proliferative disease.
  • said sample is selected from the group consisting of whole blood, blood serum, blood, plasma, urine, bronchoalveolar lavage fluid and synovial liquid. In some embodiments, said sample is from synovial fluid. In some embodiments, said sample is from blood serum or blood plasma. In some embodiments, said sample is a human sample. In some embodiments, said compound specifically binds the soluble form of the human TREM-l receptor. In some embodiments, said compound capable of binding the soluble form of the human TREM-l receptor is an antibody raised against all or part of the TREM-l receptor. In some embodiments, said level of soluble form of the human TREM-l receptor is measured by an immunochemical technique.
  • said method further comprisesan additional step of measuring the level of TREM-l -Ligand in one or more biological samples obtained from said subject.
  • said imaging probe is selected from the group comprising Gd(III), Mn(II), Mn(III), Cr(II), Cr(III), Cu(II), Fe (III), Pr(III), Nd(III) Sm(III), Tb(III), Yb(III) Dy(III), Ho(III), Eu(II), Eu(III), and Er(III), T1201, K42, Inl l l, Fe.59, Tc99m, Cr5l, Ga67, Ga68, Cu64, Rb82,Mo99, Dyl65, Fluorescein, Carboxyfluorescein, Calcein, F18, Xel33, 1125, 1131, 1123, P32, Cl l, N13, 015, Br76, Kr8l, Diatrizoate, Metrizoate, Isopaque, Iox
  • said at least one said TREM-l inhibitor comprises a variant TREM-l inhibitory peptide sequence derived from transmembrane domain sequences of human or animal TREM-l and/or its signaling subunit, DAP-12, thereof. In some embodiments, said at least one said TREM-l inhibitor comprises LR12 and/or LP17 peptide variants and the like.
  • the invention provides a method for treating cancer in a patient in need thereof, said method comprising administering to said patient an amount of a TREM-l inhibitor that is effective for inhibiting the TREM-1/DAP-12 signaling pathway and suppressing tumor growth and an amount of an anticancer vaccine, an anticancer immunotherapy agent, anti cancer immunomodulatory agent, an additional anticancer therapeutic, radiation therapy, or a combination thereof.
  • said method further comprises administering the amount of the TREM-l inhibitor together with a pharmaceutically acceptable excipient, carrier, diluents, or a combination thereof.
  • said anticancer vaccine is selected from the group consisting of Gardasil, Cervarix, and Sipuleucel-T/Provenge.
  • said anticancer immunotherapy agent is selected from the group consisting of Alemtuzumab, Ipilimumab, Nivolumab, Pembrolizumab, Rituximab, Interferon, Interleukin, and a combination thereof.
  • said anti-cancer immunomodulatory agent is selected from the group consisting of thalidomide, lenolidomide, pomalidomide, and a combination thereof.
  • said additional anti-cancer therapeutic is selected from the group consisting of an alkylating agent, a tubulin inhibitor, a topoisomerase inhibitor, proteasome inhibitor, a CHK1 inhibitor, a CHK2 inhibitor, PARP inhibitor, doxorubicin, epirubicin, vinblastine, etoposide, topotecan, bleomycin, and mytomycin c.
  • said alkylating agent is selected from the group consisting of dacarbazine, Procarbazine, Carmustine, Lomustine, Uramustine, BuSulfan, Streptozocin, Altreamine, Ifosfamine, Chrormethine, Cyclophasphamide, Cyclophosphamide, Chlorambucil, Fluorouracil (5-Fu), Melphalan, Triplatin tetranitrate, Satraplatin, Nedaplatin, Cisplatin, Carboplatin, and Oxaliplatin.
  • said tubulin inhibitor is selected from the group consisting of Taxol, Docetaxel, Vinblastin, Epothilone, Colchicine, Cryptophycin, BMS 347550, Rhizoxin, Ecteinascidin, Dolastin 10, Cryptophycin 52, and IDN-5109.
  • said topoisomerase inhibitor is a topoisomerase I inhibitor selected from the group consisting of Irinotecan, Topotecan, and Camptothecins (CPT).
  • said topoisomerase inhibitor is a topoisomerase II inhibitor selected from the group consisting of Amsacrine, Etoposide, Teniposide, Epipodophyllotoxins, and ellipticine.
  • said proteasome inhibitor is selected from the group consisting of Velcade (bortezomib), and Kyprolis (carfilzomib).
  • said CHK1 inhibitor is selected from the group consisting of TCS2312, PF-0047736, AZ07762, A-69002, and A-64 1397.
  • said PARP inhibitor is selected from the group consisting of Olaparib, ABT-888, (veliparib), KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the like.
  • a radiation therapy is administered to said patient.
  • said at least one said TREM-l inhibitor comprises a variant TREM-l inhibitory peptide sequence derived from transmembrane domain sequences of human or animal TREM-l and/or its signaling subunit, DAP-12, thereof. In some embodiments, said at least one said TREM-l inhibitor comprises LR12 and/or LP17 peptide variants and the like.
  • the invention provides a method for detecting TREM-1/DAP-12 expression levels in a patient with cancer in need thereof, said method comprising administering to said patient an amount of a TREM-l inhibitor that is conjugated to at least one imaging probe, or a combination thereof.
  • said an imaging probe is selected from the group comprising Gd(III), Mn(II), Mn(III), Cr(II), Cr(III), Cu(II), Fe (III), Pr(III), Nd(III) Sm(III), Tb(III), Yb(III) Dy(III), Ho(III), Eu(II), Eu(III), and Er(III), T1201, K42, Inl l l, Fe.59, Tc99m, Cr5l, Ga67, Ga68, Cu64, Rb82,Mo99, Dyl65, Fluorescein, Carboxyfluorescein, Calcein, F18, Xel33, 1125, 1131, 1123, P32, Cl l, N13, 015, Br76, Kr8l, Diatrizoate, Metrizoate, Isopaque, Ioxaglate, Iopamidol, Iohexol, Iodixanol.
  • said at least one said TREM-l inhibitor comprises a variant TREM-l inhibitory peptide sequence derived from transmembrane domain sequences of human or animal TREM-l and/or its signaling subunit, DAP- 12, thereof.
  • said at least one said TREM-l inhibitor comprises LR12 and/or LP17 peptide variants and the like.
  • the invention provides a method for treating cancer in a patient in need thereof, said method comprising administering to said patient an amount of a TREM-l inhibitor that is effective for inhibiting the TREM-1/DAP-12 signaling pathway and suppressing tumor growth and an amount of an anticancer vaccine, an anticancer immunotherapy agent, anti cancer immunomodulatory agent, an additional anticancer therapeutic, radiation therapy, or a combination thereof.
  • said TREM-l inhibitor comprises a variant TREM-l inhibitory peptide sequence derived from transmembrane domain sequences of human or animal TREM-l and/or its signaling subunit, DAP-12, thereof.
  • said a variant TREM-l inhibitory peptide sequence comprises amino acid sequence Gly-Phe-Leu-Ser-Lys-Ser- Leu-Val-Phe, wherein Gly is glycine, Phe is phenylalanine, Leu is leucine, Ser is serine, Lys is lysine, and Val is valine.
  • said variant TREM-l inhibitory peptide sequence is conjugated to at least one unmodified or modified amphipathic peptide sequence.
  • said an unmodified or modified amphipathic peptide sequence is derived from amino acid sequences of apolipoproteins selected from the group consisting of A-I, A-II, A- IV, B, C-I, C-II, C-III, and E, and any combination thereof.
  • said a modified amphipathic peptide sequence derived from amino acid sequences of apolipoproteins selected from the group consisting of A-I, A-II, A-IV, B, C-I, C-II, C-III, and E, and any combination thereof contains at least one amino acid residue which is chemically or enzymatically modified.
  • said a chemically or enzymatically modified amino acid residue is oxidized, halogenated or nitrated.
  • said an oxidized amino acid residue is the methionine residue.
  • said an unmodified amphipathic peptide sequence is derived from an apolipoprotein A-I amino acid sequence and comprises amino acid sequence Pro-Tyr-Leu-Asp-Asp-Phe-Gln-Lys-Lys-Trp-Gln-Glu-Glu-Met- Glu-Leu-Tyr-Arg-Gln-Lys-Val-Glu, wherein Pro is proline, Tyr is tyrosine, Leu is leucine, Asp, asparagine, Phe is phenylalanine, Gln is glutamine, Lys is lysine, Trp is tryptophan, Glu is glutamic acid, Met is methionine, Arg is arginine, and Val is
  • said an unmodified amphipathic peptide sequence is derived from an apolipoprotein A-I amino acid sequence and comprises amino acid sequence Pro-Leu-Gly-Glu-Glu-Met-Arg-Asp-Arg-Ala-Arg- Ala-His-Val-Asp-Ala-Leu-Arg-Thr-His-Leu-Ala, wherein Pro is proline, Leu is leucine, Gly is glycine, Glu is glutamic acid, Met is methionine, Arg is arginine, Asp, asparagine, Ala is alanine, His is histidine, Val is valine, and Thr is threonine.
  • said a modified amphipathic peptide sequence is derived from an apolipoprotein A-I amino acid sequence and comprises amino acid sequence Pro-Tyr-Leu-Asp-Asp-Phe-Gln-Lys-Lys-Trp-Gln-Glu-Glu- Met(0)-Glu-Leu-Tyr-Arg-Gln-Lys-Val-Glu, wherein Pro is proline, Tyr is tyrosine, Leu is leucine, Asp, asparagine, Phe is phenylalanine, Gln is glutamine, Lys is lysine, Trp is tryptophan, Glu is glutamic acid, Met(O) is methionine sulfoxide, Arg is arginine, and Val is valine.
  • said a modified amphipathic peptide sequence is derived from an apolipoprotein A-I amino acid sequence and comprises amino acid sequence Pro-Leu-Gly-Glu-Glu-Met(O)- Arg-Asp-Arg-Ala-Arg-Ala-His-Val-Asp-Ala-Leu-Arg-Thr-His-Leu-Ala, wherein Pro is proline, Leu is leucine, Gly is glycine, Glu is glutamic acid, Met is methionine sulfoxide, Arg is arginine, Asp, asparagine, Ala is alanine, His is histidine, Val is valine, and Thr is threonine.
  • said B is conjugated to an additional peptide sequence to enhance the targeting efficacy.
  • said an additional peptide sequence comprises amino acid sequence Arg-Gly-Asp (RGD), wherein Arg is arginine; Gly is glycine; and Asp is asparagine.
  • said A is conjugated to at least one additional therapeutic agent to enhance the therapeutic efficacy.
  • said an additional therapeutic agent is selected from the group of anticancer, antibacterial, antiviral, autoimmune, anti-inflammatory and cardiovascular agents, antioxidants, therapeutic peptides, and any combination thereof.
  • said anticancer therapeutic agent is selected from the group comprising paclitaxel, valrubicin, doxorubicin, taxotere, campotechin, etoposide, and any combination thereof.
  • said A and/or B are conjugated to at least one imaging probe.
  • said an imaging probe is selected from the group comprising Gd(III), Mn(II), Mn(III), Cr(II), Cr(III), Cu(II), Fe (III), Pr(III), Nd(III) Sm(III), Tb(III), Yb(III) Dy(III), Ho(III), Eu(II), Eu(III), and Er(III), T1201, K42, Inl l l, Fe.59, Tc99m, Cr5l, Ga67, Ga68, Cu64, Rb82,Mo99, Dyl65, Fluorescein, Carboxyfluorescein, Calcein, F18, Xel33, 1125, 1131, 1123, P32, Cl l, N13, 015, Br76, Kr8l, Diatrizoate, Metrizoate, Isopaque, Ioxaglate, Iopamidol, Iohexol, Iodixanol.
  • the invention provides a method of making a synthetic lipopeptide nanoparticle, said method comprising: a) co-dissolving a predetermined amount of a mixture of neutral and/or charged lipids with: i. a predetermined amount of cholesterol; and ii. a predetermined amount of triglycerides and/or cholesteryl ester; b) drying the mixture of step (a) under nitrogen; c) co-dissolving the dried mixture of step (b) with: i. a predetermined amount of sodium cholate; and ii.
  • lipid is conjugated to at least one imaging probe.
  • said an imaging probe is selected from the group comprising Gd(III), Mn(II), Mn(III), Cr(II), Cr(III), Cu(II), Fe (III), Pr(III), Nd(III) Sm(III), Tb(III), Yb(III) Dy(III), Ho(III), Eu(II), Eu(III), and Er(III), T1201, K42, Inl l l, Fe.59, Tc99m, Cr5l, Ga67, Ga68, Cu64, Rb82,Mo99, Dyl65, Fluorescein, Carboxyfluorescein, Calcein, F18, Xel33, 1125, 1131, 1123, P32, Cl l, N13, 015, Br76, Kr8l, Diatrizoate, Metrizoate, Isopaque, Ioxaglate, Iopamidol, Iohexol, Iodixanol.
  • said lipid is selected from the group comprising cholesterol, a cholesteryl ester, a phospholipid, a gly colipid, a sphingolipid, a cationic lipid, a diacylglycerol, and a triacyl glycerol.
  • said phospholipid is selected from the group comprising phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), phosphatidylglycerol (PG), cardiolipin (CL), sphingomyelin (SM), phosphatidic acid (PA), and any combination thereof.
  • said lipid is polyethylene glycol(PEG)ylated.
  • the invention provides a method of imaging a myeloid cell-related condition, comprising a) providing; i) a patient having at least one symptom of a disease or condition in which myeloid cells are involved or recruited, and ii) a labeled probe, wherein the labeled probe includes the compositions of claims 1, 3, 4, and 21-25 having an affinity for TREM-l and an imaging probe; b) administering said composition to said patient in a detectably effective amount c) imaging at least a portion of the patient; and d) detecting the labeled probe, wherein the location of the labeled probe corresponds to at least one symptom of the myeloid cell-related condition.
  • said a myeloid cell-related condition is selected from the group comprising cancer including but not limited to lung, pancreatic, breast, stomach, prostate, colon, brain and skin cancers, cancer cachexia, heart disease, atherosclerosis, peripheral artery disease, restenosis, stroke, bacterial infectious diseases, acquired immune deficiency syndrome (AIDS), allergic diseases, acute radiation syndrome, inflammatory bowel disease, empyema, acute mesenteric ischemia, hemorrhagic shock, multiple sclerosis, autoimmune diseases (e.g., rheumatoid arthritis, Sjogrens, scleroderma, systemic lupus erythematosus, non specific vasculitis, Kawasaki's disease, psoriasis, type I diabetes, pemphigus vulgaris), granulomatous diseases (e.g., tuberculosis, sarcoidosis, lymphomatoid granulomatosis, Wegener's granulomatosus), Gau
  • the invention provides a method of treating a myeloid cell-related condition, comprising: a) providing; i) a patient having at least one symptom of a disease or condition in which myeloid cells are involved or recruited, and ii) the compositions of claims 1, 3, 4, and 23 capable of inhibiting TREM-l; b) administering said composition to said patient under conditions such that said at least one symptom is reduced.
  • said a myeloid cell-related condition is selected from the group comprising cancer including but not limited to lung, pancreatic, breast, stomach, prostate, colon, brain and skin cancers, cancer cachexia, heart disease, atherosclerosis, peripheral artery disease, restenosis, stroke, bacterial infectious diseases, acquired immune deficiency syndrome (AIDS), allergic diseases, acute radiation syndrome, inflammatory bowel disease, empyema, acute mesenteric ischemia, hemorrhagic shock, multiple sclerosis, autoimmune diseases (e.g., rheumatoid arthritis, Sjogrens, scleroderma, systemic lupus erythematosus, non-specific vasculitis, Kawasaki's disease, psoriasis, type I diabetes, pemphigus vulgaris), granulomatous diseases (e.g., tuberculosis, sarcoidosis, lymphomatoid granulomatosis, Wegener's granulomatosus),
  • cancer including
  • the invention provides a method of imaging a T cell-related condition, comprising a) providing; i) a patient having at least one symptom of a disease or condition in which T cells are involved or recruited, and ii) a labeled probe, wherein the labeled probe includes the compositions of claims 1, 5, 6, and 21-25 having an affinity for TCR and an imaging probe; b) administering said composition to said patient in a detectably effective amount c) imaging at least a portion of the patient; and d) detecting the labeled probe, wherein the location of the labeled probe corresponds to at least one symptom of the T cell-related condition.
  • the invention provides a method of treating a T cell-related condition, comprising: a) providing; i) a patient having at least one symptom of a disease or condition in which T cells are involved or recruited, and ii) the compositions of claims 1, 5, 6, and 23 capable of inhibiting TCR; b) administering said composition to said patient under conditions such that said at least one symptom is reduced.
  • said a T cell- related condition is selected from the group including but not limited to include, but are not limited to, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, scleroderma, type I diabetes, gastroenterological conditions e.g.
  • inflammatory bowel disease Crohn’s disease, celiac disease, Guillain-Barre syndrome, Hashimoto's disease, pernicious anaemia, primary biliary cirrhosis, chronic active hepatitis; skin problems e.g. atopic dermatitis, psoriasis, pemphigus vulgaris; cardiovascular problems e.g. autoimmune pericarditis, allergic diathesis e.g. delayed type hypersensitivity, contact dermatitis, AIDS virus, herpes simplex/zoster, respiratory conditions e.g. allergic alveolitis, inflammatory conditions e.g. myositis, ankylosing spondylitis, tissue/organ rejection, and other diseases and conditions where T cells are involved or recruited.
  • skin problems e.g. atopic dermatitis, psoriasis, pemphigus vulgaris
  • cardiovascular problems e.g. autoimmune pericarditis, allergic diathesis e.g. delayed type
  • the invention provides for a method of predicting response of the subject to the treatment by using the modulators of TREM-1/DAP-12 signaling pathway in standalone or combination-therapy regimen by: (a) obtaining a biological sample from the subject; (b) determining the expression of CSF-l, CSF-1R, IL-6, TREM-l and/or number of CD68-positive TAMs or a combination thereof, wherein the higher is the expression of CSF-l, CSF-1R, IL-6, TREM-l or the higher is number of CD68-positive TAMs or a combination thereof, the better the patient is predicted to respond to a therapy that involves the modulators.
  • the invention provides for a method of diagnosing cancer in which myeloid cells are involved or recruited in the subject and/or predicting response of the subject to the treatment by using the modulators of TREM-1/DAP-12 signaling pathway in standalone or combination-therapy regimen by: (a) administering to said patient an amount of at least one modulator capable of binding TREM-l that is conjugated to at least one imaging probe, or a combination thereof, in a detectably effective amount; (b) imaging at least a portion of the patient; (c) detecting the labeled probe, wherein the location and amount of the labeled probe corresponds to at least one symptom of the myeloid cell-related cancer condition and the TREM- 1 expression levels and the higher the expression level is, the better the patient is predicted to respond to a therapy that involves the modulators.
  • the invention relates to personalized medical treatments for scleroderma (systemic sclerosis, SSc). More specifically, the invention provides for treatment of scleroderma or a related autoimmune or a fibrotic condition by using modulators of the TREM-1/DAP-12 pathway standalone or together with other antifibrotic therapies and the use of such combinations in the treatment of scleroderma.
  • these modulators may possess the antifibrotic activity. In some embodiments, these modulators may not possess the antifibrotic activity. In certain embodiments, these modulators may possess the anti-inflammatory activity.
  • these modulators include peptide variants and compositions that are capable of binding TREM-l and reducing or blocking TREM-l activity (signaling and/or activation). In one embodiment these peptide variants and compositions modulate the TREM-l -mediated immunological responses beneficial for the treatment of scleroderma or a related autoimmune or a fibrotic condition. In one embodiment, the peptides and compositions of the present invention modulate TREM-1/DAP-12 receptor complex expressed on monocytes, macrophages and neutrophils. In one embodiment, the peptides and compositions of the present invention modulate TREM-1/DAP-12 receptor complex expressed on SSc-associated macrophages.
  • the invention provides a method for predicting the efficacy of standalone or combination-therapy treatment that involve TREM-l -targeting therapies in scleroderma by analyzing biological samples from cancer patients for the presence of myeloid cells and for the expression levels of TREM-l, CSF-l, CSF-1R, IL-6 and other markers.
  • the peptides and compositions of the invention are conjugated to an imaging probe.
  • the invention provides for detecting the TREM-l -expressing cells and tissues in an individual with scleroderma using imaging techniques and the peptides and compositions of the invention containing an imaging probe.
  • the peptides and compositions of the invention are used in combinations thereof.
  • the peptides and compositions of the invention are used in combinations with other antifibrotic therapeutic agents.
  • the present invention relates to the targeted treatment, prevention and/or detection of scleroderma including but not limited to calcinosis, Raynaud’s phenomenon, esophageal dysmotility, scleroderma, or telangiectasia syndrome (CREST).
  • the invention provides for a method of treating scleroderma (SSc) or a related autoimmune or a fibrotic condition in an individual in need thereof by administering to the individual an effective amount of an inhibitor of the TREM-1/DAP-12 pathway.
  • the inhibitors are selected from peptide variants and compositions that suppress tumor growth by modulating the TREM-1/DAP-12 signaling pathway.
  • any or both the domains comprise minimal biologically active amino acid sequence.
  • the peptide variant comprises a cyclic peptide sequence.
  • the peptide variant comprises a disulfide-linked dimer.
  • the peptide variant includes amino acids selected from the group of natural and unnatural amino acids including, but not limited to, L- amino acids, or D-amino acids.
  • an imaging probe and/or an additional therapeutic agent is conjugated to the peptide variants and compositions of the invention.
  • the imaging agent is a Gd-based contrast agent (GBCA) for magnetic resonance imaging (MRI).
  • the imaging agent is a [ 64 Cu] -containing imaging probe for imaging systems such as a positron emission tomography (PET) imaging systems (and combined PET/computer tomography (CT) and PET/MRI systems).
  • PET positron emission tomography
  • CT computer tomography
  • the peptides and compositions of the invention are used in combinations thereof.
  • the peptides and compositions of the invention are used in combinations with other antifibrotic therapeutic agents.
  • the peptide variants and compositions of the present invention are incorporated into long half-life synthetic lipopeptide particles (SLP).
  • the peptide variants and compositions of the invention may incorporate into lipopeptide particles (LP) in vivo upon administration to the individual.
  • the peptides and compositions of the invention can cross the blood-brain barrier (BBB), blood-retinal barrier (BRB) and blood-tumor barrier (BTB).
  • BBB blood-brain barrier
  • BRBB blood-retinal barrier
  • BTB blood-tumor barrier
  • the invention provides for a method for suppressing tumor growth in an individual in need thereof by administering to the individual an amount of a TREM-l inhibitor that is effective for suppressing inflammation and fibrosis.
  • scleroderma is a systemic sclerosis, which is a systemic autoimmune disease or systemic connective tissue disease.
  • SSc is often characterized by deposition of collagen in the skin. In some cases, SSc involves deposition of collagen in organs, such as the kidneys, heart, lungs and/or stomach.
  • scleroderma is a diffuse scleroderma. Diffuse scleroderma typically affects the skin and organs such as the heart, lungs, gastrointestinal tract, and kidneys. Still in other embodiments, scleroderma is a limited scleroderma that affects primarily the skin including, but not limited to, that of the face, neck and distal elbows and knees. Still in other embodiments, scleroderma is a limited scleroderma. In some instances, the limited scleroderma includes clinical conditions that affect the hands, arms, and face.
  • scleroderma is a localized scleroderma.
  • the invention provides for a method of predicting the efficacy of TREM-l targeted therapies in an individual with scleroderma by: (a) obtaining a biological sample from the individual; (b) determining the number of myeloid cells in the biological sample; (c) determining the expression levels of TREM-l in the cells contained within the biological sample.
  • the invention provides for a method of detecting TREM-l expression levels in an individual with scleroderma by: (a) administering to the individual the peptide variants and composition of the present invention having an affinity for TREM-l and an imaging probe in a detectably effective amount; (b) imaging at least a portion of the patient; (c) detecting the labeled probe, wherein the location of the labeled probe corresponds to at least one symptom of the myeloid cell-related condition.
  • the present invention provides the compounds and compositions for TREM-l -targeted treatment of SSc and the methods for predicting the efficacy of these compositions.
  • the invention further provides a method of using these compounds and compositions.
  • the invention provides a method for treating cancer in a patient in need thereof by modulating immune system activity, said method comprising administering to said patient an amount of a TREM-l inhibitor that is effective for inhibiting the TREM-l/DAP- 12 signaling pathway and suppressing tumor growth, or a combination thereof.
  • said method further comprises administering the amount of the TREM-l inhibitor together with a pharmaceutically acceptable excipient, carrier, diluents, or a combination thereof.
  • said method further comprises administering to said patient an anticancer vaccine, an anticancer immunotherapy agent, anti-cancer immunomodulatory agent, an additional anticancer therapeutic, radiation therapy or a combination thereof.
  • said anticancer vaccine is selected from the group consisting of Gardasil, Cervarix, and Sipuleucel-T/Provenge.
  • said anticancer immunotherapy agent is selected from the group consisting of Alemtuzumab, Ipilimumab, Nivolumab, Pembrolizumab, Rituximab, Interferon, Interleukin, and a combination thereof.
  • said anti-cancer immunomodulatory agent is selected from the group consisting of thalidomide, lenolidomide, pomalidomide, and a combination thereof.
  • said additional anti-cancer therapeutic is selected from the group consisting of an alkylating agent, a tubulin inhibitor, a topoisom erase inhibitor, proteasome inhibitor, a CHK1 inhibitor, a CHK2 inhibitor, PARP inhibitor, doxorubicin, epirubicin, vinblastine, etoposide, topotecan, bleomycin, and mytomycin c.
  • said alkylating agent is selected from the group consisting of dacarbazine, Procarbazine, Carmustine, Lomustine, Uramustine, BuSulfan, Streptozocin, Altreamine, Ifosfamine, Chrormethine, Cyclophasphamide, Cyclophosphamide, Chlorambucil, Fluorouracil (5-Fu), Melphalan, Triplatin tetranitrate, Satraplatin, Nedaplatin, Cisplatin, Carboplatin, and Oxaliplatin.
  • said tubulin inhibitor is selected from the group consisting of Taxol, Docetaxel, Vinblastin, Epothilone, Colchicine, Cryptophycin, BMS 347550, Rhizoxin, Ecteinascidin, Dolastin 10, Cryptophycin 52, and IDN- 5109.
  • said topoisomerase inhibitor is a topoisomerase I inhibitor selected from the group consisting of Irinotecan, Topotecan, and Camptothecins (CPT).
  • said topoisomerase inhibitor is a topoisomerase II inhibitor selected from the group consisting of Amsacrine, Etoposide, Teniposide, Epipodophyllotoxins, and ellipticine.
  • said proteasome inhibitor is selected from the group consisting of Velcade (bortezomib), and Kyprolis (carfilzomib).
  • said CHK1 inhibitor is selected from the group consisting of TCS2312, PF-0047736, AZ07762, A-69002, and A-64 1397.
  • said PARP inhibitor is selected from the group consisting of Olaparib, ABT- 888, (veliparib), KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the like.
  • said method further comprises a radiation therapy administered to said patient.
  • said at least one said TREM-l inhibitor comprises a variant TREM-l inhibitory peptide sequence derived from transmembrane domain sequences of human or animal TREM-l and/or its signaling subunit, DAP-12, thereof. In some embodiments, said at least one said TREM-l inhibitor comprises LR12 and/or LP17 peptide variants and the like.
  • the invention provides a method for detecting TREM-1/DAP-12 expression levels in a patient with cancer in need thereof, said method comprising administering to said patient an amount of a TREM-l inhibitor that is conjugated to at least one imaging probe, or a combination thereof.
  • said an imaging probe is selected from the group comprising Gd(III), Mn(II), Mn(III), Cr(II), Cr(III), Cu(II), Fe (III), Pr(III), Nd(III) Sm(III), Tb(III), Yb(III) Dy(III), Ho(III), Eu(II), Eu(III), and Er(III), Tl 201 , K 42 , In 111 , Fe.
  • said TREM-l inhibitor comprises a variant TREM-l inhibitory peptide sequence derived from transmembrane domain sequences of human or animal TREM-l and/or its signaling subunit, DAP-12, thereof.
  • said at least one said TREM-l inhibitor comprises LR12 and/or LP17 peptide variants and the like.
  • the invention provides a method for treating cancer in a patient in need thereof by modulating immune system activity, said method comprising administering to said patient an amount of a TREM-l inhibitor that is effective for inhibiting the TREM-1/DAP-12 signaling pathway and suppressing tumor growth, or a combination thereof.
  • said TREM-l inhibitor comprises a variant TREM-l inhibitory peptide sequence derived from transmembrane domain sequences of human or animal TREM-l and/or its signaling subunit, DAP- 12, thereof.
  • said variant TREM-l inhibitory peptide sequence comprises amino acid sequence Gly-Phe-Leu-Ser-Lys-Ser-Leu-Val-Phe, wherein Gly is glycine, Phe is phenylalanine, Leu is leucine, Ser is serine, Lys is lysine, and Val is valine.
  • said variant TREM-l inhibitory peptide sequence is conjugated to at least one unmodified or modified amphipathic peptide sequence.
  • said unmodified or modified amphipathic peptide sequence is derived from amino acid sequences of apolipoproteins selected from the group consisting of A-I, A-II, A-IV, B, C-I, C-II, C-III, and E, and any combination thereof.
  • said modified amphipathic peptide sequence derived from amino acid sequences of apolipoproteins selected from the group consisting of A-I, A-II, A-IV, B, C-I, C-II, C-III, and E, and any combination thereof contains at least one amino acid residue which is chemically or enzymatically modified.
  • said chemically or enzymatically modified amino acid residue is oxidized, halogenated or nitrated.
  • said oxidized amino acid residue is the methionine residue.
  • said unmodified amphipathic peptide sequence is derived from an apolipoprotein A-I amino acid sequence and comprises amino acid sequence Pro-Tyr-Leu-Asp-Asp-Phe-Gln-Lys-Lys-Trp-Gln-Glu-Glu-Met-Glu-Leu-Tyr-Arg-Gln-Lys-Val- Glu, wherein Pro is proline, Tyr is tyrosine, Leu is leucine, Asp, asparagine, Phe is phenylalanine, Gln is glutamine, Lys is lysine, Trp is tryptophan, Glu is glutamic acid, Met is methionine, Arg is arginine, and Val is valine.
  • said unmodified amphipathic peptide sequence is derived from an apolipoprotein A-I amino acid sequence and comprises amino acid sequence Pro-Leu-Gly-Glu-Glu-Met-Arg-Asp-Arg-Ala-Arg-Ala-His-Val- Asp-Ala-Leu-Arg-Thr-His-Leu-Ala, wherein Pro is proline, Leu is leucine, Gly is glycine, Glu is glutamic acid, Met is methionine, Arg is arginine, Asp, asparagine, Ala is alanine, His is histidine, Val is valine, and Thr is threonine.
  • said modified amphipathic peptide sequence is derived from an apolipoprotein A-I amino acid sequence and comprises amino acid sequence Pro-Tyr-Leu-Asp-Asp-Phe-Gln-Lys-Lys-Trp-Gln-Glu-Glu-Met(0)-Glu- Leu-Tyr-Arg-Gln-Lys-Val-Glu, wherein Pro is proline, Tyr is tyrosine, Leu is leucine, Asp, asparagine, Phe is phenylalanine, Gln is glutamine, Lys is lysine, Trp is tryptophan, Glu is glutamic acid, Met(O) is methionine sulfoxide, Arg is arginine, and Val is valine.
  • said modified amphipathic peptide sequence is derived from an apolipoprotein A-I amino acid sequence and comprises amino acid sequence Pro-Leu-Gly-Glu-Glu-Met(0)-Arg- Asp-Arg-Ala-Arg-Ala-His-Val-Asp-Ala-Leu-Arg-Thr-His-Leu-Ala, wherein Pro is proline, Leu is leucine, Gly is glycine, Glu is glutamic acid, Met is methionine sulfoxide, Arg is arginine, Asp, asparagine, Ala is alanine, His is histidine, Val is valine, and Thr is threonine.
  • said B is conjugated to an additional peptide sequence to enhance the targeting efficacy.
  • said an additional peptide sequence comprises amino acid sequence Arg-Gly-Asp (RGD), wherein Arg is arginine; Gly is glycine; and Asp is asparagine.
  • said A is conjugated to at least one additional therapeutic agent to enhance the therapeutic efficacy.
  • said an additional therapeutic agent is selected from the group of anticancer, antibacterial, antiviral, autoimmune, anti-inflammatory and cardiovascular agents, antioxidants, therapeutic peptides, and any combination thereof.
  • said anticancer therapeutic agent is selected from the group comprising paclitaxel, valrubicin, doxorubicin, taxotere, campotechin, etoposide, and any combination thereof.
  • said A and/or B are conjugated to at least one imaging probe.
  • said an imaging probe is selected from the group comprising Gd(III), Mn(II), Mn(III), Cr(II), Cr(III), Cu(II), Fe (III), Pr(III), Nd(III) Sm(III), Tb(III), Yb(III) Dy(III), Ho(III), Eu(II), Eu(III), and Er(III), Tl 201 , K 42 , In 111 , Fe.
  • the invention provides a method of making a synthetic lipopeptide nanoparticle, said method comprising: a) co-dissolving a predetermined amount of a mixture of neutral and/or charged lipids with: i. a predetermined amount of cholesterol; and ii. a predetermined amount of triglycerides and/or cholesteryl ester; b) drying the mixture of step (a) under nitrogen; c) co-dissolving the dried mixture of step (b) with: i. a predetermined amount of sodium cholate; and ii.
  • lipid is conjugated to at least one imaging probe.
  • said imaging probe is selected from the group comprising Gd(III), Mn(II), Mn(III), Cr(II), Cr(III), Cu(II), Fe (III), Pr(III), Nd(III) Sm(III), Tb(III), Yb(III) Dy(III), Ho(III), Eu(II), Eu(III), and Er(III), Tl 201 , K 42 , In 111 , Fe.
  • said lipid is selected from the group comprising cholesterol, a cholesteryl ester, a phospholipid, a glycolipid, a sphingolipid, a cationic lipid, a diacylglycerol, and a triacylglycerol.
  • said phospholipid is selected from the group comprising phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidyl serine (PS), phosphatidylinositol (PI), phosphatidylglycerol (PG), cardiolipin (CL), sphingomyelin (SM), phosphatidic acid (PA), and any combination thereof.
  • said lipid is polyethylene glycol(PEG)ylated.
  • the invention provides a method of imaging a myeloid cell-related condition, comprising a) providing; i) a patient having at least one symptom of a disease or condition in which myeloid cells are involved or recruited, and ii) a labeled probe, wherein the labeled probe includes the compositions of claims 1, 3, 4, and 21-25 having an affinity for TREM-l and an imaging probe; b) administering said composition to said patient in a detectably effective amount c) imaging at least a portion of the patient; and d) detecting the labeled probe, wherein the location of the labeled probe corresponds to at least one symptom of the myeloid cell-related condition.
  • said myeloid cell-related condition is selected from the group comprising cancer including but not limited to lung, pancreatic, breast, stomach, prostate, colon, brain and skin cancers, cancer cachexia, heart disease, atherosclerosis, peripheral artery disease, restenosis, stroke, bacterial infectious diseases, acquired immune deficiency syndrome (AIDS), allergic diseases, acute radiation syndrome, inflammatory bowel disease, empyema, acute mesenteric ischemia, hemorrhagic shock, multiple sclerosis, autoimmune diseases (e.g., rheumatoid arthritis, Sjogrens, scleroderma, systemic lupus erythematosus, non specific vasculitis, Kawasaki's disease, psoriasis, type I diabetes, pemphigus vulgaris), granulomatous diseases (e.g., tuberculosis, sarcoidosis, lymphomatoid granulomatosis, Wegener's granulomatosus), Gaucher’
  • cancer including
  • the invention provides a method of treating a myeloid cell-related condition, comprising: a) providing; i) a patient having at least one symptom of a disease or condition in which myeloid cells are involved or recruited, and ii) the compositions of claims 1, 3, 4, and 23 capable of inhibiting TREM-l; b) administering said composition to said patient under conditions such that said at least one symptom is reduced.
  • said myeloid cell-related condition is selected from the group comprising cancer including but not limited to lung, pancreatic, breast, stomach, prostate, colon, brain and skin cancers, cancer cachexia, heart disease, atherosclerosis, peripheral artery disease, restenosis, stroke, bacterial infectious diseases, acquired immune deficiency syndrome (AIDS), allergic diseases, acute radiation syndrome, inflammatory bowel disease, empyema, acute mesenteric ischemia, hemorrhagic shock, multiple sclerosis, autoimmune diseases (e.g., rheumatoid arthritis, Sjogrens, scleroderma, systemic lupus erythematosus, non-specific vasculitis, Kawasaki's disease, psoriasis, type I diabetes, pemphigus vulgaris), granulomatous diseases (e.g., tuberculosis, sarcoidosis, lymphomatoid granulomatosis, Wegener's granulomatosus), Gaucher
  • the invention provides a method of imaging a T cell-related condition, comprising a) providing; i) a patient having at least one symptom of a disease or condition in which T cells are involved or recruited, and ii) a labeled probe, wherein the labeled probe includes the compositions of claims 1, 5, 6, and 21-25 having an affinity for TCR and an imaging probe; b) administering said composition to said patient in a detectably effective amount c) imaging at least a portion of the patient; and d) detecting the labeled probe, wherein the location of the labeled probe corresponds to at least one symptom of the T cell-related condition.
  • said T cell-related condition is selected from the group including but not limited to include, but are not limited to, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, scleroderma, type I diabetes, gastroenterological conditions e.g. inflammatory bowel disease, Crohn’s disease, celiac disease, Guillain-Barre syndrome, Hashimoto's disease, pernicious anaemia, primary biliary cirrhosis, chronic active hepatitis; skin problems e.g. atopic dermatitis, psoriasis, pemphigus vulgaris; cardiovascular problems e.g.
  • autoimmune pericarditis e.g. delayed type hypersensitivity, contact dermatitis, AIDS virus, herpes simplex/zoster, respiratory conditions e.g. allergic alveolitis, inflammatory conditions e.g. myositis, ankylosing spondylitis, tissue/organ rejection, and other diseases and conditions where T cells are involved or recruited.
  • allergic diathesis e.g. delayed type hypersensitivity
  • contact dermatitis e.g. delayed type hypersensitivity
  • contact dermatitis e.g. delayed type hypersensitivity
  • contact dermatitis e.g. delayed type hypersensitivity
  • contact dermatitis e.g. delayed type hypersensitivity
  • contact dermatitis e.g. delayed type hypersensitivity
  • contact dermatitis e.g. delayed type hypersensitivity
  • contact dermatitis e.g. delayed type hypersensitivity
  • contact dermatitis e.g. delayed type hypersensitivity
  • contact dermatitis e.g. delayed type hypersensitivity
  • the invention provides a method of treating a T cell-related condition, comprising: a) providing; i) a patient having at least one symptom of a disease or condition in which T cells are involved or recruited, and ii) the compositions of claims 1, 5, 6, and 23 capable of inhibiting TCR; b) administering said composition to said patient under conditions such that said at least one symptom is reduced.
  • said T cell- related condition is selected from the group including but not limited to include, but are not limited to, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, scleroderma, type I diabetes, gastroenterological conditions e.g.
  • inflammatory bowel disease Crohn’s disease, celiac disease, Guillain-Barre syndrome, Hashimoto's disease, pernicious anaemia, primary biliary cirrhosis, chronic active hepatitis; skin problems e.g. atopic dermatitis, psoriasis, pemphigus vulgaris; cardiovascular problems e.g. autoimmune pericarditis, allergic diathesis e.g. delayed type hypersensitivity, contact dermatitis, AIDS virus, herpes simplex/zoster, respiratory conditions e.g. allergic alveolitis, inflammatory conditions e.g. myositis, ankylosing spondylitis, tissue/organ rejection, and other diseases and conditions where T cells are involved or recruited.
  • skin problems e.g. atopic dermatitis, psoriasis, pemphigus vulgaris
  • cardiovascular problems e.g. autoimmune pericarditis, allergic diathesis e.g. delayed type
  • FIG. 1 presents an exemplary schematic representation of one embodiment of a trifunctional peptide of the present invention comprising amino acid domains A and B where amino acid domain A represents a therapeutic peptide sequence with or without an attached drug compound and/or imaging probe that functions to treat, prevent and/or detect a disease or condition, whereas amino acid domain B represents an amphipathic alpha helical peptide sequence, with or without an additional targeting peptide sequence, and functions to 1) assist in the self-assembly of synthetic lipoprotein/lipopeptide nanoparticles (SLP) upon interaction with lipids or lipid mixtures in vitro , for use in transporting these trifunctional peptides as lipoprotein nanoparticles to sites of interest in vitro or in vivo and/or 2) form long half-life lipopeptide/lipoprotein particles upon interaction with endogenous lipoproteins for transporting these trifunctional peptides to the sites of interest.
  • Endogenous lipoproteins may be lipoproteins added to or found in cell cultures,
  • FIG. 2 presents schematic representations of embodiments of a TREM-l -related trifunctional peptide (TREM-l /TRIOPEP).
  • GE31 GFL SK SL VFP YLDDF QKKW QEEM(0)EL YRQK VE, M(O), methionine sulfoxide
  • GE31 comprises amino acid domain A and B
  • domain A represents a 9 amino acids-long human TREM-l inhibitory therapeutic SCHOOL peptide sequence and functions to treat and/or prevent a TREM-l -related disease or condition
  • domain B represents a 22 amino acids-long human apolipoprotein A-I helix 4 peptide sequence with a sulfoxidized methionine residue and functions to assist in the self-assembly of synthetic lipopeptide particles (SLP) in vitro for targeting the particles to myeloid cells (e.g. macrophages).
  • SLP synthetic lipopeptide particles
  • FIG. 3 presents a schematic representation of one embodiment of a TREM-l -related trifunctional peptide (TREM-l /TRIOPEP) of the present invention comprising amino acid domains A and B.
  • TREM-l /TRIOPEP TREM-l -related trifunctional peptide
  • sub 50 nm- sized SLP particles of discoidal (TREM-l/TRIOPEP-dSLP) or spherical (TREM-l /TRIOPEP- sSLP) morphology are self-assembled upon binding of the trifunctional peptide to lipids.
  • apo apolipoprotein
  • SCHOOL signaling chain homooligomerization
  • TREM-l triggering receptor expressed on myeloid cells-l.
  • FIG. 4A illustrates a hypothesized molecular mechanism of action of one embodiment of a trifunctional peptide (TRIOPEP) of the present invention comprising amino acid domains A and B where domain A represents a 9 amino acids-long TREM-l inhibitory therapeutic peptide sequence and functions to treat and/or prevent a TREM-l -related disease or condition (shown for atherosclerosis), whereas domain B represents a 22 amino acids-long apolipoprotein A-I helix 4 or 6 peptide sequence with a sulfoxidized methionine residue and functions to assist in the self- assembly of synthetic lipopeptide particles (SLP) and to target the particles to TREM-l - expressing macrophages as applied to the treatment and/or prevention of atherosclerosis.
  • SLP synthetic lipopeptide particles
  • FIG. 4B illustrates a hypothesized molecular mechanism of action of one embodiment of a trifunctional peptide (TRIOPEP) of the present invention comprising amino acid domains A and B where domain A is a 9 amino acids-long TREM-l inhibitory therapeutic peptide sequence and functions to treat and/or prevent a TREM-l -related disease or condition (shown for cancer), whereas domain B is a 22 amino acids-long apolipoprotein A-I helix 4 or 6 peptide sequence with a sulfoxidized methionine residue and functions to assist in the self-assembly of synthetic lipopeptide particles (SLP) and to target the particles to TREM-l -expressing macrophages as applied to the treatment and/or prevention of cancer.
  • SLP synthetic lipopeptide particles
  • FIG. 4C shows a symbol key used in FIGS. 4A-B.
  • FIG. 5 illustrates one embodiment of a specific disruption of intramembrane interactions between TREM-l and DAP-12 by the trifunctional peptide of the present invention comprising two amino acid domains A and B where domain A is a 9 amino acids-long TREM-l inhibitory therapeutic peptide sequence, whereas domain B is a 22 amino acids-long apolipoprotein A-I helix 4 or 6 peptide sequence with a sulfoxidized methionine residue. While not being bound to any particular theory, it is believed that this disruption results in“pre-dissociation” of a receptor complex and upon ligand stimulation, leads to inhibition of TREM-l and silencing the TREM-l signaling pathway.
  • FIG. 6A-C shows images depicting colocalization of the sulfoxidized methionine residue- containing TREM-l -related trifunctional peptide (TREM-l /TRIOPEP) GE31 with TREM-l in the cell membrane (FIG. 6A), TREM-l immunohistochemstry staining (FIG. 6B) and a merged image (FIG. 6C).
  • FIG. 7A-B presents the exemplary data showing the endocytosis of synthetic lipopeptide particles (SLP) of discoidal (dSLP) and spherical (sSLP) morphology that contain an equimolar mixture of the TREM-l -related trifunctional peptides (TREM-l /TRIOPEP) GA 31 and GE 31 (TREM- 1 /TRIOPEP-d SLP and TREM-l/TRIOPEP-sSLP, respectively).
  • SLP synthetic lipopeptide particles
  • dSLP discoidal
  • sSLP spherical
  • FIG. 8 presents the exemplary data showing suppression of tumor necrosis factor-alpha (TNF- alpha), interleukin (IL)-6 and IL-lbeta production by lipopolysaccharide (LPS)-stimulated macrophages incubated for 24 hour (hr) at 37°C with an equimolar mixture of the sulfoxidized methionine residue-containing TREM-l -related trifunctional peptides (TREM-l/TRIOPEP) GA 31 and GE 31 in free form or incorporated into synthetic lipopeptide particles (SLP) particles of discoidal (TREM- l/TRIOPEP-dSLP) and spherical (TREM-l/TRIOPEP-sSLP) morphology.
  • TNF- alpha tumor necrosis factor-alpha
  • IL-6 interleukin-6
  • LPS lipopolysaccharide
  • FIG. 9A-C presents the exemplary data showing that scavenger receptors SR-A and SR-B1 mediate the macrophage endocytosis of GF9-sSLP (GF9-HDL) and GA/E31-HDL (TREM- l/TRIOPEP-sSLP).
  • FIG. 9A Schematic representation of TREM-l signaling and the SCHOOL mechanism of TREM-l blockade.
  • FIG. 9A1 left panel
  • Activation of the TREM-1/DAP12 receptor complex expressed on macrophages leads to phosphorylation of the DAP 12 cytoplasmic signaling domain and subsequent downstream inflammatory cytokine response (left panel).
  • SR- mediated endocytosis of sSLP -bound GF9, GA31 and GE31 peptide inhibitors by macrophages results in the release of GF9 or GA31 and GE31 into the cytoplasm, which self-penetrate into the cell membrane and block intramembrane interactions between TREM-l and DAP 12, thereby preventing DAP12 phosphorylation and downstream signaling cascade (FIG. 9A1, right panel).
  • FIG. 9A2 left panel
  • Activation of the TREM-1/DAP12 receptor complex expressed on Kupffer cells leads to phosphorylation of the DAP12 cytoplasmic signaling domain, subsequent SYK recruitment, and the downstream inflammatory cytokine response.
  • FIG. 9A2 right panel SR-mediated endocytosis of HDL-bound GF9 peptide inhibitors by Kupffer cells results in the release of GF9 (GA31 or GE31) into the cytoplasm; GF9 self-penetrates the cell membrane and blocks intramembrane interactions between TREM-l and DAP 12, thereby preventing DAP 12 phosphorylation and the downstream signaling cascade.
  • FIG. 9B-9C Macrophage endocytosis of GF9-sSLP (GF9-HDL) and GA/E31-HDL (TREM- l/TRIOPEP-sSLP) in vitro is SR-mediated in a time-dependent manner and is largely driven by SR-A (FIG. 9B, FIG.
  • J774 macrophages were cultured at 37°C overnight with medium. Prior to uptake of GF9-HDL and GA/E3 l-HDL, cells were treated for 1 hour at 37°C with 40 mM cytochalasin D and either (FIG. 9B) 400 pg/mL fucoidan or (FIG. 9C) 10 pM BLT-l, as indicated. Cells were then incubated for either 4 hours or 22 hours with medium containing 2 pM rhodamine B (rho B)-labeled GF9-sSLP (gray bars) or TREM-l/TRIOPEP-sSLP (black bars), respectively.
  • rho B rhodamine B
  • FIG. 10 presents the exemplary data showing suppression of tumor necrosis factor-alpha (TNF- alpha), interleukin (IL)-6 and IL-lbeta production in mice at 90 min post lipopolysaccharide (LPS) challenge treated 1 h before LPS challenge with phosphate-buffer saline (PBS), dexamethasone (DEX), control peptide and with an equimolar mixture of the sulfoxidized methionine residue-containing TREM-l -related trifunctional peptides (TREM-l/TRIOPEP) GA 31 and GE 31 in free form or incorporated into synthetic lipopeptide particles (SLP) particles of discoidal (TREM- l/TRIOPEP-dSLP) and spherical (TREM-l/TRIOPEP-sSLP) morphology.
  • TNF- alpha tumor necrosis factor-alpha
  • IL-6 interleukin-6
  • IL-lbeta production at 90 min post lipopol
  • Control peptide represents an equimolar mixture of two peptides, each of them comprising two amino acid domains A and B where domain A represents a non-functional 9 amino acids-long sequence of the TREM-l inhibitory therapeutic peptide sequence wherein, Lys is substituted with Alas, whereas domain B is a sulfoxidized methionine residue-containing 22 amino acids- long apolipoprotein A-I helix 4 or 6 peptide sequence, respectively.
  • FIG. 11A-B presents the exemplary data showing inhibition of tumor growth in the human non small cell lung cancer H292 (FIG. 11 A) and A549 (FIG. 11B) xenograft mice treated with an equimolar mixture of the sulfoxidized methionine residue-containing TREM-l -related trifunctional peptides (TREM-l /TRIOPEP) GA 31 and GE 31 in free form.
  • PTX paclitaxel.
  • FIG. 12A-B presents the exemplary data showing inhibition of tumor growth in the human non small cell lung cancer H292 (FIG. 12 A) and A549 (FIG. 12B) xenograft mice treated with an equimolar mixture of the sulfoxidized methionine residue-containing TREM-l -related trifunctional peptides (TREM-l /TRIOPEP) GA 31 and GE 31 incorporated into synthetic lipopeptide particles (SLP) particles of discoidal (TREM-l/TRIOPEP-dSLP) and spherical (TREM-l/TRIOPEP-sSLP) morphology.
  • SLP synthetic lipopeptide particles
  • PTX paclitaxel. ****, p ⁇ 0.0001 as compared with vehicle-treated animals.
  • FIG. 13 presents the exemplary data showing average tumor weights in the A549 xenograft mice treated with an equimolar mixture of the sulfoxidized methionine residue-containing TREM-l - related trifunctional peptides (TREM-l /TRIOPEP) GA 31 and GE 31 in free form or
  • SLP synthetic lipopeptide particles
  • TX paclitaxel
  • FIG. 14A-C presents the exemplary data showing inhibition of tumor growth (FIG. 14A) and TREM-l blockade-mediated suppression of intratumoral macrophage infiltration (FIG. 14B,
  • FIG. 14C in the human pancreatic cancer BxPC-3 xenograft mice treated with an equimolar mixture of the sulfoxidized methionine residue-containing TREM-l -related trifunctional peptides (TREM-l /TRIOPEP) GA 31 and GE 31 in free form or incorporated into synthetic lipopeptide particles (SLP) particles of discoidal (TREM-l/TRIOPEP-dSLP) and spherical (TREM- l/TRIOPEP-sSLP) morphology.
  • SLP synthetic lipopeptide particles
  • TREM-l/TRIOPEP-dSLP spherical
  • TREM-l/TRIOPEP-sSLP synthetic lipopeptide particles
  • FIG. 15A-B presents the exemplary data showing improved survival of lipopolysaccharide (LPS)-challenged mice treated with an equimolar mixture of the sulfoxidized methionine residue-containing TREM-l -related trifunctional peptides (TREM-l/TRIOPEP) GA 31 and GE 31 in free form (FIG. 15 A) or incorporated into synthetic lipopeptide particles (SLP) particles of discoidal (TREM- l/TRIOPEP-dSLP) and spherical (TREM-l/TRIOPEP-sSLP) morphology.
  • LPS lipopolysaccharide
  • TREM-l/TRIOPEP sulfoxidized methionine residue-containing TREM-l -related trifunctional peptides
  • FIG. 16 presents exemplary data showing average weights of healthy C57BL/6 mice treated with increasing concentrations of an equimolar mixture of the sulfoxidized methionine residue- containing TREM-l -related trifunctional peptides (TREM-l/TRIOPEP) GA 31 and GE 31 in free form.
  • TREM-l/TRIOPEP sulfoxidized methionine residue- containing TREM-l -related trifunctional peptides
  • FIG. 17A-B presents the exemplary data showing average clinical arthritis score (FIG. 17A) and mean body weight (BW) changes (FIG. 17B) calculated as a percentage of the difference between beginning (day 24) and final (day 38) BWs of the collagen-induced arthritis (CIA) mice treated with an equimolar mixture of the sulfoxidized methionine residue-containing TREM-l- related trifunctional peptides (TREM-l/TRIOPEP) GA 31 and GE 31 incorporated into synthetic lipopeptide particles (SLP) particles of discoidal (TREM-l/TRIOPEP-dSLP) and spherical (TREM-l/TRIOPEP-sSLP) morphology.
  • DEX dexamethasone. *,p ⁇ 0.05, **, p ⁇ 0.01; ***, > ⁇ 0.001 as compared with vehicle-treated or naive animals.
  • FIG. 18A-D presents the exemplary data showing reduction of pathological retinal
  • neovascularization area (FIG. 18A), avascular area (FIG. 18B) and retinal TREM-l (FIG. 18C) and M-CSF/CSF-l (FIG. 18D) expression in the retina of the mice with oxygen-induced retinopathy (OIR) treated with an equimolar mixture of the sulfoxidized methionine residue- containing TREM-l -related trifunctional peptides (TREM-l/TRIOPEP) GA 31 and GE 31 incorporated into synthetic lipopeptide particles (TREM-l/TRIOPEP-SLP) particles of spherical morphology (TREM- l/TRIOPEP-s SLP).
  • OIR oxygen-induced retinopathy
  • FIG. 19 presents exemplary data showing penetration of the blood-brain barrier (BBB) and blood-retinal barrier (BRB) by systemically (intraperitoneally) administered rhodamine B- labeled spherical self-assembled particles (sSLP) that contain Gd-containing contrast agent (Gd- sSLP) for magnetic resonance imaging (MRI), TREM-l inhibitory peptide GF9 (GF9-sSLP) or an equimolar mixture of the sulfoxidized methionine residue-containing TREM-l -related trifunctional peptides GA 31 and GE 31 (TREM-l /TRIOPEP-sSLP) .
  • BBB blood-brain barrier
  • BBB blood-retinal barrier
  • sSLP rhodamine B- labeled spherical self-assembled particles
  • Gd- sSLP Gd-containing contrast agent
  • MRI magnetic resonance imaging
  • TREM-l inhibitory peptide GF9
  • FIG. 20A-B presents exemplary data showing TREM-l /TRIOPEP-sSLP suppresses the expression of fibrinogenesis marker molecules, FIG. 20A Pro-Collagen la and FIG. 20B a- Smooth Muscle Actin, at the RNA level, as measured in whole-liver lysates of mice with (alcohol-fed) and without (pair-fed) alcoholic liver disease (ALD).
  • * indicates significance level compared to the non-treated pair-fed (PF) group; # indicates significance level compared to the non-treated alcohol-fed group o indicates significance level compared to the vehicle-treated alcohol-fed group.
  • the significant levels are as follows: *, 0.05 > P > 0.01; **, 0.01 > P > 0.001; ***, 0.001 > P > 0.0001; ****, p ⁇ 0.0001.
  • FIG. 21A-D presents exemplary data showing that TREM-l /TRIOPEP-sSLP suppresses the production of alanine aminotransferase (ALT) in mice with alcoholic liver disease (ALD), as measured in serum of mice with (alcohol-fed) and without (pair-fed) ALD, in addition to improving indicators of liver disease and inflammation.
  • * indicates significance level compared to the alcohol-fed group treated with vehicle - synthetic lipopeptide particles of spherical morphology that contained an equimolar mixture of PE22 and PA22 (sSLP) but no TREM-l inhibitory peptide GF9.
  • # indicates significance level compared to the non-treated alcohol-fed group.
  • FIG. 21 A Serum ALT levels were measured using a kinetic method. Exemplary data showing TREM-l /TRIOPEP- sSLP suppresses alanine aminotransferase in serum of alcohol fed mice over TREM-l peptide alone.
  • FIG. 21B-D Liver sections were stained with (B,C) Oil Red O and (FIG.
  • FIG. 22 presents an exemplary schematic representation of one embodiment of a TREM-l - related trifunctional peptide (TREM-l/TRIOPEP) G-HV21 of the present invention comprising amino acid domains A and B where domain A represents a 9 amino acids-long human TREM-l inhibitory therapeutic peptide sequence GF9 and functions to treat and/or prevent a TREM-l - related disease or condition, whereas domain B represents a 12 amino acids-long amino acid sequence GV12 that contains a sulfoxidized methionine residue and is derived from human apolipoprotein A-I amino acid sequence.
  • domain A represents a 9 amino acids-long human TREM-l inhibitory therapeutic peptide sequence GF9 and functions to treat and/or prevent a TREM-l - related disease or condition
  • domain B represents a 12 amino acids-long amino acid sequence GV12 that contains a sulfoxidized methionine residue and is derived from human apolipoprotein A-I amino acid sequence.
  • a resulting amphipathic alpha helical peptide G-HV21 upon interaction with native lipoproteins, forms naturally long half-life lipopeptide/lipoprotein particles and targets these particles to myeloid cells (e.g. macrophages).
  • myeloid cells e.g. macrophages.
  • TREM-l triggering receptor expressed on myeloid cells- 1
  • TRIOPEP trifunctional peptide.
  • FIG. 23 presents an exemplary schematic representation of one embodiment of a TREM-l - related trifunctional peptide (TREM-l/TRIOPEP) G-KV21 of the present invention comprising amino acid domains A and B where domain A represents a 9 amino acids-long human TREM-l inhibitory therapeutic peptide sequence GF9 and functions to treat and/or prevent a TREM-l - related disease or condition, whereas domain B represents a 12 amino acids-long amino acid sequence WV12 that contains a sulfoxidized methionine residue and is derived from human apolipoprotein A-I amino acid sequence.
  • TREM-l - related trifunctional peptide TREM-l/TRIOPEP
  • a resulting amphipathic alpha helical peptide G-KV21 upon interaction with native lipoproteins, forms naturally long half-life lipopeptide/lipoprotein particles and targets these particles to myeloid cells (e.g. macrophages).
  • myeloid cells e.g. macrophages.
  • TREM-l triggering receptor expressed on myeloid cells- 1
  • TRIOPEP trifunctional peptide.
  • FIG. 24 presents an exemplary schematic representation of one embodiment of a TREM-l - related control peptide G-TE21 of the present invention comprising amino acid domains A and B where domain A represents a 9 amino acids-long human TREM-l inhibitory therapeutic peptide sequence GF9, whereas domain B represents a 12 amino acids-long amino acid sequence TE12 that contains a sulfoxidized methionine residue and is derived from bovine serum albumin amino acid sequence. While not being bound to any particular theory, it is believed that a resulting non- amphipathic peptide G-TE21 does not interact with native lipoproteins and therefore does not form naturally long half-life lipopeptide/lipoprotein particles.
  • TREM-l triggering receptor expressed on myeloid cells-l.
  • FIG. 25 presents an exemplary schematic representation of one embodiment of a TCR-related trifunctional peptide (TCR/TRIOPEP) M-VE32 of the present invention comprising amino acid domains A and B where domain A represents a 10 amino acids-long human TCR inhibitory therapeutic peptide sequence MF10 and functions to treat and/or prevent a TCR-related disease or condition, whereas domain B represents a 22 amino acids-long amino acid sequence PE22 that is derived from human apolipoprotein A-I amino acid sequence. While not being bound to any particular theory, it is believed that a resulting amphipathic alpha helical peptide M-VE32 upon interaction with native lipoproteins, forms naturally long half-life lipopeptide/lipoprotein particles.
  • TCR T cell receptor
  • TRIOPEP trifunctional peptide.
  • FIG. 26 presents a schematic representation of one embodiment of a TCR-related control peptide M-TK32 of the present invention comprising amino acid domains A and B where domain A represents a 10 amino acids-long human TCR inhibitory therapeutic peptide sequence MF10, whereas domain B represents a random 22 amino acids-long amino acid sequence LK22. While not being bound to any particular theory, it is believed that a resulting non-amphipathic peptide M-TK32 does not interact with native lipoproteins and therefore does not form naturally long half-life lipopeptide/lipoprotein particles.
  • TCR T cell receptor.
  • FIG. 27 presents an exemplary schematic representation and the exemplary data showing that ultracentrifugation of whole mouse serum with added rho B-labeled TREM-l -related trifunctional peptides (TREM-l /TRIOPEP) G-HV21 and G-KV21 results in floatation of these peptides with mouse lipoproteins.
  • rho B-labeled TREM inhibitory peptide GF9 or rho B-labeled TREM-l -related control peptide G-TE21 sedimentate with serum proteins upon ultracentrifugation.
  • TREM-l/TRIOPEP G-HV21 and G-KV21 sedimentate with serum proteins upon ultracentrifugation. While not being bound to any particular theory, it is believed that TREM-l/TRIOPEP G-HV21 and G-KV21 interact with native lipoproteins of a whole mouse serum and/or their lipid components and form lipopeptide/lipoprotein particles that mimic serum lipoproteins and float under the same ultracentrifugation conditions.
  • TREM-l triggering receptor expressed on myeloid cells-l
  • rho B rhodamine B.
  • FIG. 28 presents exemplary data showing the endocytosis of rho B-labeled GF9, G-TE21, G- HV-21 and G-KV21 by macrophages in the absence (white bars) or presence (black bars) of HDL.
  • GF9 and TREM-l -related control peptide G-TE21 the in vitro macrophage uptake of TREM-l/TRIOPEP G-HV21 and G-KV21 significantly increases in the presence of HDL.
  • *** p ⁇ 0.001 Presence vs. absence of HDL).
  • HDL high density lipoproteins
  • rho B rhodamine B
  • n.s. not significant.
  • FIG. 29A-C shows exemplary images depicting colocalization of the sulfoxidized methionine residue-containing TREM-l/TRIOPEP G-KV21 (pre-incubated with HDL) with TREM-l in the J774 cell membrane FIG. 29A.
  • FIG. 29B TREM-l immunostaining.
  • FIG. 29C merged image.
  • FIG. 30A illustrates a hypothesized molecular mechanism of action of TREM-l -related trifunctional peptides (TREM-l/TRIOPEP) of the present invention (shown for atherosclerosis). While not being bound to any particular theory, it is believed that upon interaction with native lipoproteins including HDL, the modified methionine residue in the TREM-l/TRIOPEP domain B mediates the recognition of the formed lipopeptide/lipoprotein particles by macrophage scavenger receptors and results in an irreversible binding to and consequent uptake by macrophages of such particles. It is further believed that accumulation of these particles in intraplaque macrophages is accompanied by accumulation of TREM-l/TRIOPEP released within these cells. In contrast, native HDL particles are not recognized by intraplaque macrophages and return to the circulation.
  • FIG. 30B Abbreviations: TREM-l, triggering receptor expressed on myeloid cells- 1; HDL, high-density lipoproteins.
  • FIG. 31 A illustrates a hypothesized molecular mechanism of action of TREM-l -related trifunctional peptides (TREM-l /TRIOPEP) of the present invention (shown for cancer). While not being bound to any particular theory, it is believed that upon intreaction with native lipoproteins including HDL, the modified methionine residue in the TREM-l /TRIOPEP domain B mediates the recognition of the formed lipopeptide/lipoprotein particles by macrophage scavenger receptors and results in an irreversible binding to and consequent uptake by macrophages of such particles. It is further believed that accumulation of these particles in tumor-associated macrophages is accompanied by accumulation of TREM-l /TRIOPEP released within these cells. In contrast, native HDL particles are not recognized by intraplaque macrophages and return to the circulation.
  • FIG. 31B Abbreviations: TREM-l, triggering receptor expressed on myeloid cells- 1; HDL, high-density lipoproteins.
  • FIG. 32 illustrates one embodiment of a specific disruption of intramembrane interactions between TREM-l and DAP -12 by the TREM-l -related trifunctional peptide (TREM-l /TRIOPEP) of the present invention delivered to and released within TREM-l -expressing cells by the lipopeptide/lipoprotein particles formed upon interaction of TREM-l /TRIOPEP with native lipoproteins. While not being bound to any particular theory, it is believed that this disruption results in“pre-dissociation” of a receptor complex and upon ligand stimulation, leads to inhibition of TREM-l and silencing the TREM-l signaling pathway.
  • TREM-l /TRIOPEP TREM-l -related trifunctional peptide
  • TREM-l triggering receptor expressed on myeloid cells-l
  • DAP-12 DNAX-activation protein 12
  • M- CSF/CSF-l macrophage colony stimulating factor-l
  • MCP-1/CCL2 monocyte chemoattractant protein-l
  • IL interleukin
  • TNF tumor necrosis factor
  • FIG. 33 presents exemplary data showing cytokine production by LPS-stimulated macrophages incubated for 24 h at 37°C with GF9, G-TE21, G-HV21 and G-KV21 in the presence of HDL.
  • GF9 and TREM-l -related control peptide G-TE21 TREM-l /TRIOPEP G-HV21 and G-KV21 significantly inhibit the cytokine release in the presence of HDL.
  • G-HV21 does not affect the cytokine production.
  • TREM-l triggering receptor expressed on myeloid cells-l
  • LPS LPS
  • IL interleukin
  • TNF tumor necrosis factor
  • HDL high density lipoproteins.
  • FIG. 34A-C presents exemplary LPS-challenged J774 macrophages: Cytokine release data showing that scavenger receptors SR-A and SR-B1 mediate the macrophage endocytosis of TREM- 1 /TRIOPEP G-HV21 and G-KV21 in the presence of HDL.
  • FIG. 34A Schematic representation of TREM-l signaling and the SCHOOL mechanism of TREM-l blockade.
  • TREM-1/DAP12 receptor complex Activation of the TREM-1/DAP12 receptor complex expressed on macrophages leads to phosphorylation of the DAP12 cytoplasmic signaling domain and subsequent downstream inflammatory cytokine response (left panel).
  • SR-mediated macrophage endocytosis of the lipopeptide/lipoprotein particles formed upon interaction of TREM-l /TRIOPEP with native lipoproteins results in the release of TREM-l /TRIOPEP into the cytoplasm. Then, the released TREM-l /TRIOPEP self-penetrate into the cell membrane and block intramembrane interactions between TREM-l and DAP 12, thereby preventing DAP 12 phosphorylation and downstream signaling cascade (FIG. 34A, right panel).
  • Macrophage endocytosis of G-HV21 and G-KV21 in the presence of HDL in vitro is SR-mediated in a time- dependent manner and is largely driven by SR-A (B, C).
  • J774 macrophages were cultured at 37°C overnight with medium.
  • cells were treated for 1 h at 37°C with 40 mM cytochalasin D, 400 pg/mL fucoidan (FIG. 34B) or 10 pM BLT-l (FIG. 34C) as indicated.
  • TREM-l triggering receptor expressed on myeloid cells-l
  • DAP-12 DNAX-activation protein 12
  • M-CSF/CSF-l macrophage colony stimulating factor
  • MCP-1/CCL2 monocyte
  • FIG. 35 presents exemplary data showing serum cytokine production at 90 min post LPS challenge in mice treated at 1 h before LPS challenge with PBS, DEX, GF9, TREM-l -related control peptide G-TE21 or with TREM-l -related trifunctional peptides G-HV21 and G-KV21.
  • G-HV21 and G-KV21 significantly inhibit the LPS-induced cytokine release. 0.001 as compared with PBS-treated animals.
  • TREM-l triggering receptor expressed on myeloid cells-l
  • LPS LPS
  • IL interleukin
  • TNF tumor necrosis factor
  • DEX dexamethasone
  • PBS phosphate-buffer saline
  • FIG. 36A-B presents the exemplary data showing survival of LPS-challenged mice treated with PBS (vehicle), TREM-l -related control peptide G-TE21, TREM-l -related trifunctional peptides G-HV21 and G-KV21 (FIG. 36A) or with TREM-l inhibitory peptide GF9 at different doses (FIG. 36B).
  • PBS vehicle
  • TREM-l -related control peptide G-TE21 TREM-l -related control peptides G-HV21 and G-KV21
  • TREM-l inhibitory peptide GF9 TREM-l inhibitory peptide GF9 at different doses
  • FIG. 36A presents the exemplary data showing survival of LPS-challenged mice treated with PBS (vehicle), TREM-l -related control peptide G-TE21, TREM-l -related trifunctional peptides G-HV21 and G-KV21
  • TREM-l triggering receptor expressed on myeloid cells-l
  • LPS lipopolysaccharide
  • PBS phosphate-buffer saline
  • FIG. 37A-B presents the exemplary data showing tumor growth in the human non-small cell lung cancer H292 mouse xenograft (FIG. 37 A) and A549 mouse xenograft (FIG. 37B) xenograft mice treated with PBS (vehicle), PTX, TREM-l -related control peptide G-TE21 or with TREM- 1 -related trifunctional peptides G-HV21 and G-KV21. In contrast to G-TE21, G-HV21 and G- KV21 significantly inhibit the tumor growth. ****, > ⁇ 0.0001 as compared with vehicle-treated animals. Abbreviations: PTX, paclitaxel; PBS, phosphate-buffer saline.
  • FIG. 38 presents exemplary A549 mouse xenograft data showing average tumor weights in the A549 xenograft mice treated with PBS (vehicle), PTX, TREM-l -related control peptide G-TE21 or with TREM-l -related trifunctional peptides G-HV21 and G-KV21.
  • PBS vehicle
  • PTX TREM-l -related control peptide
  • TREM-l -related trifunctional peptides G-HV21 and G-KV21 In contrast to G-TE21, G- HV21 and G-KV21 significantly decrease the tumor weight. **, > ⁇ 0.01 as compared with vehicle-treated animals.
  • TREM-l triggering receptor expressed on myeloid cells- 1
  • PTX paclitaxel
  • PBS phosphate-buffer saline
  • n.s. not significant.
  • FIG. 39A-B presents exemplary data showing tumor growth (A) and, infiltration of macrophages into the tumor as evaluated by F4/80 staining (B) in the human pancreatic cancer BxPC-3 xenograft mice treated with PBS (vehicle), TREM-l -related control peptide G-TE21 or with TREM-l -related trifunctional peptides G-HV21 and G-KV21.
  • G-TE21 G-HV21 and G-KV21 in a BxPC-3 mouse xenograft significantly inhibits the tumor growth (FIG. 389) and reduce macrophage infiltration into the tumor (FIG. 39B).
  • TREM-l triggering receptor expressed on myeloid cells-l;
  • PBS phosphate-buffer saline
  • FIG. 40A-B presents exemplary data showing PANC-l mouse xenograft tumor growth (FIG.
  • FIG. 40A A) and survival (FIG. 40B) in the human pancreatic cancer PANC-l xenograft mice treated with PBS (vehicle) and TREM-l -related trifunctional peptide G-KV21 with or without chemotherapy treatment (GEM+ABX).
  • G-KV21 sensitizes the tumor to chemotherapy (FIG. 40A) and significantly improves survival (FIG. 40B).
  • the median survival times (FIG. 40B) are indicated in parentheses.
  • TREM-l triggering receptor expressed on myeloid cells-l
  • PBS phosphate-buffer saline
  • GEM gemcitabine
  • ABX Abraxane (nanoparticle albumin-bound paclitaxel).
  • FIG. 41 presents the exemplary data showing average weights of Healthy C57BL/6 mice treated with TREM-l -related control peptide G-TE21 or with TREM-l -related trifunctional peptides G- HV21 and G-KV21. No toxicity was observed for all three peptides. Abbreviations: TREM-l, triggering receptor expressed on myeloid cells-l.
  • FIG. 42A-B presents exemplary data showing average clinical arthritis score (Collagen-induced arthritis: Score FIG. 42A) and Collagen-induced arthritis: Body weight change mean BW changes (FIG. 42B) calculated as a percentage of the difference between beginning (day 24) and final (day 38) BWs of the CIA mice treated with PBS (vehicle), DEX, TREM-l -related control peptide G-TE21, TCR-related control peptide M-TK32, TCR-related trifunctional peptide M- VE32 or with TREM-l -related trifunctional peptides G-HV21 and G-KV21.
  • G-HV21, G-KV21 and M-VE32 all ameliorate the disease (FIG. 42A) and are well -tolerated by arthritic mice (FIG. 42B).
  • TREM-l triggering receptor expressed on myeloid cells-l
  • CIA collagen-induced arthritis
  • PBS phosphate-buffer saline
  • DEX dexamethasone
  • TCR T cell receptor
  • BW body weight.
  • FIG. 43A-D Oxygen-induced retinopathy presents exemplary data showing pathological RNV (FIG. 43 A) and avascular (FIG. 43B) areas as well as expression of TREM-l (FIG. 43C) and M- CSF (FIG. 43D) in the retina of the mice with OIR treated with PBS (vehicle), TREM-l -related control peptide G-TE21 or TREM-l -related trifunctional peptide G-KV21.
  • G-KV21 significantly suppresses pathological RNV and inhibits tissue expression of TREM-l and M-CSF.
  • TREM-l triggering receptor expressed on myeloid cells-l
  • OIR oxygen-induced retinopathy
  • PBS phosphate-buffer saline
  • M-CSF macrophage colony stimulating factor
  • RNV retinal neovascularization.
  • FIG. 44 presents exemplary data showing penetration of the BBB and BRB by systemically (mice - intraperitoneally; rats and rabbits - intravenously) administered rhodamine B-labeled TREM-l -related trifunctional peptide G-KV21.
  • TREM-l triggering receptor expressed on myeloid cells-l
  • BBB blood-brain barrier
  • BRB blood-retinal barrier.
  • FIG. 45A-E TREM-l pathway inhibition.
  • TREM-l pathway inhibition suppresses the expression of (FIG. 45A) TREM-l and inflammatory cytokines (FIG. 45B) MCP-l, (FIG. 45C) TNF-a, (FIG. 45D) IL-lp, and (FIG. 45E) MIP-la but not (FIG. 45F) RANTES at the mRNA level as measured in whole-liver lysates by real-time quantitative PCR.
  • * indicates significance level compared to nontreated PF group; # indicates significance level compared to nontreated alcohol-fed group; o indicates significance level compared to vehicle-treated alcohol-fed group. Significance levels are as follows: * /#/o P ⁇ 0.05; ** /##/oo P ⁇ 0.01; *** /ooo P ⁇ 0.001;
  • FIG. 46AE-G TREM-l blockade and inflammatory cytokine levels. TREM-l blockade reduces inflammatory cytokine levels in (FIG. 46A) serum and (FIG. 46B-D) whole-liver lysates as measured with specific ELISA kits.
  • FIG. 46E-G Total liver protein was analyzed for total SYK and activated p-SYK Y525/526 expression by western blotting using b-actin as a loading control.
  • FIG. 47A-H Effects of TREM-l inhibition.
  • TREM-l inhibition suppresses the mRNA expression of macrophage cell markers in the liver as measured by real time quantitative PCR.
  • FIG. 47C, FIG. 47D Both TREM-l inhibitors attenuated F4/80 as shown by IHC.
  • FIG. 47E, FIG. 47F TREM-l inhibition suppresses the mRNA expression of neutrophil cell markers in the liver as measured by real-time quantitative PCR.
  • FIG. 47G, H Both TREM-l inhibitors attenuated MPO-positive cell infiltration as shown by IHC.
  • * indicates significance level compared to the nontreated PF group; # indicates significance level compared to the nontreated alcohol-fed group; o indicates significance level compared to the vehicle- treated alcohol-fed group. Significance levels are as follows: * /#/o P ⁇ 0.05; ** /## P ⁇ 0.01;
  • FIG. 48A-F Measurement of mRNA expression. mRNA expression of genes involved in (FIG. 48A, FIG. 48B) lipid synthesis (SERBF1, ACC1), (FIG. 48C) the lipid accumulation marker (ADRP), and (FIG. 48D-F) lipid oxidation (PPARa, CPTla, MCAD) were measured in whole liver.
  • FIG. 49A presents a schematic representation of one embodiment of the proposed role of inhibition of TREM-l expressed on tumor-associated macrophages (TAMs) in pancreatic cancer.
  • Pancreatic ductal adenocarcinoma cells, cancer-associated fibroblasts (CAFs) and TAMs play a role in generating a tumor favorable microenvironment, in part by producing such cytokines and growth factors as interleukin (IL)-la, IL-6 and macrophage colony-stimulating factor (M-CSF).
  • IL interleukin
  • M-CSF macrophage colony-stimulating factor
  • 49B presents a schematic representation of one embodiment of suppressing tumor favorable microenvironment by inhibition of TREM-l expressed on tumor-associated macrophages (TAMs) and reduction of cytokines and growth factors including but not limited to interleukin (IL)-6, IL-l, monocyte chemoattractant protein-l (MCP-l; also referred to in the art as CCL2) and macrophage colony-stimulating factor 1 (CSF-l; also referred to in the art as M- CSF).
  • IL interleukin
  • MCP-l monocyte chemoattractant protein-l
  • CSF-l macrophage colony-stimulating factor 1
  • the figure further presents a schematic representation of one embodiment of modulating the TREM-1/DAP-12 signaling pathway by type I TREM-l inhibitors that bind either TREM-l (type la inhibitors; e.g., anti-TREM-l blocking antibodies, , etc.) or its ligand (type lb inhibitors; e.g., inhibitory peptides LP17 and LR12 that act as a decoy TREM-l receptor), thereby blocking binding between TREM-l and its yet uncertain ligand(s).
  • type la inhibitors e.g., anti-TREM-l blocking antibodies, , etc.
  • ligand type lb inhibitors
  • inhibitory peptides LP17 and LR12 that act as a decoy TREM-l receptor
  • FIG. 50 presents a schematic representation of one embodiment of TREM-l modulatory peptide variants and compositions of the present invention that are rationally designed using the Signaling Chain HOmoOLigomerization (SCHOOL approach) to inhibit TREM-l in a ligand- independent manner by blocking intramembrane interactions between TREM-l and its signaling partner DAP-12 (type II inhibitors).
  • SCHOOL peptides can be employed in either free form or incorporated into macrophage-targeted (macrophage-specific) synthetic lipopeptide particles (SLP), which allows them to reach their site of action from either outside (Route 1) or inside the cell (Route 2).
  • FIG. 51A-F shows images of one embodiment depicting colocalization of the TREM-l modulatory peptide GF9 (GFLSKSLVF) with trifunctional TREM-l in the cell membrane.
  • Fig. 51 A shows exemplary peptide GF9.
  • Fig. 51B and 51E shows exemplary TREM-l.
  • Fig. 51C and F shows exemplary merged Images.
  • Fig. 51 A shows exemplary inhibitory peptide GE31 ((GFL SK SL VFP YLDDF QKKW QEEM(0)EL YRQK VE) where M(O) is a methionine sulfoxide residue with TREM-l in the cell membrane.
  • FIG. 51B shows images of one embodiment depicting colocalization of the TREM-l modulatory peptide GF9 (GFLSKSLVF) and trifunctional TREM-l
  • FIG. 52 presents the exemplary data of one embodiment showing that treatment with free TREM-l modulatory peptide GF9 (GFLSKSLVF) or GF9 incorporated into the a carrier, e.g. synthetic lipopeptide particle (SLP) of discoidal (dSLP) or spherical (sSLP) morphology suppresses tumor growth in experimental pancreatic cancer.
  • GFLSKSLVF free TREM-l modulatory peptide GF9
  • SLP synthetic lipopeptide particle
  • dSLP discoidal
  • sSLP spherical
  • mice were randomized into groups and intraperitoneally (i.p.) administered once daily 5 times per week (5qw) with either vehicle (black diamonds), GF9 (dark gray squares), GF9-loaded discoidal SLP (GF9-dSLP, light gray circles) or GF9-loaded spherical SLP (GF9-sSLP, white circles) at indicated doses.
  • vehicle black diamonds
  • GF9 dark gray squares
  • GF9-dSLP GF9-loaded discoidal SLP
  • GF9-sSLP GF9-spherical SLP
  • Mean tumor volumes are calculated and plotted.
  • FIG. 53 presents the exemplary data of one embodiment showing that treatment with free TREM-l modulatory peptide GF9 (GFLSKSLVF) or GF9 incorporated into the a carrier, e.g. synthetic lipopeptide particle (SLP) of discoidal (dSLP) or spherical (sSLP) morphology (GF9- dSLP and GF9-sSLP, respectively) suppresses tumor growth in experimental pancreatic cancer without affecting body weight (well-tolerable in long term-treated mice).
  • a carrier e.g. synthetic lipopeptide particle (SLP) of discoidal (dSLP) or spherical (sSLP) morphology
  • mice were randomized into groups and intraperitoneally (i.p.) administered once daily 5 times per week (5qw) with either vehicle (black diamonds), GA/E3 l-dSLP (light gray triangles) or GA/E3 l-sSLP (white triangles) at indicated doses.
  • vehicle black diamonds
  • GA/E3 l-dSLP light gray triangles
  • GA/E3 l-sSLP white triangles
  • tumor volumes were compared between the drug-treated and control groups. **, p ⁇ 0.01; ***, p ⁇ 0.001; **** p ⁇ 0.0001 (versus vehicle).
  • FIG. 55 presents the exemplary data of one embodiment showing that treatment with synthetic lipopeptide particle (SLP) of discoidal (dSLP) or spherical (sSLP) morphology loaded with an equimolar mixture of the 31 amino acids-long TREM-l modulatory peptide GA31 (GFLSKSLVFPLGEEM(O)RDRARAHVDALRTHLA) where M(O) is a methionine sulfoxide residue and the 31 amino acids-long TREM-l modulatory peptide GE31 (GFL SK SL VFP YLDDF QKKW QEEM(0)EL YRQK VE) where M(O) is a methionine sulfoxide residue (GA/E3 l-dSLP and GA/E3 l-sSLP, respectively) suppresses tumor growth in experimental pancreatic cancer without affecting body weight (i.e.
  • SLP synthetic lipopeptide particle
  • dSLP discoidal
  • sSLP spher
  • FIG. 56 presents the exemplary data of one embodiment showing that treatment with free TREM-l modulatory peptide GF9 (GFLSKSLVF) or GF9 incorporated into synthetic lipopeptide particle (SLP) of discoidal (dSLP) or spherical (sSLP) morphology (GF9-dSLP and GF9-sSLP, respectively) prolongs survival in experimental pancreatic cancer.
  • GFLSKSLVF free TREM-l modulatory peptide GF9
  • SLP synthetic lipopeptide particle
  • dSLP discoidal
  • sSLP spherical morphology
  • mice were randomized into groups and intraperitoneally (i.p.) administered once daily 5 times per week (5qw) with either vehicle (black diamonds), GF9 (dark gray circles), GF9-dSLP (light gray circles) or GF9-sSLP (white circles) at indicated doses. Treatment persisted for 31, 29 and 29 days for mice containing AsPC-l, BxPC-3 and Capan-l tumor xenografts, respectively.
  • FIG. 57 presents the exemplary data of one embodiment showing that treatment with synthetic lipopeptide particle (SLP) of discoidal (dSLP) or spherical (sSLP) morphology loaded with an equimolar mixture of the 31 amino acids-long TREM-l modulatory peptide GA31 (GFLSKSLVFPLGEEM(O)RDRARAHVDALRTHLA) where M(O) is a methionine sulfoxide residue and the 31 amino acids-long TREM-l modulatory peptide GE31 (GFL SK SL VFP YLDDF QKKW QEEM(0)EL YRQK VE) where M(O) is a methionine sulfoxide residue (GA/E3 l-dSLP and GA/E3 l-sSLP, respectively) prolongs survival in experimental pancreatic cancer.
  • SLP synthetic lipopeptide particle
  • mice were randomized into groups and intraperitoneally (i.p.) administered once daily 5 times per week (5qw) with either vehicle (black diamonds), GA/E3 l-dSLP (light gray triangles) or GA/E3 l-sSLP (white triangles) at indicated doses. Treatment persisted for 31, 29 and 29 days for mice containing AsPC-l, BxPC-3 and Capan-l tumor xenografts, respectively.
  • FIG. 58 presents the exemplary data of one embodiment showing that the antitumor efficacy of TREM-l blockade correlates with the intratumoral macrophage content in experimental pancreatic cancer.
  • FIG. 59 presents the exemplary data of one embodiment showing that TREM-l blockade suppresses intratumoral macrophage infiltration in experimental pancreatic cancer.
  • Intratumoral macrophage content was quantified by F4/80 staining using F4/80 antibodies.
  • Data are shown for the groups of BxPC-3 -bearing mice treated with either vehicle (black bars), free GF9 (GFLSKSLVF, dark grey bars), GF9 incorporated into a carrier, e.gs. synthetic lipopeptide particle of spherical morphology (GF9-sSLP, light grey bars) and sSLP that contain an equimolar mixture of TREM-l modulatory peptides GA31
  • FIG. 60 presents the exemplary data of one embodiment showing the representative F4/80 images demonstrating that TREM-l blockade suppresses intratumoral macrophage infiltration in experimental pancreatic cancer. Intratumoral macrophage content was quantified by F4/80 staining using F4/80 antibodies.
  • FIG. 61 presents the exemplary data of one embodiment showing that TREM-l blockade suppresses serum proinflammatory cytokines in xenograft mouse models of pancreatic cancer.
  • Serum interleukin- la (IL-la), IL-6 and macrophage colony-stimulating factor (M-CSF/CSF-l) levels were analyzed on study days 1 and 8 in AsPC-l-, BxPC-3- and Capan-l -bearing mice treated daily 5 times per week (5qw) with either vehicle (black diamonds), GF9 (dark gray squares) or GF9-loaded spherical synthetic lipopeptide particles (GF9-sSLP, white circles) at indicated doses.
  • FIG. 62 presents the exemplary data of one embodiment showing that treatment with free TREM-l modulatory peptide GF9 (GFLSKSLVF) or GF9 incorporated into lipopeptide complex (GF9-LPC) suppresses serum proinflammatory cytokines colony-stimulating factor 1 (CSF1) and interleukin 6 (IL-6) but not vascular endothelial growth factor (VEGF) in the AsPC-l xenograft mouse model of pancreatic cancer.
  • GFLSKSLVF free TREM-l modulatory peptide GF9
  • GF9-LPC lipopeptide complex
  • CSF1 colony-stimulating factor 1
  • IL-6 interleukin 6
  • VEGF vascular endothelial growth factor
  • FIG. 63 presents the exemplary data of one embodiment showing that treatment with free TREM-l modulatory peptide GF9 (GFLSKSLVF) or GF9 incorporated into lipopeptide complex (GF9-LPC) suppresses serum proinflammatory cytokines colony-stimulating factor 1 (CSF1) and interleukin 6 (IL-6) but not vascular endothelial growth factor (VEGF) in the BxPC-3 xenograft mouse model of pancreatic cancer.
  • GFLSKSLVF free TREM-l modulatory peptide GF9
  • GF9-LPC lipopeptide complex
  • CSF1 colony-stimulating factor 1
  • IL-6 interleukin 6
  • VEGF vascular endothelial growth factor
  • FIG. 64 presents the exemplary data of one embodiment showing that treatment with free TREM-l modulatory peptide GF9 (GFLSKSLVF) or GF9 incorporated into lipopeptide complex (GF9-LPC) suppresses serum proinflammatory cytokines colony-stimulating factor 1 (CSF1) and interleukin 6 (IL-6) but not vascular endothelial growth factor (VEGF) in the CAPAN-l xenograft mouse model of pancreatic cancer.
  • GFLSKSLVF free TREM-l modulatory peptide GF9
  • GF9-LPC lipopeptide complex
  • CSF1 colony-stimulating factor 1
  • IL-6 interleukin 6
  • VEGF vascular endothelial growth factor
  • FIG. 65 presents the exemplary data of one embodiment showing that combining of Gemcitabine and Abraxane chemotherapy with TREM-l modulatory peptide GF9 (GFLSKSLVF) incorporated into synthetic lipopeptide particle (SLP) of spherical (sSLP) morphology (GF9-sSLP) has a synergistic effect in experimental pancreatic cancer.
  • GFLSKSLVF TREM-l modulatory peptide GF9
  • SLP synthetic lipopeptide particle
  • sSLP spherical morphology
  • mice were randomized into groups and intraperitoneally (i.p.) administered with either vehicle (black diamonds; once daily 5 times per week, 5qw), GF9-sSLP (black squares; once daily 5 times per week, 5qw), Gemcitabine and Abraxane (black circles; days 1, 4, 8, 11, 15) or GF9-sSLP (once daily 5 times per week, 5qw) in combination with Gemcitabine and Abraxane (days 1, 4, 8, 11, 15) (Black triangles). Treatment with GF9-sSLP persisted for 28 days. Mean tumor volumes are calculated and plotted.
  • BBB blood-brain barrier
  • BBB blood-retinal barrier
  • BBB blood-brain barrier
  • BRB blood-retinal barrier
  • sSLP rhodamine B- labeled spherical synthetic lipopeptide particles
  • Gd-sSLP Gd-containing contrast agent
  • MRI magnetic resonance imaging
  • GF9- sSLP TREM-l modulatory peptide GF9
  • equimolar mixture of the sulfoxidized methionine residue-containing TREM-l modulatory peptides i.e.
  • Fig. 67 presents the exemplary data of one embodiment showing that TREM-l blockade with GF9, GF9 incorporated into the carrier - spherical synthetic lipopeptide particles (GF9-sSLP) or sSLP that carried an equimolar mixture of the 31 amino acids-long TREM-l modulatory peptide GA31 (GFL SK SL VFPLGEEM(0)RDR ARAHVD ALRTHL A) where M(O) is a methionine sulfoxide residue and the 31 amino acids-long TREM-l modulatory peptide GE31 (GFL SK SL VFP YLDDF QKKW QEEM(0)EL YRQK VE) where M(O) is a methionine sulfoxide residue (GA/E3 l-sSLP) significantly reduces tissue expression of colony-stimulating factor 1 (CSF-l) and TREM-l in the retina of mice with oxygen-induced retinopathy (OIR) at postnatal
  • Fig. 68 presents the exemplary data of one embodiment showing that combining gemcitabine (GEM) and abraxane (ABX) chemotherapy with TREM-l modulatory peptide GF9 (GFLSKSLVF) incorporated into a carrier, e.g. synthetic lipopeptide particle (SLP) of spherical (sSLP) morphology (GF9-sSLP) has a synergistic therapeutic effect in experimental pancreatic cancer.
  • GEM gemcitabine
  • ABX abraxane
  • GF9-sSLP TREM-l modulatory peptide GF9
  • mice were randomized into groups and intraperitoneally (i.p.) administered at indicated doses with either vehicle (black diamonds; once daily 5 times per week, 5qw), GF9-LPC (black circles-black squares; once daily 5 times per week, 5qw), GEM and ABX (black squares-(black circles; days 1, 4, 8, 11, 15) or GF9-LPC (once daily 5 times per week, 5qw) in combination with GEM and ABX (days 1, 4, 8, 11, 15) (half black half white hexagons-Black triangles). Treatment with GF9-LPC persisted for 28 days. Mean tumor volumes are calculated and plotted.
  • Fig. 69 presents the exemplary data of one embodiment showing that TREM-l blockade treatment with TREM-l modulatory peptide GF9 (GFLSKSLVF) incorporated into a , e.g. synthetic lipopeptide particle (SLP) of spherical (sSLP) morphology (GF9-sSLP) alone, lipopeptide complex (GF9-LPC) alone or in combination with gemcitabine (GEM) and abraxane (ABX) chemotherapy is well tolerable in mice with human PANC-l pancreatic cancer xenografts.
  • SLP synthetic lipopeptide particle
  • sSLP spherical
  • GF9-sSLP lipopeptide complex
  • GEM gemcitabine
  • ABX abraxane
  • mice were randomized into groups and intraperitoneally (i.p.) administered at indicated doses with either vehicle (black diamonds; once daily 5 times per week, 5qw), GF9- LPC (black circles; once daily 5 times per week, 5qw), GEM and ABX (black squares; days 1, 4, 8, 11, 15) or GF9-LPC (once daily 5 times per week, 5qw) in combination with GEM and ABX (days 1, 4, 8, 11, 15) (half black half white hexagons).
  • Treatment with GF9-LPC (GF9-sSLP) persisted for 28 days. Body weighs are plotted. All results are expressed as the mean ⁇ SEM (n 6 mice per group).
  • Fig. 70 presents the exemplary data of one embodiment showing that treatment with TREM-l modulatory peptide GF9 incorporated into a carrie, e.g. synthetic lipopeptide complex (GF9- LPC) and particle (SLP) of spherical (sSLP) morphology (GF9-sSLP), synergistically prolongs survival rate in experimental pancreatic cancer (e.g. PANC-l) when combined with gemcitabine (GEM) and abraxane (ABX) chemotherapy.
  • GF9- LPC synthetic lipopeptide complex
  • SLP particle
  • sSLP spherical morphology
  • PANC-l spherical morphology
  • GEM gemcitabine
  • ABX abraxane
  • Fig. 71 presents the exemplary data of one embodiment showing that treatment with free TREM- 1 modulatory peptide GF9 (GFLSKSLVF) is well tolerable in mice up to at least 300 mg/kg.
  • GFLSKSLVF free TREM- 1 modulatory peptide GF9
  • Fig.72 presents the exemplary data of one embodiment showing that treatment with free TREM- 1 modulatory peptide GF9 (GFLSKSLVF) or GF9 incorporated into lipopeptide complex (GF9- LPC) or LPC comprising lipids and an equimolar mixture of the 31 amino acids-long TREM-l modulatory peptide GA31 (GFLSKSLVFPLGEEM(O)RDRARAHVDALRTHLA) where M(O) is a methionine sulfoxide residue and the 31 amino acids-long TREM-l modulatory peptide GE31 (GFL SK SL VFP YLDDF QKK W QEEM(0)EL YRQK VE) where M(O) is a methionine sulfoxide residue (GA/E31-LPC) suppresses tumor growth in experimental pancreatic cancer.
  • GFLSKSLVFPLGEEM(O)RDRARAHVDALRTHLA the 31 amino acids-long TREM-l modulatory peptide
  • Fig.73 presents the exemplary data of one embodiment showing that treatment with free TREM- 1 modulatory peptide GF9 (GFLSKSLVF) or GF9 incorporated into lipopeptide complex (GF9- LPC) or LPC comprising lipids and an equimolar mixture of the 31 amino acids-long TREM-l modulatory peptide GA31 (GFLSKSLVFPLGEEM(O)RDRARAHVDALRTHLA) where M(O) is a methionine sulfoxide residue and the 31 amino acids-long TREM-l modulatory peptide GE31 (GFL SK SL VFP YLDDF QKK W QEEM(0)EL YRQK VE) where M(O) is a methionine sulfoxide residue (GA/E31-LPC) is well tolerable in mice with human pancreatic cancer xenografts.
  • GFLSKSLVFPLGEEM(O)RDRARAHVDALRTHLA the 31 amino acids-long
  • Fig.74 presents the exemplary data of one embodiment showing that treatment with free TREM- 1 modulatory peptide GF9 (GFLSKSLVF) or GF9 incorporated into lipopeptide complex (GF9- LPC) or LPC comprising lipids and an equimolar mixture of the 31 amino acids-long TREM-l modulatory peptide GA31 (GFLSKSLVFPLGEEM(O)RDRARAHVDALRTHLA) where M(O) is a methionine sulfoxide residue and the 31 amino acids-long TREM-l modulatory peptide GE31 (GFL SK SL VFP YLDDF QKK W QEEM(0)EL YRQK VE) where M(O) is a methionine sulfoxide residue (GA/E31-LPC) suppresses tumor growth as effectively as 20 mg/kg paclitaxel and is well tolerable in mice with human non-small cell lung cancer xenografts.
  • Fig.75 presents the exemplary data of one embodiment showing that treatment with free TREM- 1 modulatory peptide GF9 (GFLSKSLVF) or GF9 incorporated into lipopeptide complex (GF9- LPC) or LPC comprising lipids and an equimolar mixture of the 31 amino acids-long TREM-l modulatory peptide GA31 (GFLSKSLVFPLGEEM(O)RDRARAHVDALRTHLA) where M(O) is a methionine sulfoxide residue and the 31 amino acids-long TREM-l modulatory peptide GE31 (GFL SK SL VFP YLDDF QKK W QEEM(0)EL YRQK VE) where M(O) is a methionine sulfoxide residue (GA/E31-LPC) suppresses intratumoral macrophage infiltration in experimental pancreatic cancer.
  • GFLSKSLVFPLGEEM(O)RDRARAHVDALRTHLA the 31 amino acids-long TREM-
  • Fig.76 presents the exemplary data of one embodiment showing that treatment with free TREM- 1 modulatory peptide GF9 (GFLSKSLVF) or GF9 incorporated into lipopeptide complex (GF9- LPC) or LPC comprising lipids and an equimolar mixture of the 31 amino acids-long TREM-l modulatory peptide GA31 (GFLSKSLVFPLGEEM(O)RDRARAHVDALRTHLA) where M(O) is a methionine sulfoxide residue and the 31 amino acids-long TREM-l modulatory peptide GE31 (GFL SK SL VFP YLDDF QKK W QEEM(0)EL YRQK VE) where M(O) is a methionine sulfoxide residue (GA/E31-LPC) ameliorates arthritis in mice with collagen-induced arthritis (CIA).
  • GFLSKSLVFPLGEEM(O)RDRARAHVDALRTHLA the 31 amino acids-long TREM-l modulatory peptid
  • mice with CIA were intraperitoneally (i.p.) administered daily for 14 consecutive days with vehicle (black diamonds), dexamethasone (black squares), GF9 (white circles), GF9-LPC (black circles) and GA/E31-LPC (half black half white circles) at indicated doses.
  • Daily clinical scores were given on a scale of 0- 5 for each of the paws on days 24-38.
  • Fig.77 presents the exemplary data of one embodiment showing that treatment with free TREM- 1 modulatory peptide GF9 (GFLSKSLVF) or GF9 incorporated into lipopeptide complex (GF9- LPC) or LPC comprising lipids and an equimolar mixture of the 31 amino acids-long TREM-l modulatory peptide GA31 (GFLSKSLVFPLGEEM(O)RDRARAHVDALRTHLA) where M(O) is a methionine sulfoxide residue and the 31 amino acids-long TREM-l modulatory peptide GE31 (GFL SK SL VFP YLDDF QKK W QEEM(0)EL YRQK VE) where M(O) is a methionine sulfoxide residue is well tolerable in mice with collagen-induced arthritis (CIA).
  • GFLSKSLVFPLGEEM(O)RDRARAHVDALRTHLA the 31 amino acids-long TREM-l modulatory peptide GA31
  • BW Mouse body weight
  • Fig.78 presents the exemplary data of one embodiment showing that treatment with free TREM- 1 modulatory peptide GF9 (GFLSKSLVF) or GF9 incorporated into lipopeptide complex (GF9- LPC) or LPC comprising lipids and an equimolar mixture of the 31 amino acids-long TREM-l modulatory peptide GA31 (GFLSKSLVFPLGEEM(O)RDRARAHVDALRTHLA) where M(O) is a methionine sulfoxide residue and the 31 amino acids-long TREM-l modulatory peptide GE31 (GFL SK SL VFP YLDDF QKK W QEEM(0)EL YRQK VE) where M(O) is a methionine sulfoxide residue (GA/E31-LPC) prevents pathological appearances from collagen-induced arthritis (CIA) in mice.
  • GFLSKSLVFPLGEEM(O)RDRARAHVDALRTHLA the 31 amino acids-long TREM-l
  • toluidine blue staining of the joints from mice with CIA treated with TREM-l inhibitory GF9 sequences or control peptide GF9-G was performed.
  • Photomicrographs of fore paws, hind paws, knees and ankles from representative mice are shown for each treatment group.
  • paws original magnification 16c
  • ankles original magnification 40x
  • arrows identify affected joints.
  • large arrow identifies cartilage damage
  • small arrowhead identifies bone resorption.
  • W wrist; S, synovium.
  • Fig.79 presents the exemplary data of one embodiment showing that treatment with free TREM- 1 modulatory peptide GF9 (GFLSKSLVF) or GF9 incorporated into lipopeptide complex (GF9- LPC) or LPC comprising lipids and an equimolar mixture of the 31 amino acids-long TREM-l modulatory peptide GA31 (GFLSKSLVFPLGEEM(O)RDRARAHVDALRTHLA) where M(O) is a methionine sulfoxide residue and the 31 amino acids-long TREM-l modulatory peptide GE31 (GFL SK SL VFP YLDDF QKK W QEEM(0)EL YRQK VE) where M(O) is a methionine sulfoxide residue (GA/E31-LPC) reduces plasma cytokines in mice with collagen-induced arthritis (CIA).
  • GFLSKSLVFPLGEEM(O)RDRARAHVDALRTHLA the 31 amino acids-long TREM-l
  • Plasma was collected on days 24, 30 and 38 from arthritic mice treated with vehicle (black diamonds), GF9 (white circles), GF9-LPC (black circles) and GA/E31-LPC (half black half white circles). Plasma samples were analyzed for concentrations of interleukin- lb (IL- lb), IL-6, and colony-stimulating factor 1 (CSF1). Results are expressed as the mean ⁇ SEM (n 5 mice per group).
  • Fig. 80 presents the exemplary data of one embodiment showing that treatment with free TREM- 1 modulatory peptide GF9 (GFLSKSLVF) or GF9 incorporated into lipopeptide complex (GF9- LPC) or LPC comprising lipids and an equimolar mixture of the 31 amino acids-long TREM-l modulatory peptide GA31 (GFLSKSLVFPLGEEM(O)RDRARAHVDALRTHLA) where M(O) is a methionine sulfoxide residue and the 31 amino acids-long TREM-l modulatory peptide GE31 (GFL SK SL VFP YLDDF QKK W QEEM(0)EL YRQK VE) where M(O) is a methionine sulfoxide residue (GA/E31-LPC) significantly reduces tissue expression of colony-stimulating factor 1 (CSF1) and TREM-l in the retina of mice with oxygen-induced retinopathy (OIR) at postnatal day 17 (P17).
  • Fig. 81 shows exemplary illustrations of peptide GF9 blocking TREM-l signaling by disruption of intramembrane interactions with its signaling partner, DAP-12.
  • Fig. 82 shows exemplary illustrations of LPC delivering of peptide GF9 to macrophages, as two exemplary embodiments, e.g. each as Route 2.
  • Fig. 83 shows exemplary results using Pancreas Cancer: PANC-l Xenografts demonstrating GF9 treatment inhibits tumor growth as effective as chemotherapy (Gemcitabine, GEM + nab-PTX, ABX) and Adding GF9 treatment sensitizes the tumor to chemotherapy and at least triples survival rate.
  • Fig. 84 shows exemplary results using Pancreas Cancer: AsPC-l Xenografts demonstrating GF9 treatment alone does not inhibit tumor growth. Adding of the GF9 treatment sensitizes the tumor to chemotherapy. NOTE: Most tumors - abscessed.
  • Fig. 85 shows exemplary results using Pancreas Cancer: MiaPaca-2 Xenografts demonstrating GF9 treatment inhibits tumor growth as effective as chemotherapy (Gemcitabine, GEM + nab- PTX, ABX) and Adding of the GF9 treatment to chemo does not affect.
  • Fig. 86 shows exemplary results using Pancreas Cancer: BxPC-3 Xenografts demonstrating GF9 treatment inhibits tumor growth as effective as chemotherapy (Gemcitabine, GEM + nab-PTX, ABX) and Adding of the GF9 treatment to chemo does not significantly affect survival rate.
  • Fig. 87 shows exemplary results using Pancreas Cancer: BxPC-3 Xenografts demonstrating GF9 treatment reduces macrophage content in the tumor, Vehicle, 2.5 mg/kg GF9-LPC (5 qw, 4 wk). Shen and Sigalov, Mol Pharm 2017,14:4572, 2017.
  • Fig. 88 shows exemplary results using Pancreas Cancer: BxPC-3 Xenografts demonstrating GF9 treatment reduces serum cytokine levels, Vehicle, 2.5 mg/kg GF9-LPC. Shen and Sigalov, Mol Pharm 2017,14:4572, 2017.
  • Fig. 89 shows exemplary results using Pancreas Cancer: Xenografts demonstrating GF9
  • Fig. 90 shows exemplary results demonstrating that GF9 peptide is well-tolerable by healthy mice up to at least, 300 mg/kg.
  • Fig. 91 shows exemplary results demonstrating that in mice with collagen-induced arthritis
  • CIA dexamethasone
  • DEX dexamethasone
  • Study Day Treatment: Days 24-38. I, inflammation; P, pannus; CD, cartilage damage; BR, bone resorption; PBF, periosteal new bone formation. Shen and Sigalov, Mol Pharm 2017,14:4572, 2017. Fig. 92 shows exemplary results demonstrating that in mice with collagen-induced arthritis (CIA), GF9 treatment reduces serum H_rlb ⁇ TNFal, IL-6 and CSF-l . Shen and Sigalov, Mol Pharm 2017, 14:4572, 2017.
  • Fig. 93 shows exemplary results demonstrating that in mice with collagen-induced arthritis (CIA), GF9 treatment is well-tolerable: no body weight changes or other clinical symptoms are observed. Shen and Sigalov, Mol Pharm 2017, 14:4572, 2017.
  • Fig. 94 shows exemplary results demonstrating that in NSCLC: A549 Xenograft ⁇ CF9 inhibits tumor growth as effectively as c hemo (20 mg/kg Paclitaxel, PTX). Sigalov, 2014, 21 :208.
  • Fig. 95 shows exemplary results demonstrating that in Capan-l xenografts, GF9 inhibits tumor growth and reduces serum cytokines, including CSF-l (but not VEGF). Shen and Sigalov, Mol Pharm 2017,14:4572, 2017.
  • Fig. 96 shows exemplary results demonstrating that GF9 is well-tolerated by long term treated cancer mice inCapan-l Xenografts and A549 Xenografts CF9 inhibits tumor growth as effectively as c hemo (20 mg/kg Paclitaxel, PTX). Sigalov, 2014, 21 :208.
  • Fig. 97A-C shows exemplary current approaches for blocking TREM-l binding to its uncertain ligand (Bouchon et al. 2001, Schenk et al. 2007, Gibot et al. 2008, Gibot et al. 2009, Murakami et al. 2009, Luo et al. 2010, Derive et al. 2013, Derive et al. 2014)
  • Fig. 97A In contrast, GF9 self-penetrates into the membrane and disrupts TREM-l / DAP12 interactions Fig. 97B when colocalizes with TREM-l Fig. 97C.
  • Fig. 98A-B shows exemplary results demonstrating that GF9 is non-toxic in healthy mice Fig. 98A and reduces TREM-l and M-CSF overexpression in the retina of mice with oxygen-induced retinopathy Fig. 98B.
  • Fig. 98A Graph.
  • Fig. 98B Blot.
  • Fig. 99A-C shows exemplary results demonstrating that Oxidized apo A-I peptides in LPC increase J774 intracellular uptake of GF9-LPC in vitro Fig. 99A, 99B and enable in vivo delivery to macrophages Fig.
  • Fig. 99C (as shown using magnetic resonance imaging (MRI) and confocal microscopy (Sigalov 2014, Sigalov 2014, Shen and Sigalov 2017)).
  • Fig. 99A IN VITRO.
  • Fig. 99B CONFOCAL red: Rho B-PE; green: 488-GF9; blue: 405-apo A-I PE22.
  • Fig. 99C MOUSE AORTA.
  • Fig. 100A-D shows exemplary results demonstrating that GF9-dLPC (disks) and GF9-sLPC (spheres) reduce LPS-induced cytokine release in vitro Fig. 100A and in vivo Fig. 100B and prolong survival Fig. 100C (Sigalov 2014).
  • GF9 and GF9-LPC treatments inhibit production of CSF-l/M-CSF but not VEGF Fig. 100D (Shen and Sigalov 2017).
  • Fig. 100A CYTOKINES IN VITRO.
  • Fig. 100B CYTOKINES IN VIVO.
  • Fig. 100C SURVIVAL IN LPS- INDUCED SEPTIC MICE.
  • Fig. 100D M-CSF / VEGF RELEASE IN CANCER MICE.
  • Fig. 101 shows exemplary results demonstrating that Different rate and efficiency of GF9-dLPC and GF9-sLPC in vitro uptake by J774 macrophages (Sigalov 2014).
  • Fig. 102 shows exemplary results demonstrating that Stability of GF9-LPC.
  • GF9-LPC AT 4°C.
  • Fig. 103 A-D shows exemplary results demonstrating that GF9-LPC daily i.p. administered at 2.5 mg/kg suppress the expression of TREM-l, MCP-1/CCL2 and early fibrosis marker molecules in mice with ALD.
  • Fig. 102B MCP-1/CCL2.
  • Fig. 102C Pro-Colll alpha.
  • Fig. 102D alpha-SMA.
  • Fig. 104A-D shows exemplary results demonstrating that GF9 and GF9-LPC daily i.p.
  • Fig. 104A suppress macrophage infiltration into the tumor Fig. 104B, 104C and inhibit release of CSF-l/M-CSF but not VEGF Fig. 104D.
  • Scale bar 200 pm. *,p ⁇ 0.05; **,p ⁇ 0.01; ***, > ⁇ 0.001; ****, > ⁇ 0.0001 (vs vehicle).
  • Fig. 104A BODY WEIGHT.
  • Fig. 104C MACROPHAGE INFILTRATION.
  • Fig. 104D M-CSF / VEGF RELEASE IN CANCER MICE.
  • Fig. 105 A- C shows exemplary results demonstrating that in mice with autoimmune arthritis, GF9, discoidal GF9-LPC (GF9-dHDL) and spherical GF9-LPC (GF9-sHDL) i.p. administered daily are well-tolerated Fig. A, ameliorate the disease Fig. 105B and inhibit production of cytokines and M-CSF Fig. C (Shen and Sigalov 2017).
  • Fig. 105A BODY WEIGHT CHANGES.
  • Fig. 105C CYTOKINE RELEASE IN
  • composition refers to any mixture of substances comprising a peptide and/or compound contemplated by the present invention. Such a composition may include the substances individually or in any combination.
  • lipoprotein such as VLDL (very low density lipoproteins)
  • LDL low density lipoproteins
  • HDL high density lipoproteins
  • the chemical composition of each lipoprotein differs, for examples, HDL has a higher proportion of protein versus lipid, whereas the VLDL has a lower proportion of protein versus lipid.
  • the term“native” refers to naturally-occurring (e.g., a“wild-type”) lipoproteins.
  • APOAl_HUMAN “Apolipoprotein A-I”,“Apolipoprotein A-l”,“APOA1”, “ApoA-I”,“Apo-AI”,“ApoA-l”,“apo-Al”,“apoA-l” and“Apo-Al” refer to the naturally occurring human protein listed in the ETniProt Knowledgebase (UniProtKB, www.uniprot.org) under the name“APOA1 HUMAN”.
  • the protein amino acid sequence can be found under the entry UniProt KB/Swiss-Prot P02647 (www.uniprot.org/uniprot/P02647).
  • “APOA2 HUMAN”,“Apolipoprotein A-IG, Apolipoprotein A-2”,“APOA2”,“ApoA-II”, “Apo-AII”,“ApoA-2”,“apo-A2”,“apoA-2” and“Apo-A2” refer to the naturally occurring human protein listed in the UniProt Knowledgebase (UniProtKB, www.uniprot.org) under the name“APOA2_HUMAN”.
  • the protein amino acid sequence can be found under the entry UniProt KB/Swiss-Prot P02652 (http://www.uniprot.org/uniprot/P02652).
  • TREM receptor refers to a member of TREM receptor family including: TREM-l, TREM-2, TREM- 3 and TREM-4.
  • TREM 1 HUMAN refers to the naturally occurring human protein listed in the UniProt Knowledgebase (UniProtKB, www.uniprot.org) under the name“ TREM 1 HUMAN”.
  • the protein amino acid sequence can be found under the entry UniProt KB/Swiss-Prot Q9NP99.
  • TREM receptor refers to a member of TREM receptor family: TREM-l, TREM-2, TREM-3 and TREM-4.
  • T cell receptor refers to a complex of membrane proteins that participate in the activation of T cells in response to the presentation of antigen.
  • the TCR is responsible for recognizing antigens bound to major histocompatibility complex molecules.
  • TCR is composed of a heterodimer of an alpha (a) and beta (b) chain, although in some cells the TCR consists of gamma and delta (g/d) chains.
  • TCRs may exist in alpha/beta and gamma/delta forms, which are structurally similar but have distinct anatomical locations and functions.
  • each chain is composed of two extracellular domains, a variable and constant domain, in some embodiments, the TCR may be modified on any ceil comprising a TCR, including, for example, a helper T cell, a cytotoxic T cell, a memory T ceil, regulatory T cell, natural killer T cell, and gamma delta T cell.
  • a helper T cell including, for example, a helper T cell, a cytotoxic T cell, a memory T ceil, regulatory T cell, natural killer T cell, and gamma delta T cell.
  • amino acid domain is a contiguous polymer of at least 2 amino acids joined by peptide bond(s). The domain may be joined to another amino acid or amino acid domain by one or more peptide bonds.
  • An amino acid domain can constitute at least two amino acids at the N-terminus or C-terminus of a peptide or can constitute at least two amino acids in the middle of a peptide.
  • antibody herein refers to a protein, derived from a germline immunoglobulin sequence, which is capable of specifically binding to an antigen (TREM-l) or a portion thereof.
  • the term includes full length antibodies of any class or isotype (that is, IgA, IgE, IgG, IgM and/or IgY) and any single chain or fragment thereof.
  • An antibody that specifically binds to an antigen, or portion thereof may bind exclusively to that antigen, or portion thereof, or it may bind to a limited number of homologous antigens, or portions thereof.
  • a "peptide” and “polypeptide” comprises a string of at least two amino acids linked together by peptide bonds.
  • a peptide generally represents a string of between approximately 2 and 200 amino acids, more typically between approximately 6 and 64 amino acids.
  • Peptide may refer to an individual peptide or a collection of peptides.
  • Inventive peptides typically contain natural amino acids, although non-natural amino acids (i.e., compounds that do not occur in nature but that can be incorporated into a polypeptide chain and/ or amino acid analogs as are known in the art may alternatively be employed.
  • D-amino acids may be used.
  • peptide sequence or “amino acid sequence” is the order in which amino acid residues, connected by peptide bonds, lie in the chain in peptides. The sequence is generally reported from the N-terminal end containing free amino group to the C-terminal end containing free carboxyl group.
  • eptide sequence is often called “protein sequence” if it represents the primary structure of a protein (http://en.wikipedia.org/wiki/Peptide_sequence).
  • Peptides and compositions of the present invention made synthetically may include substitutions of amino acids not naturally encoded by DNA (e.g., non-naturally occurring or unnatural amino acid).
  • non-naturally occurring amino acids include D-amino acids, an amino acid having an acetylaminomethyl group attached to a sulfur atom of a cysteine, a pegylated amino acid, the omega amino acids of the formula NH 2 (CH2) n COOH wherein n is 2-6, neutral nonpolar amino acids, such as sarcosine, t-butyl alanine, t-butyl glycine, N-methyl isoleucine, and norleucine.
  • Phenylglycine may substitute for Trp, Tyr, or Phe; citrulline and methionine sulfoxide are neutral nonpolar, cysteic acid is acidic, and ornithine is basic. Proline may be substituted with hydroxyproline and retain the conformation conferring properties.
  • Naturally occurring residues are divided into groups based on common side chain properties: as described herein.
  • Analogues may be generated by substitutional mutagenesis and retain the biological activity of the original trifunctional peptides. Examples of substitutions identified as“conservative substitutions” are shown in TABLE 1. If such substitutions result in a change not desired, then other type of substitutions, denominated“exemplary substitutions” in TABLE 1, or as further described herein in reference to amino acid classes, are introduced and the products screened for their capability of executing three functions.
  • amphipathic is used herein to describe a molecule that has both polar and non-polar parts and as such, has two different affinities, as a polar end that is attracted to water and a nonpolar end that is repelled by it.
  • An amphipathic helix is defined as an alpha helix with opposing polar and nonpolar faces oriented along the long axis of the helix.
  • aptamer or “specifically binding oligonucleotide” refers to an oligonucleotide that is capable of forming a complex with an intended target substance.
  • modified peptide is used to describe chemically or enzymatically, or chemically and enzymatically modified oligopeptides, oligopseudopeptides, polypeptides, and pseudopolypeptides (synthetic or otherwise derived), regardless of the nature of the chemical and/or enzymatic modification.
  • pseudopeptide refers to a peptide where one or more peptide bonds are replaced by non-amido bonds such as ester or one or more amino acids are replaced by amino acid analogs.
  • peptides refers not only to those comprised of all natural amino acids, but also to those which contain unnatural amino acids or other non-coded structural units.
  • peptides when used alone, include pseudopeptides. It is worth mentioning that“modified peptides” have utility in many biomedical applications because of their increased stability against in vivo degradation, superior pharmacokinetics, and altered immunogenicity compared to their native counterparts.
  • modified peptides also includes oxidized peptides.
  • oxidized peptide refers to a peptide in which at least one amino acid residue is oxidized.
  • analog includes any peptide having an amino acid sequence substantially identical to one of the sequences specifically shown herein in which one or more residues have been conservatively substituted with a functionally similar residue and which displays the abilities as described herein.
  • conservative substitutions include the substitution of one non-polar (hydrophobic) residue such as isoleucine, valine, leucine or methionine for another, the substitution of one polar (hydrophilic) residue for another such as between arginine and lysine, between glutamine and asparagine, between glycine and serine, the substitution of one basic residue such as lysine, arginine or histidine for another, or the substitution of one acidic residue, such as aspartic acid or glutamic acid for another.
  • the term "conservative substitution”, as used herein, also includes the use of a chemically derivatized residue in place of a non-derivatized residue provided that such peptide displays the requisite inhibitory function on myeloid cells as specified herein.
  • derivative includes any chemical derivative of the peptide of the invention having one or more residues chemically derivatized by reaction of side chains or functional groups.
  • homolog or “homologous” when used in reference to a polypeptide refers to a high degree of sequence identity between two polypeptides, or to a high degree of similarity between the three-dimensional structures or to a high degree of similarity between the active site and the mechanism of action.
  • a homolog has a greater than 60% sequence identity, and more preferably greater than 75% sequence identity, and still more preferably greater than 90% sequence identity, with a reference sequence.
  • the term "substantial identity” means that two peptide sequences, when optimally aligned, such as, for example, by the programs KALIGN, DOTLET, LALIGN and DIALIGN (https://www.expasy.org/tools) using default gap weights, share at least 80 percent sequence identity, preferably at least 90 percent sequence identity, more preferably at least 95 percent sequence identity or more (e.g., 99 percent sequence identity).
  • residue positions which are not identical differ by conservative amino acid substitutions.
  • modified peptides also includes oxidized peptides.
  • oxidized peptide refers to a peptide in which at least one amino acid residue is oxidized.
  • oxidation status refers to a metric of the extent to which specific amino acid residues are replaced by corresponding oxidized amino acid residues in a peptide.
  • extent of oxidation refers to the degree to which potentially oxidizable amino acids in a peptide have undergone oxidation.
  • the peptide contains a single tyrosine residue which is potentially oxidized to 3-chlorotyrosine, then an increase in mass of about 34 Dalton (i.e., the approximate difference in mass between chlorine and hydrogen) indicates oxidation of tyrosine to 3-chlorotyrosine.
  • an increase in mass of 16 Dalton i.e., the difference in mass between methionine and methionine containing one extra oxygen indicates oxidation of methionine to methionine sulfoxides.
  • oxidation status refers to a metric of the extent to which specific amino acid residues are replaced by corresponding oxidized amino acid residues in a peptide.
  • extent of oxidation refers to the degree to which potentially oxidizable amino acids in a peptide have undergone oxidation. For example, if the peptide contains a single tyrosine residue which is potentially oxidized to 3-chlorotyrosine, then an increase in mass of about 34 Dalton (i.e., the approximate difference in mass between chlorine and hydrogen) indicates oxidation of tyrosine to 3-chlorotyrosine.
  • oxidation status can be measured by metrics known to the arts of protein and peptide chemistry (as disclosed in Caulfield, US 8,114,613 and Hazen, et al., US 8,338,110, herein incorportaed by reference) including, without limitation, assay of the number of oxidized residues, mass spectral peak intensity, mass spectral integrated area, and the like. In some embodiments, oxidation status is reported as a percentage, wherein 0% refers to no oxidation and 100% refers to complete oxidation of potentially oxidizable amino acid residues within apo A-I or apo A-II peptide fragments.
  • a "biologically active peptide motif is a peptide that induces a phenotypic response or change in an appropriate cell type when the cell is contacted with the peptide.
  • the peptide may be present either in isolated form or as part of a larger polypeptide or other molecule.
  • the ability of the peptide to elicit the response may be determined, for example, by comparing the relevant parameter in the absence of the peptide (e.g., by mutating or removing the peptide when normally present within a larger polypeptide).
  • Phenotypic responses or changes include, but are not limited to, enhancement of cell spreading, attachment, adhesion, proliferation, secretion of an extracellular matrix (ECM) molecule, or expression of a phenotype characteristic of a particular differentiated cell type.
  • ECM extracellular matrix
  • a "minimal biologically active sequence” refers to the minimum length of a sequence of a peptide that has a specific biological function.
  • -I VILL AGGFL SK SL VF S VLF A- e g., Domain A, SEQ ID NO. 47
  • -GFLSKSLVF- e.g. Domain A, SEQ ID NO. 1
  • -GFLSKSLVF- Domain A, SEQ ID NO. 1
  • -GFLSKSLVF- Domain A, SEQ ID NO. 1 is a "minimal biologically active sequence.”
  • PLGEEMRDRARAHVDALRTHLARGD and an internal sequence -GEEMRDRARAHVRGD- (Domain B, SEQ ID NO. 5) contains the sequence -RGD-; -RGD- has a cell attachment function.
  • -PLGEEMRDRARAHVDALRTHLARGD and -GEEMRDRARAHVRGD- (Domain B, SEQ ID NO. 5) also functions to assist in the formation of naturally long half-life
  • both - PLGEEMRDRARAHVDALRTHLARGD- andGEEMRDRAR AHVRGD - in addition to -RGD- are considered a "minimal biologically active sequence.”
  • the sequence -GFL SK SL VFPLGEEMRDRARAHVD ALRTHL ARGD- contains the sequence -RGD-; -RGD-has a cell attachment function.
  • - GFLSKSL VFPLGEEMRDRARAHVD ALRTHLARGD- (SEQ ID NO. 7) also has the functions of inhibition of TREM-l, assistance in the self-assembly of naturally long half-life lipopeptide particles upon binding to lipid or lipid mixtures particle and of interaction with scavenger receptor type I (SRBI).
  • SRBI scavenger receptor type I
  • GFLSKSL VFPLGEEMRDRARAHVD ALRTHLARGD- (SEQ ID NO. ...) and -RGD- are considered a "minimal biologically active sequence.”
  • the first and second amino acid domains of a resulting peptide contain at least one minimal biologically active sequence.
  • This minimal biologically active sequence is any length of sequence from an original peptide sequence.
  • the amino acids of any or both amino acid domain can be exchanged, added or removed according to the design of the molecule to adjust its overall hydrophilicity and/or net charge.
  • the minimal biologically active sequence refers to any one of the sequences provided in TABLE 2.
  • imaging agent or "imaging probe” as used herein refers to contrast agents used in imaging techniques such as computed tomography (CT), gamma-scintigraphy, positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), and combined imaging techniques in order to improve diagnostic performance of medical imaging.
  • CT computed tomography
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • MRI magnetic resonance imaging
  • labeling substance or label or labeled probe refers to a substance that can image whether there is a binding between the modulator and the cellular component (e.g., TREM-1/DAP-12 receptor complex), and can visualize the binding by a pattern. It may include radioactive materials, fluorescent or emitting materials.
  • carrier refers to a biocompatible nanoparticle that facilitates administration of a pharmaceutical agent to an individual.
  • encapsulation refers to the enclosure of a molecule, such as trifunctional peptides and compounds of the present invention, inside the nanoparticle.
  • incorporation refers to imbibing or adsorbing the trifunctional peptides and compounds onto the nanoparticle.
  • reconstituted and “recombinant” as used herein both refer to synthetic lipopeptide particles that represent both discoidal and spherical nanoparticles and mimic native HDL particles.
  • naturally occurring means found in nature.
  • a naturally occurring biomolecule is, in general, synthesized by an organism that is found in nature and is unmodified by the hand of man, or is a degradation product of such a molecule.
  • a molecule that is synthesized by a process that involves the hand of man e.g., through chemical synthesis not involving a living organism or through a process that involves a living organism that has been manipulated by the hand of man or is descended from such an organism
  • that is identical to a molecule that is synthesized by an organism that is found in nature and is unmodified by the hand of man is also considered a naturally occurring molecule.
  • a "site of interest" on a target as used herein is a site to which modified peptides and compounds of the present invention bind.
  • target site refers to sites/tissue areas of interest.
  • target cells or target tissues refer to those cells or tissues, respectively that are intended to be targeted using the compositions of the present invention delivered in accord with the invention.
  • Target cells or target tissues take up or link with the modified peptides and compounds of the invention.
  • target cells or target tissues refer to those cells or tissues, respectively that are intended to be treated and/or visualized in imaging techniques such as CT, gamma-scintigraphy, PET, SPECT, MRI, and combined imaging techniques, using the compositions of the present invention delivered in accord with the invention.
  • Target cells are cells in target tissue, and the target tissue includes, but is not limited to, atherosclerotic plaques, vascular endothelial tissue, abnormal vascular walls of tumors, solid tumors, tumor-associated macrophages, and other tissues or cells related to cancer, cardiovascular, inflammatory, autoimmune diseases, and the like. Further, target cells include virus-containing cells, and parasite-containing cells. Also included among target cells are cells undergoing substantially more rapid division as compared to non-target cells.
  • target cells also includes, but is not limited to, microorganisms such as bacteria, viruses, fungi, parasites, and infectious agents.
  • target cell is not limited to living cells but also includes infectious organic particles such as viruses.
  • target compositions or “target biological components” include, but are not be limited to: toxins, peptides, polymers, and other compounds that may be selectively and specifically identified as an organic target that is intended to be visualized in imaging techniques using the compositions of the present invention.
  • therapeutic agent or “drug” as used herein refers to any compound or composition having preventive, therapeutic or diagnostic activity, primarily but not exclusively in the treatment of patients with macrophage (myeloid cell)-related diseases.
  • myeloid cells include monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, and megakaryocytes to platelets.
  • microphage-associated includes diseases associated with macrophages as disclosed in Low and Turk, US 8,916,167, herein incorportaed by reference in its entirety.
  • plaque includes, for example, an atherosclerotic plaque.
  • myeloid cell-mediated pathology refers to any condition in which an inappropriate myeloid cell response is a component of the pathology.
  • the term is intended to include both diseases directly mediated by myeloid cells, and also diseases in which an inappropriate myeloid cell response contributes to the production of abnormal antibodies, antibodies, as well as graft rejection.
  • ligand-induced myeloid cell activation refers to myeloid cell activation in response to the stimulation by the specific ligand.
  • stimulation refers to a primary response induced by ligation of a cell surface moiety.
  • such stimulation entails the ligation of a receptor and a subsequent signal transduction event.
  • stimulation of a myeloid cell refers to the ligation of a myeloid cell surface moiety that in one embodiment subsequently induces a signal transduction event, such as binding the TREM- l/DAP- 12 complex.
  • the stimulation event may activate a cell and up-regulate or down- regulate expression or secretion of a molecule.
  • ligand refers to a stimulating molecule that binds to a defined population of cells.
  • the ligand may bind any cell surface moiety, such as a receptor, an antigenic determinant, or other binding site present on the target cell population.
  • the ligand may be a protein, peptide, antibody and antibody fragments thereof, fusion proteins, synthetic molecule, an organic molecule (e.g., a small molecule), or the like.
  • the ligand or antigen
  • activation refers to the state of a cell following sufficient cell surface moiety ligation to induce a noticeable biochemical or morphological change.
  • myeloid cells such activation, refers to the state of a myeloid cell that has been sufficiently stimulated to induce production of interleukin (IL) 1, 6 and/or 8 (IL-l, IL-6 and/or IL-8, respectively) and tumor necrosis factor alpha (TNF-alpha), differentiation of primary monocytes into immature dendritic cells, and enhancement of inflammatory responses to microbial products.
  • IL interleukin
  • IL-8 interleukin-8
  • TNF-alpha tumor necrosis factor alpha
  • inhibitory myeloid cell activation refers to the slowing of myeloid cell activation, as well as completely eliminating and/or preventing myeloid cell activation.
  • treating a disease or condition refers to modulating myeloid cell activation including, but not limited to, decreasing cytokine production and differentiation of primary monocytes into immature dendritic cells and/or slowing myeloid cell activation, as well as completely eliminating and/or preventing myeloid cell activation.
  • Myeloid cell-related diseases and / or conditions treatable by modulating myeloid cell activation include, but are not limited to, cancer including but not limited to lung cancer, pancreatic cancer, multiple myeloma, melanoma, leukemia, prostate cancer, breast cancer, liver cancer, bladder cancer, stomach cancer, prostate cancer, colon cancer, colorectal cancer, CNS cancer, melanoma, ovarian cancer, gastrointestinal cancer, renal cancer, or osteosarcoma and other cancers, brain and skin cancers, endometrial cancer, esophageal cancer, kidney cancer, thyroid cancer, neuroblastoma, neurofibroma, glioma, glioblastoma, glioblastoma multiforme, head and neck cancer, cervical cancer, giant cell tumor of the tendon sheath (GCTTS), tenosynovial giant cell tumor (TGCT; also referred to in the art as TSGCT), PVNS and other cancers in which myeloid cells are involved or recruited, cancer cache
  • exemplary cancers include, but are not limited to, adrenocortical carcinoma, acquired immune deficiency syndrome (AIDS)-related cancers, AIDS-related lymphoma, anal cancer, anorectal cancer, cancer of the anal canal, appendix cancer, childhood cerebellar astrocytoma, childhood cerebral astrocytoma, basal cell carcinoma, skin cancer (non-melanoma), biliary cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, uringary bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain cancer, brain tumor, brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodeimal tumors, visual pathway and hypothalamic glioma, bronchial
  • detectable refers to the ability to detect a signal over the background signal.
  • a detectably effective amount of the labeled probe of the present disclosure is defined as an amount sufficient to yield an acceptable image using equipment that is available for clinical use.
  • a detectably effective amount of the labeled probe of the present disclosure may be administered in more than one injection.
  • the detectably effective amount of the labeled probe of the present disclosure can vary according to factors such as the degree of susceptibility of the individual, the age, sex, and weight of the individual, idiosyncratic responses of the individual, and the like.
  • Detectably effective amounts of the probe of the present disclosure can also vary according to instrument and film-related factors. Optimization of such factors is well within the level of skill in the art.
  • in vivo imaging refers to methods or processes in which the structural, functional, molecular, or physiological state of a living being is examinable without the need for a life-ending sacrifice.
  • inhibiting T cell activation refers to the slowing of T cell activation, as well as completely eliminating and/or preventing T cell activation.
  • T cell-mediated pathology refers to any condition in which an inappropriate T cell response is a component of the pathology.
  • the term is intended to include both diseases directly mediated by T cells, and also diseases in which an inappropriate T cell response contributes to the production of abnormal antibodies, as well as graft rejection.
  • treating a T cell-mediated disease or condition refers to modulating T cell activation including, but not limited to, decreasing cellular proliferation, cytokine production and performance of regulatory or cytolytic effector functions and/or slowing T cell activation, as well as completely eliminating and/or preventing T cell activation.
  • T cell- related diseases and/or conditions treatable by modulating T cell activation include, but are not limited to, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, type I diabetes, gastroenterological conditions e.g.
  • inflammatory bowel disease Crohn’s disease, celiac, Guillain-Barre syndrome, Hashimotos disease, pernicious anaemia, primary biliary cirrhosis, chronic active hepatitis; skin problems e.g. atopic dermatitis, psoriasis, pemphigus vulgaris; cardiovascular problems e.g. autoimmune pericarditis, allergic diathesis e.g. delayed type hypersensitivity, contact dermatitis, AIDS virus, herpes simplex/zoster, respiratory conditions e.g. allergic alveolitis, inflammatory conditions e.g. myositis, ankylosing spondylitis, tissue/organ rejection.
  • skin problems e.g. atopic dermatitis, psoriasis, pemphigus vulgaris
  • cardiovascular problems e.g. autoimmune pericarditis, allergic diathesis e.g. delayed type hypersensitivity, contact dermatitis, AIDS virus, herpe
  • the term,“subject” or“patient”, as used herein, refers to any individual organism.
  • the organism may be a mammal, such as a primate (i.e., for example, a human) or a laboratory animal.
  • the organism may be a domesticated animal (i.e., for example, cats, dogs, etc.), livestock (i.e., for example, cattle, horses, pigs, sheep, goats, etc.), or a laboratory animal (i.e., for example, mouse, rabbit, rat, guinea pig, etc.).
  • “therapeutically effective amount”,“therapeutically effective dose” or “effective amount”, as used herein, refers to an amount needed to achieve a desired clinical result or results (e.g. inhibiting receptor-mediated cell activation) based upon trained medical observation and/or quantitative test results.
  • the potency of any administered peptide or compound determines the“effective amount” which can vary for the various compounds that inhibit myeloid cell activation (i.e., for example, compounds inhibiting TREM ligand-induced myeloid cell activation and/or TCR-mediated T cell activation).
  • the“effective amount” of a compound may vary depending on the desired result, for example, the level of myeloid cell activation inhibition desired.
  • The“therapeutically effective amount” necessary for inhibiting differentiation of primary monocytes into immature dendritic cells may differ from the “therapeutically effective amount” necessary for preventing or inhibiting cytokine production.
  • agent refers to any natural or synthetic compound (i.e., for example, a peptide, a peptide variant, or a small molecule).
  • induced helicity refers to the helicity which is adopted by a peptide in an aqueous solution.
  • a helicity inducer including, but not limited to, trifluoroethanol (TFE), detergents (e.g., sodium dodecyl sulfate, SDS) or lipids.
  • therapeutic drug refers to any pharmacologically active substance capable of being administered which achieves a desired effect.
  • Drugs or compounds can be synthetic or naturally occurring, non-peptide, proteins or peptides, oligonucleotides or nucleotides, polysaccharides or sugars.
  • Drugs or compounds may have any of a variety of activities, which may be stimulatory or inhibitory, such as antibiotic activity, antiviral activity, antifungal activity, steroidal activity, cytotoxic, cytostatic, anti-proliferative, anti-inflammatory, analgesic or anesthetic activity, or can be useful as contrast or other diagnostic agents.
  • an effective dose refers to the concentration of any compound or drug contemplated herein that results in a favorable clinical response.
  • an effective dose may range between approximately 1 ng/ml and 100 mg/ml, preferably between 100 ng/ml and 10 mg/ml, but more preferably between 500 ng/ml and 1 mg/ml.
  • effective amount or “therapeutically effective amount” refers to an amount of a drug effective to treat a disease or disorder in a subject.
  • an effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result.
  • a therapeutically effective amount of the compound or composition of the invention that modulate TREM-1/DAP-12 receptor complex signaling may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the compound or composition to elicit a desired response in the individual.
  • therapeutically effective amount encompasses an amount in which any toxic or detrimental effects of the compound or composition are outweighed by the therapeutically beneficial effects.
  • the expression "effective amount” refers to an amount of the compound or composition that is effective for treating cancer.
  • prophylactically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, but not necessarily, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount would be less than the therapeutically effective amount.
  • induction therapy refers to the first treatment given for a disease. It is often part of a standard set of treatments, such as surgery followed by chemotherapy and radiation. When used by itself, induction therapy is the one accepted as the best treatment. If it doesn’t cure the disease or it causes severe side effects, other treatment may be added or used instead. Also called first- line therapy, primary therapy, and primary treatment.
  • a “maintenance therapy” refers to a medical therapy that is designed to help a primary treatment succeed.
  • maintenance chemotherapy may be given to people who have a cancer in remission in an attempt to prevent a relapse.
  • This form of treatment is also a common approach for the management of many incurable, chronic diseases such as periodontal disease, Crohn's disease or ulcerative colitis.
  • Administration "in combination with” one or more further therapeutic agents includes simultaneous (concurrent) and consecutive (sequential) administration in any order.
  • a “pharmaceutically acceptable carrier” refers to a non-toxic solid, semisolid, or liquid filler, diluent, encapsulating material, formulation auxiliary, or carrier conventional in the art for use with a therapeutic agent that together comprise a "pharmaceutical composition" for administration to a subject.
  • a pharmaceutically acceptable carrier is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation.
  • the pharmaceutically acceptable carrier is appropriate for the formulation employed.
  • the carrier may be a gel capsule. If the therapeutic agent is to be administered subcutaneously, the carrier ideally is not irritable to the skin and does not cause injection site reaction.
  • administering refers to any method of providing a drug or compound to a patient such that the drug or compound has its intended effect on the patient.
  • one method of administering is by an indirect mechanism using a medical device such as, but not limited to a catheter, syringe etc.
  • a second exemplary method of administering is by a direct mechanism such as, local tissue administration (i.e., for example, extravascular placement), oral ingestion, transdermal patch, topical, inhalation, suppository etc.)
  • agent refers to any natural or synthetic compound (i.e., for example, a peptide, a peptide variant, or a small molecule).
  • composition refers to any mixture of substances comprising a peptide and/or compound contemplated by the present invention. Such a composition may include the substances individually or in any combination.
  • modulator refers to a substance and/or compositions contemplated by the present invention or a combination thereof with capacity to inhibit (e.g., “antagonist” activity) a functional property of biological activity or process (e.g., reducing or blocking TREM-1/DAP-12 activity - signaling and/or activation); such inhibition can be contingent on the occurrence of a specific event, such as reduction or blockade of a signal transduction pathway, and/or can be manifest only in particular cell types. For instance, small molecules such as drugs, proteins such as antibodies, hormones or growth factors, protein domains, protein motifs, and peptides or a combination thereof can act as a modulator.
  • tissue sample refers to a collection of similar cells obtained from a tissue of a subject.
  • the source of the tissue sample may be solid tissue as from a fresh, frozen and/or preserved organ or tissue sample or biopsy or aspirate; blood or any blood constituents; bodily fluids such as cerebral spinal fluid, amniotic fluid, peritoneal fluid, synovial fluid, or interstitial fluid; cells from any time in gestation or development of the subject.
  • a tissue sample is a synovial biopsy tissue sample and/or a synovial fluid sample.
  • a tissue sample is a synovial fluid sample.
  • the tissue sample may also be primary or cultured cells or cell lines.
  • the tissue sample is obtained from a disease tissue/organ.
  • the tissue sample may contain compounds that are not naturally intermixed with the tissue in nature such as preservatives, anticoagulants, buffers, fixatives, nutrients, antibiotics, or the like.
  • a "control sample” or “control tissue”, as used herein, refers to a sample, cell, or tissue obtained from a source known, or believed, not to be afflicted with the disease for which the subject is being treated.
  • a "section" of a tissue sample means a part or piece of a tissue sample, such as a thin slice of tissue or cells cut from a solid tissue sample.
  • anti-inflammatory drug means any compound, composition, or drug useful for preventing or treating inflammatory disease.
  • medical device refers broadly to any apparatus used in relation to a medical procedure. Specifically, any apparatus that contacts a patient during a medical procedure or therapy is contemplated herein as a medical device. Similarly, any apparatus that administers a drug or compound to a patient during a medical procedure or therapy is contemplated herein as a medical device.
  • Direct medical implants include, but are not limited to, urinary and intravascular catheters, dialysis catheters, wound drain tubes, skin sutures, vascular grafts and implantable meshes, intraocular devices, implantable drug delivery systems and heart valves, and the like.
  • “Wound care devices” include, but are not limited to, general wound dressings, non-adherent dressings, bum dressings, biological graft materials, tape closures and dressings, surgical drapes, sponges and absorbable hemostats.
  • Surgical devices include, but are not limited to, surgical instruments, endoscope systems (i.e., catheters, vascular catheters, surgical tools such
  • a medical device is “coated” when a medium comprising an anti-inflammatory drug (i.e., for example, the peptides, compositions, and compounds of the present invention) becomes attached to the surface of the medical device.
  • This attachment may be permanent or temporary. When temporary, the attachment may result in a controlled release of an inflammatory drug.
  • compositions and methods of treating cancer and other diseases related to activated immune cells using modulators of the TREM-1/DAP-12 signaling pathway modulate TREM- 1 -mediated immunological response as standalone and combination-therapy treatment regimen. Further, methods are provided for predicting the efficacy of TREM-l modulatory therapies in patients.
  • the present invention relates to targeted treatment, prevention and/or detection of cancer including but not limited to lung cancer including non-small cell lung cancer, pancreatic cancer, giant cell tumor of the tendon sheath, tenosynovial giant cell tumor, pigmented villonodular synovitis, cancer cachexia, etc., and other cancers associated with myeloid cell activation and recruitment. Additionally, the present invention relates to the targeted treatment, prevention and/or detection of scleroderma including but not limited to calcinosis, Raynaud’s phenomenon, esophageal dysmotility, scleroderma, or telangiectasia syndrome (CREST). The invention further relates to personalized medical treatments.
  • lung cancer including non-small cell lung cancer, pancreatic cancer, giant cell tumor of the tendon sheath, tenosynovial giant cell tumor, pigmented villonodular synovitis, cancer cachexia, etc.
  • scleroderma including but not limited to calcino
  • each trifunctional peptide is capable of at least three functions: 1) mediating formation of naturally long half-life lipopeptide/lipoprotein particles upon interaction with lipoproteins, 2) facilitation of the targeted delivery to cells of interest and/or sites of disease, and 3) treatment, prevention, and/or detection of a disease or condition.
  • the present invention relates to amphipathic trifunctional peptides consisting of two amino acid domains, wherein upon interaction with plasma lipoproteins, one amino acid domain mediates formation of naturally long half-life
  • lipopeptide/lipoprotein particles and targets these particles to macrophages, whereas the other amino acid domain inhibits the TREM-1/DAP-12 receptor signaling complex expressed on macrophages.
  • trifunctional peptides of the present invention are capable of executing at least, three functions (trifunctional peptides): 1) assistance in the self-assembly of naturally long half-life lipopeptide particles upon binding to lipid or lipid mixtures in vitro , i.e. incorporation of the trifunctional peptides as part of the lipid portion of synthetic/recombinant HDLs, then after administration; 2) facilitation of the targeted delivery to cells of interest and/or sites of disease, and 3) treatment, prevention, and/or detection of a disease or condition.
  • trifunctional peptides 1) assistance in the self-assembly of naturally long half-life lipopeptide particles upon binding to lipid or lipid mixtures in vitro , i.e. incorporation of the trifunctional peptides as part of the lipid portion of synthetic/recombinant HDLs, then after administration; 2) facilitation of the targeted delivery to cells of interest and/or sites of disease, and 3) treatment, prevention, and/or detection of a disease
  • trifunctional peptides after mixing with lipids in vitro, may assist in the self-assembly of synthetic lipopeptide particles (SLP) upon binding to a lipid or to lipids in mixtures.
  • SLP synthetic lipopeptide particles
  • the SLP of interest are synthetic nanoparticles that mimic human lipoproteins as recombinant (r)HDLs. While not being bound to any particular theory, it is believed that this interaction and ability to form lipopeptide/lipoprotein particles is mediated by the amphipathic alpha helical sequences of the trifunctional peptides described herein.
  • trifunctional peptides of the present invention were synthesized and used for targeted treatment and imaging in vivo, as either formulations with HDLs or without, i.e. trifunctional peptides in a pharmaceutical formulation without HDLs.
  • trifunctional peptides described herein in order to solve numerous problems administering therapeutic or diagnostic compounds include avoiding high dosages of other TAs (therapeutic agents) and imaging probes required; and the lack of control and reproducibility of formulations, especially in large-scale production.
  • Therapeutic peptides have relatively high synthetic and production costs, For example, the production cost of a 5000 Da molecular mass peptide exceeds the production cost of a 500 Da molecular mass small molecule, which in turn exceeds the production cost of a 500 Da molecular mass small molecule by more than lO-fold up to less than lOO-fold for each increase in magnitude of size.
  • the production cost of a 5000 Da molecular mass peptide exceeds the production cost of a 500 Da molecular mass small molecule, which in turn exceeds the production cost of a 500 Da molecular mass small molecule by more than lO-fold up to less than lOO-fold for each increase in magnitude of size.
  • the present invention encompasses the discovery that it is possible to combine multiple functions in one polypeptide amino acid sequence, i.e. a trifunctional peptide, in order to confer a variety of properties on the resulting amphipathic multipeptide.
  • each trifunctional peptide is capable of at least three functions: 1) mediating formation of naturally long half-life lipopeptide/lipoprotein particles upon interaction with lipoproteins, 2) facilitation of the targeted delivery to cells of interest and/or sites of disease, and 3) treatment, prevention, and/or detection of a disease or condition.
  • each trifunctional peptide is capable of at least three functions: 1) mediating the self-assembly of naturally long half-life lipopeptide particles upon binding to lipid or lipid mixtures, 2) facilitation of the targeted delivery to cells of interest and/or sites of disease, and 3) treatment, prevention, and/or detection of a disease or condition.
  • the present invention relates to amphipathic trifunctional peptides consisting of two amino acid domains, wherein upon interaction with plasma lipoproteins, one amino acid domain mediates formation of naturally long half-life lipopeptide/lipoprotein particles and targets these particles to macrophages, whereas the other amino acid domain inhibits the TREM- 1/DAP-12 receptor signaling complex expressed on macrophages.
  • the invention further relates to personalized medical treatments for cancer that involve targeting specific cancers by their tumor environment.
  • trifunctional peptides of the present invention comprise two amino acid domains (See FIG. 1): domain A that confers therapeutic and/or diagnostic benefits in the context of the treatment, prevention, and/or detection of a disease or condition; and domain B that confers multiple benefits in the context of: 1A) formation of long half-life lipopeptide particles upon binding to lipid or lipid mixtures in vitro 1B) formation of long half- life LP upon interaction with lipoproteins in vivo , and 2) the targeted delivery of the particles formed to cells of interest and/or sites of disease or condition.
  • the present invention includes a resulting trifunctional peptide comprising: (a) one amino acid domain that confers therapeutic and/or diagnostic benefits in the context of the treatment, prevention, and/or detection of a disease or condition; and (b) another amino acid domain that confers multiple benefits in the context of the self-assembly of naturally long half-life SLP and LP upon binding to lipid or lipid mixtures and targeted delivery of the particles formed to cells of interest and/or sites of disease or condition.
  • any or both the domains comprise minimal biologically active amino acid sequence.
  • the first amino acid domain comprises a cyclic peptide sequence.
  • the first amino acid domain comprises a disulfide-linked dimer.
  • any or both of the amino acid domains include amino acids selected from the group of natural and unnatural amino acids including, but not limited to, L-amino acids, or D-amino acids.
  • one or both amino acid domains of the peptides and compounds of the present invention are conjugated to a drug compound (therapeutic agent: TA).
  • a therapeutic agent is selected from the group including, but not limited to, anticancer, antibacterial, antiviral, autoimmune, anti-inflammatory and cardiovascular agents, antioxidants, and therapeutic peptides.
  • the therapeutic agent is a hydrophobic therapeutic agent.
  • the therapeutic agent may also be selected from the group comprising paclitaxel, valrubicin, doxorubicin, taxotere, campotechin, etoposide, and any combination thereof.
  • one or both amino acid domains of the peptides and compounds of the present invention are conjugated to an imaging probe.
  • the imaging agent is a Gd-based contrast agent (GBCA) for magnetic resonance imaging (MRI).
  • the imaging agent is a [ 64 Cu] -containing imaging probe for imaging systems such as a positron emission tomography (PET) imaging systems (and combined PET/computer tomography (CT) and PET/MRI systems).
  • PET positron emission tomography
  • CT computer tomography
  • an imaging probe and/or an additional therapeutic agent is conjugated to any or both of the domains.
  • the peptides and compounds of the present invention are used in combinations thereof.
  • the trifunctional peptides of the present invention may be administered within rHDLs, or administered in pharmaceutical formulations as part of rHDLs. In other embodiments, the trifunctional peptides of the present invention may be administered without rHDLs, or administered in pharmaceutical formulations without rHDLs.
  • the peptides of the present invention form lipopeptide particles in vitro. In one embodiment, the peptides of the present invention form lipopeptide particles in vivo. In certain embodiments, the present invention relates to peptides consisting of two amino acid domains, wherein upon binding to lipid or lipid mixtures, one amino acid domain assists in the self-assembly of naturally long half-life lipopeptide particles and targets these particles to macrophages, whereas another amino acid domain inhibits TREM-1/DAP-12 receptor complex expressed on macrophages.
  • the present invention relates to peptides comprising at least two amino acid domains, wherein upon binding to lipid or lipid mixtures, the first amino acid domain assists in the self-assembly of naturally long half-life lipopeptide particles and targets these particles to macrophages, whereas the second amino acid domain inhibits TREM-1/DAP-12 receptor complex expressed on macrophages.
  • the peptides of the present invention self-assemble upon binding to lipid or lipid mixtures in vitro to form synthetic lipopeptide particles (SLP) that mimic human lipoproteins and have a long half-life in a bloodstream.
  • SLP synthetic lipopeptide particles
  • the peptides and compounds of the present invention interact with endogenous lipoproteins in vivo and form long half-life LP.
  • the peptides and compounds of the present invention are used in combinations thereof.
  • peptides and compounds of the present invention and combinations thereof alone as well as the SLP formed upon their binding to lipid or lipid mixtures have a wide variety of uses, particularly in the areas of oncology, transplantology, dermatology, hepatology, ophthalmology, cardiovascular diseases, sepsis, autoimmune diseases, neurodegenerative diseases and other diseases and conditions. They also are useful in the production of medical devices (for example, medical implants and implantable devices).
  • the invention disclosed herein provides for methods of treating cancer using inhibitors of the TREM-l pathway. These inhibitors include peptide variants and compositions that modulate the TREM-l -mediated immunological responses beneficial for the treatment of cancer.
  • the invention also provides for predicting the efficacy of TREM-l -targeted therapies in various cancers by analyzing biological samples for the presence of myeloid cells and for the TREM-l expression levels.
  • the present invention relates to the targeted treatment, prevention and/or detection of cancer including but not limited to pancreatic cancer, breast cancer, liver cancer, multiple myeloma, leukemia, bladder cancer, CNS cancer, stomach cancer, prostate, colorectal cancer, brain cancer, ovarian cancer, renal cancer, skin cancer, osteosarcoma and other cancers and cancer cachexia.
  • cancer including but not limited to pancreatic cancer, breast cancer, liver cancer, multiple myeloma, leukemia, bladder cancer, CNS cancer, stomach cancer, prostate, colorectal cancer, brain cancer, ovarian cancer, renal cancer, skin cancer, osteosarcoma and other cancers and cancer cachexia.
  • the invention disclosed herein provides for methods of treating cancer using inhibitors of the TREM-l pathway. These inhibitors include peptide variants and compositions that modulate the TREM-l -mediated immunological responses beneficial for the treatment of cancer.
  • the invention also provides for predicting the efficacy of TREM-l -targeted therapies in various cancers by analyzing biological samples for the presence of myeloid cells and for the TREM-l expression levels.
  • the present invention relates to the targeted treatment, prevention and/or detection of cancer including but not limited to pancreatic cancer, breast cancer, liver cancer, multiple myeloma, leukemia, bladder cancer, CNS cancer, stomach cancer, prostate, colorectal cancer, brain cancer, ovarian cancer, renal cancer, skin cancer, osteosarcoma and other cancers and cancer cachexia.
  • cancer including but not limited to pancreatic cancer, breast cancer, liver cancer, multiple myeloma, leukemia, bladder cancer, CNS cancer, stomach cancer, prostate, colorectal cancer, brain cancer, ovarian cancer, renal cancer, skin cancer, osteosarcoma and other cancers and cancer cachexia.
  • the invention disclosed herein provides for methods of treating cancer using modulators of the TREM-1/DAP-12 signaling pathway. These compounds and compositions modulate the TREM-l -mediated immunological responses beneficial for the treatment of cancer in standalone and combination-therapy treatment regimen. The invention also provides for predicting the efficacy of TREM-l modulatory therapies in patients with various cancers.
  • the present invention relates to the targeted treatment, prevention and/or detection of cancer including but not limited to lung cancer including non-small cell lung cancer, pancreatic cancer, breast cancer, liver cancer, multiple myeloma, melanoma, leukemia, bladder cancer, central nervous system cancer, stomach cancer, prostate cancer, colorectal cancer, colon cancer, brain cancer, gastrointestinal cancer, gastric cancer, ovarian cancer, renal cancer, skin cancer, osteosarcoma, endometrial cancer, esophageal cancer, kidney cancer, thyroid cancer, neuroblastoma, neurofibroma, glioma, glioblastoma, glioblastoma multiforme, head and neck cancer, cervical cancer, giant cell tumor of the tendon sheath, tenosynovial giant cell tumor, pigmented villonodular synovitis, and other cancers in which myeloid cells are involved or recruited and cancer cachexia.
  • lung cancer including non-small cell lung cancer, pancreatic cancer, breast cancer, liver cancer
  • the invention disclosed herein provides for methods of treating cancer using inhibitors of the TREM-l pathway. These inhibitors include peptide variants and compositions that modulate the TREM-l -mediated immunological responses beneficial for the treatment of cancer.
  • the invention also provides for predicting the efficacy of TREM-l -targeted therapies in various cancers by analyzing biological samples for the presence of myeloid cells and for the TREM-l expression levels.
  • the present invention relates to the targeted treatment, prevention and/or detection of cancer including but not limited to pancreatic cancer, breast cancer, liver cancer, multiple myeloma, leukemia, bladder cancer, CNS cancer, stomach cancer, prostate, colorectal cancer, brain cancer, ovarian cancer, renal cancer, skin cancer, osteosarcoma and other cancers and cancer cachexia.
  • cancer including but not limited to pancreatic cancer, breast cancer, liver cancer, multiple myeloma, leukemia, bladder cancer, CNS cancer, stomach cancer, prostate, colorectal cancer, brain cancer, ovarian cancer, renal cancer, skin cancer, osteosarcoma and other cancers and cancer cachexia.
  • the invention disclosed herein provides for methods of treating scleroderma using modulators of the TREM-1/DAP-12 signaling pathway. These compounds and compositions modulate the TREM-l -mediated immunological responses beneficial for the treatment of scleroderma or a related autoimmune or a fibrotic condition in standalone and combination- therapy treatment regimen.
  • the invention also provides for predicting the efficacy of TREM-l modulatory therapies in patients with scleroderma.
  • the present invention relates to the targeted treatment, prevention and/or detection of scleroderma including but not limited to calcinosis, Raynaud’s phenomenon, esophageal dysmotility, scleroderma, or telangiectasia syndrome (CREST).
  • the present invention relates to the targeted treatment, prevention and/or detection of cancer including but not limited to lung, pancreatic, breast, stomach, prostate, colon, brain and skin cancers, cancer cachexia, atherosclerosis, allergic diseases, acute radiation syndrome, inflammatory bowel disease, empyema, acute mesenteric ischemia, hemorrhagic shock, multiple sclerosis, autoimmune diseases, including but not limited to, atopic dermatitis, lupus, scleroderma, rheumatoid arthritis and other rheumatic diseases, sepsis and other inflammatory diseases or other condition involving myeloid cell activation and, more particularly, TREM receptor-mediated cell activation, including but not limited to diabetic retinopathy and retinopathy of prematurity, Alzheimer's, Parkinson's and Huntington's diseases.
  • cancer including but not limited to lung, pancreatic, breast, stomach, prostate, colon, brain and skin cancers, cancer cachexia, atherosclerosis, allergic diseases, acute radiation syndrome,
  • the disclosure also provides for a method of treating, preventing and/or detecting an immune-related condition.
  • the method comprises providing a composition comprising peptides and compounds of the present disclosure and/or a synthetic nanoparticle formed upon their binding to lipid or lipid mixtures, a patient having at least one symptom of a disease or condition in which the immune system is involved, and administering the composition to the patient under conditions such that said one symptom is reduced.
  • the immune-related condition of the method may include a heart disease, atherosclerosis, peripheral artery disease, restenosis, stroke, multiple sclerosis, the cancers (e.g., sarcoma, lymphoma, leukemia, carcinoma and melanoma), bacterial infectious diseases, acquired immune deficiency syndrome (AIDS), allergic diseases, autoimmune diseases (e.g., atopic dermatitis, psoriasis, rheumatoid arthritis, Sjogren's syndrome, scleroderma, systemic lupus erythematosus, non-specific vasculitis, Kawasaki's disease, psoriasis, type I diabetes, pemphigus vulgaris), granulomatous diseases (e.g., tuberculosis, sarcoidosis, lymphomatoid granulomatosis, Wegener's granulomatosus), Gaucher’s disease, inflammatory diseases (e.g., sepsis, inflammatory
  • the invention relates to personalized medical treatments for scleroderma. More specifically, the invention provides for treatment of scleroderma or a related autoimmune or a fibrotic condition by using inhibitors of the TREM-1/DAP-12 pathway. These inhibitors include peptide variants and compositions that modulate the TREM- 1 -mediated immunological responses beneficial for the treatment of scleroderma. In addition, the invention provides for predicting the efficacy of TREM- 1 -targeted therapies in scleroderma by analyzing biological samples for the presence of myeloid cells and for the TREM-l expression levels. In one embodiment, the peptides and compositions of the present invention modulate TREM-1/DAP-12 receptor complex expressed on macrophages.
  • the peptides and compositions of the invention are conjugated to an imaging probe.
  • the invention provides for detecting the TREM-l -expressing cells and tissues in an individual with scleroderma using imaging techniques and the peptides and compositions of the invention containing an imaging probe.
  • the peptides and compositions of the invention are used in combinations thereof.
  • the peptides and compositions of the invention are used in combinations with other antifibrotic therapeutic agents.
  • the present invention relates to the targeted treatment, prevention and/or detection of scleroderma including but not limited to calcinosis, Raynaud’s phenomenon, esophageal dysmotility, scleroderma, or telangiectasia syndrome (CREST).
  • scleroderma including but not limited to calcinosis, Raynaud’s phenomenon, esophageal dysmotility, scleroderma, or telangiectasia syndrome (CREST).
  • the SLP self-assembled upon binding of the peptides and compounds of the present invention and combinations thereof to lipid or lipid mixtures are discoidal or spherical in shape. While the size of the particles is preferably between 5 nm and 50 nm, the diameter may be up to 200 nm.
  • the lipid of the particles may include cholesterol, a cholesteryl ester, a phospholipid, a glycolipid, a sphingolipid, a cationic lipid, a diacylglycerol, or a triacylglycerol.
  • the phospholipid may include phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), phosphatidylglycerol (PG), cardiolipin (CL), sphingomyelin (SM), or phosphatidic acid (PA).
  • the cationic lipid can be l,2-dioleoyl-3- trimethylammonium-propane (DOTAP).
  • the lipid of the synthetic nanoparticle may be polyethylene glycol(PEG)ylated.
  • the peptides and compounds of the present invention and/or the SLP and LP formed by these peptides and compounds may pass the blood-brain barrier (BBB). In one embodiment, the peptides and compounds of the present invention and/or the SLP and LP formed by these peptides and compounds may pass the blood- retinal barrier (BRB). In one embodiment, the peptides and compounds of the present invention and/or the SLP and LP formed by these peptides and compounds may pass the blood-tumor barrier (BTB).
  • BBB blood-brain barrier
  • BBB blood-brain barrier
  • BBB blood- retinal barrier
  • BTB blood-tumor barrier
  • the peptides and compounds of the present invention include an amino acid sequence derived from apo A-I, A-II, A-IV, B, C-I, C-II, C-III, or E. In one embodiment, the peptides and compounds of the present invention include an amino acid sequence derived from apo A-I, A-II, A-IV, B, C-I, C-II, C-III, or E and Arginine-glycine- aspartic acid (RGD)-peptide sequence. In certain embodiments, the peptides and compounds of the present invention include an amino acid sequence derived from transmembrane domain sequences of human or animal cell-surface receptors and of signaling subunits thereof.
  • the peptides and compounds of the present invention include an amino acid sequence derived from virus membrane fusion and structural proteins. In one embodiment, the peptides and compounds of the present invention include an amino acid sequence derived from apo A-I, A-II, A-IV, B, C-I, C-II, C-III, or E conjugated to a targeting moiety to enhance the targeting efficacy of the therapeutic agent.
  • the targeting moiety may include a polypeptide, an antibody, a receptor, a ligand, a peptidomimetic agent, an aptamer or a product of phage display.
  • the amino acid domains of the peptides and compounds of the present invention comprise unmodified or modified peptide sequences.
  • the modified peptide sequence may contain at least one amino acid residue which is chemically or enzymatically modified.
  • the modified amino acid residue may be an oxidized amino acid residue.
  • the oxidized amino acid residue may be a methionine residue.
  • the modified peptide sequence may contain at least one amino acid residue, which is oxidized, halogenated, or nitrated.
  • the modified peptide sequence may include an amphipathic amino acid sequence.
  • the present invention relates to the targeted treatment or prevention of inflammatory or other condition involving myeloid cell activation and, more particularly, TREM receptor-mediated cell activation, such as cancer including but not limited to, lung, pancreatic, breast, stomach, prostate, colon, brain and skin cancers, cancer cachexia, atherosclerosis, allergic diseases, acute radiation syndrome, inflammatory bowel disease, empyema, alcohol-induced liver disease, nonalcoholic fatty liver disease and non-alcoholic steatohepatitis, acute mesenteric ischemia, hemorrhagic shock, multiple sclerosis, sepsis, diabetic retinopathy and retinopathy of prematurity, Alzheimer's, Parkinson's and Huntington's diseases, autoimmune diseases, including but not limited to, atopic dermatitis, lupus, scleroderma, rheumatoid arthritis and other rheumatic diseases.
  • the present invention provides a pharmaceutical composition comprising the peptides and compounds and combinations
  • TREM-l-related Trifunctional peptides A. TREM-l-related Trifunctional peptides.
  • TREM-l is expressed on the majority of innate immune cells and to a lesser extent on parenchymal cells. Upon activation, TREM-l can directly amplify an inflammatory response. Although it was initially demonstrated that TREM-l was predominantly associated with infectious diseases, recent evidences demonstrate that TREM-l receptor and its signaling pathways contribute to the pathology of non-infectious acute and chronic inflammatory diseases, including but not limiting to, rheumatoid arthritis, atherosclerosis, ischemia reperfusion-induced tissue injury, colitis, fibrosis, neurodegenerative diseases, liver diseases, retinopathies, and cancer (see e.g., Tammaro, et al. Pharmacol Ther 2017, 177:81-95; Saadipour.
  • a resulting trifunctional peptide of the present invention comprises two amino acid domains, wherein one domain comprises a variant TREM-l inhibitory amino acid sequence and functions to inhibit TREM-1/DAP-12 receptor complex expressed on myeloid cells (e.g. macrophages), whereas another amino acid domain comprises the chemically and/or enzymatically modified amino acid sequence derived from apolipoprotein amino acid sequences and functions to assist in the self-assembly of SLP upon binding to lipid or lipid mixtures in vitro and/or to form LP in vivo, respectively, and to target these particles to myeloid cells (e.g. macrophages).
  • one domain comprises a variant TREM-l inhibitory amino acid sequence and functions to inhibit TREM-1/DAP-12 receptor complex expressed on myeloid cells (e.g. macrophages)
  • another amino acid domain comprises the chemically and/or enzymatically modified amino acid sequence derived from apolipoprotein amino acid sequences and functions to assist in the self-a
  • the TREM-l inhibitory amino acid domain is the N-terminal domain of a resulting peptide. In one embodiment, the TREM-l inhibitory amino acid domain is the C-terminal domain of a resulting peptide. In one embodiment, the TREM-l inhibitory amino acid domain comprises a cyclic peptide sequence. In one embodiment, the TREM-l inhibitory amino acid domain comprises a disulfide-linked dimer. In one embodiment, the TREM-l inhibitory amino acid domain includes the group of natural and unnatural amino acids including, but not limited to, L-amino acids, or D-amino acids. In one embodiment, an imaging agent is conjugated to the TREM-l inhibitory amino acid domain or to the apolipoprotein amino acid sequence-derived domain or to both.
  • TREM-l -related peptides and associated compositions of the present invention have a domain A conjugated to a domain B.
  • Domain A comprises a TREM-l modulatory peptide sequence designed using a known model of cell receptor signaling, the Signaling Chain HOmoOLigomerization model, capable of modulating TREM-l receptor expressed on myeloid cells (see e.g., Sigalov. Self Nonself 2010, 1 :4-39; Sigalov. Self Nonself 2010, 1 : 192-224; Sigalov. Trends Pharmacol Sci 2006, 27:518-524; Sigalov. Trends Immunol 2004, 25:583-589; Sigalov. Adv Protein Chem Struct Biol 2018, 111 :61-9; Sigalov. ETS 8,513,185; and Sigalov. ETS 9,981,004), all of which are herein incorporated by reference in their entirety.
  • peptides and compositions of this class further comprise the domain B comprising at least one modified or unmodified amphipathic alpha helical peptide fragment, such as a apo A-I and/or A-II peptide fragment, to form upon interaction with lipid and/or lipid mixtures.
  • exemplary trifunctional peptides comprise the domain B comprises with the amino acid sequence selected from the amino acid sequences of the major HDL protein constituent, apo A-I. In certain embodiments, this sequence comprises 22 amino acid residue-long peptide sequence of the apo A-I helix 4. In one embodiment, this sequence contains a modified amino acid residue. In one embodiment, this modified amino acid residue is methionine sulfoxide.
  • the domain B of the peptides and compositions of the invention comprises 22 amino acid residue-long peptide sequence of the apo A-I helix 6. In one embodiment, this sequence contains a modified amino acid residue. In one embodiment, this modified amino acid residue is methionine sulfoxide.
  • FIG. 1 presents an exemplary schematic representation of one embodiment of a trifunctional peptide of the present invention comprising amino acid domains A and B where amino acid domain A represents a therapeutic peptide sequence with or without an attached drug compound and/or imaging probe that functions to treat, prevent and/or detect a disease or condition, whereas amino acid domain B represents an amphipathic alpha helical peptide sequence, with or without an additional targeting peptide sequence, and functions to 1) assist in the self-assembly of synthetic lipoprotein/lipopeptide nanoparticles (SLP) upon interaction with lipids or lipid mixtures in vitro , for use in transporting these trifunctional peptides as lipoprotien nanoparticles to sites of interest in vitro or in vivo and/or 2) form long half-life lipopeptide/lipoprotein particles upon interaction with endogenous lipoproteins for transporting these trifunctional peptides to the sites of interest.
  • Endogenous lipoproteins may be lipoproteins added to or found in cell cultures
  • FIG. 2 shows the structures of representative TREM-l -related trifunctional peptides, TREM-l /TRIOPEP GE31
  • TREM-l /TRIOPEP GA31 GFL SKSLVFPLGEEMRDRARAHVD ALRTHL A
  • GFLSKSLVF is found within isoform 1 of human TREM-l (ETniProtKB - Q9NP99 (TREM 1 HUMAN), and in human TREM-l isoform CRA a
  • GFLSKSLVF is also described without an attached apo I peptide domain, in, for examples, WO 2011/047097 "Inhibition of trem receptor signaling with peptide variants.” Publication Date: 21.04.2011, US9981004B2 "Inhibition of TREM receptor signaling with peptide variants.” Published June 5, 2014, each of which is herein incorporated by reference in its entirety.
  • Sequence information was downloaded 10-25-, 10-26- or 10-27-2019.
  • GFLSKSLVF is not found within human TREM-l isoforms 2 or 3.
  • FIG. 2 presents schematic representations of embodiments of a TREM-l -related trifunctional peptide (TREM-l /TRIOPEP).
  • GE31 GFL SK SL VFP YLDDF QKKW QEEM(0)EL YRQK VE, M(O), methionine sulfoxide
  • GE31 comprises amino acid domain A and B (GFL SK SL VFP YLDDF QKKW QEEM(0)EL YRQK VE)
  • domain A represents a 9 amino acids-long human TREM-l inhibitory therapeutic SCHOOL peptide sequence and functions to treat and/or prevent a TREM-l -related disease or condition
  • domain B represents a 22 amino acids-long human apolipoprotein A-I helix 4 peptide sequence with a sulfoxidized methionine residue and functions to assist in the self-assembly of synthetic lipopeptide particles (SLP) in vitro for targeting the particles to myeloid cells (e.g
  • apo apolipoprotein
  • SCHOOL signaling chain homooligomerization
  • TREM-l triggering receptor expressed on myeloid cells-l . Imaging of TREM-1 expression.
  • FIG. 50 shows that the fluorescently labeled TREM-l /TRIOPEP peptide GE31 delivered to macrophages by the SLP particles colocalizes with TREM-l expressed on these cells. See also (Rojas et al. 2018). As described herein and in (Rojas et al. 2018), TREM-l inhibitory therapy using the modulators of the TREM-1/DAP-12 signaling pathway results in reduction of tissue TREM-l expression as measured by Western Blot (See Fig. 13).
  • the capability of the modulators of the TREM-1/DAP-12 signaling pathway described herein, including but not limited to, anti-TREM-l blocking antibodies and fragments thereof, TREM-l inhibitory SCHOOL peptides (e.g., GF9) and trifunctional TREM-l inhibitory peptides including but not limited to, GA31 and GE31, to colocalize with TREM-l can be used to visualize (image) this receptor and evaluate its expression/level in the areas of interest.
  • an imaging probe e.g. [ 64 Cu], see TABLE 3
  • an imaging probe can be conjugated to the peptide sequences, GE31
  • GFL SK SL VFP YLDDF QKKW QEEM(0)EL YRQK VE, M(O), methionine sulfoxide) (SEQ ID NO. 27) and/or GA31 (GFLSKSLVFPLGEEM(O)RDRARAHVDALRTHLA (M(O), methionine sulfoxide) (SEQ ID NO. 26).
  • methionine residues of the peptides GE31 GFL SKSL VFP YLDDF QKKWQEEMEL YRQK VE) (SEQ ID NO. 25) and GA31 (GFL SK SL VFPLGEEMRDRARAHVD ALRTHL A) (SEQ ID NO. 24) are unmodified.
  • imaging (visualization) of TREM-l levels using the labeled modulators described herein and the PET and/or other imaging techniques can be used to diagnose GBM and/or to select and monitor novel GBM therapies as disclosed in WO 2017083682A1 and described in (Johnson et al. 2017, Liu et al. 2019).
  • imaging (visualization) of TREM-l levels can be used to diagnose other TREM-l -related diseases and conditions as well as to monitor novel therapies for these diseases and conditions.
  • GF9 immunotherapy targets pathways restricted to pathological conditions and is highly competitive.
  • safe and effective GF9 therapies are contemplated for use on pancreatic cancer (PC) to be used in combination with standard first-line treatments: FOLFIRINOX (5-FU, leucovorin, irinotecan and oxaliplatin) or Gemzar® + ABRAXANE®.
  • advantages for using free GF9 peptide for treating PVNS include but are not limited to: Low toxicity; Proven efficacy in vivo, including joints; easy formulation development; easy scale-up process; Easy and fast GMP production; Low cost of production; and Stable and easy to store.
  • TREM-l -related trifunctional peptides and compositions of this class comprise the domain A comprising the TREM-l inhibitory peptide sequences LR12 and LP17 (described in Gibot, et al. Infect Immun 2006, 74:2823-2830; Gibot, et al. Shock 2009, 32:633-637; Gibot, et al. Eur J Immunol 2007, 37:456-466; Joffre, et al. J Am Coll Cardiol 2016, 68:2776-2793; Cuvier, et al. Br J Clin Pharmacol 2018, in press; Zhou, et al.
  • resulting trifunctional peptide sequences may be radiolabeled and/or contain unmodified or modified methionine residues (TABLE 2) including but not limiting to, the following sequences: LQEED AGE Y GCMPLGEEM(0)RDRARAHVD ALRTHL A (M(O), methionine sulfoxide (SEQ ID NO 7), LQEED AGEY GCMP YLDDF QKKW QEEM(0)ELYRQKVE (M(O), methionine sulfoxide (SEQ ID NO 8),
  • LQVTDSGLYRCVIYHPPPLGEEM(0)RDRARAHVDALRTHLA M(O), methinone sulfoxide (SEQ ID NO 9)
  • LQ VTD S GLYRCVIYHPPP YLDDF QKKW QEEM(0)EL YRQK VE M(O), methionine sulfoxide (SEQ ID NO 10).
  • SLP rHDL
  • SLP spherical or discoidal
  • Sigalov. Contrast Media Mol Imaging 2014, 9:372-382 Sigalov. Int Immunopharmacol 2014, 21 :208-219; Sigalov. US 20110256224; Sigalov. US 20130045161; Sigalov. US 20130039948; Shen, et al. PLoS One 2015, l0:e0l43453; Shen and Sigalov. Sci Rep 2016, 6:28672; Shen and Sigalov. J Cell Mol Med 2017, 21 :2524-2534; Shen and Sigalov.
  • amphipathic apo A-I sequences aids the assistance in the self-assembly of SLP and the structural stability of the particle formed, particularly when the particle has a discoidal shape. It further aids the ability to provide targeted delivery to the cells of interest. It further aids the ability to interact with lipids and/or lipoproteins in a bloodstream in vivo and form LP that mimic native lipoproteins. It further aids the ability to cross the BBB, BRB and BTB.
  • methionine residues of the peptides TREM-l/TRIOPEP GE31 GFL SK SLVFP YLDDF QKKW QEEMEL YRQK VE) (SEQ ID NO. 2) and TREM-l/TRIOPEP GA31 (GFLSKSLVFPLGEEMRDRARAHVDALRTHLA) (SEQ ID NO. 1) are unmodified.
  • interaction of TREM-l/TRIOPEP GA31 with lipids results in self-assembly of nanosized SLP of discoidal or spherical morphology (dSLP and sSLP, respectively) (see FIG. 3).
  • FIG. 3 presents a schematic representation of one embodiment of a TREM-l -related trifunctional peptide (TREM-l/TRIOPEP) of the present invention comprising amino acid domains A and B.
  • TREM-l/TRIOPEP TREM-l -related trifunctional peptide
  • sub 50 nm- sized SLP particles of discoidal (TREM- 1 /TRIOPEP-dSLP) or spherical (TREM- 1 /TRIOPEP- sSLP) morphology are self-assembled upon binding of the trifunctional peptide to lipids.
  • this provides targeted delivery of the SLP constituents including TREM-l/TRIOPEP to intraplaque macrophages in vivo (FIG. 4A). In one embodiment, this provides targeted delivery of the SLP constituents including TREM-l/TRIOPEP to tumor- associated macrophages (TAMs) in vivo (FIG. 4B).
  • FIG. 4A illustrates a hypothesized molecular mechanism of action of one embodiment of a trifunctional peptide (TRIOPEP) of the present invention comprising amino acid domains A and B where domain A represents a 9 amino acids-long TREM-l inhibitory therapeutic peptide sequence and functions to treat and/or prevent a TREM-l -related disease or condition (example, for atherosclerosis), whereas domain B represents a 22 amino acids-long apolipoprotein A-I helix 4 or 6 peptide sequence with a sulfoxidized methionine residue and functions to assist in the self-assembly of synthetic lipopeptide particles (SLP) and to target the particles to TREM-l - expressing macrophages as applied to the treatment and/or prevention of atherosclerosis.
  • SLP synthetic lipopeptide particles
  • FIG. 4B illustrates a hypothesized molecular mechanism of action of one embodiment of a trifunctional peptide (TRIOPEP) of the present invention comprising amino acid domains A and B where domain A is a 9 amino acids-long TREM-l inhibitory therapeutic peptide sequence and functions to treat and/or prevent a TREM-l -related disease or condition (example, for cancer), whereas domain B is a 22 amino acids-long apolipoprotein A-I helix 4 or 6 peptide sequence with a sulfoxidized methionine residue and functions to assist in the self-assembly of synthetic lipopeptide particles (SLP) and to target the particles to TREM-l -expressing macrophages as applied to the treatment and/or prevention of cancer.
  • SLP synthetic lipopeptide particles
  • FIG. 4C shows a symbol key used in FIGS. 4A-B.
  • this colocalization is accompanied by a specific disruption of intramembrane interactions between TREM-l and DAP-12 by the TREM-l -related trifunctional peptide of the present invention (see FIG. 5), resulting in ligand-independent inhibition of TREM-l upon ligand binding as described in Shen and Sigalov. Mol Pharm 2017, 14:4572-4582 and Shen and Sigalov. J Cell Mol Med 2017, 21 :2524-2534, each of which is herein incorporated by reference in its entirety.
  • FIG. 5 illustrates one embodiment of a specific disruption of intramembrane interactions between TREM-l and DAP-12 by the trifunctional peptide of the present invention comprising two amino acid domains A and B where domain A is a 9 amino acids-long TREM-l inhibitory therapeutic peptide sequence, whereas domain B is a 22 amino acids-long apolipoprotein A-I helix 4 or 6 peptide sequence with a sulfoxidized methionine residue. While not being bound to any particular theory, it is believed that this disruption results in“pre-dissociation” of a receptor complex and upon ligand stimulation, leads to inhibition of TREM-l and silencing the TREM-l signaling pathway.
  • FIG. 6 shows that the fluorescently labeled TREM-l /TRIOPEP peptide GE31 delivered to macrophages by the SLP particles of the present invention colocalizes with TREM-l expressed on these cells (see also Rojas, et al. Biochim Biophys Acta 2018, 1864:2761-2768, each of which is herein incorporated by reference in its entirety).
  • the capability of the TREM-l -related trifunctional peptides and compounds of the present invention including but not limiting to, TREM-l /TRIOPEP GA31 and TREM- l/TRIOPEP GE31, to colocalize with TREM-l can be used to visualize (image) this receptor and evaluate its expression in the areas of interest.
  • an imaging probe e.g. [ 64 Cu], see TABLE 2
  • TREM-l /TRIOPEP sequences GE31 (GFL SK SL VFP YLDDF QKKW QEEM(0)EL YRQK VE, M(O), methionine sulfoxide) (SEQ ID NO. 4) and GA31 (GFL SK SL VFPLGEEM(0)RDRARAHVD ALRTHL A (M(O), methionine sulfoxide) (SEQ ID NO. 3).
  • imaging (visualization) of TREM-l levels using PET and/or other imaging techniques can be used to diagnose glioblastoma multiforme (GBM) and/or to select and monitor novel GBM therapies (see e.g., Johnson, et al. Neuro Oncol 2017, l9:vi249 and James and Andreasson, WO 2017083682A1).
  • imaging (visualization) of TREM-l levels can be used to diagnose other TREM-l -related diseases and conditions as well as to monitor novel therapies for these diseases and conditions.
  • FIG. 6A-C shows images depicting colocalization of the sulfoxidized methionine residue- containing TREM-l -related trifunctional peptide (TREM-l /TRIOPEP) GE31 with TREM-l in the cell membrane (FIG. 6A), TREM-l immunohistochemstry staining (FIG. 6B) and a merged image (FIG. 6C).
  • TREM-l/TRIOPEP sulfoxidation of methionine residues in the TREM- l/TRIOPEP peptides GE31 and GA31 results in increased macrophage endocytosis of the SLP containing an equimolar mixture of these peptides (designated as TREM-l /TRIOPEP), TREM- l/TRIOPEP-dSLP and TREM-l/TRIOPEP-sSLP. Shen and Sigalov. Mol Pharm 2017, 14:4572- 4582 and Shen and Sigalov. J Cell Mol Med 2017, 21 :2524-2534, each of which is herein incorporated by reference in its entirety.
  • FIG. 7A-B presents the exemplary data showing the endocytosis of synthetic lipopeptide particles (SLP) of discoidal (dSLP) and spherical (sSLP) morphology that contain an equimolar mixture of the TREM-l -related trifunctional peptides (TREM-l /TRIOPEP) GA 31 and GE 31 (TREM- 1 /TRIOPEP-d SLP and TREM-l/TRIOPEP-sSLP, respectively).
  • SLP synthetic lipopeptide particles
  • dSLP discoidal
  • sSLP spherical
  • FIGS. 8 and 10 demonstrate that TREM-l /TRIOPEP in free and SLP -bound forms inhibits TREM-l function as shown by reduction of TREM-l -mediated release of pro-inflammatory cytokines, both in vitro (FIG. 8) and in vivo (in serum) (FIG. 10). While not being bound to any particular theory, it is believed that this indicates that similarly to TREM-l -inhibitory peptide GF9 (see e.g., Sigalov. Int Immunopharmacol 2014, 21 :208-219; Shen and Sigalov. Mol Pharm 2017, 14:4572-4582; and Shen and Sigalov.
  • TREM-l -related trifunctional peptides can reach their site of action from both outside (free TREM-l /TRIOPEP) and inside (SLP -bound TREM-l /TRIOPEP) the cell. It is also believed that upon administration, free TREM-l /TRIOPEP may form LP in vivo and/or interact with native lipoproteins, resulting in formation of HDL-mimi eking LP. In one embodiment, these LP may further target the cells of interest delivering their content to the areas of interest in a body.
  • FIG. 8 presents the exemplary data showing suppression of tumor necrosis factor-alpha (TNF- alpha), interleukin (IL)-6 and IL-lbeta production by lipopolysaccharide (LPS)-stimulated macrophages incubated for 24 h at 37°C with an equimolar mixture of the sulfoxidized methionine residue-containing TREM-l -related trifunctional peptides (TREM-l /TRIOPEP) GA 31 and GE 31 in free form or incorporated into synthetic lipopeptide particles (SLP) particles of discoidal (TREM- l/TRIOPEP-dSLP) and spherical (TREM-l/TRIOPEP-sSLP) morphology.
  • ***, P 0.0001 to 0.001 as compared with medium-treated LPS-challenged macrophages.
  • FIG. 10 presents the exemplary data showing suppression of tumor necrosis factor-alpha (TNF- alpha), interleukin (IL)-6 and IL-lbeta production in mice at 90 min post lipopolysaccharide (LPS) challenge treated 1 h before LPS challenge with phosphate-buffer saline (PBS), dexamethasone (DEX), control peptide and with an equimolar mixture of the sulfoxidized methionine residue-containing TREM-l -related trifunctional peptides (TREM-l /TRIOPEP) GA 31 and GE 31 in free form or incorporated into synthetic lipopeptide particles (SLP) particles of discoidal (TREM- l/TRIOPEP-dSLP) and spherical (TREM- l/TRIOPEP-s SLP) morphology.
  • TNF- alpha tumor necrosis factor-alpha
  • IL-6 interleukin-6
  • IL-lbeta production at 90 min post lip
  • Control peptide represents an equimolar mixture of two peptides, each of them comprising two amino acid domains A and B where domain A represents a non-functional 9 amino acids-long sequence of the TREM-l inhibitory therapeutic peptide sequence wherein, Lys is substituted with Alas, whereas domain B is a sulfoxidized methionine residue-containing 22 amino acids- long apolipoprotein A-I helix 4 or 6 peptide sequence, respectively.
  • SR macrophage scavenger receptors
  • SR-A and SR-B1 see FIG. 9Al,A2-C.
  • FIG. 9A macrophage scavenger receptors
  • this colocalization is accompanied by a specific disruption of intramembrane interactions between TREM-l and DAP-12 by the TREM-l -related trifunctional peptide of the present invention (see FIG. 9A), resulting in ligand-independent inhibition of TREM-l upon ligand binding as described in Shen and Sigalov. Mol Pharm 2017, 14:4572-4582 and Shen and Sigalov. J Cell Mol Med 2017, 21 :2524-2534, each of which is herein incorporated by reference in its entirety.
  • FIG. 9A1-A2-C shows schematic representations of activation of the TREM-1/DAP12 receptor complex expressed on macrophages and presents the exemplary data showing that scavenger receptors SR-A and SR-B1 mediate the macrophage endocytosis of GF9-sSLP (GF9-HDL) and GA/E31-HDL (TREM-l/TRIOPEP-sSLP).
  • FIG. 9A Schematic representation of TREM-l signaling and the SCHOOL mechanism of TREM-l blockade.
  • FIG. 9A2 left panel shows schematic representations of activation of the TREM-1/DAP12 receptor complex expressed on Kupffer cells leads to phosphorylation of the DAP12 cytoplasmic signaling domain, subsequent SYK recruitment, and the downstream inflammatory cytokine response.
  • FIG. 9A2 right panel
  • SR-mediated endocytosis of HDL-bound GF9 peptide inhibitors by Kupffer cells results in the release of GF9 (GA31 or GE31) into the cytoplasm; GF9 self-penetrates the cell membrane and blocks intramembrane interactions between TREM-l and DAP 12, thereby preventing DAP 12 phosphorylation and the downstream signaling cascade.
  • FIG. 9A2 left panel shows schematic representations of activation of the TREM-1/DAP12 receptor complex expressed on Kupffer cells leads to phosphorylation of the DAP12 cytoplasmic signaling domain, subsequent SYK recruitment, and the downstream inflammatory cytokine response.
  • FIG. 9A2 right panel
  • FIG. 9B-9C Macrophage endocytosis of GF9-sSLP (GF9-HDL) and GA/E31-HDL (TREM- l/TRIOPEP-sSLP) in vitro is SR-mediated in a time-dependent manner and is largely driven by SR-A (FIG. 9B, FIG. 9C).
  • J774 macrophages were cultured at 37°C overnight with medium.
  • Prior to uptake of GF9-HDL and GA/E31-HDL cells were treated for 1 hour at 37°C with 40 mM cytochalasin D and either (FIG. 9B) 400 pg/mL fucoidan or (FIG.
  • FIGS. 11A-B -14 demonstrate that TREM-l/TRIOPEP in free and SLP-bound forms inhibits tumor growth, reduces infiltration of macrophages into the tumor in mouse models of NSCLC and PC and is well-tolerated by cancer mice during the treatment period (see also Shen and Sigalov. Mol Pharm 2017, 14:4572-4582, each of which is herein incorporated by reference in its entirety).
  • IG. 11A-B presents the exemplary data showing inhibition of tumor growth in the human non small cell lung cancer H292 (FIG. 11 A) and A549 (FIG. 11B) xenograft mice treated with an equimolar mixture of the sulfoxidized methionine residue-containing TREM-l -related trifunctional peptides (TREM-l/TRIOPEP) GA 31 and GE 31 in free form.
  • PTX paclitaxel. ****, P ⁇ 0.0001 as compared with vehicle-treated animals.
  • FIG. 12A-B presents the exemplary data showing inhibition of tumor growth in the human non small cell lung cancer H292 (FIG. 12A) and A549 (FIG. 12B) xenograft mice treated with an equimolar mixture of the sulfoxidized methionine residue-containing TREM-l -related trifunctional peptides (TREM-l/TRIOPEP) GA 31 and GE 31 incorporated into synthetic lipopeptide particles (SLP) particles of discoidal (TREM-l/TRIOPEP-dSLP) and spherical (TREM-l /TRIOPEP-sSLP) morphology.
  • SLP synthetic lipopeptide particles
  • PTX paclitaxel. ****, p ⁇ 0.0001 as compared with vehicle-treated animals.
  • FIG. 13 presents the exemplary data showing average tumor weights in the A549 xenograft mice treated with an equimolar mixture of the sulfoxidized methionine residue-containing TREM-l - related trifunctional peptides (TREM-l/TRIOPEP) GA 31 and GE 31 in free form or incorporated into synthetic lipopeptide particles (SLP) particles of discoidal (TREM- l/TRIOPEP-dSLP) and spherical (TREM-l /TRIOPEP-sSLP) morphology.
  • SLP synthetic lipopeptide particles
  • PTX paclitaxel. ****,/> ⁇ 0.0001 as compared with vehicle-treated animals.
  • FIG. 14A-C presents the exemplary data showing inhibition of tumor growth (FIG.
  • TREM-l blockade-mediated suppression of intratumoral macrophage infiltration (FIG. 14B, FIG. 14C) in the human pancreatic cancer BxPC-3 xenograft mice treated with an equimolar mixture of the sulfoxidized methionine residue-containing TREM-l -related trifunctional peptides (TREM-l /TRIOPEP) GA 31 and GE 31 in free form or incorporated into synthetic lipopeptide particles (SLP) particles of discoidal (TREM-l/TRIOPEP-dSLP) and spherical (TREM- l/TRIOPEP-sSLP) morphology. (B) F4/80 staining.
  • SLP synthetic lipopeptide particles
  • FIG. 15 demonstrates that TREM-l /TRIOPEP in free and SLP-bound forms significantly prolongs survival in mice with lipopolysaccharide (LPS)-induced septic shock.
  • LPS lipopolysaccharide
  • FIG. 15A-B presents the exemplary data showing improved survival of lipopolysaccharide (LPS)-challenged mice treated with an equimolar mixture of the sulfoxidized methionine residue-containing TREM-l -related trifunctional peptides (TREM-l /TRIOPEP) GA 31 and GE 31 in free form (FIG. 15 A) or incorporated into synthetic lipopeptide particles (SLP) particles of discoidal (TREM- l/TRIOPEP-dSLP) and spherical (TREM-l/TRIOPEP-sSLP) morphology.
  • FIG. 16 shows that TREM-l /TRIOPEP is non-toxic in healthy mice at least up to 400 mg/kg.
  • FIG. 16 presents exemplary data showing average weights of healthy C57BL/6 mice treated with increasing concentrations of an equimolar mixture of the sulfoxidized methionine residue- containing TREM-l -related trifunctional peptides (TREM-l /TRIOPEP) GA 31 and GE 31 in free form.
  • TREM-l /TRIOPEP sulfoxidized methionine residue- containing TREM-l -related trifunctional peptides
  • FIG. 17 demonstrates that TREM-l /TRIOPEP in free and SLP- bound form ameliorates arthritis in mice with collagen-induced arthritis (CIA) and is well- tolerated by arthritic mice during the treatment period of 2 weeks (see Shen and Sigalov. J Cell Mol Med 2017, 21 :2524-2534, each of which is herein incorporated by reference in its entirety).
  • FIG. 17A-B presents the exemplary data showing average clinical arthritis score (FIG. 17A) and mean body weight (BW) changes (FIG.
  • FIG. 18 demonstrates that TREM-l/TRIOPEP-sSLP prevents pathological RNV in mice with oxygen-induced retinopathy and is well-tolerated by these mice during the treatment period (see Rojas, et al. Biochim Biophys Acta 2018, 1864:2761-2768, each of which is herein incorporated by reference in its entirety).
  • FIG. 18A-D presents the exemplary data showing reduction of pathological retinal neovascularization area (FIG. 18 A), avascular area (FIG. 18B) and retinal TREM-l (FIG. 18C) and M-CSF/CSF-l (FIG.
  • FIG. 19 shows that the self-assembled SLP of the present invention may cross the BBB, BRB and BTB, thus delivering their constituents including but not limiting to, TREM-l/TRIOPEP, GF9, GA31 and GE31, to the areas of interest in the brain, retina and tumor.
  • FIG. 63 demonstrates that the fluorescently labeled sSLP described herein may cross the BBB, BRB and BTB, thus delivering their constituents including but not limiting to, GBCA imaging probe to the areas of interest in the brain, retina and tumor.
  • these capabilities of the peptides and compositions of the present invention can be used to diagnose, treat and/or prevent cancers (including brain cancer), diabetic retinopathy and retinopathy of prematurity, neurodegenerative diseases including Alzheimer's, Parkinson's and Huntington's diseases and other diseases and conditions where delivery of the peptides and compositions of the invention to the brain, retina and/or tumor is needed.
  • cancers including brain cancer
  • diabetic retinopathy and retinopathy of prematurity neurodegenerative diseases including Alzheimer's, Parkinson's and Huntington's diseases and other diseases and conditions where delivery of the peptides and compositions of the invention to the brain, retina and/or tumor is needed.
  • FIG. 19 presents exemplary data showing penetration of the blood-brain barrier (BBB) and blood-retinal barrier (BRB) by systemically (intraperitoneally) administered rhodamine B- labeled spherical self-assembled particles (sSLP) that contain Gd-containing contrast agent (Gd- sSLP) for magnetic resonance imaging (MRI), TREM-l inhibitory peptide GF9 (GF9-sSLP) or an equimolar mixture of the sulfoxidized methionine residue-containing TREM-l -related trifunctional peptides GA 31 and GE 31 (TREM-l/TRIOPEP-sSLP) .
  • BBB blood-brain barrier
  • BBB blood-retinal barrier
  • sSLP rhodamine B- labeled spherical self-assembled particles
  • Gd- sSLP Gd-containing contrast agent
  • MRI magnetic resonance imaging
  • TREM-l inhibitory peptide GF9 GF
  • a mouse model of ALD mimics the early phase of the human disease, yet mRNA levels of early fibrosis markers Pro-Colla and a-SMA were significantly increased in alcohol-fed mice compared to PF controls in the whole-liver samples (FIG. 20A-B). Induction of these makers was remarkably attenuated in the vehicle-treated group and, importantly, further decreased by the TREM-l inhibitory formulations used (FIG. 20A-B).
  • FIG. 20A-B presents exemplary data showing TREM-l/TRIOPEP-sSLP suppresses the expression of fibrinogenesis marker molecules, FIG. 20A Pro-Collagen la and FIG. 20B a- Smooth Muscle Actin, at the RNA level, as measured in whole-liver lysates of mice with (alcohol-fed) and without (pair-fed) alcoholic liver disease (ALD).
  • FIG. 21A-D presents exemplary data showing that TREM-l /TRIOPEP-sSLP suppresses the production of alanine aminotransferase (ALT) in mice with alcoholic liver disease (ALD), as measured in serum of mice with (alcohol-fed) and without (pair-fed) ALD, in addition to improving indicators of liver disease and inflammation.
  • * indicates significance level compared to the alcohol-fed group treated with vehicle - synthetic lipopeptide particles of spherical morphology that contained an equimolar mixture of PE22 and PA22 (sSLP) but no TREM-l inhibitory peptide GF9.
  • # indicates significance level compared to the non-treated alcohol-fed group.
  • FIG. 21A Serum ALT levels were measured using a kinetic method. Exemplary data showing TREM-l /TRIOPEP- sSLP suppresses alanine aminotransferase in serum of alcohol fed mice over TREM-l peptide alone.
  • FIG. 21B-D Liver sections were stained with (B,C) Oil Red O and (FIG.
  • the T-cell receptor (TCR)-CD3 complex plays a role in T-cell differentiation, in protecting the organism from infectious agents, and in the function of T-cells.
  • the TCR is a complex of a heterodimer of TCRa and TCRb chains, which are responsible for antigen recognition and interaction with the major histocompatibility complex (MHC) molecules of antigen-presenting cells, and CD3d, CD3g, CD3e and CD3z chains, which are responsible for transmembrane signal transduction (see e.g., Manolios, et al. Cell Adh Migr 2010, 4:273-283; Sigalov. Adv Protein Chem Struct Biol 2018, 111 :61-9; Sigalov.
  • MHC major histocompatibility complex
  • the preferred TCR-related peptides and compositions of this class comprise the domain A comprising the TCR modulatory peptide sequences designed using a well-known in the art novel model of cell receptor signaling, the Signaling Chain HOmoOLigomerization model, capable of modulating TCR (see e.g., Sigalov. Self Nonself 2010, 1 :4-39; Sigalov. Self Nonself 2010, 1 : 192-224; Sigalov. Trends Pharmacol Sci 2006, 27:518-524; Sigalov. Trends Immunol 2004, 25:583-589; Sigalov. Adv Protein Chem Struct Biol 2018, 111 :61-9; Sigalov.
  • the preferred peptides and compositions of this class further comprise the domain B comprising at least one modified or unmodified amphipathic alpha helical peptide fragment.
  • the inclusion of an amphipathic amino acid sequences aids the assistance in the ability to interact with native lipoproteins in a bloodstream in vivo and to form naturally long half-life lipopeptide/lipoprotein particles LP. It further aids the ability to provide targeted delivery to the sites of interest. It further aids the ability to cross the BBB, BRB and BTB.
  • the preferred TCR-related peptides and compositions of this class comprise the domain A comprising the TCR modulatory peptide sequences designed using a well-known in the art novel model of cell receptor signaling, the Signaling Chain HOmoOLigomerization model, capable of modulating TCR (see e.g., Sigalov. Self Nonself 2010, 1 :4-39; Sigalov. Self Nonself 2010, 1 : 192-224; Sigalov. Trends Pharmacol Sci 2006, 27:518-524; Sigalov. Trends Immunol 2004, 25:583-589; Sigalov. Adv Protein Chem Struct Biol 2018, 111 :61-9; Sigalov.
  • the preferred peptides and compositions of this class further comprise the domain B comprising at least one modified or unmodified amphipathic apo A-I and/or A-II peptide fragment to form upon interaction with lipid and/or lipid mixtures, SLP structures that can be spherical or discoidal (described herein and in e.g., Sigalov. Contrast Media Mol Imaging 2014, 9:372-382; Sigalov. Int Immunopharmacol 2014, 21 :208-219; Sigalov.
  • exemplary trifunctional peptides comprise the domain B comprises with the amino acid sequence selected from the amino acid sequences of the major HDL protein constituent, apo A-I. In certain embodiments, this sequence comprises 22 amino acid residue-long peptide sequence of the apo A-I helix 4. In one embodiment, this sequence contains a modified amino acid residue. In one embodiment, this modified amino acid residue is methionine sulfoxide. In one embodiment, the domain B of the peptides and compositions of the invention comprises 22 amino acid residue-long peptide sequence of the apo A-I helix 6. In one embodiment, this sequence contains a modified amino acid residue. In one embodiment, this modified amino acid residue is methionine sulfoxide.
  • TABLE 2 demonstrates the following structures of representative TCR-related trifunctional peptides: TCR/TRIOPEP MA32
  • GVLRLLLFKLP YLDDF QKKW QEEMELYRQKVE SEQ ID NO 16
  • these peptides colocalize with TCR in the cell membrane and selectively disrupt intramembrane interactions of TCRa chain with the CD3ed heterodimer and CD3zz homodimer, resulting to specific ligand- independent inhibition of TCR upon antigen stimulation (see e.g. Sigalov. Self Nonself 2010, 1 :4-39.; Sigalov. Self Nonself 2010, 1 : 192-224; and Sigalov. Adv Protein Chem Struct Biol 2018, 111 :61-99, each of which is herein incorporated by reference in its entirety).
  • methionine residues of TCR/TRIOPEP peptides are modified.
  • TABLE 2 demonstrates the following structures of representative TCR-related trifunctional peptides: TCR/TRIOPEP LA32
  • TABLE 2 demonstrates the following structures of representative TCR-related trifunctional peptides: TCR/TRIOPEP YA32
  • these peptides colocalize with TCR in the cell membrane and selectively disrupt intramembrane interactions of CD3zz homodimer with TCRa chain, resulting to specific ligand-independent inhibition of TCR upon antigen stimulation (see e.g. Sigalov. Self Nonself 2010, 1 :4-39; Sigalov. Self Nonself 2010, 1 : 192-224; and Sigalov. Adv Protein Chem Struct Biol 2018, 111 :61-99).
  • TABLE 2 demonstrates the following structures of representative TCR-related trifunctional peptides: TCR/TRIOPEP IA32
  • these peptides colocalize with TCR in the cell membrane and selectively disrupt intramembrane interactions of CD3ed heterodimer with TCRa chain, resulting to specific ligand-independent inhibition of TCR upon antigen stimulation (see e.g. Sigalov. Self Nonself 2010, 1 :4-39; Sigalov. Self Nonself 2010, 1 : 192-224; and Sigalov. Adv Protein Chem Struct Biol 2018, 111 :61-99, each of which is herein incorporated by reference in its entirety).
  • TABLE 2 demonstrates the following structures of representative TCR-related trifunctional peptides: TCR/TRIOPEP FA32
  • these peptides colocalize with TCR in the cell membrane and selectively disrupt intramembrane interactions of CD3eg heterodimer with TCRb chain, resulting to specific ligand-independent inhibition of TCR upon antigen stimulation (see e.g. Sigalov. Self Nonself 2010, 1 :4-39; Sigalov. Self Nonself 2010, 1 : 192-224; and Sigalov. Adv Protein Chem Struct Biol 2018, 111 :61-99, each of which is herein incorporated by reference in its entirety).
  • TABLE 2 demonstrates the following structures of representative TCR-related trifunctional peptides: TCR/TRIOPEP IA32e
  • methionine residues of TCR/TRIOPEP peptides are modified.
  • the capability of the TCR-related peptides and compounds of the present invention including but not limiting to those described above, to inhibit TCR can be used to treat and/or prevent TCR-related diseases and conditions including but not limiting to, allergic diathesis e.g. delayed type hypersensitivity, contact dermatitis; autoimmune disease e.g. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, diabetes, Guillain-Barre syndrome, Hashimotos disease, pernicious anaemia; gastroenterological conditions e.g. inflammatory bowel disease, Crohn’s disease, primary biliary cirrhosis, chronic active hepatitis; skin problems e.g.
  • allergic diathesis e.g. delayed type hypersensitivity, contact dermatitis
  • autoimmune disease e.g. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, diabetes, Guillain-Barre syndrome
  • the capability of the TCR-related peptides and compounds of the present invention can be used to visualize (image) this receptor and evaluate its expression in the areas of interest.
  • an imaging probe e.g. [ 64 Cu], see TABLE 2
  • imaging (visualization) of TCR levels using PET and/or other imaging techniques can be used to diagnose TCR-related diseases and conditions as well as to monitor novel therapies for these diseases and conditions.
  • NKG2D is an activating receptor expressed by natural killer (NK) and T cells.
  • the NKG2D is a complex of an NKG2D chain, which is responsible for ligand recognition, and DAP 10 homodimer, which is responsible for transmembrane signal transduction (see e.g. Sigalov. Trends Pharmacol Sci 2006, 27:518-524; Sigalov. Trends Immunol 2004, 25:583-589; Sigalov. Self Nonself 2010, 1 :4-39; and Sigalov. Self Nonself 2010, 1 : 192-224, each of which is herein incorporated by reference in its entirety).
  • NKG2D ligands show a restricted expression in normal tissues, but they are frequently overexpressed in cancer and infected cells.
  • NKG2D The binding of NKG2D to its ligands activates NK and T cells and promotes cytotoxic lysis of the cells expressing these molecules.
  • the preferred NKG2D-related peptides and compositions of this class comprise the domain A comprising the NKG2D modulatory peptide sequences designed using a well-known in the art novel model of cell receptor signaling, the Signaling Chain HOmoOLigomerization model, capable of modulating NKG2D (see e.g., Sigalov. Self Nonself 2010, 1 :4-39; Sigalov. Self Nonself 2010, 1 : 192-224; Sigalov. Trends Pharmacol Sci 2006, 27:518-524; Sigalov. Trends Immunol 2004, 25:583-589; Sigalov. Adv Protein Chem Struct Biol 2018, 111 :61-9, each of which is herein incorporated by reference in its entirety).
  • the preferred peptides and compositions of this class further comprise the domain B comprising at least one modified or unmodified amphipathic apo A-I and/or A-II peptide fragment to form upon interaction with lipid and/or lipid mixtures, SLP structures that can be spherical or discoidal (described herein and in e.g., Sigalov. Contrast Media Mol Imaging 2014, 9:372-382; Sigalov. Int Immunopharmacol 2014, 21 :208-219; Sigalov. US 20110256224; Sigalov. US 20130045161; Shen, et al. PLoS One 2015, l0:e0l43453; Shen and Sigalov.
  • an amphipathic apo A-I sequences aids the assistance in the self-assembly of SLP and the structural stability of the particle formed, particularly when the particle has a discoidal shape. It further aids the ability to provide targeted delivery to the cells of interest. It further aids the ability to interact with lipids and/or lipoproteins in a bloodstream in vivo and form LP that mimic native lipoproteins. It further aids the ability to cross the BBB, BRB and BTB.
  • exemplary trifunctional peptides comprise the domain B comprises with the amino acid sequence selected from the amino acid sequences of the major HDL protein constituent, apo A-I. In certain embodiments, this sequence comprises 22 amino acid residue-long peptide sequence of the apo A-I helix 4. In one embodiment, this sequence contains a modified amino acid residue. In one embodiment, this modified amino acid residue is methionine sulfoxide. In one embodiment, the domain B of the peptides and compositions of the invention comprises 22 amino acid residue-long peptide sequence of the apo A-I helix 6. In one embodiment, this sequence contains a modified amino acid residue. In one embodiment, this modified amino acid residue is methionine sulfoxide.
  • TABLE 2 demonstrates the following structures of representative NKG2D-related trifunctional peptides: NKG2D/TRIOPEP IA36
  • the capability of the NKG2D-related peptides and compounds of the present invention including but not limiting to those described above, to inhibit NKG2D can be used to treat and/or prevent NKG2D-related diseases and conditions including but not limiting to, celiac disease, type I diabetes, hepatitis, and rheumatoid arthritis, and any other disorder where NKG2D cells are involved/recruited.
  • the present invention provides methods and compositions for preventing NK cell-mediated graft rejection.
  • the capability of the NKG2D-related peptides and compounds of the present invention can be used to visualize (image) this receptor and evaluate its expression in the areas of interest.
  • an imaging probe e.g. [ 64 Cu], see TABLE 2
  • imaging (visualization) of NKG2D levels using PET and/or other imaging techniques can be used to diagnose NKG2D- related diseases and conditions as well as to monitor novel therapies for these diseases and conditions.
  • GPVI glycoprotein
  • the preferred GPVI-related peptides and compositions of this class comprise the domain A comprising the GPVI modulatory peptide sequences designed using a well-known in the art novel model of cell receptor signaling, the Signaling Chain HOmoOLigomerization model, capable of modulating GPVI (see e.g., Sigalov. Self Nonself 2010, 1 :4-39; Sigalov. Self Nonself 2010, 1 : 192-224; Sigalov. Trends Pharmacol Sci 2006, 27:518-524; Sigalov. Trends Immunol 2004, 25:583-589; Sigalov. Adv Protein Chem Struct Biol 2018, 111 :61-9; Sigalov.
  • the preferred peptides and compositions of this class further comprise the domain B comprising at least one modified or unmodified amphipathic apo A-I and/or A-II peptide fragment to form upon interaction with lipid and/or lipid mixtures, SLP structures that can be spherical or discoidal (described herein and in e.g., Sigalov. Contrast Media Mol Imaging 2014, 9:372-382; Sigalov. Int Immunopharmacol 2014, 21 :208-219; Sigalov.
  • exemplary trifunctional peptides comprise the domain B comprises with the amino acid sequence selected from the amino acid sequences of the major HDL protein constituent, apo A-I.
  • this sequence comprises 22 amino acid residue-long peptide sequence of the apo A-I helix 4. In one embodiment, this sequence contains a modified amino acid residue. In one embodiment, this modified amino acid residue is methionine sulfoxide. In one embodiment, the domain B of the peptides and compositions of the invention comprises 22 amino acid residue-long peptide sequence of the apo A-I helix 6. In one embodiment, this sequence contains a modified amino acid residue. In one embodiment, this modified amino acid residue is methionine sulfoxide.
  • TABLE 2 demonstrates the following structures of representative GPVI-related trifunctional peptides: GPVI/TRIOPEP GA32
  • GNLVRICLGAPLGEEMRDRARAHVDALRTHLA SEQ ID NO. 29
  • GPVI/TRIOPEP GE32 GNLVRICLGAPYLDDF QKKW QEEMELYRQKVE
  • these peptides colocalize with GPVI in the cell membrane and selectively disrupt intramembrane interactions of GPVI chain with the FcRg signaling homodimer, resulting to specific ligand-independent inhibition of GPVI upon ligand stimulation (see e.g. Sigalov. Self Nonself 2010, 1 :4-39.; Sigalov. Self Nonself 2010, 1 : 192-224; Sigalov.
  • methionine residues of GPVI/TRIOPEP peptides are modified.
  • the capability of the GPVI-related peptides and compounds of the present invention including but not limiting to those described above, to inhibit GPVI can be used to treat and/or prevent GPVI-related diseases and conditions including but not limiting to, ischemic and thromboinflarnmatory diseases, and any other disorder where platelets are involved/recruited.
  • the capability of the GPVI-related peptides and compounds of the present invention can be used to visualize (image) this receptor and evaluate its expression in the areas of interest.
  • an imaging probe e.g. [ 64 Cu], see TABLE 2
  • imaging (visualization) of GPVI levels using PET and/or other imaging techniques can be used to diagnose GPVI-related diseases and conditions as well as to monitor novel therapies for these diseases and conditions.
  • the DAP 10 and DAP 12 signaling subunits are highly conserved in evolution and associate with a large family of receptors in hematopoietic cells, including dendritic cells, plasmacytoid dendritic cells, neutrophils, basophils, eosinophils, mast cells, monocytes, macrophages, natural killer cells, and some B and T cells. Some receptors are able to associate with either DAP10 or DAP12, which contribute unique intracellular signaling functions. DAP- 10- and DAP-l2-associated receptors have been shown to recognize both host-encoded ligands and ligands encoded by microbial pathogens, indicating that they play a role in innate immune responses. See e.g. Lanier.
  • the preferred DAP-10 and DAP-l2-related peptides and compositions of this class comprise the domain A comprising the DAP-10 or DAP-12 modulatory peptide sequences, respectively, designed using a well-known in the art novel model of cell receptor signaling, the Signaling Chain HOmoOLigomerization model, capable of modulating DAP- 10- and DAP- 12- associated receptors (see e.g., Sigalov. Self Nonself 2010, 1 :4-39; Sigalov. Self Nonself 2010, 1 : 192-224; Sigalov. Trends Pharmacol Sci 2006, 27:518-524; Sigalov. Trends Immunol 2004, 25:583-589; Sigalov.
  • the preferred peptides and compositions of this class further comprise the domain B comprising at least one modified or unmodified amphipathic apo A-I and/or A-II peptide fragment to form upon interaction with lipid and/or lipid mixtures, SLP structures that can be spherical or discoidal (described herein and in e.g., Sigalov. Contrast Media Mol Imaging 2014, 9:372-382; Sigalov. Int Immunopharmacol 2014, 21 :208-219;
  • an amphipathic apo A-I sequences aids the assistance in the self-assembly of SLP and the structural stability of the particle formed, particularly when the particle has a discoidal shape. It further aids the ability to provide targeted delivery to the cells of interest. It further aids the ability to interact with lipids and/or lipoproteins in a bloodstream in vivo and form LP that mimic native lipoproteins. It further aids the ability to cross the BBB, BRB and BTB.
  • exemplary trifunctional peptides comprise the domain B comprises with the amino acid sequence selected from the amino acid sequences of the major HDL protein constituent, apo A-I. In certain embodiments, this sequence comprises 22 amino acid residue-long peptide sequence of the apo A-I helix 4. In one embodiment, this sequence contains a modified amino acid residue. In one embodiment, this modified amino acid residue is methionine sulfoxide. In one embodiment, the domain B of the peptides and compositions of the invention comprises 22 amino acid residue-long peptide sequence of the apo A-I helix 6. In one embodiment, this sequence contains a modified amino acid residue. In one embodiment, this modified amino acid residue is methionine sulfoxide.
  • TABLE 2 demonstrates the following structures of
  • these peptides colocalize with DAP-lO-associated cell receptors in the cell membrane and selectively disrupt intramembrane interactions of the receptor with the DAP-10 signaling homodimer, resulting to specific ligand-independent inhibition of the receptor upon ligand stimulation (see e.g. Sigalov. Self Nonself 2010, 1 :4-39.; Sigalov.
  • methionine residues of DAP-10/TRIOPEP peptides are modified.
  • TABLE 2 demonstrates the following structures of
  • VMGDLVLTVLPLGEEMRDRARAHVDALRTHLA SEQ ID NO. 31
  • DAP- 12/TRIOPEP VE32 VMGDLVLTVLP YLDDF QKKW QEEMEL YRQKVE
  • these peptides colocalize with DAP-l2-associated cell receptors in the cell membrane and selectively disrupt intramembrane interactions of the receptor with the DAP-12 signaling homodimer, resulting to specific ligand-independent inhibition of the receptor upon ligand stimulation (see e.g. Sigalov. Self Nonself 2010, 1 :4-39.; Sigalov.
  • methionine residues of DAP-12/TRIOPEP peptides are modified.
  • the capability of the DAP- 10- and DAP-l2-related peptides and compounds of the present invention including but not limiting to those described above, to inhibit the DAP-10- and DAP-l2-associated receptors, respectively, can be used to treat and/or prevent any diseases and conditions where these receptors are involved.
  • the capability of the DAP- 10- and DAP-l2-related peptides and compounds of the present invention can be used to visualize (image) these receptors and evaluate their expression in the areas of interest.
  • an imaging probe e.g. [ 64 Cu], see TABLE 2
  • imaging probe can be conjugated to the DAP-10/TRIOPEP and DAP-12/TRIOPEP sequences.
  • EGF epidermal growth factor
  • ErbB ErbB family
  • RTKs oncogenic receptor tyrosine kinases
  • HER2/ErbB2 is overexpressed on the surface of 25-30% of breast cancer cells, and it has been associated with a high risk of relapse and death.
  • EGFR amplification and mutations have been associated with many carcinomas.
  • the EGFR pathway appears to play a role in pancreatic carcinoma. See e.g. Overholser, et al. Cancer 2000, 89:74-82; Bennasroune, et al. Mol Biol Cell 2004, 15:3464- 3474; Sigalov.
  • the preferred EGFR-related peptides and compositions of this class comprise the domain A comprising the EGFR modulatory peptide sequences, designed using a well-known in the art novel model of cell receptor signaling, the Signaling Chain HOmoOLigomerization model, capable of modulating EGFR (see e.g., Sigalov. Self Nonself 2010, 1 :4-39; Sigalov. Self Nonself 2010, 1 : 192-224; Sigalov. Trends Pharmacol Sci 2006, 27:518-524; Sigalov. Trends Immunol 2004, 25:583-589; Sigalov. Adv Protein Chem Struct Biol 2018, 111 :61-9, each of which is herein incorporated by reference in its entirety).
  • the preferred peptides and compositions of this class further comprise the domain B comprising at least one modified or unmodified amphipathic apo A-I and/or A-II peptide fragment to form upon interaction with lipid and/or lipid mixtures, SLP structures that can be spherical or discoidal (described herein and in e.g., Sigalov. Contrast Media Mol Imaging 2014, 9:372-382; Sigalov. Int Immunopharmacol 2014, 21 :208-219;
  • an amphipathic apo A-I sequences aids the assistance in the self-assembly of SLP and the structural stability of the particle formed, particularly when the particle has a discoidal shape. It further aids the ability to provide targeted delivery to the cells of interest. It further aids the ability to interact with lipids and/or lipoproteins in a bloodstream in vivo and form LP that mimic native lipoproteins. It further aids the ability to cross the BBB, BRB and BTB.
  • exemplary trifunctional peptides comprise the domain B comprises with the amino acid sequence selected from the amino acid sequences of the major HDL protein constituent, apo A-I. In certain embodiments, this sequence comprises 22 amino acid residue-long peptide sequence of the apo A-I helix 4. In one embodiment, this sequence contains a modified amino acid residue. In one embodiment, this modified amino acid residue is methionine sulfoxide. In one embodiment, the domain B of the peptides and compositions of the invention comprises 22 amino acid residue-long peptide sequence of the apo A-I helix 6. In one embodiment, this sequence contains a modified amino acid residue. In one embodiment, this modified amino acid residue is methionine sulfoxide.
  • TABLE 2 demonstrates the following structures of
  • these peptides colocalize with EGFR in the cell membrane and selectively disrupts intramembrane interactions between the receptors, resulting to specific ligand-independent inhibition of the receptor (see e.g. Sigalov. Self Nonself 2010, 1 :4-39.; Sigalov. Self Nonself 2010, 1 : 192-224; Sigalov. Adv Protein Chem Struct Biol 2018, 111 :6l-99, each of which is herein incorporated by reference in its entirety).
  • methionine residues of EGFR/TRIOPEP peptides are modified.
  • the capability of the EGFR and/or ErB-related peptides and compounds of the present invention including but not limiting to those described above, to inhibit the receptors of the EGFR and/or ErB receptor families, respectively, can be used to treat and/or prevent any diseases and conditions where these receptors are involved.
  • the capability of the EGFR- and/or ErB-related peptides and compounds of the present invention can be used to visualize (image) these receptors and evaluate their expression in the areas of interest.
  • an imaging probe e.g. [ 64 Cu]
  • imaging (visualization) of levels of the receptors of the EGFR and/or ErB receptor families using PET and/or other imaging techniques can be used to diagnose any diseases and conditions where these receptors are involved as well as to monitor novel therapies for these diseases and conditions.
  • Additional therapeutic peptide sequences and/or other therapeutic agents can comprise the domain A of the peptides and compositions of the present invention. Additional examples are provided in, for e.gs., Vlieghe, et al. Drug Discov Today 2010, 15:40-56; Tsung, et al. Shock 2007, 27:364-369; Chang, et al. PLoS One 2009, 4:e4l7l; Tjin Tham Sjin, et al. Cancer Res 2005, 65:3656-3663; Ladetzki-Baehs, et al. Endocrinology 2007, 148:332-336; Khan, et al. Hum Immunol 2002, 63: 1-7; Banga.
  • Therapeutic peptides and proteins formulation, processing, and delivery systems. 2nd ed. Boca Raton, FL: Taylor & Francis Group; 2006; Stevenson. Curr Pharm Biotechnol 2009, 10: 122-137; Wu and Chi, US 9,387,257; Wu, et al., US 8,415,453; Faure, et al., US 8,013,116; Faure, et al., US 9,273,111; Eggink and Hoober, US 7,811,995; Eggink and Hoober, US 8,496,942; Morgan and Pandha. US 2012/0177672 Al; Broersma, et al., US 5,681,925), each of which is herein incorporated by reference in its entirety.
  • this domain comprises the Toll Like Receptor (TLR) modulatory sequence (see e.g. Tsung, et al. Shock 2007, 27:364-369).
  • TLR Toll Like Receptor
  • compositions of this class further comprise the domain B comprising at least one modified or unmodified amphipathic apo A-I and/or A-II peptide fragment to form upon interaction with lipid and/or lipid mixtures, SLP structures that can be spherical or discoidal (described herein and in e.g., Sigalov. Contrast Media Mol Imaging 2014, 9:372-382; Sigalov. Int
  • an amphipathic apo A-I sequences aids the assistance in the self-assembly of SLP and the structural stability of the particle formed, particularly when the particle has a discoidal shape. It further aids the ability to provide targeted delivery to the cells of interest. It further aids the ability to interact with lipids and/or lipoproteins in a bloodstream in vivo and form LP that mimic native lipoproteins. It further aids the ability to cross the BBB, BRB and BTB.
  • exemplary trifunctional peptides comprise the domain B comprises with the amino acid sequence selected from the amino acid sequences of the major HDL protein constituent, apo A-I. In certain embodiments, this sequence comprises 22 amino acid residue-long peptide sequence of the apo A-I helix 4. In one embodiment, this sequence contains a modified amino acid residue. In one embodiment, this modified amino acid residue is methionine sulfoxide. In one embodiment, the domain B of the peptides and compositions of the invention comprises 22 amino acid residue-long peptide sequence of the apo A-I helix 6. In one embodiment, this sequence contains a modified amino acid residue. In one embodiment, this modified amino acid residue is methionine sulfoxide.
  • TABLE 2 demonstrates the following structures of
  • TLR/TRIOPEP DE32 DI VKLT VYD CIRRRRRRRRRP YLDDF QKK W QEEMEL YRQK VE.
  • methionine residues of TLR/TRIOPEP peptides are modified.
  • the capability of the TLR-related peptides and compounds of the present invention including but not limiting to those described above, to inhibit TLR can be used to treat and/or prevent TLR-related diseases and conditions including but not limiting to, sepsis and other infectious diseases, and any other disorder where TLR receptors are involved.
  • the capability of the TLR-related peptides and compounds of the present invention can be used to visualize (image) this receptor and evaluate its expression in the areas of interest.
  • an imaging probe e.g. [ 64 Cu]
  • imaging (visualization) of TLR levels using PET and/or other imaging techniques can be used to diagnose TLR-related diseases and conditions as well as to monitor novel therapies for these diseases and conditions.
  • the domain A of the peptides and compositions of the invention comprises the Atrial Natriuretic Peptide (ANP) receptor (ANPR)-modulatory sequence (see e.g. Ladetzki-Baehs, et al. Endocrinology 2007, 148:332-336).
  • the preferred peptides and compositions of this class further comprise the domain B comprising at least one modified or unmodified amphipathic apo A-I and/or A-II peptide fragment to form upon interaction with lipid and/or lipid mixtures, SLP structures that can be spherical or discoidal (described herein and in e.g., Sigalov. Contrast Media Mol Imaging 2014, 9:372-382; Sigalov. Int
  • an amphipathic apo A-I sequences aids the assistance in the self-assembly of SLP and the structural stability of the particle formed, particularly when the particle has a discoidal shape. It further aids the ability to provide targeted delivery to the cells of interest. It further aids the ability to interact with lipids and/or lipoproteins in a bloodstream in vivo and form LP that mimic native lipoproteins. It further aids the ability to cross the BBB, BRB and BTB.
  • exemplary trifunctional peptides comprise the domain B comprises with the amino acid sequence selected from the amino acid sequences of the major HDL protein constituent, apo A-I. In certain embodiments, this sequence comprises 22 amino acid residue-long peptide sequence of the apo A-I helix 4. In one embodiment, this sequence contains a modified amino acid residue. In one embodiment, this modified amino acid residue is methionine sulfoxide. In one embodiment, the domain B of the peptides and compositions of the invention comprises 22 amino acid residue-long peptide sequence of the apo A-I helix 6. In one embodiment, this sequence contains a modified amino acid residue. In one embodiment, this modified amino acid residue is methionine sulfoxide.
  • TABLE 2 demonstrates the following structures of
  • the capability of the ANPR-related peptides and compounds of the present invention including but not limiting to those described above, to inhibit ANPRs can be used to treat and/or prevent ANPR-related diseases and conditions including but not limiting to, cardiovascular and inflammatory diseases, and any other disorder where ANP receptors are involved.
  • the capability of the ANPR-related peptides and compounds of the present invention can be used to visualize (image) this receptor and evaluate its expression in the areas of interest.
  • an imaging probe e.g. [ 64 Cu]
  • imaging (visualization) of ANPR levels using PET and/or other imaging techniques can be used to diagnose ANPR-related diseases and conditions as well as to monitor novel therapies for these diseases and conditions.
  • other therapeutic agents including but not limiting to, to those described in Page and Takimoto. Principles of chemotherapy. In: Pazdur R, Wagman LD, Camphausen KA, editors. Cancer Management: A Multidisciplinary Approach. 1 lth ed.
  • Lipoproteins inlcuding circulating lipoproteins in blood plasma, are natural complexes that contain both proteins (apolipoproteins, apo) and lipids bound to the proteins, which allow water-insoluble molecules such as fats to move through the water inside and outside cells.
  • Lipoproteins serve to emulsify the lipid molecules.
  • examples include the plasma lipoprotein particles classified under high-density lipoproteins (HDL), which enable cholesterol and other hydrophobic lipid molecules to be carried in the bloodstream.
  • HDL high-density lipoproteins
  • HDL transport cholesterol and other water insoluble or poorly soluble lipids from the peripheral tissues to the liver.
  • HDLs as delivery vehicles was proposed however in order to properly function in vivo for delivery of drugs or imaging agents to sites of interest, HDLs should mimic native lipoproteins as close as possible.
  • HDL exists in two forms: nascent or discoidal HDL and spherical HDL.
  • isolated plasma lipoproteins, including isolated HDLs, as delivery vehicles is impractical.
  • long half-life lipoprotein particles that mimic native HDL can be readily reconstituted (synthesized) from lipid formulations and apolipoproteins (apo) resulting in, for example, sub 30 nm-sized particles of discoidal or spherical morphology.
  • Morphology of rHDLs is determined by the composition of lipid and apo mixtures and preparation procedures.
  • rHDLs were evaluated both clinically and experimentally as a delivery system for administering hydrophobic agents and for mitigating the toxic effects associated with administration of imaging probes such as Gd-containing contrast agents (GBCAs) for magnetic resonance imaging (MRI).
  • GBCAs Gd-containing contrast agents
  • MRI magnetic resonance imaging
  • rHDL As delivery vehicles, rHDL have several competitive advantages as compared with other delivery platforms: 1) apo A-I, a major HDL protein, is used for rHDL preparation as it's recombinant or synthesized peptide/protein represents an endogenous protein that does not trigger immunoreactions; 2) apo A-I's small size allows rHDL to pass through blood vessel walls, enter and then accumulate in the places of interest, including for treatment and/or detection, such as tumor sites, areas of disease, such as liver tissue, etc., or atherosclerotic plaques; 3) rHDL's small particle size also allows for intravenous, intramuscular and
  • rHDL's naturally long half-life extends the half-life of incorporated drugs and/or imaging agents in a bloodstream; and 5) a variety of drugs and imaging agents can be incorporated into this platform.
  • rHDL should mimic native lipoproteins including but not limited to HDL as close as possible. This is a complicated task because two functions, assistance in the self-assembly of rHDL and therapeutic and/or imaging action in vivo , have to be executed by at least, two separate rHDL ingredients such as human apolipoprotein and therapeutic agent and/or imaging probe.
  • rHDL in contrast to, for example, native HDL that are normally target the liver, rHDL have to be able to target other sites of interest such as, for example, macrophages which results in the need of targeting moieties thus adding the third function of rHDL ingredients - targeting.
  • An alternative, fully synthetic lipopeptide system for targeted treatment and/or imaging that closely mimics native lipoproteins and exhibits the advantageous properties of rHDL as well as superior stability, uniformity, ease of use, and reproducibility of preparation is needed for administration and targeted delivery of therapeutic agents (e.g. anti-cancer and anti-sepsis agents, other anti-inflammatory drugs) and/or imaging probes.
  • therapeutic agents e.g. anti-cancer and anti-sepsis agents, other anti-inflammatory drugs
  • imaging probes e.g. anti-cancer and anti-sepsis agents, other anti-inflammatory drugs
  • the invention provides such a system and a method of using the system (e.g., for delivery of anti-cancer, anti-arthritic, anti-sepsis, anti- angiogenic and other therapeutic agents and/or imaging probes to a subject).
  • Additional contemplative advantages of a lipoprotein delivery platform includes increasing activity due to specific targeting, sequestration of the drug at the target site, protection of the drug from rapid metabolism, amplified therapeutic effect due to packaging of numerous drug molecules in each particle, and decreased toxicity due to altered pharmacokinetics. Due to the naturally long half-life of native discoidal and spherical HDL in normal subjects being 12-20 hrs and 3-5 days, respectively, rHDL represent a promising versatile delivery platform in particular for therapeutic peptides that have a bloodstream half-life of minutes.
  • the invention addresses these needs, among others, and provides such a system/molecule and a method of using the system (e.g., for delivery of anti-cancer, anti-arthritic, anti-sepsis, anti -angiogenic, anti-inflammatory and other therapeutic agents and/or imaging probes to a subject).
  • a method of using the system e.g., for delivery of anti-cancer, anti-arthritic, anti-sepsis, anti -angiogenic, anti-inflammatory and other therapeutic agents and/or imaging probes to a subject.
  • TREM-l-related Trifunctional peptides TREM-l Signaling Pathway and Its Blockade.
  • TREM-l is expressed on the majority of innate immune cells and to a lesser extent on parenchymal cells. Upon activation, TREM-l can directly amplify an inflammatory response. Although it was initially demonstrated that TREM-l was predominantly associated with infectious diseases, recent evidences demonstrate that TREM-l receptor and its signaling pathways contribute to the pathology of non-infectious acute and chronic inflammatory diseases, including but not limiting to, rheumatoid arthritis, atherosclerosis, ischemia reperfusion-induced tissue injury, colitis, fibrosis, neurodegenerative diseases, liver diseases, retinopathies, and cancer (see e.g., Tammaro, et al. Pharmacol Ther 2017, 177:81-95; Saadipour.
  • TREM-l -related peptides and associated compositions of the present invention have a domain A conjugated to a domain B.
  • Domain A comprises a TREM-l modulatory peptide sequence designed using a known model of cell receptor signaling, the Signaling Chain HOmoOLigomerization model, capable of modulating TREM-l receptor expressed on myeloid cells (see e.g., Sigalov. Self Nonself 2010, 1 :4-39; Sigalov. Self Nonself 2010, 1 : 192-224; Sigalov. Trends Pharmacol Sci 2006, 27:518-524;
  • peptides and compositions of the present invention comprise the TREM-l modulatory peptide sequences designed using a well-known in the art novel model of cell receptor signaling, the Signaling Chain HOmoOLigomerization model.
  • peptides and compositions of this class further comprise the domain B comprising at least one modified or unmodified amphipathic alpha helical peptide fragment, such as a apo A-I and/or A-II peptide fragment, to form upon interaction with lipid and/or lipid mixtures.
  • exemplary trifunctional peptides comprise the domain B comprises with the amino acid sequence selected from the amino acid sequences of the major HDL protein constituent, apo A-I. In certain embodiments, this sequence comprises 22 amino acid residue-long peptide sequence of the apo A-I helix 4. In one embodiment, this sequence contains a modified amino acid residue. In one embodiment, this modified amino acid residue is methionine sulfoxide.
  • the domain B of the peptides and compositions of the invention comprises 22 amino acid residue-long peptide sequence of the apo A-I helix 6. In one embodiment, this sequence contains a modified amino acid residue. In one embodiment, this modified amino acid residue is methionine sulfoxide.
  • preferred peptides and compositions of the invention further comprise at least one modified or unmodified amphipathic apo A-I and/or A-II peptide fragment capable upon interaction with lipid and/or lipid mixtures, to form synthetic lipopeptide particles (SLP) structures that can be spherical or discoidal (described herein and in e.g., Sigalov. Contrast Media Mol Imaging 2014, 9:372-382; Sigalov. Int Immunopharmacol 2014, 21 :208-219;
  • SLP synthetic lipopeptide particles
  • the inclusion of an amphipathic apo A-I sequences in the peptides and compositions of the invention further aids the ability to provide targeted delivery to the cells of interest. It further aids the ability to interact with lipids and/or lipoproteins in a bloodstream in vivo and form LP that mimic native lipoproteins. It further aids the ability to cross the BBB, BRB and BTB.
  • FIG. 1 presents an exemplary schematic representation of one embodiment of a trifunctional peptide of the present invention comprising amino acid domains A and B where amino acid domain A represents a therapeutic peptide sequence with or without an attached drug compound and/or imaging probe that functions to treat, prevent and/or detect a disease or condition, whereas amino acid domain B represents an amphipathic alpha helical peptide sequence, with or without an additional targeting peptide sequence, and functions to 1) assist in the self-assembly of synthetic lipoprotein/lipopeptide nanoparticles (SLP) upon interaction with lipids or lipid mixtures in vitro , for use in transporting these trifunctional peptides as lipoprotien nanoparticles to sites of interest in vitro or in vivo and/or 2) form long half-life lipopeptide/lipoprotein particles upon interaction with endogenous lipoproteins for transporting these trifunctional peptides to the sites of interest.
  • Endogenous lipoproteins may be lipoproteins added to or found in cell cultures
  • FIG. 2 shows the structures of representative TREM-l -related trifunctional peptides, TREM-l /TRIOPEP GE31
  • TREM-l /TRIOPEP GA31 GFL SKSLVFPLGEEMRDRARAHVD ALRTHL A
  • GFLSKSLVF is found within isoform 1 of human TREM-l (UniProtKB - Q9NP99 (TREM1 HUMAN), and in human TREM-l isoform CRA a (UniProtKB - Q38L15 (Q38L15 HUMAN), both downloaded 10-24-2018)).
  • GFLSKSLVF is not found within human TREM-l isoforms 2 or 3.
  • FIG. 2 presents schematic representations of embodiments of a TREM-l -related trifunctional peptide (TREM-l /TRIOPEP).
  • GE31 GFL SK SL VFP YLDDF QKKW QEEM(0)EL YRQK VE, M(O), methionine sulfoxide comprising amino acid domain A and B
  • domain A represents a 9 amino acids-long human TREM-l inhibitory therapeutic SCHOOL peptide sequence and functions to treat and/or prevent a TREM-l -related disease or condition
  • domain B represents a 22 amino acids-long human apolipoprotein A-I helix 4 peptide sequence with a sulfoxidized methionine residue and functions to assist in the self-assembly of synthetic lipopeptide particles (SLP) in vitro for targeting the particles to myeloid cells (e.g. macrophages).
  • SLP synthetic lipopeptide particles
  • apo apolipoprotein
  • SCHOOL signaling chain homooligomerization
  • TREM-l triggering receptor expressed on myeloid cells-l .
  • TREM-l -related trifunctional peptides and compositions of this class comprise the domain A comprising the TREM-l inhibitory peptide sequences LR12 and LP17 (described in Gibot, et al. Infect Immun 2006, 74:2823-2830; Gibot, et al. Shock 2009, 32:633-637; Gibot, et al. Eur J Immunol 2007, 37:456-466; Joffre, et al. J Am Coll Cardiol 2016, 68:2776-2793; Cuvier, et al. Br J Clin Pharmacol 2018, in press; Zhou, et al.
  • resulting trifunctional peptide sequences may be radiolabeled and/or contain unmodified or modified methionine residues (TABLE 2) including but not limiting to, the following sequences:
  • LQEED AGEY GCMPLGEEM(0)RDRARAHVD ALRTHL A M(O), methionine sulfoxide (SEQ ID NO 7), LQEED AGE Y GCMP YLDDF QKKW QEEM(0)EL YRQK VE (M(O), methionine sulfoxide (SEQ ID NO 8),
  • LQVTDSGLYRCVIYHPPPLGEEM(0)RDRARAHVDALRTHLA M(O), methinone sulfoxide (SEQ ID NO 9), LQ VTD S GLYRC VI YHPPP YLDDF QKKW QEEM(0)EL YRQK VE (M(O), methionine sulfoxide (SEQ ID NO 10).
  • SLP (rHDL) structures that can be spherical or discoidal (described herein and in e.g., Sigalov. Contrast Media Mol Imaging 2014, 9:372-382; Sigalov. Int Immunopharmacol 2014, 21 :208-219; Sigalov. US 20110256224; Sigalov.
  • amphipathic apo A-I sequences aids the assistance in the self-assembly of SLP and the structural stability of the particle formed, particularly when the particle has a discoidal shape. It further aids the ability to provide targeted delivery to the cells of interest. It further aids the ability to interact with lipids and/or lipoproteins in a bloodstream in vivo and form LP that mimic native lipoproteins. It further aids the ability to cross the BBB, BRB and BTB.
  • methionine residues of the peptides TREM-l/TRIOPEP GE31 GFL SK SL VFP YLDDF QKKW QEEMEL YRQK VE) (SEQ ID NO. 2) and TREM-l/TRIOPEP GA31 (GFLSKSLVFPLGEEMRDRARAHVDALRTHLA) (SEQ ID NO. 1) are unmodified.
  • interaction of TREM-l/TRIOPEP GA31 with lipids results in self-assembly of nanosized SLP of discoidal or spherical morphology (dSLP and sSLP, respectively) (see FIG. 3).
  • FIG. 3 presents a schematic representation of one embodiment of a TREM-l -related
  • trifunctional peptide of the present invention comprising amino acid domains A and B.
  • sub 50 nm- sized SLP particles of discoidal (TREM-l/TRIOPEP-dSLP) or spherical (TREM- 1 /TRIOPEP- sSLP) morphology are self-assembled upon binding of the trifunctional peptide to lipids.
  • apo apolipoprotein
  • SCHOOL signaling chain homooligomerization
  • TREM-l triggering receptor expressed on myeloid cells-l.
  • this provides targeted delivery of the SLP constituents including TREM-l/TRIOPEP to intraplaque macrophages in vivo (FIG. 4A). In one embodiment, this provides targeted delivery of the SLP constituents including TREM-l/TRIOPEP to tumor- associated macrophages (TAMs) in vivo (FIG. 4B).
  • FIG. 4A illustrates a hypothesized molecular mechanism of action of one embodiment of a trifunctional peptide (TRIOPEP) of the present invention comprising amino acid domains A and B where domain A represents a 9 amino acids-long TREM-l inhibitory therapeutic peptide sequence and functions to treat and/or prevent a TREM-l -related disease or condition (example, for atherosclerosis), whereas domain B represents a 22 amino acids-long apolipoprotein A-I helix 4 or 6 peptide sequence with a sulfoxidized methionine residue and functions to assist in the self-assembly of synthetic lipopeptide particles (SLP) and to target the particles to TREM-l - expressing macrophages as applied to the treatment and/or prevention of atherosclerosis.
  • SLP synthetic lipopeptide particles
  • FIG. 4B illustrates a hypothesized molecular mechanism of action of one embodiment of a trifunctional peptide (TRIOPEP) of the present invention comprising amino acid domains A and B where domain A is a 9 amino acids-long TREM-l inhibitory therapeutic peptide sequence and functions to treat and/or prevent a TREM-l -related disease or condition (example, for cancer), whereas domain B is a 22 amino acids-long apolipoprotein A-I helix 4 or 6 peptide sequence with a sulfoxidized methionine residue and functions to assist in the self-assembly of synthetic lipopeptide particles (SLP) and to target the particles to TREM-l -expressing macrophages as applied to the treatment and/or prevention of cancer.
  • SLP synthetic lipopeptide particles
  • FIG. 4C shows a symbol key used in FIGS. 4A-B.
  • this colocalization is accompanied by a specific disruption of intramembrane interactions between TREM-l and DAP -12 by the TREM-l -related trifunctional peptide of the present invention (see FIG. 5), resulting in ligand-independent inhibition of TREM-l upon ligand binding as described in Shen and Sigalov. Mol Pharm 2017, 14:4572-4582 and Shen and Sigalov. J Cell Mol Med 2017, 21 :2524-2534, each of which is herein incorporated by reference in it's entirety
  • FIG. 5 illustrates one embodiment of a specific disruption of intramembrane interactions between TREM-l and DAP -12 by the trifunctional peptide of the present invention comprising two amino acid domains A and B where domain A is a 9 amino acids-long TREM-l inhibitory therapeutic peptide sequence, whereas domain B is a 22 amino acids-long apolipoprotein A-I helix 4 or 6 peptide sequence with a sulfoxidized methionine residue. While not being bound to any particular theory, it is believed that this disruption results in“pre-dissociation” of a receptor complex and upon ligand stimulation, leads to inhibition of TREM-l and silencing the TREM-l signaling pathway.
  • FIG. 6 shows that the fluorescently labeled TREM-l /TRIOPEP peptide GE31 delivered to macrophages by the SLP particles of the present invention colocalizes with TREM-l expressed on these cells (see also Rojas, et al. Biochim Biophys Acta 2018, 1864:2761-2768).
  • the capability of the TREM-l -related trifunctional peptides and compounds of the present invention including but not limiting to, TREM- 1 /TRIOPEP GA31 and TREM-l /TRIOPEP GE31, to colocalize with TREM-l can be used to visualize (image) this receptor and evaluate its expression in the areas of interest.
  • an imaging probe e.g. [ 64 Cu], see TABLE 2
  • imaging (visualization) of TREM-l levels using PET and/or other imaging techniques can be used to diagnose glioblastoma multiforme (GBM) and/or to select and monitor novel GBM therapies (see e.g., Johnson, et al.
  • FIG. 6A-C shows images depicting colocalization of the sulfoxidized methionine residue- containing TREM-l -related trifunctional peptide (TREM-l/TRIOPEP) GE31 with TREM-l in the cell membrane (FIG. 6A), TREM-l immunohistochemstry staining (FIG. 6B) and a merged image (FIG. 6C).
  • TREM-l/TRIOPEP sulfoxidation of methionine residues in the TREM- l/TRIOPEP peptides GE31 and GA31 results in increased macrophage endocytosis of the SLP containing an equimolar mixture of these peptides (designated as TREM-l/TRIOPEP), TREM- l/TRIOPEP-dSLP and TREM-l/TRIOPEP-sSLP. Shen and Sigalov. Mol Pharm 2017, 14:4572- 4582 and Shen and Sigalov. J Cell Mol Med 2017, 21 :2524-2534, all of which are herein incorporated in their entirety.
  • FIG. 7A-B presents the exemplary data showing the endocytosis of synthetic lipopeptide particles (SLP) of discoidal (dSLP) and spherical (sSLP) morphology that contain an equimolar mixture of the TREM-l -related trifunctional peptides (TREM-l/TRIOPEP) GA 31 and GE 31 (TREM- 1 /TRIOPEP-d SLP and TREM-l/TRIOPEP-sSLP, respectively).
  • SLP synthetic lipopeptide particles
  • dSLP discoidal
  • sSLP spherical
  • FIGS. 8 and 10 demonstrate that TREM-l/TRIOPEP in free and SLP -bound forms inhibits TREM-l function as shown by reduction of TREM-l -mediated release of pro-inflammatory cytokines both in vitro (FIG. 8) and in vivo (FIG. 10). While not being bound to any particular theory, it is believed that this indicates that similarly to TREM-l - inhibitory peptide GF9 (see e.g., Sigalov. Int Immunopharmacol 2014, 21 :208-219; Shen and Sigalov. Mol Pharm 2017, 14:4572-4582; and Shen and Sigalov.
  • TREM-l -related trifunctional peptides can reach their site of action from both outside (free TREM-l/TRIOPEP) and inside (SLP-bound TREM-l/TRIOPEP) the cell. It is also believed that upon administration, free TREM-l/TRIOPEP may form LP in vivo and/or interact with native lipoproteins, resulting in formation of HDL-mimicking LP. In one embodiment, these LP may further target the cells of interest delivering their content to the areas of interest in a body.
  • FIG. 8 presents the exemplary data showing suppression of tumor necrosis factor-alpha (TNF- alpha), interleukin (IL)-6 and IL-lbeta production by lipopolysaccharide (LPS)-stimulated macrophages incubated for 24 h at 37°C with an equimolar mixture of the sulfoxidized methionine residue-containing TREM-l -related trifunctional peptides (TREM-l/TRIOPEP) GA 31 and GE 31 in free form or incorporated into synthetic lipopeptide particles (SLP) particles of discoidal (TREM- l/TRIOPEP-dSLP) and spherical (TREM-l/TRIOPEP-sSLP) morphology.
  • ***, P 0.0001 to 0.001 as compared with medium-treated LPS-challenged macrophages.
  • FIG. 10 presents the exemplary data showing suppression of tumor necrosis factor-alpha (TNF- alpha), interleukin (IL)-6 and IL-lbeta production in mice at 90 min post lipopolysaccharide (LPS) challenge treated 1 h before LPS challenge with phosphate-buffer saline (PBS), dexamethasone (DEX), control peptide and with an equimolar mixture of the sulfoxidized methionine residue-containing TREM-l -related trifunctional peptides (TREM-l/TRIOPEP) GA 31 and GE 31 in free form or incorporated into synthetic lipopeptide particles (SLP) particles of discoidal (TREM- l/TRIOPEP-dSLP) and spherical (TREM- l/TRIOPEP-s SLP) morphology.
  • TNF- alpha tumor necrosis factor-alpha
  • IL-6 interleukin-6
  • IL-lbeta production at 90 min post lipo
  • Control peptide represents an equimolar mixture of two peptides, each of them comprising two amino acid domains A and B where domain A represents a non-functional 9 amino acids-long sequence of the TREM-l inhibitory therapeutic peptide sequence wherein, Lys is substituted with Alas, whereas domain B is a sulfoxidized methionine residue-containing 22 amino acids- long apolipoprotein A-I helix 4 or 6 peptide sequence, respectively.
  • SR macrophage scavenger receptors
  • SR-A and SR-B1 macrophage scavenger receptors
  • FIG. 9A-C macrophage scavenger receptors
  • this colocalization is accompanied by a specific disruption of intramembrane interactions between TREM-l and DAP- 12 by the TREM-l -related trifunctional peptide of the present invention (see FIG. 9A), resulting in ligand-independent inhibition of TREM-l upon ligand binding as described in Shen and Sigalov. Mol Pharm 2017, 14:4572-4582 and Shen and Sigalov. J Cell Mol Med 2017, 21 :2524-2534, each of which is herein incorporated by reference in it's entirety.
  • FIG. 9A1-A2-C shows schematic representations of activation of the TREM-1/DAP12 receptor complex expressed on macrophages and presents the exemplary data showing that scavenger receptors SR-A and SR-B1 mediate the macrophage endocytosis of GF9-sSLP (GF9-HDL) and GA/E31-HDL (TREM-l/TRIOPEP-sSLP).
  • FIG. 9A Schematic representation of TREM-l signaling and the SCHOOL mechanism of TREM-l blockade.
  • FIG. 9A2 left panel shows schematic representations of activation of the TREM-1/DAP12 receptor complex expressed on Kupffer cells leads to phosphorylation of the DAP12 cytoplasmic signaling domain, subsequent SYK recruitment, and the downstream inflammatory cytokine response.
  • FIG. 9A2 right panel
  • SR-mediated endocytosis of HDL-bound GF9 peptide inhibitors by Kupffer cells results in the release of GF9 (GA31 or GE31) into the cytoplasm;
  • GF9 self-penetrates the cell membrane and blocks intramembrane interactions between TREM-l and DAP 12, thereby preventing DAP 12 phosphorylation and the downstream signaling cascade.
  • FIG. 9B-9C Macrophage endocytosis of GF9-sSLP (GF9-HDL) and GA/E31-HDL (TREM- l/TRIOPEP-sSLP) in vitro is SR-mediated in a time-dependent manner and is largely driven by SR-A (FIG. 9B, FIG. 9C).
  • J774 macrophages were cultured at 37°C overnight with medium.
  • Prior to uptake of GF9-HDL and GA/E3 l-HDL cells were treated for 1 hour at 37°C with 40 mM cytochalasin D and either (FIG. 9B) 400 pg/mL fucoidan or (FIG.
  • FIGS. 11 A-B -14A-C demonstrate that TREM-l/TRIOPEP in free and SLP-bound forms inhibits tumor growth, reduces infiltration of macrophages into the tumor in mouse models of NSCLC and PC and is well-tolerated by cancer mice during the treatment period (see also Shen and Sigalov. Mol Pharm 2017, 14:4572-4582).
  • FIG. 11 A-B presents the exemplary data showing inhibition of tumor growth in the human non small cell lung cancer H292 (FIG. 11 A) and A549 (FIG. 11B) xenograft mice treated with an equimolar mixture of the sulfoxidized methionine residue-containing TREM-l -related trifunctional peptides (TREM-l/TRIOPEP) GA 31 and GE 31 in free form.
  • PTX paclitaxel. ****, P ⁇ 0.0001 as compared with vehicle-treated animals.
  • FIG. 12A-B presents the exemplary data showing inhibition of tumor growth in the human non small cell lung cancer H292 (FIG. 12 A) and A549 (FIG. 12B) xenograft mice treated with an equimolar mixture of the sulfoxidized methionine residue-containing TREM-l -related trifunctional peptides (TREM-l/TRIOPEP) GA 31 and GE 31 incorporated into synthetic lipopeptide particles (SLP) particles of discoidal (TREM-l/TRIOPEP-dSLP) and spherical (TREM-l/TRIOPEP-sSLP) morphology.
  • SLP synthetic lipopeptide particles
  • PTX paclitaxel. ****, p ⁇ 0.0001 as compared with vehicle-treated animals.
  • FIG. 13 presents the exemplary data showing average tumor weights in the A549 xenograft mice treated with an equimolar mixture of the sulfoxidized methionine residue-containing TREM-l - related trifunctional peptides (TREM-l/TRIOPEP) GA 31 and GE 31 in free form or
  • SLP synthetic lipopeptide particles
  • TX paclitaxel
  • FIG. 14A-C presents the exemplary data showing inhibition of tumor growth (FIG. 14A) and TREM-l blockade-mediated suppression of intratumoral macrophage infiltration (FIG. 14B, FIG. 14C) in the human pancreatic cancer BxPC-3 xenograft mice treated with an equimolar mixture of the sulfoxidized methionine residue-containing TREM-l -related trifunctional peptides (TREM-l/TRIOPEP) GA 31 and GE 31 in free form or incorporated into synthetic lipopeptide particles (SLP) particles of discoidal (TREM-l/TRIOPEP-dSLP) and spherical (TREM- l/TRIOPEP-sSLP) morphology.
  • SLP synthetic lipopeptide particles
  • FIG. 15 demonstrates that TREM-l /TRIOPEP in free and SLP-bound forms significantly prolongs survival in mice with lipopolysaccharide (LPS)-induced septic shock.
  • LPS lipopolysaccharide
  • FIG. 15A-B presents the exemplary data showing improved survival of lipopolysaccharide (LPS)-challenged mice treated with an equimolar mixture of the sulfoxidized methionine residue-containing TREM-l -related trifunctional peptides (TREM-l /TRIOPEP) GA 31 and GE 31 in free form (FIG. 15 A) or incorporated into synthetic lipopeptide particles (SLP) particles of discoidal (TREM- l/TRIOPEP-dSLP) and spherical (TREM-l/TRIOPEP-sSLP) morphology.
  • FIG. 16 shows that TREM-l /TRIOPEP is non-toxic in healthy mice at least up to 400 mg/kg.
  • FIG. 16 presents exemplary data showing average weights of healthy C57BL/6 mice treated with increasing concentrations of an equimolar mixture of the sulfoxidized methionine residue- containing TREM-l -related trifunctional peptides (TREM-l /TRIOPEP) GA 31 and GE 31 in free form.
  • TREM-l /TRIOPEP sulfoxidized methionine residue- containing TREM-l -related trifunctional peptides
  • FIG. 17 demonstrates that TREM-l /TRIOPEP in free and SLP- bound form ameliorates arthritis in mice with collagen-induced arthritis (CIA) and is well- tolerated by arthritic mice during the treatment period of 2 weeks (see Shen and Sigalov. J Cell Mol Med 2017, 21 :2524-2534).
  • CIA collagen-induced arthritis
  • FIG. 17A-B presents the exemplary data showing average clinical arthritis score (FIG. 17A) and mean body weight (BW) changes (FIG. 17B) calculated as a percentage of the difference between beginning (day 24) and final (day 38) BWs of the collagen-induced arthritis (CIA) mice treated with an equimolar mixture of the sulfoxidized methionine residue-containing TREM-l - related trifunctional peptides (TREM-l /TRIOPEP) GA 31 and GE 31 incorporated into synthetic lipopeptide particles (SLP) particles of discoidal (TREM-l/TRIOPEP-dSLP) and spherical (TREM-l/TRIOPEP-sSLP) morphology.
  • DEX dexamethasone. *, p ⁇ 0.05, **, p ⁇ 0.01; *** , P ⁇ 0.001 as compared with vehicle-treated or naive animals.
  • FIG. 18 demonstrates that TREM-l/TRIOPEP-sSLP prevents pathological RNV in mice with oxygen-induced retinopathy and is well-tolerated by these mice during the treatment period (see Rojas, et al. Biochim Biophys Acta 2018, 1864:2761-2768).
  • FIG. 18A-D presents the exemplary data showing reduction of pathological retinal
  • FIG. 18A neovascularization area
  • FIG. 18B retinal TREM-l
  • FIG. 18C retinal TREM-l
  • FIG. 18D M-CSF/CSF-l
  • OIR oxygen-induced retinopathy
  • GA 31 sulfoxidized methionine residue- containing TREM-l -related trifunctional peptides
  • TREM-l /TRIOPEP oxygen-induced retinopathy
  • GA 31 and GE 31 incorporated into synthetic lipopeptide particles
  • TREM-l/TRIOPEP-SLP particles of spherical morphology
  • FIG. 19 shows that the self-assembled SLP of the present invention may cross the BBB, BRB and BTB, thus delivering their constituents including but not limiting to, TREM-l /TRIOPEP to the areas of interest in the brain, retina and tumor. While not being bound to any particular theory, it is believed that the brain-, retina-, and tumor-penetrating capabilities of these SLP can be mediated by interaction of SRBI with the domain B amino acid sequences that correspond to the sequences of human apo A-I helices 4 and/or 6 (see e.g. Liu, et al. J Biol Chem 2002, 277:21576-21584, each of which is herein incorporated by reference in it's entirety).
  • these capabilities of the peptides and compositions of the present invention can be used to diagnose, treat and/or prevent cancers (including brain cancer), diabetic retinopathy and retinopathy of prematurity, neurodegenerative diseases including Alzheimer's, Parkinson's and Huntington's diseases and other diseases and conditions where delivery of the peptides and compositions of the invention to the brain, retina and/or tumor is needed.
  • cancers including brain cancer
  • diabetic retinopathy and retinopathy of prematurity neurodegenerative diseases including Alzheimer's, Parkinson's and Huntington's diseases and other diseases and conditions where delivery of the peptides and compositions of the invention to the brain, retina and/or tumor is needed.
  • FIG. 19 presents exemplary data showing penetration of the blood-brain barrier (BBB) and blood-retinal barrier (BRB) by systemically (intraperitoneally) administered rhodamine B- labeled spherical self-assembled particles (sSLP) that contain Gd-containing contrast agent (Gd- sSLP) for magnetic resonance imaging (MRI), TREM-l inhibitory peptide GF9 (GF9-sSLP) or an equimolar mixture of the sulfoxidized methionine residue-containing TREM-l -related trifunctional peptides GA 31 and GE 31 (TREM-l /TRIOPEP-sSLP) .
  • BBB blood-brain barrier
  • BRB blood-retinal barrier
  • sSLP rhodamine B- labeled spherical self-assembled particles
  • Gd- sSLP Gd-containing contrast agent
  • MRI magnetic resonance imaging
  • TREM-l inhibitory peptide GF9 T
  • Mouse model of ALD mimics the early phase of the human disease, yet mRNA levels of early fibrosis markers Pro-Colla and a-SMA were significantly increased in alcohol-fed mice compared to PF controls in the whole-liver samples (FIG. 20A-B). Induction of these makers was remarkably attenuated in the vehicle-treated group and, importantly, further decreased by the TREM-l inhibitory formulations used (FIG. 20A-B).
  • FIG. 20A-B presents exemplary data showing TREM-l /TRIOPEP-sSLP suppresses the expression of fibrinogenesis marker molecules, FIG. 20A Pro-Collagen la and FIG. 20B a- Smooth Muscle Actin, at the RNA level, as measured in whole-liver lysates of mice with (alcohol-fed) and without (pair-fed) alcoholic liver disease (ALD).
  • * indicates significance level compared to the non-treated pair-fed (PF) group; # indicates significance level compared to the non-treated alcohol-fed group o indicates significance level compared to the vehicle-treated alcohol-fed group.
  • the significant levels are as follows: *, 0.05 > P > 0.01; **, 0.01 > P > 0.001; ***, 0.001 > P > 0.0001; ****, p ⁇ 0.0001.
  • TREM-l inhibitor effects were evaluated on hepatocyte damage and steatosis in liver.
  • Serum ALT levels obtained during week 5 of the alcohol feeding showed significant increases in alcohol-fed mice compared to PF controls. This ALT increase was attenuated in both TREM-l inhibitor-treated groups, indicating attenuation of liver injury (Fig. 4A).
  • FIG. 21A-D presents exemplary data showing that TREM-l /TRIOPEP-sSLP suppresses the production of alanine aminotransferase (ALT) in mice with alcoholic liver disease (ALD), as measured in serum of mice with (alcohol-fed) and without (pair-fed) ALD, in addition to improving indicators of liver disease and inflammation.
  • * indicates significance level compared to the alcohol-fed group treated with vehicle - synthetic lipopeptide particles of spherical morphology that contained an equimolar mixture of PE22 and PA22 (sSLP) but no TREM-l inhibitory peptide GF9.
  • # indicates significance level compared to the non-treated alcohol-fed group.
  • FIG. 21 A Serum ALT levels were measured using a kinetic method. Exemplary data showing TREM-l /TRIOPEP- sSLP suppresses alanine aminotransferase in serum of alcohol fed mice over TREM-l peptide alone.
  • FIG. 21B-D Liver sections were stained with (B,C) Oil Red O and (FIG.
  • the T-cell receptor (TCR)-CD3 complex plays a role in T-cell differentiation, in protecting the organism from infectious agents, and in the function of T-cells.
  • the TCR is a complex of a heterodimer of TCRa and TCRb chains, which are responsible for antigen recognition and interaction with the major histocompatibility complex (MHC) molecules of antigen-presenting cells, and CD3d, CD3g, CD3e and CD3z chains, which are responsible for transmembrane signal transduction (see e.g., Manolios, et al. Cell Adh Migr 2010, 4:273-283; Sigalov. Adv Protein Chem Struct Biol 2018, 111 :61-9; Sigalov.
  • MHC major histocompatibility complex
  • the preferred TCR-related peptides and compositions of this class comprise the domain A comprising the TCR modulatory peptide sequences designed using a well-known in the art novel model of cell receptor signaling, the Signaling Chain HOmoOLigomerization model, capable of modulating TCR (see e.g., Sigalov. Self Nonself 2010, 1 :4-39; Sigalov. Self Nonself 2010, 1 : 192-224; Sigalov. Trends Pharmacol Sci 2006, 27:518-524; Sigalov. Trends Immunol 2004, 25:583-589; Sigalov. Adv Protein Chem Struct Biol 2018, 111 :61-9; Sigalov.
  • the preferred peptides and compositions of this class further comprise the domain B comprising at least one modified or unmodified amphipathic alpha helical peptide fragment.
  • the inclusion of an amphipathic amino acid sequences aids the assistance in the ability to interact with native lipoproteins in a bloodstream in vivo and to form naturally long half-life lipopeptide/lipoprotein particles LP. It further aids the ability to provide targeted delivery to the sites of interest. It further aids the ability to cross the BBB, BRB and BTB.
  • the preferred TCR-related peptides and compositions of this class comprise the domain A comprising the TCR modulatory peptide sequences designed using a well-known in the art novel model of cell receptor signaling, the Signaling Chain HOmoOLigomerization model, capable of modulating TCR (see e.g., Sigalov. Self Nonself 2010, 1 :4-39; Sigalov. Self Nonself 2010, 1 : 192-224; Sigalov. Trends Pharmacol Sci 2006, 27:518-524; Sigalov. Trends Immunol 2004, 25:583-589; Sigalov. Adv Protein Chem Struct Biol 2018, 111 :61-9; Sigalov.
  • the preferred peptides and compositions of this class further comprise the domain B comprising at least one modified or unmodified amphipathic apo A-I and/or A-II peptide fragment to form upon interaction with lipid and/or lipid mixtures, SLP structures that can be spherical or discoidal (described herein and in e.g., Sigalov. Contrast Media Mol Imaging 2014, 9:372-382; Sigalov. Int
  • exemplary trifunctional peptides comprise the domain B comprises with the amino acid sequence selected from the amino acid sequences of the major HDL protein constituent, apo A-I. In certain embodiments, this sequence comprises 22 amino acid residue-long peptide sequence of the apo A-I helix 4.
  • this sequence contains a modified amino acid residue. In one embodiment, this modified amino acid residue is methionine sulfoxide. In one embodiment, the domain B of the peptides and compositions of the invention comprises 22 amino acid residue-long peptide sequence of the apo A-I helix 6. In one embodiment, this sequence contains a modified amino acid residue. In one embodiment, this modified amino acid residue is methionine sulfoxide.
  • TABLE 2 demonstrates the following structures of
  • TCR-related trifunctional peptides TCR/TRIOPEP MA32
  • TCR/TRIOPEP ME32 MWKTPTLKYFP YLDDF QKKW QEEMEL YRQKVE
  • TCR/TRIOPEP GA36 (GARSMTLT V Q ARQLPLGEEMRDRARAHVD ALRTHL A) (SEQ ID NO 13)
  • TCR/TRIOPEP GE36 (GARSMTLT V QARQLP YLDDF QKKW QEEMEL YRQKVE) (SEQ ID NO 14)
  • TCR/TRIOPEP GA32 (GVLRLLLFKLPLGEEMRDRARAHVDALRTHLA) (SEQ ID NO 15)
  • TCR/TRIOPEP GE32 (GARSMTLT V Q ARQLPLGEEMRDRARAHVD ALRTHL A)
  • TCR/TRIOPEP GE36 (GARSMTLT V QARQLP YLDDF QKKW QEEMEL YRQKVE) (SEQ ID NO 14)
  • TCR/TRIOPEP GA32 (GVLRLLLFKLPLGEEMRDRARAHVDALRTHLA) (SEQ ID NO 15)
  • GVLRLLLFKLP YLDDF QKKW QEEMEL YRQKVE SEQ ID NO 16
  • these peptides colocalize with TCR in the cell membrane and selectively disrupt intramembrane interactions of TCRa chain with the CD3ed heterodimer and CD3zz homodimer, resulting to specific ligand- independent inhibition of TCR upon antigen stimulation (see e.g. Sigalov. Self Nonself 2010, 1 :4-39.; Sigalov. Self Nonself 2010, 1 : 192-224; and Sigalov. Adv Protein Chem Struct Biol 2018, 111 :6l-99, each of which is herein incorporated by reference in it's entirety).
  • methionine residues of TCR/TRIOPEP peptides are modified.
  • TABLE 2 demonstrates the following structures of
  • TCR-related trifunctional peptides TCR/TRIOPEP LA32
  • TABLE 2 demonstrates the following structures of
  • TCR-related trifunctional peptides TCR/TRIOPEP YA32
  • YLLDGILFIYPLGEEMRDRARAHVDALRTHLA SEQ ID NO. 19
  • TCR/TRIOPEP YE32 YLLDGILFI YP YLDDF QKKW QEEMEL YRQK VE
  • these peptides colocalize with TCR in the cell membrane and selectively disrupt intramembrane interactions of CD3zz homodimer with TCRa chain, resulting to specific ligand-independent inhibition of TCR upon antigen stimulation (see e.g. Sigalov. Self Nonself 2010, 1 :4-39; Sigalov. Self Nonself 2010,
  • TABLE 2 demonstrates the following structures of
  • TCR-related trifunctional peptides TCR/TRIOPEP IA32
  • these peptides colocalize with TCR in the cell membrane and selectively disrupt intramembrane interactions of CD3ed heterodimer with TCRa chain, resulting to specific ligand-independent inhibition of TCR upon antigen stimulation (see e.g. Sigalov. Self Nonself 2010, 1 :4-39; Sigalov. Self Nonself 2010,
  • TABLE 2 demonstrates the following structures of
  • TCR-related trifunctional peptides TCR/TRIOPEP FA32
  • these peptides colocalize with TCR in the cell membrane and selectively disrupt intramembrane interactions of CD3eg heterodimer with TCRb chain, resulting to specific ligand-independent inhibition of TCR upon antigen stimulation (see e.g. Sigalov. Self Nonself 2010, 1 :4-39; Sigalov. Self Nonself 2010,
  • TABLE 2 demonstrates the following structures of
  • TCR-related trifunctional peptides TCR/TRIOPEP IA32e
  • these peptides colocalize with TCR in the cell membrane and selectively disrupt intramembrane interactions of CD3eg and CD3ed heterodimers with TCRb and TCRa chains, respectively, resulting to specific ligand- independent inhibition of TCR upon antigen stimulation (see e.g. Sigalov. Self Nonself 2010, 1 :4-39; Sigalov. Self Nonself 2010, 1 :192-224; and Sigalov. Adv Protein Chem Struct Biol 2018, 111 :6l-99, all of which are herein incorporated by reference in their entirety).
  • methionine residues of TCR/TRIOPEP peptides are modified as described herein.
  • the capability of the TCR-related peptides and compounds of the present invention including but not limiting to those described above, to inhibit TCR can be used to treat and/or prevent TCR-related diseases and conditions including but not limiting to, allergic diathesis e.g. delayed type hypersensitivity, contact dermatitis; autoimmune disease e.g. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, diabetes, Guillain-Barre syndrome, Hashimotos disease, pernicious anaemia; gastroenterological conditions e.g. inflammatory bowel disease, Crohn’s disease, primary biliary cirrhosis, chronic active hepatitis; skin problems e.g.
  • allergic diathesis e.g. delayed type hypersensitivity, contact dermatitis
  • autoimmune disease e.g. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, diabetes, Guillain-Barre syndrome
  • the capability of the TCR-related peptides and compounds of the present invention can be used to visualize (image) this receptor and evaluate its expression in the areas of interest.
  • an imaging probe e.g. [ 64 Cu], see TABLE 2
  • imaging (visualization) of TCR levels using PET and/or other imaging techniques can be used to diagnose TCR-related diseases and conditions as well as to monitor novel therapies for these diseases and conditions.
  • NKG2D is an activating receptor expressed by natural killer (NK) and T cells.
  • the NKG2D is a complex of an NKG2D chain, which is responsible for ligand recognition, and DAP 10 homodimer, which is responsible for transmembrane signal transduction (see e.g.
  • NKG2D ligands show a restricted expression in normal tissues, but they are frequently overexpressed in cancer and infected cells. The binding of NKG2D to its ligands activates NK and T cells and promotes cytotoxic lysis of the cells expressing these molecules.
  • the preferred NKG2D-related peptides and compositions of this class comprise the domain A comprising the NKG2D modulatory peptide sequences designed using a well-known in the art novel model of cell receptor signaling, the Signaling Chain HOmoOLigomerization model, capable of modulating NKG2D (see e.g., Sigalov. Self Nonself 2010, 1 :4-39; Sigalov. Self Nonself 2010, 1 : 192-224; Sigalov. Trends Pharmacol Sci 2006, 27:518-524; Sigalov.
  • the preferred peptides and compositions of this class further comprise the domain B comprising at least one modified or unmodified amphipathic apo A-I and/or A-II peptide fragment to form upon interaction with lipid and/or lipid mixtures, SLP structures that can be spherical or discoidal (described herein and in e.g., Sigalov. Contrast Media Mol Imaging 2014, 9:372-382; Sigalov. Int
  • an amphipathic apo A-I sequences aids the assistance in the self-assembly of SLP and the structural stability of the particle formed, particularly when the particle has a discoidal shape. It further aids the ability to provide targeted delivery to the cells of interest. It further aids the ability to interact with lipids and/or lipoproteins in a bloodstream in vivo and form LP that mimic native lipoproteins. It further aids the ability to cross the BBB, BRB and BTB.
  • exemplary trifunctional peptides comprise the domain B comprises with the amino acid sequence selected from the amino acid sequences of the major HDL protein constituent, apo A-I. In certain embodiments, this sequence comprises 22 amino acid residue-long peptide sequence of the apo A-I helix 4. In one embodiment, this sequence contains a modified amino acid residue. In one embodiment, this modified amino acid residue is methionine sulfoxide. In one embodiment, the domain B of the peptides and compositions of the invention comprises 22 amino acid residue-long peptide sequence of the apo A-I helix 6. In one embodiment, this sequence contains a modified amino acid residue. In one embodiment, this modified amino acid residue is methionine sulfoxide.
  • TABLE 2 demonstrates the following structures of
  • NKG2D/TRIOPEP IE36 (IAVAMGIRFIIM VAP YLDDF QKKW QEEMEL YRQKVE) (SEQ ID NO. 28). While not being bound to any particular theory, it is believed that in one embodiment, these peptides colocalize with NKG2D in the cell membrane and selectively disrupt
  • NKG2D/TRIOPEP peptides are modified.
  • the capability of the NKG2D-related peptides and compounds of the present invention including but not limiting to those described above, to inhibit NKG2D can be used to treat and/or prevent NKG2D-related diseases and conditions including but not limiting to, celiac disease, type I diabetes, hepatitis, and rheumatoid arthritis, and any other disorder where NKG2D cells are involved/recruited.
  • the present invention provides methods and compositions for preventing NK cell-mediated graft rejection.
  • the capability of the NKG2D-related peptides and compounds of the present invention can be used to visualize (image) this receptor and evaluate its expression in the areas of interest.
  • an imaging probe e.g. [ 64 Cu], see TABLE 2
  • imaging (visualization) of NKG2D levels using PET and/or other imaging techniques can be used to diagnose NKG2D- related diseases and conditions as well as to monitor novel therapies for these diseases and conditions.
  • GPVI glycoprotein
  • the preferred GPVI-related peptides and compositions of this class comprise the domain A comprising the GPVI modulatory peptide sequences designed using a well-known in the art novel model of cell receptor signaling, the Signaling Chain HOmoOLigomerization model, capable of modulating GPVI (see e.g., Sigalov. Self Nonself 2010, 1 :4-39; Sigalov. Self Nonself 2010, 1 : 192-224; Sigalov. Trends Pharmacol Sci 2006, 27:518-524; Sigalov. Trends Immunol 2004, 25:583-589; Sigalov. Adv Protein Chem Struct Biol 2018, 111 :61-9; Sigalov. J Thromb Haemost 2007, 5:2310-2312; Sigalov. Expert Opin Ther Targets 2008, 12:677-692, each of which is herein incorporated by reference in it's entirety).
  • compositions of this class further comprise the domain B comprising at least one modified or unmodified amphipathic apo A-I and/or A-II peptide fragment to form upon interaction with lipid and/or lipid mixtures, SLP structures that can be spherical or discoidal (described herein and in e.g., Sigalov. Contrast Media Mol Imaging 2014, 9:372-382; Sigalov. Int
  • an amphipathic apo A-I sequences aids the assistance in the self-assembly of SLP and the structural stability of the particle formed, particularly when the particle has a discoidal shape. It further aids the ability to provide targeted delivery to the cells of interest. It further aids the ability to interact with lipids and/or lipoproteins in a bloodstream in vivo and form LP that mimic native lipoproteins. It further aids the ability to cross the BBB, BRB and BTB.
  • exemplary trifunctional peptides comprise the domain B comprises with the amino acid sequence selected from the amino acid sequences of the major HDL protein constituent, apo A-I. In certain embodiments, this sequence comprises 22 amino acid residue-long peptide sequence of the apo A-I helix 4. In one embodiment, this sequence contains a modified amino acid residue. In one embodiment, this modified amino acid residue is methionine sulfoxide. In one embodiment, the domain B of the peptides and compositions of the invention comprises 22 amino acid residue-long peptide sequence of the apo A-I helix 6. In one embodiment, this sequence contains a modified amino acid residue. In one embodiment, this modified amino acid residue is methionine sulfoxide.
  • TABLE 2 demonstrates the following structures of
  • GNLVRICLGAPLGEEMRDRARAHVDALRTHLA SEQ ID NO. 29
  • GPVI/TRIOPEP GE32 GNL VRICLGAP YLDDF QKKW QEEMEL YRQKVE
  • these peptides colocalize with GPVI in the cell membrane and selectively disrupt intramembrane interactions of GPVI chain with the FcRg signaling homodimer, resulting to specific ligand-independent inhibition of GPVI upon ligand stimulation (see e.g. Sigalov. Self Nonself 2010, 1 :4-39.;
  • methionine residues of GPVI/TRIOPEP peptides are modified.
  • the capability of the GPVI-related peptides and compounds of the present invention including but not limiting to those described above, to inhibit GPVI can be used to treat and/or prevent GPVI-related diseases and conditions including but not limiting to, ischemic and thromboinflammatory diseases, and any other disorder where platelets are involved/recruited.
  • the capability of the GPVI-related peptides and compounds of the present invention can be used to visualize (image) this receptor and evaluate its expression in the areas of interest.
  • an imaging probe e.g. [ 64 Cu], see TABLE 2
  • imaging (visualization) of GPVI levels using PET and/or other imaging techniques can be used to diagnose GPVI-related diseases and conditions as well as to monitor novel therapies for these diseases and conditions.
  • the DAP 10 and DAP 12 signaling subunits are highly conserved in evolution and associate with a large family of receptors in hematopoietic cells, including dendritic cells, plasmacytoid dendritic cells, neutrophils, basophils, eosinophils, mast cells, monocytes, macrophages, natural killer cells, and some B and T cells. Some receptors are able to associate with either DAP10 or DAP12, which contribute unique intracellular signaling functions. DAP- 10- and DAP-l2-associated receptors have been shown to recognize both host-encoded ligands and ligands encoded by microbial pathogens, indicating that they play a role in innate immune responses. See e.g. Lanier.
  • the preferred DAP-10 and DAP-l2-related peptides and compositions of this class comprise the domain A comprising the DAP-10 or DAP-12 modulatory peptide sequences, respectively, designed using a well-known in the art novel model of cell receptor signaling, the Signaling Chain HOmoOLigomerization model, capable of modulating DAP- 10- and DAP- 12- associated receptors (see e.g., Sigalov. Self Nonself 2010, 1 :4-39; Sigalov. Self Nonself 2010, 1 : 192-224; Sigalov. Trends Pharmacol Sci 2006, 27:518-524; Sigalov. Trends Immunol 2004, 25:583-589; Sigalov.
  • the preferred peptides and compositions of this class further comprise the domain B comprising at least one modified or unmodified amphipathic apo A-I and/or A-II peptide fragment to form upon interaction with lipid and/or lipid mixtures, SLP structures that can be spherical or discoidal (described herein and in e.g., Sigalov. Contrast Media Mol Imaging 2014, 9:372-382; Sigalov. Int Immunopharmacol 2014, 21 :208-219;
  • exemplary trifunctional peptides comprise the domain B comprises with the amino acid sequence selected from the amino acid sequences of the major HDL protein constituent, apo A-I.
  • this sequence comprises 22 amino acid residue-long peptide sequence of the apo A-I helix 4. In one embodiment, this sequence contains a modified amino acid residue. In one embodiment, this modified amino acid residue is methionine sulfoxide. In one embodiment, the domain B of the peptides and compositions of the invention comprises 22 amino acid residue-long peptide sequence of the apo A-I helix 6. In one embodiment, this sequence contains a modified amino acid residue. In one embodiment, this modified amino acid residue is methionine sulfoxide.
  • TABLE 2 demonstrates the following structures of
  • these peptides colocalize with DAP-lO-associated cell receptors in the cell membrane and selectively disrupt intramembrane interactions of the receptor with the DAP-10 signaling homodimer, resulting to specific ligand-independent inhibition of the receptor upon ligand stimulation (see e.g. Sigalov. Self Nonself 2010, 1 :4-39.; Sigalov.
  • methionine residues of DAP-10/TRIOPEP peptides are modified.
  • TABLE 2 demonstrates the following structures of
  • VMGDLVLTVLPLGEEMRDRARAHVDALRTHLA SEQ ID NO. 31
  • DAP- 12/TRIOPEP VE32 VMGDLVLTVLP YLDDF QKKW QEEMEL YRQKVE
  • these peptides colocalize with DAP-l2-associated cell receptors in the cell membrane and selectively disrupt intramembrane interactions of the receptor with the DAP-12 signaling homodimer, resulting to specific ligand-independent inhibition of the receptor upon ligand stimulation (see e.g. Sigalov. Self Nonself 2010, 1 :4-39.; Sigalov.
  • methionine residues of DAP-12/TRIOPEP peptides are modified.
  • the capability of the DAP- 10- and DAP-l2-related peptides and compounds of the present invention including but not limiting to those described above, to inhibit the DAP-10- and DAP-l2-associated receptors, respectively, can be used to treat and/or prevent any diseases and conditions where these receptors are involved.
  • the capability of the DAP- 10- and DAP-l2-related peptides and compounds of the present invention can be used to visualize (image) these receptors and evaluate their expression in the areas of interest.
  • an imaging probe e.g. [ 64 Cu], see TABLE 2
  • imaging probe can be conjugated to the DAP-10/TRIOPEP and DAP-12/TRIOPEP sequences.
  • EGF epidermal growth factor
  • ErbB ErbB family
  • RTKs oncogenic receptor tyrosine kinases
  • HER2/ErbB2 is overexpressed on the surface of 25-30% of breast cancer cells, and it has been associated with a high risk of relapse and death.
  • EGFR amplification and mutations have been associated with many carcinomas.
  • the EGFR pathway appears to play a role in pancreatic carcinoma. See e.g. Overholser, et al. Cancer 2000, 89:74-82; Bennasroune, et al. Mol Biol Cell 2004, 15:3464- 3474; Sigalov.
  • the preferred EGFR-related peptides and compositions of this class comprise the domain A comprising the EGFR modulatory peptide sequences, designed using a well-known in the art novel model of cell receptor signaling, the Signaling Chain HOmoOLigomerization model, capable of modulating EGFR (see e.g., Sigalov. Self Nonself 2010, 1 :4-39; Sigalov. Self Nonself 2010, 1 : 192-224; Sigalov. Trends Pharmacol Sci 2006, 27:518-524; Sigalov. Trends Immunol 2004, 25:583-589; Sigalov. Adv Protein Chem Struct Biol 2018, 111 :61-9, all of which are herein incorporated by reference in their entirety).
  • the preferred peptides and compositions of this class further comprise the domain B comprising at least one modified or unmodified amphipathic apo A-I and/or A-II peptide fragment to form upon interaction with lipid and/or lipid mixtures, SLP structures that can be spherical or discoidal (described herein and in e.g., Sigalov. Contrast Media Mol Imaging 2014, 9:372-382; Sigalov. Int Immunopharmacol 2014, 21 :208-219; Sigalov. US 20110256224; Sigalov. US 20130045161; Shen, et al. PLoS One 2015, l0:e0l43453; Shen and Sigalov.
  • an amphipathic apo A-I sequences aids the assistance in the self-assembly of SLP and the structural stability of the particle formed, particularly when the particle has a discoidal shape. It further aids the ability to provide targeted delivery to the cells of interest. It further aids the ability to interact with lipids and/or lipoproteins in a bloodstream in vivo and form LP that mimic native lipoproteins. It further aids the ability to cross the BBB, BRB and BTB.
  • TREM-l inhibitory SCHOOL peptide GF9 described herein is incorporated into SLP that contain apo A-I peptide fragments comprising 22 amino acid residue- long peptide sequences of the apo A-I helix 4 and/or helix 6.
  • the inclusion of an amphipathic apo A-I sequences in the peptides and compositions of the invention further aids the ability to provide targeted delivery to the cells of interest. It further aids the ability to interact with lipids and/or lipoproteins in a bloodstream in vivo and form lipopeptide particles (LP) that mimic native lipoproteins. It further aids the ability to cross the blood-brain barrier (BBB), blood-retinal barrier (BRB) and blood-tumor barrier (BTB).
  • BBB blood-brain barrier
  • BBB blood-retinal barrier
  • BTB blood-tumor barrier
  • exemplary trifunctional peptides comprise the domain B comprises with the amino acid sequence selected from the amino acid sequences of the major HDL protein constituent, apo A-I. In certain embodiments, this sequence comprises 22 amino acid residue-long peptide sequence of the apo A-I helix 4. In one embodiment, this sequence contains a modified amino acid residue. In one embodiment, this modified amino acid residue is methionine sulfoxide. In one embodiment, the domain B of the peptides and compositions of the invention comprises 22 amino acid residue-long peptide sequence of the apo A-I helix 6. In one embodiment, this sequence contains a modified amino acid residue. In one embodiment, this modified amino acid residue is methionine sulfoxide.
  • TABLE 2 demonstrates the following structures of
  • these peptides colocalize with EGFR in the cell membrane and selectively disrupts intramembrane interactions between the receptors, resulting to specific ligand-independent inhibition of the receptor (see e.g. Sigalov. Self Nonself 2010, 1 :4-39.; Sigalov. Self Nonself 2010, 1 : 192-224; Sigalov. Adv Protein Chem Struct Biol 2018, 111 :6l-99, all of which are herein incorporated by reference in their entirety).
  • methionine residues of EGFR/TRIOPEP peptides are modified.
  • the capability of the EGFR and/or ErB-related peptides and compounds of the present invention including but not limiting to those described above, to inhibit the receptors of the EGFR and/or ErB receptor families, respectively, can be used to treat and/or prevent any diseases and conditions where these receptors are involved.
  • the capability of the EGFR- and/or ErB-related peptides and compounds of the present invention can be used to visualize (image) these receptors and evaluate their expression in the areas of interest.
  • an imaging probe e.g. [ 64 Cu]
  • imaging (visualization) of levels of the receptors of the EGFR and/or ErB receptor families using PET and/or other imaging techniques can be used to diagnose any diseases and conditions where these receptors are involved as well as to monitor novel therapies for these diseases and conditions.
  • this domain comprises the Toll Like Receptor (TLR) modulatory sequence (see e.g. Tsung, et ah Shock 2007, 27:364-369, herein incorpoated by referene in it's entirety).
  • TLR Toll Like Receptor
  • the preferred peptides and compositions of this class further comprise the domain B comprising at least one modified or unmodified amphipathic apo A-I and/or A-II peptide fragment to form upon interaction with lipid and/or lipid mixtures, SLP structures that can be spherical or discoidal (described herein and in e.g., Sigalov. Contrast Media Mol Imaging 2014, 9:372-382; Sigalov. Int Immunopharmacol 2014, 21 :208-219; Sigalov. US 20110256224;
  • an amphipathic apo A-I sequences aids the assistance in the self-assembly of SLP and the structural stability of the particle formed, particularly when the particle has a discoidal shape. It further aids the ability to provide targeted delivery to the cells of interest. It further aids the ability to interact with lipids and/or lipoproteins in a bloodstream in vivo and form LP that mimic native lipoproteins. It further aids the ability to cross the BBB, BRB and BTB.
  • exemplary trifunctional peptides comprise the domain B comprises with the amino acid sequence selected from the amino acid sequences of the major HDL protein constituent, apo A-I. In certain embodiments, this sequence comprises 22 amino acid residue-long peptide sequence of the apo A-I helix 4. In one embodiment, this sequence contains a modified amino acid residue. In one embodiment, this modified amino acid residue is methionine sulfoxide. In one embodiment, the domain B of the peptides and compositions of the invention comprises 22 amino acid residue-long peptide sequence of the apo A-I helix 6. In one embodiment, this sequence contains a modified amino acid residue. In one embodiment, this modified amino acid residue is methionine sulfoxide.
  • TABLE 2 demonstrates the following structures of
  • TLR/TRIOPEP DE32 DI VKLT VYD CIRRRRRRRRRP YLDDF QKK W QEEMEL YRQK VE.
  • methionine residues of TLR/TRIOPEP peptides are modified.
  • the capability of the TLR-related peptides and compounds of the present invention including but not limiting to those described above, to inhibit TLR can be used to treat and/or prevent TLR-related diseases and conditions including but not limiting to, sepsis and other infectious diseases, and any other disorder where TLR receptors are involved.
  • the capability of the TLR-related peptides and compounds of the present invention can be used to visualize (image) this receptor and evaluate its expression in the areas of interest.
  • an imaging probe e.g. [ 64 Cu]
  • imaging (visualization) of TLR levels using PET and/or other imaging techniques can be used to diagnose TLR-related diseases and conditions as well as to monitor novel therapies for these diseases and conditions.
  • the domain A of the peptides and compositions of the invention comprises the Atrial Natriuretic Peptide (ANP) receptor (ANPR)-modulatory sequence (see e.g. Ladetzki-Baehs, et al. Endocrinology 2007, 148:332-336).
  • the preferred peptides and compositions of this class further comprise the domain B comprising at least one modified or unmodified amphipathic apo A-I and/or A-II peptide fragment to form upon interaction with lipid and/or lipid mixtures, SLP structures that can be spherical or discoidal (described herein and in e.g., Sigalov. Contrast Media Mol Imaging 2014, 9:372-382; Sigalov. Int
  • an amphipathic apo A-I sequences aids the assistance in the self-assembly of SLP and the structural stability of the particle formed, particularly when the particle has a discoidal shape. It further aids the ability to provide targeted delivery to the cells of interest. It further aids the ability to interact with lipids and/or lipoproteins in a bloodstream in vivo and form LP that mimic native lipoproteins. It further aids the ability to cross the BBB, BRB and BTB.
  • exemplary trifunctional peptides comprise the domain B comprises with the amino acid sequence selected from the amino acid sequences of the major HDL protein constituent, apo A-I. In certain embodiments, this sequence comprises 22 amino acid residue-long peptide sequence of the apo A-I helix 4. In one embodiment, this sequence contains a modified amino acid residue. In one embodiment, this modified amino acid residue is methionine sulfoxide. In one embodiment, the domain B of the peptides and compositions of the invention comprises 22 amino acid residue-long peptide sequence of the apo A-I helix 6. In one embodiment, this sequence contains a modified amino acid residue. In one embodiment, this modified amino acid residue is methionine sulfoxide.
  • TABLE 2 demonstrates the following structures of
  • the capability of the ANPR-related peptides and compounds of the present invention including but not limiting to those described above, to inhibit ANPRs can be used to treat and/or prevent ANPR-related diseases and conditions including but not limiting to, cardiovascular and inflammatory diseases, and any other disorder where ANP receptors are involved.
  • the capability of the ANPR-related peptides and compounds of the present invention can be used to visualize (image) this receptor and evaluate its expression in the areas of interest.
  • an imaging probe e.g. [ 64 Cu]
  • imaging (visualization) of ANPR levels using PET and/or other imaging techniques can be used to diagnose ANPR-related diseases and conditions as well as to monitor novel therapies for these diseases and conditions.
  • other therapeutic agents including but not limiting to, to those described in Page and Takimoto. Principles of chemotherapy. In: Pazdur R, Wagman LD, Camphausen KA, editors. Cancer Management: A Multidisciplinary Approach. 1 lth ed.
  • the present invention encompasses the recognition that it is possible to produce compositions that possess the advantages typically associated with a fully synthetic material and yet also possess certain desirable features of materials derived from natural sources.
  • peptides and compounds of the present invention e.g.
  • trifunctional peptides with rHDLs (including discoidal and/or spherical HDLs) or without rHDLs (such as in therapeitic compositions as free trifunctional peptides), are contemplated for use in preventative treatments for diseases associated with activated macrophages and/or T-cells, in particular for preventing one or more symptoms associated with the disease.
  • peptides and compounds of the present invention are contemplated for use preventative treatments for diseases associated with activated macrophages and/or T-cells, in particular for reducing one or more symptoms associated with the disease.
  • peptides and compounds of the present invention are contemplated for use diagnostic applications for detecting/identifying; determining disease progression; determining results of disease treatment, for diseases associated with activated macrophages and/or T-cells.
  • diseases associated with activated macrophages and/or T-cells include but are not limited to including but not limited to lung cancer, such as non small-cell lung cancer (NSCLC); pancreatic cancer (PC); glioblastoma multiforme (GBM, or brain cancer), with or without radiation therapy; breast cancer with or without radiation therapy;_sepsis; retinopathy; rheumatoid arthritis (RA); sepsis; and alcoholic liver disease (ALD).
  • NSCLC non small-cell lung cancer
  • PC pancreatic cancer
  • GBM glioblastoma multiforme
  • RA rheumatoid arthritis
  • ALD alcoholic liver disease
  • diseases associated with activated macrophages and/or T-cells include but are not limited to 1) Alcohol-induced neuroinflammation and brain damage; 2) Radiation-induced multiple organ dysfunction syndrome; 3) Scleroderma; 4) Atopic dermatitis; 5) Atherosclerosis; 6) Alzheimer's, Parkinson's and/or Huntington's diseases.
  • the present invention relates to the targeted treatment, prevention and/or detection of cancer including but not limited to lung, pancreatic, breast, stomach, prostate, colon, brain and skin cancers, cancer cachexia, atherosclerosis, allergic diseases, acute radiation syndrome, inflammatory bowel disease, empyema, acute mesenteric ischemia, hemorrhagic shock, multiple sclerosis, liver diseases, autoimmune diseases, including but not limited to, atopic dermatitis, lupus, scleroderma, rheumatoid arthritis, psoriatic arthritis and other rheumatic diseases, sepsis and other inflammatory diseases or other condition involving myeloid cell activation and, more particularly, TREM receptor-mediated cell activation, including but not limited to diabetic retinopathy and retinopathy of prematurity, Alzheimer's, Parkinson's and Huntington's diseases.
  • cancer including but not limited to lung, pancreatic, breast, stomach, prostate, colon, brain and skin cancers, cancer cachexia, athe
  • trifunctonal peptides as described herein are contemplated for administration to a subject for reducing a disease symptom. In some embodiments, trifunctonal peptides as described herein are contemplated for administration to a subject for delaying onset of a disease symptom. In some embodiments, trifunctonal peptides as described herein are contemplated for administration to a subject for preventing a disease symptom. In some embodiments, trifunctonal peptides as described herein are contemplated for administration to a subject receiving therapy for a disease. In some embodiments, trifunctonal peptides as described herein are contemplated for administration to a subject receiving anti-cancer therapy.
  • trifunctonal peptides as described herein are contemplated for administration to a subject as anti-cancer therapy.
  • trifunctonal peptides as described herein, further comprising a drug compound are contemplated for administration to a subject as anti-cancer therapy.
  • trifunctonal peptides as described herein, further comprising a Paclitaxel compound are contemplated for administration to a subject as anti-cancer therapy.
  • trifunctonal peptide as described herein is administered to said subject at any point along the disease progression for reducing disease progression, in part as described herein.
  • trifunctonal peptides as described herein are contemplated for administration to a subject for reducing a liver disease symptom, including but not limited to reducing one or more of ALT, procollegen I-alpha and alpha- SM A.
  • trifunctonal peptides as described herein are contemplated for administration to a subject for reducing a liver disease symptom, in combination with one or more of steroid drugs, ursodiol, etc., in order to delay or prevent further progression of liver degeneration to cirrhosis.
  • trifunctonal peptides as described herein are contemplated for administration to a subject for reducing a liver disease symptom in combination with one or more of steroid drugs, ursodiol, etc., in order to improve function of a diseased liver.
  • trifunctonal peptides as described herein are contemplated for
  • trifunctonal peptides as described herein are contemplated for administration to a subject for treating colitis and colitis-associated tumorigenesis.
  • trifunctonal peptides as described herein are contemplated for administration to a subject for decreasing neovascularization.
  • trifunctonal peptides as described herein are selected from the group consisting of G-KV21, G-HV21, G-TE21, M-VE32 and M-TK32, and mixtures thereof.
  • a trifunctonal peptide as described herein is GE31.
  • a trifunctonal peptide as described herein is GA31.
  • a trifunctonal peptide as described herein is a mixture of GE31 and GA31.
  • FIG. 4B illustrates a hypothesized molecular mechanism of action of one embodiment of a trifunctional peptide (TRIOPEP) of the present invention comprising amino acid domains A and B where domain A is a 9 amino acids-long TREM-l inhibitory therapeutic peptide sequence and functions to treat and/or prevent a TREM-l -related disease or condition (shown for cancer), whereas domain B is a 22 amino acids-long apolipoprotein A-I helix 4 or 6 peptide sequence with a sulfoxidized methionine residue and functions to assist in the self-assembly of synthetic lipopeptide particles (SLP) and to target the particles to TREM-l -expressing macrophages as applied to the treatment and/or prevention of cancer.
  • SLP synthetic lipopeptide particles
  • FIG. 4C shows a symbol key used in FIGS. 4A-B.
  • the present invention encompasses the recognition that it is possible to prevent and treat different types of cancer including but not limited to, pancreatic cancer, multiple myeloma, leukemia, prostate cancer, breast cancer, liver cancer, bladder cancer, colorectal cancer, lung cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, or osteosarcoma and other cancers, and cancer cachexia by blocking the TREM-l signaling pathway using the peptide variants and compositions that possess the advantages typically associated with a fully synthetic material and yet possess certain desirable features of materials derived from natural sources.
  • the invention further encompasses the recognition that it is possible to use imaging techniques and the peptide variants and compositions of the invention conjugated to an imaging probe for detecting the labeled probe in an individual with cancer, wherein the location of the labeled probe corresponds to at least one symptom of the myeloid cell-related condition.
  • the invention further encompasses that it is possible to predict the efficacy of the peptides and compositions of the invention by determining the number of myeloid cells in the biological sample from the individual with cancer and determining the expression levels of TREM-l in the cells contained within the biological sample.
  • Inflammatory responses play decisive roles at different stages of tumor development, including initiation, promotion, malignant conversion, invasion, and metastasis (Grivennikov et al. 2010). Inflammation also affects immune surveillance and responses to therapy (Grivennikov et al. 2010). Many solid tumors are characterized by a marked infiltration of macrophages, inflammatory cells, into the stromal compartment (Shih et al. 2006, Solinas et al. 2009), a process which is mediated by cancer-associated fibroblasts (CAFs) and plays a key role in disease progression and its response to therapy (see FIG. 49).
  • CAFs cancer-associated fibroblasts
  • TAMs tumor-associated macrophages
  • cytokines cytokines
  • chemokines enzymes that regulate tumor growth, angiogenesis, invasion, and metastasis
  • FIG. 49 High macrophage infiltration correlates with the promotion of tumor growth and metastasis development (Solinas et al. 2009, Grivennikov et al. 2010).
  • macrophage infiltration begins during the preinvasive stage of the disease and increases progressively (Clark et al. 2007).
  • the number of TAMs is significantly higher in patients with metastases (Gardian et al. 2012).
  • TREM-l is upregulated in cancer and its overexpression correlates with survival of cancer patients.
  • TREM-l expression in TAMs is associated with cancer recurrence and poor survival of patients with NSCLC: patients with low TREM-l expression have a 4-year survival rate of over 60%, compared with less than 20% in patients with high TREM-l expression (Ho et al. 2008).
  • Activation of the TREM-1/DAP-12 signaling pathway results in release of multiple cytokines, chemokines and growth factors most of which are increased in cancer patients and their upregulation correlates with poor prognosis (See FIG. 1).
  • the present invention encompasses the recognition that it is possible to prevent and treat different types of cancer in which myeloid cells are involved or recruited and cancer cachexia by combining cancer therapies with a therapeutically effective amount of at least one compound and/or composition ("modulator") which affects myeloid cells by action on the TREM-1/DAP-12 signaling pathway.
  • modulator a compound and/or composition which affects myeloid cells by action on the TREM-1/DAP-12 signaling pathway.
  • TAMs tumor-associated macrophages
  • CCL2 chemokines
  • CSF-1R CSF-l receptor
  • CSF-l The level of CSF-l in tumors has been shown to correlate with the level of TAMs in the tumor. Higher levels of TAMs have been found to correlate with poorer patient prognoses in the majority of cancers. Increased pretreatment serum CSF-l is a strong independent predictor of poor survival in NSCLC (Baghdadi et al. 2018). In addition, CSF-l has been found to promote tumor growth and progression to metastasis in, for example, human breast cancer xenografts in mice (Paulus et al. 2006). Further, CSF-1R plays a role in osteolytic bone destruction in bone metastasis (Ohno et al. 2006).
  • TAMs promote tumor growth, in part, by suppressing anti-tumor T cell effector function through the release of immunosuppressive cytokines and the expression of T cell inhibitory surface proteins.
  • Blockade of CSF-l or CSF-1R not only suppresses tumor angiogenesis and lymphangiogenesis (Kubota et al. 2009) but also improves response to T-cell checkpoint immunotherapies that target programmed cell death protein 1 (PD-l), programmed death-ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) (Zhu et al. 2014).
  • PD-l programmed cell death protein 1
  • PD-L1 programmed death-ligand 1
  • CTLA-4 cytotoxic T lymphocyte antigen-4
  • continuous CSF-l inhibition affects pathological angiogenesis but not healthy vascular and lymphatic systems outside tumors (Kubota et al. 2009).
  • VEGF vascular endothelial growth factor
  • the present invention provides a method of treating these and other types of cancers by using modulators of the TREM-1/DAP-12 signaling pathway that are capable of binding TREM-l and modulating TREM-1/DAP-12 receptor complex activity in combination- therapy treatments together with other cancer therapies.
  • the invention further provides the methods for predicting response of a cancer patient to the treatment by using these modulators in combination-therapy regimen.
  • the invention further encompasses the recognition that it is possible to predict response of the subject to the treatment by using the modulators of TREM-1/DAP-12 signaling pathway in combination-therapy regimen by: (a) obtaining a biological sample from the subject; (b) determining the expression of CSF-l, CSF-1R, IL-6, TREM-l and/or number of CD68-positive TAMs or a combination thereof, wherein the higher is the expression of CSF-l, CSF-1R, IL-6, TREM-l or the higher is number of CD68-positive TAMs or a combination thereof, the better the patient is predicted to respond to a therapy that involves the modulators.

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Abstract

La présente invention concerne des compositions et des procédés de traitement du cancer et d'autres maladies liées à des cellules immunes activées à l'aide de modulateurs de voie de signalisation TREM-1/DAP-12. Les compositions, incluant des peptides et des variantes de peptides, modulent une réponse immunologique mandatée par TREM-1 en tant que régime de traitement autonome et par combinaison de traitements thérapeutiques. La présente invention concerne en outre des procédés pour prédire l'efficacité de thérapies modulatoires de TREM-1 sur des patients. Dans un mode de réalisation, la présente invention concerne le traitement ciblé, la prévention ciblée et/ou la détection ciblée du cancer incluant, entre autres, le cancer du poumon incluant un cancer du poumon non à petites cellules, le cancer du pancréas, une tumeur de cellule géante de la gaine de tendon, une tumeur de cellules géantes ténosynoviales, une synovite villonodulaire pigmentée, une cachexie cancéreuse, etc., et d'autres cancers associés à l'activation et au recrutement de cellules myéloïdes. De plus, la présente invention concerne le traitement ciblé, la prévention ciblée et/ou la détection ciblée d'une sclérodermie incluant, entre autres, la calcinose, le phénomène de Raynaud, une dysmotilité œsophagienne, une sclérodermie, ou un syndrome de télangiectasie (CREST). La présente invention concerne en outre des traitements médicaux personnalisés.
PCT/US2019/046392 2018-08-13 2019-08-13 Peptides et compositions pour traitement et imagerie ciblés WO2020036987A1 (fr)

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WO2022245553A3 (fr) * 2021-05-19 2022-12-29 Signablk, Inc. Inhibiteurs de trem-2/dap-12 pour traiter des maladies et des lésion pulmonaires et combinaisons de ceux-ci

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