US20020147144A1 - Casein derived peptides and uses thereof in therapy - Google Patents

Casein derived peptides and uses thereof in therapy Download PDF

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US20020147144A1
US20020147144A1 US09/942,121 US94212101A US2002147144A1 US 20020147144 A1 US20020147144 A1 US 20020147144A1 US 94212101 A US94212101 A US 94212101A US 2002147144 A1 US2002147144 A1 US 2002147144A1
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peptide
pharmaceutical composition
casein
derived
seq
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Zvi Sidelman
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Peptera Pharmaceuticals Ltd
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CHAY 13 MEDICAL RESEARCH GROUP NV
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Assigned to CHAY 13 MEDICAL RESEARCH GROUP N.V. reassignment CHAY 13 MEDICAL RESEARCH GROUP N.V. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SIDELMAN, ZVI
Priority to AU2002324323A priority Critical patent/AU2002324323A2/en
Priority to EA200400376A priority patent/EA007814B1/ru
Priority to CA002458924A priority patent/CA2458924A1/en
Priority to MXPA04001890A priority patent/MXPA04001890A/es
Priority to BRPI0212625-7A priority patent/BR0212625A/pt
Priority to IL16054802A priority patent/IL160548A0/xx
Priority to PL02375113A priority patent/PL375113A1/xx
Priority to CNA028216741A priority patent/CN1694719A/zh
Priority to KR10-2004-7002884A priority patent/KR20040078639A/ko
Priority to JP2003523265A priority patent/JP2005511499A/ja
Priority to PCT/IL2002/000720 priority patent/WO2003018606A2/en
Priority to CZ2004335A priority patent/CZ2004335A3/cs
Priority to EP02758768A priority patent/EP1556074A4/en
Priority to HU0500995A priority patent/HUP0500995A3/hu
Publication of US20020147144A1 publication Critical patent/US20020147144A1/en
Priority to ZA200401574A priority patent/ZA200401574B/en
Priority to NO20040880A priority patent/NO20040880L/no
Assigned to PEPTERA PHARMACEUTICALS LTD. reassignment PEPTERA PHARMACEUTICALS LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHAY 13 MEDICAL RESEARCH GROUP N.V.
Priority to US11/518,400 priority patent/US7741274B2/en
Priority to US12/764,996 priority patent/US20100298216A1/en
Abandoned legal-status Critical Current

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    • 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
    • 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
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic 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
    • A61P7/06—Antianaemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4732—Casein
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P21/00—Preparation of peptides or proteins
    • C12P21/06—Preparation of peptides or proteins produced by the hydrolysis of a peptide bond, e.g. hydrolysate products

Definitions

  • the present invention relates to biologically active peptides that are derived from or are similar to sequences identical with the N-terminus of the oS1 fraction of milk casein. These peptides are capable of stimulating and enhancing immune response, protecting against viral infection, normalizing serum cholesterol levels, and stimulating hematopoiesis.
  • the casein-derived peptides are non-toxic and can be used to treat and prevent immune pathologies, hypercholesterolemia, hematological disorders and viral-related diseases.
  • Casein the predominant milk protein, has been traditionally defined as composed of three fractions, o, ⁇ , and ⁇ , according to their electrophoretic mobility [N. J. Hipp, et al. (1952), Dairy Sci., 35:272].
  • Today casein is defined according to the amino acid sequences of each of the subgroups oS1, oS2, ⁇ and ⁇ [W. N. Engel et al. (1984), J. Dairy Sci. 67: 1599].
  • casein proteins are subjected to proteolytic cleavage by acid proteases such as chymosin (rennin), trypsin and pepsin, producing shorter peptides and causing curdling and calcium sequestration by the resultant protein fragments.
  • acid proteases such as chymosin (rennin), trypsin and pepsin
  • U.S. Pat. No. 3,764,670 discloses proteolytic casein digests possessing antibiotic properties against microorganisms.
  • Israel Patent No. 42863 describes a casein-derived peptide consisting of 23 amino acids of the N-terminus of casein, possessing anti-bacterial activity.
  • other physiologically active properties such as opioid and growth factor-like activities have been proposed for casein or its derivatives [Kitts, D. D., (1999), ibid.].
  • G-CSF granulocyte colony stimulation factor
  • GM-CSF granulocyte macrophage colony stimulating factor
  • hematopoietic growth factors may be prohibitive in patients with tumor cells bearing G-CSF or GM-CSF receptors such as in acute and chronic myeloid leukemias and in myelodysplastic syndromes.
  • G-CSF GM-CSF receptors
  • thrombocytopenia no progress has been made in the treatment of thrombocytopenia.
  • rhIL3 recombinant human interleukin-3
  • rhIL6 recombinant human interleukin-6
  • TPO Thrombopoetin
  • TPO appears to be the major regulator of platelet production in vivo, although increase in the kidney- and liver-derived growth factor in platelet deficiencies is not caused by adaptation of TPO biosynthesis in these organs. Rather, a “feed-back loop” seems to exist in which the number of circulating platelets determines how much of the circulating TPO is available to the bone marrow for platelet production.
  • TPO is an early acting cytokine with important multilineage effects: TPO alone, or in combination with other early acting cytokines, can (i) promote viability and suppress apoptosis in progenitor cells; (ii) regulate hematopoietic stem cell production and function; (iii) trigger cell division of dormant multipotent cells; (iv) induce multilineage differentiation and (v) enhance formation of multilineage colonies containing granulocytes, erythrocytes, macrophages, and megakaryocytes (MK, CFU-GEMM).
  • MK megakaryocytes
  • TPO stimulates the production of more limited progenitors for granulocyte/monocyte, megakaryocyte and erythroid colonies, and stimulates adhesion of primitive human bone marrow and megakaryocytic cells to fibronectin and fibrinogen.
  • TPO is an important cytokine for clinical hematologists/transplanters: for the mobilization, amplification and ex vivo expansion of stem cells and committed precursor cells for autologous and allogeneic transplantation (von dem Borne, A.E.G.Kr., et al., (1998) Thrombopoietin: it's role in platelet disorders and as a new drug in clinical medicine. In Ba Amsterdam Clin. Hematol. June:11 (2), 427-45.
  • this potent growth factor primes platelets for various agonists and modulates platelet-extracellular matrix interactions. Although it does not itself cause platelet aggregation, TPO upregulates ADP-induced aggregation, especially on the second wave of aggregation, upregulates granule (ADP, ATP, serotonin, etc.) release and production of thromboxane B2, increases platelet attachment to collagen and potentiates shear-induced platelet aggregation. TPO also stimulates PMN activation, inducing IL-8 release and priming oxygen metabolite production, likely enhancing antimicrobial defense.
  • TPO idiopathic aplastic anemia
  • AA idiopathic aplastic anemia
  • TPO is elevated in other forms of aplastic thrombocytopenia as well, but not in conditions of increased platelet destruction.
  • the reactive increase in TPO production is insufficient in cases of destructive thrombocytopenia.
  • TPO is not only a therapeutic option for aplastic, but also for destructive thrombocytopenia.
  • Thrombopoietic agents are of great clinical interest, for prevention and/or treatment of pathological or treatment-induced thrombocytopenia, and as a substitute for platelet transfusions.
  • cytokines Of the cytokines evaluated, all but the marginally potent IL-11 have been deemed unacceptable for clinical use.
  • TPO is widely believed to become the cytokine of choice for throbocytopenia treatment.
  • Recombinant human TPO (Genentech) has recently become available, enabling accurate pharmacokinetic determinations and clinical trials.
  • TPO's potential applications encompass the realms of supportive care (post chemo/radio-therapy, bone marrow and stem cell transplantation), hematological disease (AA, myelodysplasia, congenital and acquired thrombocytopenia), liver diseases, transfusion (expansion, harvest, mobilization and storage of platelets) and surgery (including liver transplantation).
  • supportive care post chemo/radio-therapy, bone marrow and stem cell transplantation
  • AA myelodysplasia
  • congenital and acquired thrombocytopenia liver diseases
  • transfusion expansion, harvest, mobilization and storage of platelets
  • surgery including liver transplantation.
  • TPO/EPO/G-CSF cocktail for myelodysplasia, G-CSF and TPO combination for peripheral stem cell mobilization and TPO in harvesting CD 34+cells and ex vivo expansion of megakaryocytes for superior platelet reconstitution.
  • TPO is costly and potentially antigenic at therapeutically effective levels.
  • the oS1 fraction of casein can be obtained from milk proteins by various methods [D. G. Schmidth and T. A. J. Paynes (1963), Biochim., Biophys. Acta, 78:492; M. P. Thompson and C. A. Kiddy (1964), J. Dairy Sci., 47:626; J. C. Mercier, et al. (1968), Bull. Soc. Chim. Biol. 50:521], and the complete amino acid sequence of the oS1 fraction of casein was determined by J. C. Mercier et al. (1971) (Eur. J. Biochem. 23:41).
  • Dairy Res., 60:401] as has the intestinal absorption and appearance of this fragment in mammalian plasma following ingestion of whole milk proteins [Fiat, A.M., et al. (1998) Biochimie, 80(2):2155-65].
  • Meisel, H. and Bockelmann, W. [(1999), Antonie Van Leeuwenhoek, 76:207-15] detected amino acid sequences of immunopeptides, casokinins and casomorphins in peptides liberated by lactic acid bacteria digests of o and p casein fractions.
  • Of particular interest is the anti-aggregating and thrombolytic activity demonstrated for C-terminal portions of the o- and ⁇ -casein fractions [Chabance, B.
  • a method of preventing or treating an autoimmune disease comprising administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of preventing or treating a viral disease comprising administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of preventing viral infection comprising administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of inducing hematopoiesis comprising administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of inducing hematopoietic stem cells proliferation comprising administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of inducing hematopoietic stem cells proliferation and differentiation comprising administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of inducing megakaryocytopoiesis comprising administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of inducing erythropoiesis comprising administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of inducing leukocytopoiesis comprising administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of inducing plasma cell proliferation comprising administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of inducing dendritic cell proliferation comprising administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of inducing macrophage cell proliferation comprising administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of preventing or treating thrombocytopenia comprising administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of preventing or treating pancytopenia comprising administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of preventing or treating granulocytopenia comprising administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of preventing or treating hyperlipidemia comprising administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of preventing or treating hypercholesterolemia comprising administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of preventing or treating glucosuria comprising administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of preventing or treating diabetes comprising administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of preventing or treating AIDS comprising administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of preventing or treating infection by HIV comprising administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • ASCT autologous bone marrow or peripheral blood stem cell transplantation
  • BMT allogeneic bone marrow transplantation
  • a method of treating a thrombopoietin treatable condition comprising administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of augmenting the effect of thrombopoietin comprising administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of enhancing peripheral stem cell mobilization comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising effective amounts of thrombopoietin and a peptide derived from an N terminus portion of a SI casein.
  • a pharmaceutical composition for preventing or treating an autoimmune disease comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for preventing or treating a viral disease comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for preventing viral infection comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for inducing hematopoiesis comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for inducing hematopoietic stem cells proliferation comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for inducing hematopoietic stem cells proliferation and differentiation comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for inducing megakaryocytopoiesis comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for inducing erythropoiesis comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for inducing leukocytopoiesis comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for inducing thrombocytopoiesis comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for inducing plasma cell proliferation comprising, as an active ingredient a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for inducing dendritic cell proliferation comprising, as an active ingredient a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for inducing macrophage proliferation comprising, as an active ingredient a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for preventing or treating thrombocytopenia comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for preventing or treating pancytopenia comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for preventing or treating granulocytopenia comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for preventing or treating hyperlipidemia comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for preventing or treating hypercholesterolemia comprising, as an active ingredient, a peptide derived from an N terminus portion of oS 1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for preventing or treating glucosuria comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for preventing or treating diabetes comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for preventing or treating AIDS comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for preventing or treating infection by HIV comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • ASCT autologous bone marrow or peripheral blood stem cell transplantation
  • BMT allogeneic bone marrow transplantation
  • a pharmaceutical composition for treating a thrombopoietin treatable condition comprising, as an active ingredient a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for augmenting the effect of thrombopoietin comprising, as an active ingredient a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for enhancing peripheral stem cell mobilization comprising, as active ingredients thrombopoietin and a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for enhancing hematopoiesis comprising, as active ingredients thrombopoietin and a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for enhancing hematopoietic stem cell proliferation comprising, as active ingredients thrombopoietin and a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for enhancing hematopoietic stem cell proliferation and differentiation comprising, as active ingredients thrombopoietin and a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for enhancing megakaryocytopoiesis comprising, as active ingredients thrombopoietin and a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for enhancing erythropoiesis comprising, as active ingredients thrombopoietin and a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for enhancing leukocytopoiesis comprising, as active ingredients thrombopoietin and a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for enhancing thrombocytopoiesis comprising, as active ingredients thrombopoietin and a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for preventing or treating thrombocytopenia comprising, as active ingredients thrombopoietin and a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for preventing or treating pancytopenia comprising, as active ingredients thrombopoietin and a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for preventing or treating granulocytopenia comprising, as active ingredients thrombopoietin and a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for treating or preventing an indication selected from the group consisting of hematological disease, hematological deficiencies, thrombocytopenia, pancytopenia, granulocytopenia, dendrite cell deficiencies, macrophage deficiencies, hematopoietic stem cell disorders including platelet, lymphocyte, plasma cell and neutrophil disorders, pre-leukemic conditions, leukemic conditions, myelodysplastic syndrome, aplastic anemia and bone marrow insufficiency, the pharmaceutical composition comprising, as active ingredients, thrombopoietin and a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a method of enhancing colonization of donated blood stem cells in a myeloablated recipient comprising treating a donor of the donated blood stem cells with a peptide derived from an N terminus portion of oS1 casein prior to donation and implanting the donated blood stem cells in the recipient.
  • a method of enhancing colonization of donated blood stem cells in a myeloablated recipient comprising treating the donated blood stem cells with a peptide derived from an N terminus portion of oS1 casein prior to implanting the donated blood stem cells in the recipient.
  • a method of enhancing colonization of blood stem cells in a myeloablated recipient comprising treating the blood stem cells with a peptide derived from an N terminus portion of oS1 casein prior to implanting the blood stem cells in the recipient.
  • a method of enhancing colonization of donated blood stem cells in a myeloablated recipient comprising treating a donor of the donated blood stem cells with a peptide derived from an N terminus portion of oS1 casein and thrombopoietin prior to donation and implanting the donated blood stem cells in the recipient.
  • a method of enhancing colonization of donated blood stem cells in a myeloablated recipient comprising treating the donated blood stem cells with a peptide derived from an N terminus portion of oS1 casein and thrombopoietin prior to implanting the donated blood stem cells in the recipient.
  • a method of enhancing colonization of blood stem cells in a myeloablated recipient comprising treating the blood stem cells with a peptide derived from an N terminus portion of oS1 casein and thrombopoietin prior to implanting the blood stem cells in the recipient.
  • the peptide is a fragment derived by fragmentation of oS1 casein.
  • the peptide is a synthetic peptide.
  • the peptide has a sequence as set forth in one of SEQ ID NOs:1-25.
  • a pharmaceutical composition comprising a purified peptide having an amino acid sequence selected from the group consisting of SEQ ID NOs:1-25 and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising thrombopoietin and a purified peptide having an amino acid sequence selected from the group consisting of SEQ ID NOs:1-25 and a pharmaceutically acceptable carrier.
  • the present invention successfully addresses the shortcomings of the presently known configurations by providing peptides for the treatment of human disease, which peptides are derived from the N terminus portion of o S1 casein and posses no detectable toxicity and high therapeutic efficacy.
  • FIG. 1 depicts the stimulation of Natural Killer (NK) cell activity in cultured murine bone marrow cells by peptides derived from natural casein. Lysis of 35 S labeled YAC target cells by cultured murine bone marrow cells incubated in the presence or absence of 100 ⁇ g per ml peptides derived from natural casein is expressed as the fraction of total radioactivity released from the YAC cells into the culture supernatant (% Release 35 S).
  • FIG. 1 represents NK activity at an effector:target cell ratio of 25:1 and 50:1.
  • FIGS. 2 a and 2 b depict the stimulation of Natural Killer (NK) cell activity in cultured human Peripheral Blood Stem Cells (PBSC) by peptides derived from natural casein. Lysis of 35 S labeled K562 target cells by cultured human PBSC from Granulocyte Colony Stimulating Factor (G-CSF) treated donors incubated without (0 ⁇ g) or with increasing concentrations (5-500 ⁇ g per ml) of peptides derived from natural casein is expressed as the fraction of total radioactivity released from the K562 cells into the culture supernatant (% Release 35 S).
  • G-CSF Granulocyte Colony Stimulating Factor
  • FIG. 2 a represents NK activity of two blood samples from the same patient, incubated at different effector:target cell ratios (1:25 and 1:50).
  • FIG. 2 b represents NK activity of blood samples from normal and affected donors incubated at the same effector:target cell ratio. Squares represent an effector:target cell ratio of 100:1, diamonds represent an effector:target cell ratio of 50:1.
  • FIGS. 3 a - c depict the stimulation of proliferation of Natural Killer (NK) and T-lymphocyte (T) cells from cultured human Peripheral Blood Stem Cells (PBSC) by peptides derived from natural casein.
  • NK and T cell proliferation in cultured PBSC from Granulocyte Colony Stimulating Factor treated donors incubated with or without peptides derived from natural casein is expressed as the percentage (%) of cells binding the anti-CD 3 /FITC fluorescent anti-T cell antibody UCHT 1 , or the anti CD 56 /RPE fluorescent anti-NK cell antibody MOC-1 (DAKO A/S Denmark). Controls are FITC and RPE-conjugated anti-mouse IgG antibody.
  • FIG. 3 a represents the percentage of cultured human PBSC binding fluorescent antibody CD 56 (5 independent samples) after 10 days incubation with (peptides) or without (control) 100 ⁇ g per ml peptides derived from natural casein.
  • FIG. 3 b represents the percentage of cultured human PBSC cells binding fluorescent anti-CD 3 (T cell) antibody, following 14 days of incubation with (peptides) or without (control) 100 ⁇ g per ml peptides derived from natural casein.
  • FIG. 3 b represents the percentage of cultured human PBSC cells binding fluorescent anti-CD 3 (T cell) antibody, following 14 days of incubation with (peptides) or without (control) 100 ⁇ g per ml peptides derived from natural casein.
  • 3 c represents the percentage of cultured human PBSC cells binding fluorescent anti-CD 3 (T cell) antibody and cells binding both CD 3 and CD 56 (T and NK-like cells) antibodies after 28 days incubation with (peptides) or without (control) 100 ⁇ g per ml peptides derived from natural casein.
  • FIG. 4 depicts the stimulation of Natural Killer (NK) cell activity in cultured human Peripheral Blood Stem Cells (PBSC) by synthetic peptides derived from casein. Lysis of 35 S labeled K562 target cells by cultured human PBSC (from a breast cancer patient) incubated without (0 ⁇ g) or with increasing concentrations (10-500 ⁇ g per ml) of synthetic peptides derived from casein is expressed as the fraction of total radioactivity released from the K562 cells into the culture supernatant (% Release).
  • NK Natural Killer
  • Peptides represent N-terminal sequences of 1-10 (1a, diamonds), 1-11 (2a, squares) and 1-12 (3a, triangles) first amino acids of the N terminus portion of oS1 casein (see Table 3 below for sequences of synthetic peptides).
  • FIGS. 5 a - c depict the stimulation of proliferation of cultured human cells of diverse origin by peptides derived from natural casein. Proliferation of the cultured human cells after 14-21 days incubation with increasing concentrations of the peptides derived from natural casein is expressed as the amount of [ 3 H]-thymidine incorporated into each sample.
  • FIG. 5 a represents the incorporation of label into two samples (PBSC 1, squares, 15 days incubation; and PBSC 2, diamonds, 20 days incubation) of human Peripheral Blood Stem Cells incubated with or without (ctrl) 50-600 ⁇ g per ml peptides derived from natural casein.
  • FIG. 1 represents the incorporation of label into two samples (PBSC 1, squares, 15 days incubation; and PBSC 2, diamonds, 20 days incubation) of human Peripheral Blood Stem Cells incubated with or without (ctrl) 50-600 ⁇ g per ml peptides
  • FIG. 5 b represents the incorporation of [ 3 H]-thymidine into cultured human bone marrow cells after 21 days incubation with or without (ctrl) 50-600 ⁇ g per ml peptides derived from natural casein. Bone marrow was donated by cancer patients in remission (BM Auto, squares, BM 1, triangles, and BM 2,-?-) or healthy volunteers (BM normal, diamons).
  • FIG. 5 c represents incorporation of [ 3 H]-thymidine into cultured human Cord Blood cells after 14 days incubation with or without (ctrl) 50-1000 ⁇ g per ml peptides derived from natural casein. Cord Blood cells were donated by two separate donors (C. B. 1, triangles, C. B. 2, squares).
  • FIG. 6 shows a Table depicting the proliferation of blood cell progenitors from human bone marrow and cord blood in response to incubation with peptides derived from natural casein.
  • FIG. 7 shows a table depicting the effect of in-vitro incubation with Synthetic peptides derived from casein on the relative distribution of Megakaryocyte, Erythroid, Plasma and Dendritic cells (differential count) in CFU-GEMM colonies from murine bone marrow progenitor cells.
  • Cells were scored in the macroscopic colonies grown from murine bone marrow cells prepared similarly to the CFU-GEMM colonies previously described. Cells were incubated with hematopoietic factors, and 25 ⁇ g or more of Synthetic peptides derived from casein for 14 days.
  • the differential count is expressed as the percentage of total cells represented by individual cell types.
  • FIG. 8 depicts the stimulation of peripheral white blood cell reconstitution in myeloablated, bone marrow transplanted mice in response to treatment with peptides derived from natural casein.
  • Cell counts represent the number of white blood cells ( ⁇ 10 4 per ml, as counted in a haemocytometer).
  • FIG. 9 depicts the stimulation of platelet reconstitution in myeloablated, bone marrow transplanted mice in response to treatment with peptides derived from natural casein.
  • Platelet (PLT) counts represent the number of thrombocytes ( ⁇ 10 3 per ml, as counted in a haemocytometer).
  • FIGS. 10 a - f depict the penetration and nuclear uptake of FITC-conjugated peptides derived from natural casein in cultured human T-lymphocyte cells, as recorded by fluorescent microscopy.
  • F1 and F2 are identical fractions of the FITC-conjugated peptides derived from natural casein.
  • Sup-T 1 cells were incubated with 100 ⁇ g per ml FITC-conjugated peptides derived from natural casein as described in the Examples section that follows. At the indicated times, the cells were washed of free label, fixed in formalin and prepared for viewing and recording by Laser Scanning Confocal Microscopy.
  • 10 a through 10 f are selected images of cells from consecutive incubation times, demonstrating FITC-conjugated peptides derived from natural casein penetrating the Sup-T 1 cell membrane (FIGS. 10 a , 10 b ) and concentrating in the nucleus (FIGS. 10 c - 10 f ).
  • FIG. 11 shows a Table depicting the stimulation of Sup-T1 Lymphocyte cell proliferation in response to incubation with peptides derived from natural casein.
  • Sup-T1 cells (5000 per well) were incubated with increasing concentrations (50-1000 ⁇ g per ml) of peptides derived from natural casein, counted in their wells at the indicated times post culture and pulsed with [ 3 H]-thymidine for 18 hours.
  • Proliferation index is the ratio of the average of the incorporation of [ 3 H]-thymidine into triplicate samples divided by the incorporation into cells cultured without peptides derived from natural casein (control).
  • FIG. 12 shows a Table depicting inhibition of HIV-1 infection of CEM lymphocytes by peptides derived from natural casein.
  • CEM cells were preincubated with increasing concentrations (50-1000 ⁇ g per ml) of peptides derived from natural casein for the indicated number of hours (3, 24 and 48 hours) before contact with HIV-1 virus, as described in the Examples section that follows.
  • On day 15 post infection cells were counted for cell numbers and assayed for severity of HIV-1 infection by the P34 antigen assay, as described in the Examples section that follows.
  • Control cultures were IF: CEM cells contacted with HIV-1 virus without pretreatment with peptides derived from natural casein, and UIF: CEM cells cultured under identical conditions without peptides derived from natural casein and without contact with HIV-1 virus.
  • FIG. 13 shows a Table depicting inhibition of HIV-1 infection of CEM lymphocytes by Synthetic peptides derived from casein.
  • CEM cells were preincubated with various concentrations (10-250 ⁇ g per ml) of peptides derived from natural casein (1P, 3P and 4P) for 3 hours before contact with HIV-1 virus, as described in the Examples section that follows.
  • On day 7 post infection cells were counted for cell numbers and assayed for severity of HIV-1 infection by the P34 antigen assay, as described in the Examples section that follows.
  • Control cultures (IF) were CEM cells contacted with HIV-1 virus without pretreatment with peptides derived from natural casein.
  • FIG. 14 depicts the prevention by peptides derived from natural casein of Juvenile (Type I, IDDM) Diabetes in female Non Obese Diabetic mice.
  • Glucosuria was monitored at intervals during 365 days post treatment in female NOD mice receiving a once (triangles) or twice (squares) weekly injection of 100 ⁇ g peptides derived from natural casein for 5 weeks (6 or 11 injections total) and untreated controls. All the controls developed glucosuria and subsequently died.
  • FIG. 15 depicts the reduction by Synthetic peptides derived from casein of diet-induced hypercholesterol/hyperlipidemia in female C57 Black/6j mice.
  • Total cholesterol (TC), High Density (HDL) and Low Density Lipoproteins (LDL) were assayed in pooled blood of two (2) mice per sample from hypercholesterol/hyperlipidemic mice receiving (IP) casein-derived peptides B, C, 2a or 3P, or no treatment (control). “Normal” samples represent control mice not fed the atherogenic diet.
  • FIG. 16 shows a Table depicting the stimulation of hematopoiesis in cancer patients in response to injections of peptides derived from natural casein.
  • WBC White Blood Cells
  • PHT Platelets
  • RBC Erythrocytes
  • RBC Erythrocytes
  • Hemoglobin gm per dl
  • Patient 1 relates to G.T.
  • patient 2 relates to E.C.
  • patient 3 relates to E.S.
  • patient 4 relates to J.R.
  • FIG. 17 depicts the stimulation by peptides derived from natural casein of thrombocytopoiesis in a platelet-resistant patient with Acute Myeloid Leukemia (M-1). Thrombocyte reconstitution was expressed as the change in platelet content of peripheral blood (PLA, ⁇ 10 6 per ml), counted as described above at the indicated intervals following intramuscular injection (as described in the Examples section that follows) of 100 ⁇ g peptides derived from natural casein.
  • PPA peripheral blood
  • FIG. 18 depicts the stimulation by peptides derived from natural casein of thrombocytopoiesis in a platelet-resistant patient with Acute Myeloid Leukemia (M-2).
  • M-2 Acute Myeloid Leukemia
  • Thrombocyte reconstitution was expressed as the change in platelet content of peripheral blood (PLA, ⁇ 10 6 per ml), counted as described above at the indicated intervals following intramuscular injection (as described in the Examples section that follows) of 100 ⁇ g peptides derived from natural casein.
  • the present invention is of biologically active peptides that are derived from or are similar to sequences identical with the N-terminus of the oS1 fraction of milk casein, compositions containing same and methods of utilizing same in, for example, stimulating and enhancing immune response, protecting against viral infection, normalizing serum cholesterol levels, and stimulating hematopoiesis.
  • the casein-derived peptides are non-toxic and can be used to treat and prevent, for example, immune pathologies, hypercholesterolemia, hematological disorders and viral-related diseases.
  • treating includes substantially inhibiting, slowing or reversing the progression of a disease, substantially ameliorating clinical symptoms of a disease.
  • preventing includes substantially preventing the appearance of clinical symptoms of a disease.
  • peptide includes native peptides (either degradation products, synthetically synthesized peptides or recombinant peptides) and peptido-mimetics (typically, synthetically synthesized peptides), such as peptoids and semipeptoids which are peptide analogs, which may have, for example, modifications rendering the peptides more stable while in a body.
  • Such modifications include, but are not limited to, cyclization, N terminus modification, C terminus modification, peptide bond modification, including, but not limited to, CH 2 —NH, CH 2 —S, CH 2 —S ⁇ O, O ⁇ C—NH, CH 2 —O, CH 2 —CH 2 , S ⁇ C—NH, CH ⁇ CH or CF ⁇ CH, backbone modification and residue modification.
  • Methods for preparing peptido-mimetic compounds are well known in the art and are specified, for example, in Quantitative Drug Design, C. A. Ramsden Gd., Chapter 17.2, F. Choplin Pergamon Press (1992), which is incorporated by reference as if fully set forth herein. Further detail in this respect are provided hereinunder.
  • a peptide according to the present invention can be a cyclic peptide.
  • Cyclization can be obtained, for example, through amide bond formation, e.g., by incorporating Glu, Asp, Lys, Orn, di-amino butyric (Dab) acid, di-aminopropionic (Dap) acid at various positions in the chain (—CO—NH or —NH—CO bonds).
  • Peptide bonds (—CO—NH—) within the peptide may be substituted, for example, by N-methylated bonds (—N(CH 3 )—CO—), ester bonds (—C(R)H—C—O—O—C(R)—N—), ketomethylen bonds (—CO—CH 2 —), o-aza bonds (—NH—N(R)—CO—), wherein R is any alkyl, e.g., methyl, carba bonds (—CH 2 —NH—), hydroxyethylene bonds (—CH(OH)—CH 2 —), thioamide bonds (—CS—NH—), olefinic double bonds (—CH ⁇ CH—), retro amide bonds (—NH—CO—), peptide derivatives (—N(R)—CH 2 —CO—), wherein R is the “normal” side chain, naturally presented on the carbon atom.
  • Natural aromatic amino acids, Trp, Tyr and Phe may be substituted for synthetic non-natural acid such as TIC, naphthylelanine (Nol), ring-methylated derivatives of Phe, halogenated derivatives of Phe or o-methyl-Tyr.
  • synthetic non-natural acid such as TIC, naphthylelanine (Nol), ring-methylated derivatives of Phe, halogenated derivatives of Phe or o-methyl-Tyr.
  • Tables 1-2 below list all the naturally occurring amino acids (Table 1) and non-conventional or modified amino acids (Table 2). TABLE 1 Three-Letter One-Letter Amino Acid Abbreviation Symbol Alanine Ala A Arginine Arg R Asparagine Asn N Aspartic acid Asp D Cysteine Cys C Glutamine Gln Q Glutamic Acid Glu E Glycine Gly G Histidine His H Isoleucine Ile I Leucine Leu L Lysine Lys K Methionine Met M Phenylalanine Phe F Proline Pro P Serine Ser S Threonine Thr T Tryptophan Trp W Tyrosine Tyr Y Valine Val V Any amino acid as above Xaa X
  • Non-conventional amino acid Code Non-conventional amino acid Code ⁇ -aminobutyric acid Abu L-N-methylalanine Nmala ⁇ -amino- ⁇ -methylbutyrate Mgabu L-N-methylarginine Nmarg aminocyclopropane- Cpro L-N-methylasparagine Nmasn Carboxylate L-N-methylaspartic acid Nmasp aminoisobutyric acid Aib L-N-methylcysteine Nmcys aminonorbornyl- Norb L-N-methylglutamine Nmgin carboxylate L-N-methylglutamic acid Nmglu cyclohexylalanine Chexa L-N-methylhistidine Nmhis cyclopentylalanine Cpen L-N-methylisolleucine Nmile D-alanine Dal L-N-methylleucine Nmleu D-arginine Darg L-N-methyllysine Nmlys D-
  • a peptide according to the present invention can be used in a self standing form or be a part of moieties such as proteins and display moieties such as display bacteria and phages.
  • the peptides of the invention can also be chemically modified to give active dimers or multimers, in one polypeptide chain or covalently crosslinked chains.
  • a peptide according to the present invention includes at least two, optionally at least three, optionally at least four, optionally at least five, optionally at least six, optionally at least seven, optionally at least eight, optionally at least nine, optionally at least ten, optionally at least eleven, optionally at least twelve, optionally at least thirteen, optionally at least fourteen, optionally at least fifteen, optionally at least sixteen, optionally at least seventeen, optionally at least eighteen, optionally at least nineteen, optionally at least twenty, optionally at least twenty-one, optionally at least twenty-two, optionally at least twenty-three, optionally at least twenty-four, optionally at least twenty-five, optionally at least twenty-six, optionally between twenty-seven and sixty, or more amino acid residues (also referred to herein interchangeably as amino acids).
  • amino acid or “amino acids” is understood to include the 20 naturally occurring amino acids; those amino acids often modified post-translationally in vivo, including, for example, hydroxyproline, phosphoserine and phosphothreonine; and other unusual amino acids including, but not limited to, 2-aminoadipic acid, hydroxylysine, isodesmosine, nor-valine, nor-leucine and ornithine.
  • amino acid includes both D- and L-amino acids.
  • derived from an N terminus portion of oS1 casein refers to peptides as this term is defined herein, e.g., cleavage products of oS1 casein (referred to herein as peptides derived from natural casein), synthetic peptides chemically synthesized to correspond to the amino acid sequence of an N terminus portion of oS1 casein (referred to herein as synthetic peptides derived from casein), peptides similar (homologous) to an N terminus portion of oS1 casein, for example, peptides characterized by one or more amino acid substitutions, such as, but not limited to, permissible substitutions, provided that at least 70%, preferably at least 80%, more preferably at least 90% similarity is maintained, and functional homologues thereof.
  • the terms “homologues” and “functional homologues” as used herein mean peptides with any insertions, deletions and substitutions which do not affect the biological activity of the
  • oS1 casein refers to oS1 casein of a mammal, including, but not limited to, livestock mammals (e.g., cow, sheep, goat, mare, camel, deer and buffalo) human beings and marine mammals.
  • livestock mammals e.g., cow, sheep, goat, mare, camel, deer and buffalo
  • the following provides a list of oS1 caseins having a known amino acid sequence, identified by their GenBank (NCBI) Accession Nos.
  • CAA26982 (Ovis aries (sheep)), CAA51022 (Capra hircus (goat)), CAA42516 (Bos taurus (bovine)), CAA55185 (Homo sapiens), CAA38717 (Sus scrofa (pig)), P09115 (rabbit) and 097943 (Camelus dromedurius (camel)).
  • N terminus portion refers to M amino acids of oS1 casein derived from the first 60 amino acids of oS 1 casein, wherein M is any of the integers between 2 and 60 (including the integers 2 and 60).
  • M is any of the integers between 2 and 60 (including the integers 2 and 60).
  • the term refers to the first M amino acids of oS1 casein.
  • the peptides of the invention can be obtained by extraction from milk as previously described, or by solid phase peptide synthesis, which is a standard method known to the man skilled in the art. Purification of the peptides of the invention is performed by standard techniques, known to the man skilled in the art, such as high performance liquid chromatography (HPLC). Milk casein fragmentation to obtain the peptides of the invention may be effected using various enzymatic and/or chemical means.
  • HPLC high performance liquid chromatography
  • the peptides of the present invention have a variety of therapeutic effects.
  • the Examples section there are provided numerous assays with which one of ordinary skills in the art can test a specific peptide designed in accordance with the teachings of the present invention for a specific therapeutic effect.
  • Any of the peptides described herein can be administered per se or be formulated into a pharmaceutical composition which can be used for treating or preventing a disease.
  • a pharmaceutical composition includes as an active ingredient any of the peptides described herein and a pharmaceutically acceptable carrier.
  • a “pharmaceutical composition” refers to a preparation of one or more of the peptides described herein, with other chemical components such as pharmaceutically suitable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
  • the term “pharmaceutically acceptable carrier” refers to a carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • examples, without limitations, of carriers are:
  • excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • Suitable routes of administration may, for example, include oral, rectal, transmucosal, transdermal, intestinal or parenteral delivery, including intramuscular, subcutaneous and intramedullary injections as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.
  • compositions of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active peptides into preparations which, can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the peptides of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer with or without organic solvents such as propylene glycol, polyethylene glycol.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer with or without organic solvents such as propylene glycol, polyethylene glycol.
  • organic solvents such as propylene glycol, polyethylene glycol.
  • penetrants are used in the formulation. Such penetrants are generally known in the art.
  • the peptides can be formulated readily by combining the active peptides with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the peptides of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient.
  • Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carbomethylcellulose; and/or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active ingredient doses.
  • compositions which can be used orally, include push-fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active peptides may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for the chosen route of administration.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the peptides according to the present invention are conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the peptides described herein may be formulated for parenteral administration, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multidose containers with optionally, an added preservative.
  • the compositions may be suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active preparation in water-soluble form. Additionally, suspensions of the active peptides may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate, triglycerides or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the peptides to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile, pyrogen-free water
  • the peptides of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides.
  • compositions herein described may also comprise suitable solid of gel phase carriers or excipients.
  • suitable solid of gel phase carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene glycols.
  • a therapeutically effective amount also referred to as a therapeutically effective dose
  • a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC 50 or the IC 100 as determined in cell culture. Such information can be used to more accurately determine useful doses in humans.
  • Initial dosages can also be estimated from in vivo data. Using these initial guidelines one having ordinary skill in the art could determine an effective dosage in humans.
  • toxicity and therapeutic efficacy of the peptides described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD 50 and the ED 50 .
  • the dose ratio between toxic and therapeutic effect is the therapeutic index and can be expressed as the ratio between LD 50 and ED 50 .
  • Peptides which exhibit high therapeutic indices are preferred.
  • the data obtained from these cell cultures assays and animal studies can be used in formulating a dosage range that is not toxic for use in human.
  • the dosage of such peptides lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition (see, e.g., Fingl et al., 1975, In: The Pharmacological Basis of Therapeutics, chapter 1, page 1).
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active ingredient which are sufficient to maintain therapeutic effect.
  • Usual patient dosages for oral administration range from about 50-2000 mg/kg/administration, commonly from about 100-1000 mg/kg/administration, preferably from about 150-700 mg/kg/administration and most preferably from about 250-500 mg/kg/administration.
  • therapeutically effective serum levels will be achieved by administering multiple doses each day.
  • the effective local concentration of the drug may not be related to plasma concentration.
  • One having skill in the art will be able to optimize therapeutically effective local dosages without undue experimentation.
  • dosing can also be a single administration of a slow release composition, with course of treatment lasting from several days to several weeks or until cure is effected or diminution of the disease state is achieved.
  • compositions of the present invention may, if desired, be presented in a pack or dispenser device, such as FDA approved kit, which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may, for example, comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions or human or veterinary administration.
  • compositions comprising a peptide of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment or prevention of an indicated condition or induction of a desired event.
  • Suitable indica on the label may include treatment and/or prevention of an autoimmune disease or condition, viral disease, viral infection, bacterial infection, hematological disease, hematological deficiencies, thrombocytopenia, pancytopenia, granulocytopenia, hyperlipidemia, hypercholesterolemia, glucosuria, hyperglycemia, diabetes, AIDS, infection with HIV-1, helper T-cell disorders, dendrite cell deficiencies, macrophage deficiencies, hematopoietic stem cell disorders including platelet, lymphocyte, plasma cell and neutrophil disorders, hematopoietic stem cell proliferation, hematopoietic stem cell proliferation and differentiation, pre-leukemic conditions, leukemic conditions, immune system disorders resulting from chemotherapy or radiation therapy, and human immune system disorders resulting from treatment of diseases of immune deficiency.
  • an autoimmune disease or condition may include treatment and/or prevention of an autoimmune disease or condition, viral disease, viral infection, bacterial infection, hematological disease, hematological deficiencies, thrombo
  • compositions according to the invention may be useful in maintaining and/or restoring blood system constituents, in balancing blood cell counts, in balancing levels of metabolites in the blood including sugar, cholesterol, calcium, uric acid, urea and enzymes such as alkaline phosphatase. Further, the pharmaceutical compositions of the invention may be useful in inducing blood cell proliferation, modulating white and/or red blood cell counts, particularly increasing white and/or red blood cell counts, elevating haemoglobin blood level and in modulating platelet counts.
  • balancing as used herein with relation to levels of certain physiological parameters, means changing the levels of referred parameters and bringing them closer to normal values.
  • normal values as used herein with relation to physiological parameters, means values which are in the range of values of healthy humans or animals.
  • the peptides of the invention balance counts of red blood cells, white blood cells, platelets and haemoglobin level.
  • the pharmaceutical compositions of the invention may be used for activating blood cell proliferation.
  • compositions may be used for the treatment and/or prevention of hemopoietic stem cell disorders, including platelet, lymphocyte, plasma cell and neutrophil disorders, as well as deficiency and malfunction in pre-leukemic and leukemic conditions and thrombocytopenia.
  • the pharmaceutical compositions may be used for the treatment and/or prevention of cell proliferative diseases.
  • the pharmaceutical compositions of the invention are advantageous in the stimulation of the immune response during chemotherapy or radiation treatments, in alleviating the negative effects, reducing chemotherapy and irradiation-induced vomiting and promoting a faster recovery.
  • compositions of the invention may be used for the stimulation of human immune response during treatment of diseases associated with immune deficiency, for example HIV and autoimmune diseases.
  • compositions of the invention may also be intended for veterinary use.
  • the pharmaceutical compositions of the invention may be used in the treatment and/or prevention of, for example, disorders involves abnormal levels of blood cells, disorders involving hemopoietic stem cells production and differentiation, treatment of platelet, lymphocyte and/or neutrophil disorders, for the treatment of pre-leukemic and leukemic conditions and for the treatment of thrombocytopenia.
  • the pharmaceutical compositions of the invention may also be used in the treatment of cell proliferative diseases and diseases involving immune deficiency, such as HIV, and of autoimmune diseases. Further, the pharmaceutical compositions of the invention may be used for modulating the immune response during chemotherapy or radiation treatments, for example for reducing chemotherapy-associated vomiting.
  • TPO thrombopoietin
  • Thrombopoietin is an early acting cytokine with important multilineage effects: TPO alone, or in combination with other early acting cytokines, can (i) promote viability and suppress apoptosis in progenitor cells; (ii) regulate hematopoietic stem cell production and function; (iii) trigger cell division of dormant multipotent cells; (iv) induce multilineage differentiation and (v) enhance formation of multilineage colonies containing granulocytes, erythrocytes, macrophages, and megakaryocytes (MK, CFU-GEMM).
  • TPO alone, or in combination with other early acting cytokines, can (i) promote viability and suppress apoptosis in progenitor cells; (ii) regulate hematopoietic stem cell production and function; (iii) trigger cell division of dormant multipotent cells; (iv) induce multilineage differentiation and (v) enhance formation of multilineage colonies containing
  • TPO stimulates the production of more limited progenitors for granulocyte/monocyte, megakaryocyte and erythroid colonies, stimulates adhesion of primitive human bone marrow and megakaryocytic cells to fibronectin and fibrinogen.
  • TPO is an important cytokine for clinical hematologists/transplanters: for the mobilization, amplification and ex vivo expansion of stem cells and committed precursor cells for autologous and allogeneic transplantation.
  • administration of TPO to healthy platelet donors has been employed to enhance pheresis yields.
  • clinical application of TPO therapy is complicated by, among other considerations, relatively high costs of the recombinant human cytokine rhTPO, and the potential antigenicity of TPO with repeated administration.
  • Combined treatment with TPO and the peptide of the present invention can provide inexpensive, proven non-toxic augmentation of TPOs effects on target cell proliferation and function.
  • the peptide of the present invention may be applied to the treatment of, in addition to the abovementioned conditions, disorders such as myelodysplastic syndrome (MDS), aplastic anemia and complications of liver failure.
  • MDS myelodysplastic syndrome
  • Pre-treatment of platelet donors with the peptide of the present invention, alone or in combination with TPO may even further enhance the efficiency of pheresis yields.
  • a method of treating a thrombopoietin treatable condition the method effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of augmenting the effect of thrombopoietin the method effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of enhancing peripheral stem cell mobilization the method effected by administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising effective amounts of thrombopoietin and a peptide derived from an N terminus portion of a SI casein.
  • a pharmaceutical composition for treating a thrombopoietin treatable condition comprising, as an active ingredient a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for augmenting the effect of thrombopoietin comprising, as an active ingredient a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for enhancing peripheral stem cell mobilization comprising, as active ingredients thrombopoietin and a peptide derived from an N terminus portion of a SI casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for inducing hematopoiesis comprising, as active ingredients, thrombopoietin and a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for inducing hematopoietic stem cells proliferation comprising, as active ingredients, thrombopoietin and a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for inducing hematopoietic stem cells proliferation and differentiation comprising, as active ingredients, thrombopoietin and a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for inducing megakaryocytopoiesis comprising, as active ingredients, thrombopoietin and a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for inducing erythropoiesis comprising, as active ingredients, thrombopoietin and a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for inducing leukocytopoiesis comprising, as active ingredients, thrombopoietin and a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for inducing thrombocytopoiesis comprising, as active ingredients, thrombopoietin and a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for preventing or treating thrombocytopenia comprising, as active ingredients, thrombopoietin and a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for preventing or treating pancytopenia comprising, as active ingredients, tbrombopoietin and a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for preventing or treating granulocytopenia comprising, as active ingredients, thrombopoietin and a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for treating or preventing an indication selected from the group consisting of hematological disease, hematological deficiencies, thrombocytopenia, pancytopenia, granulocytopenia, dendrite cell deficiencies, macrophage deficiencies, hematopoietic stem cell disorders including platelet, lymphocyte, plasma cell and neutrophil disorders, pre-leukemic conditions, leukemic conditions, myelodysplastic syndrome, aplastic anemia and bone marrow insufficiency, the pharmaceutical composition comprising, as active ingredients, thrombopoietin and a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising thrombopoietin and a purified peptide having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-25 and a pharmaceutically acceptable carrier.
  • a method of enhancing colonization of donated blood stem cells in a myeloablated recipient the method effected by treating a donor of the donated blood stem cells with a peptide derived from an N terminus portion of oS1 casein and thrombopoietin prior to donation and implanting the donated blood stem cells in the recipient.
  • a method of enhancing colonization of donated blood stem cells in a myeloablated recipient the method effected by treating the donated blood stem cells with a peptide derived from an N terminus portion of oS1 casein and thrombopoietin prior to implanting the donated blood stem cells in the recipient.
  • a method of enhancing colonization of blood stem cells in a myeloablated recipient comprising treating the blood stem cells with a peptide derived from an N terminus portion of oS1 casein and thrombopoietin prior to implanting the blood stem cells in the recipient.
  • the invention further relates to anti-bacterial pharmaceutical compositions comprising as active ingredient at least one peptide of the invention and to the use of the peptides of the invention as anti-bacterial agents.
  • a method of preventing or treating an autoimmune disease the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of preventing or treating a viral disease is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of preventing viral infection is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of inducing hematopoiesis is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of inducing hematopoietic stem cells proliferation is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of inducing hematopoietic stem cells proliferation and differentiation is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of inducing megakaryocytopoiesis the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of inducing erythropoiesis is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of inducing leukocytopoiesis the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of inducing thrombocytopoiesis the method is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of inducing plasma cell proliferation is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of inducing dendritic cell proliferation is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of inducing macrophage cell proliferation is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of preventing or treating thrombocytopenia is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of preventing or treating pancytopenia is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of preventing or treating granulocytopenia is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of preventing or treating hyperlipidemia is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of preventing or treating hypercholesterolemia is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of preventing or treating glucosuria is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of preventing or treating diabetes is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of preventing or treating AIDS is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • a method of preventing or treating infection by HIV is effected by administering to a subject in need thereof a therapeutically effective amount of a peptide derived from an N terminus portion of oS1 casein.
  • ASCT autologous bone marrow or peripheral blood stem cell transplantation
  • BMT allogeneic bone marrow transplantation
  • a pharmaceutical composition for preventing or treating an autoimmune disease comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for preventing or treating a viral disease comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for preventing viral infection comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for inducing hematopoiesis comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for inducing hematopoietic stem cells proliferation comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for inducing hematopoietic stem cells proliferation and differentiation comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for inducing megakaryocytopoiesis comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for inducing erythropoiesis comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for inducing leukocytopoiesis comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for inducing thrombocytopoiesis comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for inducing plasma cell proliferation comprising, as an active ingredient a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for inducing dendritic cell proliferation comprising, as an active ingredient a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for inducing macrophage proliferation comprising, as an active ingredient a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for preventing or treating thrombocytopenia comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for preventing or treating pancytopenia comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for preventing or treating granulocytopenia comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for preventing or treating hyperlipidemia comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for preventing or treating hypercholesterolemia comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for preventing or treating glucosuria comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for preventing or treating diabetes comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for preventing or treating AIDS comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for preventing or treating infection by HIV comprising, as an active ingredient, a peptide derived from an N terminus portion of oS1 casein and a pharmaceutically acceptable carrier.
  • ASCT autologous bone marrow or peripheral blood stem cell transplantation
  • BMT allogeneic bone marrow transplantation
  • a pharmaceutical composition comprising a purified peptide having an amino acid sequence selected from the group consisting of SEQ ID NOs:1-25 and a pharmaceutically acceptable carrier.
  • the present invention successfully addresses the shortcomings of the presently known configurations by providing peptides for the treatment of human disease, which peptides are derived from the N terminus portion of o S1 casein and posses no detectable toxicity and high therapeutic efficacy.
  • the casein fraction of cow's milk was isolated as described by Hipp et al. (1952), ibid., and subjected to exhaustive proteolytic digestion with chymosin (also known as rennin) (20 ng per ml) at 30° C. Upon completion of the reaction, the solution was heated to inactivate the enzyme, and the digest was precipitated as paracaseinate by acidification with an organic acid, acetic or trichloracetic acid. Paracaseinate was separated by centrifugation, and the supernatant fraction, containing the peptide fragments of interest, was dialyzed and re-precipitated as caseicidin by higher acid concentrations. The resulting caseicidin, following re-suspension, dialysis and neutralization was lyophilized. The resulting powdered preparation was assayed for biological activity as described below, and separated by HPLC for peptide analysis.
  • chymosin also known as rennin
  • NOD mice are a commonly used model for research of autoimmune disease and human Juvenile Diabetes.
  • Six week old female NOD mice received either one or two injections per week of 100 ⁇ g of peptides derived from natural casein, for a total of 5 or 11 treatments.
  • Control mice received no treatment.
  • the severity of disease was determined according to glucosuria, which was measured using Combi test sticks [Gross, D. J. et al. (1994), Diabetology, 37:1195]. Results were expressed as the percent of glucosuria-free mice in each sample over a 365-day period.
  • IPGTT Intraperitoneal Glucose Tolerance Test
  • the glucose tolerance test is the definitive method for investigating glucose metabolism and diabetic tendencies in mammals. Twenty five (25) weeks after receiving Synthetic peptides derived from casein, response to a glucose load was assessed with an intraperitoneal glucose tolerance test. Glucose injection consisted of 1 g/kg body weight. Glycemic values were determined from blood drawn prior to test (0 minutes) and 60 minutes after loading. Plasma glucose levels were determined with a Glucose Analyzer 2 (Beckman Instruments, Fullerton, Calif.) and expressed as mmol/L. Normal values do not exceed 140 mmol/L.
  • PBSC Peripheral Blood Stem Cells
  • PBSC of G-CSF treated subjects were separated on a FICOLL gradient, washed twice with RPMI-1640 medium and seeded into 1.5 ml wells with or without peptides derived from natural casein or synthetic peptides derived from casein, as indicated, (0-500 ⁇ g per ml). Following two days incubation the cells were assayed for Natural Killer activity by measuring radioactivity released from 35 S-labeled K562 target cells (NEG-709A, 185.00 MBq, 2.00 mCi EASYTAGth Methionine, L-[ 35 S] 43.48 TBq per mmol, 1175.0 Ci per mmol, 0.488 ml, Boston USA).
  • effector cells Two concentrations of effector cells (2.5 ⁇ 10 4 and 5 ⁇ 10 4 cells per well) were incubated with 5 ⁇ 10 3 target cells per well (effector:target cell ratios of 50:1 and 100:1, respectively) in U-bottomed 96 well tissue culture plates. The cells were incubated for 5 hours at 37° C. in 5% CO 2 , 95% air and precipitated by 5 minutes centrifugation at 1000 rpm. 35 S release was measured in 50 ⁇ l samples of the supernatant liquid.
  • Bone marrow was collected from 4 untreated BALB/c and C57B1/6 mice. Bone marrow was harvested from the long bones of front and hind limbs of the mice by injection of medium using a 25 Gauge needle. Aspirated cells were washed with RPMI 1640, counted in a haemocytometer and vital-stained (20 ⁇ of cells in 380 ⁇ l acetic acid-trypan blue), then seeded in culture bottles at 2-5 ⁇ 106 cells per ml in RPMI-1640 containing 10% Fetal Calf Serum, antibiotics and glutamine with or without 100 ⁇ g per ml peptides derived from natural casein.
  • the cell cultures were incubated in 5% CO 2 , 95% air for 12-15 days at 37° C., harvested by 10 minutes centrifugation at 1500 rpm, counted, and seeded in U-bottom wells with 51 Cr (Chromium-51, 740 MBq, 2.00 mCi activity) or 35 S (NEG-709A, 185.00 MBq, 2.00 mCi EASYTAGth Methionine, L-[ 35 S] 43.48 TBq per mmol, 1175.0 Ci per mmol, 0.488 ml, Boston USA) labeled murine lymphoma (YAC) cells at either 25:1 or 50:1 effector:target cell ratio.
  • NK activity is expressed as the percent radioactivity in the cell-free supernatants.
  • PB Peripheral blood
  • BM Bone marrow cells
  • Umbilical cord blood was collected during normal births. Human cells of the various origins were separated on a FICOLL gradient, washed twice with RPMI-1640 medium, and seeded into 0.2 ml flat bottom tissue culture wells at the indicated concentrations with or without peptides derived from natural casein or with or without synthetic peptides derived from casein, as indicated. All treatments, including controls, were repeated in triplicate.
  • thymidine methyl-[ 3 H]
  • ICN Corp. radioactive thymidine
  • Colon and K526 are established lines of cancer cells grown in culture. Both cell lines were grown in culture bottles in 5% CO 2 , 95% air at 37° C., harvested and washed with medium before seeding in tissue culture wells at 4 ⁇ 10 5 cells (K562) or 3 ⁇ 10 3 cells (Colon) per well. Peptides derived from natural casein were added to the wells, at the indicated concentrations, and after 9 (K562) or 3 (Colon) days of incubation labeled thymidine was added as described above. Harvesting and measurement of radioactive uptake was as described above.
  • PBSC Peripheral Blood Stem Cells
  • PBSC Peripheral Blood Stem cells
  • T cells CD 3 surface antigen
  • NK cells CD 56 surface antigen
  • direct immunofluorescence using anti-CD 3 fluorescent antibody (CD 3 /FITC clone UHCT 1 ), anti-CD 56 fluorescent antibody (CD 56 /RPE clone MOC-1) (DAKO A/S, Denmark) and mouse IgG1/RPE and IgG1/FITC antibodies as a control.
  • Detection of fluorescently tagged cells was performed using fluorescence activated cell sorting (FACS) and fluorescent microscopy.
  • Colonies were scored after 8-9 days using an Olympus dark field microscope. They were picked with a micropipette, cytocentrifuged and stained with May-Grunwald-Giemsa for differential counts. At least 700 cells were counted for each preparation.
  • CFU-GEMM Multipotent (CFU-GEMM) colonies grown from primary bone marrow cells as described for the assay of megakaryocyte proliferation above were collected, stained and counted for dendritic cells. At least 700 cells were counted for each preparation.
  • Multipotent (CFU-GEMM) colonies grown from primary bone marrow cells as described for the assay of megakaryocyte proliferation above were collected, stained and counted for plasma cells. At least 700 cells were counted for each preparation.
  • Multipotent (CFU-GEMM) colonies grown from primary bone marrow cells as described for the assay of megakaryocyte proliferation above were collected, stained and counted for macrophage cells. At least 700 cells were counted for each preparation.
  • Multipotent (CFU-GEMM) colonies grown from primary bone marrow cells as described for the assay of megakaryocyte proliferation above were collected, stained and counted for red blood cells. At least 700 cells were counted for each preparation.
  • Multipotent (CFU-GEMM) colonies grown from primary bone marrow cells as described for the assay of megakaryocyte proliferation above were collected, stained and counted for polymorphonuclear cells. At least 700 cells were counted for each preparation.
  • a sample of bone marrow from an apparently healthy human being was processed by density gradient separation using Histopaque-107 (Sigma Diagnostics) to obtain a purified population of mononuclear cells (MNC).
  • Colony assays were performed in a plating medium containing final concentrations of 0.92% methyl cellulose (4000 centripase powder, Sigma Diagnostic), rehydrated in Iscoves modified Dulbecco's medium containing 36 mM sodium bicarbonate (Gibco), 30% fetal bovine serum (FBS) (Hyclone), 0.292 mg/ml glutamine, 100 units per ml penicillin and 0.01 mg per ml streptomycin (Biological Industries, Beit Haemek). Cord blood from normal births was collected and prepared as mentioned above.
  • Colony assay medium containing 105 MNC per ml was plated in triplicate wells within a 24 well tissue culture plate (Greiner), 0.33 ml per well. The cultures were incubated at 37° C. in 5% C0 2 , 95% air and 55% relative humidity with or without peptides derived from natural casein or synthetic peptides derived from casein, at the indicated concentrations. Plates were scored after 14 days for colonies containing more than 50 cells. Megakaryocytes were identified by indirect immunofluorescence using a highly specific rabbit antibody recognizing human platelet glycoproteins, and an FITC-conjugated goat anti-rabbit IgG.
  • GM-CSF leucomax
  • CM granulocyte-monocyte colonies
  • EPO Erythropoietin
  • human bone marrow cells from consenting volunteer donors or patients undergoing autologous bone marrow transplantation were precultured in medium containing 10-1000 ⁇ g per ml peptides derived from natural casein, grown in semi-solid agar, and scored for granulocyte-macrophage hematopoietic colonies (GM-CFU) at 7 or 14 days post treatment.
  • GM-CFU granulocyte-macrophage hematopoietic colonies
  • Megakaryocytopoiesis was measured in normal bone marrow cells from healthy consenting human donors by either scoring of the number of megakaryocytes in samples of liquid culture (RPMI-1640 plus 10% human AB serum, glutamine and antibiotics) with or without 100 ⁇ g per ml peptides derived from natural casein, or in a methylcellulose assay for assessing colony formation. 2 ⁇ 10 5 bone marrow cells were seeded in the presence of a standard growth factor combination with or without peptides derived from natural casein. In the methylcellulose assay megakaryocytes were counted with an inverted microscope on days 12-14 after seeding.
  • a single dose containing 50 mg peptides derived from natural casein was administered intra-muscular to human subjects in 3 depots, over a period of 2 hours. Clinical parameters were monitored at the indicated intervals.
  • patients at various stages of treatment for and/or remission from cancer and metastatic disease received peptides derived from natural casein once or twice, and were monitored for changes in the cell count of peripheral blood.
  • Peptides Peptides (either peptides derived from natural casein or s synthetic peptides derived from casein (1-25 amino acids in length, see table 3) supplied as lyophilized powder were resuspended in RPMI complete medium and added to cell cultures at a final concentrations of 50 to 1000 ⁇ g per ml.
  • Cells Several types of freshly isolated human cells (primary cells) and cell lines are known to be susceptible to in vitro HIV-1 infection, although essentially any cell displaying even low surface levels of the CD 4 molecule can be considered a potential target for HIV-1 infection. Two commonly used human cell lines which are highly sensitive for HIV-1 infection were chosen, CEM and Sup-T1.
  • CEM is a human T4-lymphoblastoid cell line initially derived by G. E. Foley et al. [(1965), Cancer 18:522] from peripheral blood buffy coat of a 4-year old caucasian female with acute lymphoblastic leukemia. These cells were continuously maintained in suspension in medium, and have been used widely for analysis of infectivity, antiviral agents and neutralizing antibodies.
  • Sup-T1 is a human T-lymphoblastoid cell line isolated from a pleural effusion of an 8-year old male with Non-Hodgkin's T-cell lymphoma [Smith, S. D. et al. [(1984) Cancer Research 44:5657]. This cell expresses high levels of surface CD 4 and is useful in studies of cell fusion, cytopathic effect and infectivity of HIV-1. Sup-TI cells are grown in suspension in enriched medium.
  • HIV virus strain employed was HIV-1IIIB, originally designated HTLV-IIIB. Concentrated culture fluids of peripheral blood from several patients with AIDS or related diseases were used to establish a permanent productive infection in H-9 cells. This subtype B virus has high capacity to replicate in human T-cell lines. Viral titer was 5.38 ng per ml in stock solution.
  • FITC-labeled peptides FITC F-1300 (Fluorescein isothiocyanate, isomer I, Sigma (F25o-2) St. Louis, MI, USA) having excitation/emission maxima of about 494/520 nm, respectively, was employed.
  • the amine-reactive fluorescein derivative is probably the most common fluorescent derivatization reagent for covalently labeling proteins.
  • FITC-conjugated peptides derived from natural casein were prepared by covalent binding of FITC to the amine groups of lysine.
  • HIV-1 P24 antigen capture assay An HIV-1 P24 Antigen capture assay kit employed was designed to quantitate the HIV-1 P24 core antigen, which is proportionally related to the degree of viral production in cells. This kit was purchased from the AIDS Vaccine program of the SAIC-NCI-Frederick Cancer Research Institute, P.O. Box B, Frederick, M.D. 21702, USA and included 96 well plates coated with monoclonal antibody to HIV-1 P24, primary antibody-rabbit anti-HIV P24 serum, secondary antibody-Goat anti-rabbit-IgG (H+L) peroxidase conjugated antibody, TMB peroxidase substrate system and lysed HIV-1 P24 standard. The HIV-1 P24 antigen capture assay was analyzed by Organon-Technica ELISA reader at 450 nm with a reference at 650 nm.
  • HIV-1 P24 antigen capture ELISA HIV infection was measured with an indirect enzyme immunoassay which detects HIV-1 P24 core antigens in tissue culture media. Tissue culture supernatant was reacted with primary rabbit anti-HIV-1 P24 antigen and visualized by peroxidase conjugated goat anti rabbit IgG. The reaction was terminated by adding 4N H 2 SO 4 , wherein the intensity of the color developed is proportional to the amount of HIV-1 antigen present in the tissue culture supernatant.
  • Biological hazard level (BL-3) laboratory All virus production isolation and infection, tissue culture of HIV-1 infected cells, P24 antigen containing supernatant harvesting and P24 antigen capture ELISA, were performed in BL-3 facility of the Hebrew University, Hadassah Medical School and were in accordance with the bio safety practices set by the NIH and CDC (USA).
  • Flow cytometry A FACSort cell sorter (Becton & Dickinson, San Jose, Calif. USA) was used to (i) determine the percentage of CD4 positive CEM and sup-T1 cells batches before infection with HIV-1 in order to assure the same degree of infection in each experiment; and (ii) detect T cells that harbor FITC conjugated peptides derived from natural casein in their cytoplasm and nuclei.
  • CO 2 incubator For viral culture production cells with HIV-1, cells and virus pretreated with peptides derived from natural casein and cells which were further incubated with HIV-1, were all kept in humidified C0 2 incubator for the duration of the experiment.
  • HIV infection of human cultured CD 4 +cells The cells (CEM, Sup-TI) were preincubated with several increasing concentrations of peptides derived from natural casein (50-1000 ⁇ g per ml) or synthetic peptides derived from casein (10-500 ⁇ g per ml) for 3, 24 (for synthetic and natural peptides) and 48 (only for natural peptides) hours and HIV-1IIIB (45 ⁇ g per ml final concentration) was added to each well thereafter. HIV-1IIIB was preincubated with the peptides for 3 hours and then added to cells (5000 cells/well) in tissue culture plates.
  • Controls were IF (Infected, cells cultured with HIV-1 and without peptides), UIF (Uninfected, cells cultured without HIV-1 and without peptides) and UI +Ch (Uninfected +peptides derived from natural casein, cells cultured in the presence of peptides derived from natural casein ⁇ 50-1000 ⁇ g per ml ⁇ ) to test the effect of peptides derived from natural casein and synthetic peptides derived from casein on cell viability and growth. Cells were counted for viability and proliferation rate on day 7, 10 and day 14 post infection (the day of P24 antigen culture supernatant harvest).
  • [0306]-thymidine incorporation test In order to test the effect of peptides derived from natural casein on T cell proliferation, several concentrations of peptides derived from natural casein (1 ⁇ g/ml stock in RPMI) were added to Sup-T1 cell cultures in 96 flat bottom microwell plate (5000 cells/well), as described for HIV-1 infection in Sup-TI cells. Cells were counted and their viability was determined by trypan blue dye exclusion.
  • Intramuscular, or intravenous injections of up to 5,000 mg peptides derived from natural casein per kg animal were administered in a single dose, or in three doses to normal.
  • a variety of strains were employed, including BALB/c, C3H/HeJ and Non-Obese Diabetic (NOD) mice. The mice were either monitored for 10 months before sacrifice and post-mortem examination (toxicity assay) or observed for 200 days (survival rate).
  • Guinea pigs received a single intramuscular injection of 20 mg peptides derived from natural casein per animal. Fifteen days later they were sacrificed and examined for pathology.
  • mice were lethally irradiated at a source to skin distance of 70 cm, dosage of 50 cGy per minute, for a total of 600 cGy.
  • the irradiated mice were reconstituted with syngeneic bone marrow as described above and injected intravenously 24 hours later with 1 mg per animal peptides derived from natural casein, synthetic peptides derived from casein (13-26 amino acids, see Table 3 above), or human serum albumin (controls), following a double-blinded protocol.
  • Leukocyte reconstitution was determined according to cell count in peripheral blood collected at indicated intervals from 6 to 12 days post treatment. Platelet reconstitution was determined by cell count in blood collected from the retro orbital plexus, into heparinized capillaries, at indicated intervals from day 6 to day 15 post treatment.
  • CBA mice were lethally irradiated (900 cGy), reconstituted and treated with peptides derived from natural casein or human serum albumin as described above. Platelet reconstitution was assayed as mentioned above.
  • mice were irradiated (800 cGy), reconstituted and injected intraperitoneally with 100 ⁇ g synthetic peptides derived from casein (peptides 3a and 4P, representing the first 6 and 12 amino acids of the N terminus of ⁇ S1 casein, respectively—see Table 3 above) daily, on days 4, 5, 6 and 7 post-transplantation. Platelet reconstitution was assayed at 10 and 12 days post-transplantation.
  • mice were lethally irradiated at a source to skin distance of 70 cm, dosage of 50 cGy per minute, for a total of 600 cGy.
  • the irradiated mice were reconstituted with syngeneic bone marrow from mice which were either treated a day prior to bone marrow aspiration with 1 mg per animal peptides derived from natural casein or not treated, following a double-blinded protocol. In one experiment mice survival was monitored for 18 days. In another experiment mice were sacrificed after 10 days and spleen colonization monitored.
  • mice were divided into groups of 8. One control group was fed a normal diet. A second control group was fed the modified Thomas Hartroft diet containing cholate (#TD 88051: Teklad, Madison, Wis.) [Gerber, D. W. et al.(2000), Journal of Lipid Research. 42, 2001]. The remaining experimental groups were all fed the modified Thomas Hartroft diet. After one week on the diet, serum cholesterol values increased significantly and the synthetic peptides derived from casein were injected intraperitoneally, 1 mg per mouse, followed by a second injection of 0.1 mg one week later.
  • mice were divided into groups of 8. One control group was fed a normal diet. A second control group was fed the modified Thomas Hartroft diet containing cholate (#TD 88051: Teklad, Madison, Wis.) [Gerber, D. W. et al.(2000), Journal of Lipid Research. 42, 2001]. The remaining experimental groups were all fed the modified Thomas Hartroft diet. After one week on the diet, serum cholesterol values increased
  • a major component of the crude peptides derived from natural casein preparation is the N-terminal fragment of oS1 casein.
  • peptides derived from natural casein were safe when administered to humans as well. Comparison of blood and urine samples from seven healthy human volunteers before, during and 7 days after intramuscular injection of peptides derived from natural casein revealed no changes in any of the clinical parameters. No other negative effects were observed.
  • Spleens derived from irradiated mice that received bone marrow from treated mice included about twice to three times as many colonies per spleen, as compared to spleens of irradiated mice that received bone marrow from non treated mice (1-5 colonies as compared to 0-3 colonies).
  • NK and cytotoxic T cells are crucial to the immune system's ability to protect against invasion by both infectious pathogens and cancer cells, by both active cytotoxicity and the secretion of immunoregulatory lymphokines. Immune compromise, such as in AIDS or following chemotherapy, results in abnormal, weakened T or NK cell activity.
  • NK cell activity When normal murine bone marrow cells from BALB/c and C57B1/6 mice were cultured in the presence of 100 ⁇ g per ml peptides derived from natural casein, a clear increase in NK activity was observed in both effector:target cell ratio groups. Moreover, comparison between the two groups revealed a clear dose response relationship.
  • NK activity was elevated from 13.93% to 30.77% and at the 1:50 effector:target cell ratio the average NK activity was elevated from 13.68% to 44.05% (FIG. 1).
  • FIG. 2 a NK activity was measured in blood samples taken from one patient and incubated at two effector:target cell ratios with increasing peptides derived from natural casein concentration. Only 4% 35 S release was measured in the control, untreated PBSC culture.
  • PBSC Peripheral Blood Stem Cells
  • peptides derived from natural casein for 10, 14, or 28 days, then assayed for proliferation of the CD 56 antigen.
  • a sometimes dramatic increase in CD 56 antigen detection was observed in the peptide-treated cells from all the donors but one (patient 1).
  • FIG. 3 a A representative response is depicted in FIG. 3 a : Following 10 days of incubation with or without peptides derived from natural casein, the presence of CD56 surface antigen-positive (NK) cells was detected by direct immunofluorescent staining. % Overall, incubation with peptides derived from natural casein increased the mean percentage of the cells positively stained for CD56 from 0.64% in the control group to 2.0% following treatment (FIG. 3 a ).
  • PBSCs from 7 patients were incubated with peptides derived from natural casein for 28 days, and the effect on proliferation of NK/T cells (CD56 and CD3 surface antigen-positive) was detected by direct immunofluoresence.
  • Incubation with peptides derived from natural casein stimulated proliferation of T-cell up greater than 5 fold in some cases (patient 6), while the mean percentage of the CD3- positive (T-) cells increased from 2.08% in the control group to 6.49% in the treated group
  • the number of both CD56 and CD3 surface antigen-positive (NK/T) cells was increased from 1.1% in the control to 4.3% in the treated group (FIG. 3 c ).
  • peptides derived from natural casein stimulate the proliferation of both T-lymphocytes and Natural Killer cells from normal murine and human blood cell progenitors.
  • the greatest immune-stimulatory effect of the peptides derived from natural casein was noted in human donors having initially low T- and NK cell levels (FIGS. 3 a - c ).
  • peptides containing the first 10 residues of the N-terminal sequence of oS1 casein are capable of selectively stimulating in vitro lymphocyte proliferation in cells from cancer patients. Similar stimulation of NK cell activity was observed when PBS cells from human donors with hematopoietic disease were incubated with Synthetic peptides derived from casein representing the first 3 amino acid residues of o S1 casein. Incubation of the PBS cells with the peptides increased target cell lysis from 2- to greater then 8-fold that of the untreated controls. Of the 5 patients tested, three (3) responded to 25 ⁇ g/ml peptide concentration, one (1) responded to 100 ⁇ g/ml peptide concentration and one (1) to 250 ⁇ g/ml.
  • Blood cell progenitors differentiate into a variety of blood cells: macrophages, monocytes, granulocytes, lymphocytes, erythrocytes and megakaryocytes. Progenitor cells are abundant in bone marrow, but are also found in peripheral blood after Granulocyte Colony Stimulating Factor treatment (PBSC cells), in fresh Cord Blood. When increasing concentrations (50-600 ⁇ g per ml) of peptides derived from natural casein were added to cultures of human Bone Marrow, PBSC and Cord Blood, an increase in cell proliferation, as measured by [ 3 H]-thymidine incorporation was noted (FIGS. 5 a - 5 c ).
  • PBSC cells Granulocyte Colony Stimulating Factor treatment
  • Human PBSC proliferation was most greatly effected by 300 ⁇ g per ml (FIG. 5 a ) after 15 days in culture. An even greater effect was noted for Cord Blood cells in culture (3 to 4 fold increase in [ 3 H]-thymidine incorporation) after 14 days incubation (but not after 7 days) with peptides derived from natural casein (600 ⁇ g per ml, FIG. 5 c ). Cultured human bone marrow cells from three out of four donors also reacted strongly (3 to 5 fold increase in incorporation) to peptides derived from natural casein (300 ⁇ g per ml) after 21 days incubation (FIG. 5 b ).
  • peptides derived from natural casein stimulate proliferation of human blood cell progenitors from bone marrow as well as other sources.
  • incubation of cultured human K562 (Chronic Myeloid Leukemia) and Colon (Colon cancer) cell lines with high concentrations (up to 500 ⁇ g per ml) of peptides derived from natural casein under similar conditions had no effect on [ 3 H]-thymidine incorporation.
  • peptides derived from natural casein stimulate proliferation of human blood cell progenitors but not growth of cancerous cells.
  • Multinucleated megakaryocytes develop in the bone marrow from primitive stem cells, mature to giant cells and give rise to thousands of thrombocytes per megakaryocyte. Thrombocytes are crucial for clot formation and thrombocytopenia is a major concern in myeloablative conditions (following chemotherapy or radiotherapy).
  • CFU-GM Granulocyte and Megakaryocyte
  • CFU-GEMM Granulocyte, Erythroid, Macrophage and Megakaryocyte
  • CFU-GM colony formation was increased with or without additional stimulating factors (GM-CSF, CM).
  • Peptides derived from natural casein also stimulated erythroid cell forming colonies in the presence of erythropoietin.
  • TPO thrombopoietin
  • MK megakaryocyte
  • the relative cell number counts in the cultured human bone marrow and cord blood colonies reflect megakaryocyte cell proliferation in response to addition of 25 ⁇ g per ml peptides derived from natural casein (see Table shown in FIG. 6).
  • incubation of cultured human primary bone marrow and cord blood cells with peptides derived from natural casein stimulates the development and proliferation of both committed megakaryocyte and erythroid cell colonies.
  • Synthetic peptides derived from casein on plasma cell proliferation in murine primary bone marrow cells was demonstrated under the same conditions outlined for the stimulation of megakaryocytes.
  • Synthetic peptides derived from casein representing the first: 2, 3, 5, 7, 11, 16, 17, 18, 19, 20, 21, 22, 23 and 24 and 26 amino acids of oS1 casein, significantly stimulated the proliferation of plasma cells, from 1.5% and up 12.3% of total cell count, compared with 0.3% of total without Synthetic peptides derived from casein (FIG. 7).
  • Myeloablative therapy may lead to life-threatening reduction in thrombocytes and leukocytes, which may persist despite administration of blood cells and growth factors.
  • the following demonstrates the effect of peptides derived from natural casein following irradiation and bone marrow transplantation.
  • mice treated with the peptides derived from natural casein demonstrating a significant increase over the human serum albumin-treated controls which became even more pronounced by day 15 (FIG. 9).
  • peptides derived from natural casein enhance platelet and leukocyte reconstitution following transplantation with limiting numbers of bone marrow cells. It is expected that this effect will be further increased in reconstitution with optimal, rather than limiting numbers of bone marrow cells.
  • mice In order to confirm the observed ability of synthetic peptides derived from casein to enhance megakaryocyte proliferation in hematopoietic stem cell cultures (see FIGS. 6 and 7), the peptides' effects on platelet reconstitution in vivo was investigated.
  • Treatment with peptide 4P increased counts by 29% (872 ⁇ 10 3 /ml compared with 676 ⁇ 10 3 /ml in the control group) at 12 days post transplantation while treatment with peptide 3a increased counts by up to 35.5% (229 ⁇ 10 3 /ml compared with 169 ⁇ 10 3 /ml in the control group) at 10 days, and up to 13.5% (622 ⁇ 10 3 /ml compared with 461 ⁇ 10 3 /ml in the control group) at 12 days post transplantation.
  • the same synthetic peptides derived from casein enhance megakaryocyte proliferation in vitro and platelet reconstitution following bone marrow transplantation in vivo.
  • peptides derived from natural casein are expected to be useful both at preventing HIV infection and for post infection treatment of HIV infected and AIDS patients.
  • HIV-1 infection levels in the same cells measured by the HIV-P 24 antigen assay at 7 days post infection, was significantly reduced in the peptide treated cells (0.17 and 0.14ng P24 Antigen/ml with 100 ⁇ g/ml and 500 ⁇ g/ml respectively), as compared to the untreated controls(0.52 ng P Ag/ml).
  • HIV-P24 antigen assay at 7 days post infection revealed significant reduction in HIV-1 infection levels in treated cultures (0.26 and 0.18ng P24 Ag per ml for 10 and 25 ⁇ g per ml respectively, as compared to the control of s15 0.52 ng P24 Ag per ml).
  • Assay of HIV-P 24 antigen at 7 days post infection revealed a dose dependent reduction in viral particles as compared to the untreated, infected control cultures (FIG. 13).Thus, the protection from HIV-1 infection afforded lymphocyte cells by the peptides derived from natural casein is retained in Synthetic peptides derived from casein representing as few as the first five N-terminal amino acids of ⁇ S-1 casein.
  • Non-Obese Diabetic mice spontaneously develop Juvenile (Type I, IDDM) Diabetes, an autoimmune condition causing inflammation of the pancreatic ⁇ cells and ending in disease and death.
  • Female NOD mice are extremely susceptible, demonstrating evidence of macrophage invasion of the pancreatic islet interstitial matrix as early as 5 weeks old.
  • a once or twice weekly injection of 100 ⁇ g peptides derived from natural casein for 5 weeks (6 or 11 injections total) were completely effective in preventing the glucosuria associated with the onset and course of the disease.
  • IPGT glucose tolerance
  • Peptides derived from natural casein stimulates hematopoiesis in cancer patients: The hematology profiles of six cancer patients who had received or were receiving chemotherapy were examined before and following administration of peptides derived from natural casein, as indicated. Special attention was paid to changes in the Platelet (PLT), Leukocyte (WBC), Erythrocyte (RBC) and Hemoglobin (HGB) values, representing thrombocytopoiesis, leukocytopoiesis, and erythrocytopoiesis, respectively.
  • PKT Platelet
  • WBC Leukocyte
  • RBC Erythrocyte
  • HGB Hemoglobin
  • administration of peptides derived from natural casein to cancer patients results in improved hematological profiles, specifically enhanced erythropoiesis, leukocytopoiesis and thrombocytopoiesis, and is capable of moderating and shortening the duration of chemotherapy-induced depression of blood components.
  • Prolonged transfusion-resistant thrombocytopenia with episodes of severe bleeding may be a life threatening complication of bone marrow transfusion, especially where traditional therapies are ineffective.
  • Two patients with severe resistant thrombocytopenia were treated with peptides derived from natural casein.
  • Patient is a 75 year old male suffering from anemia and hypoglobinemia (depressed RBC, HGB, HCT, MCH and MCHC) associated with extensive occult bleeding.
  • RBC approached normal values (4.32 instead of 3.44 M per ⁇ l)
  • HGB increased (11.3 instead of 8.9 g per dl)
  • HCT, MCH and MCHC all improved to nearly normal values, despite the persistence of occult bleeding.
  • one injection of peptides derived from natural casein seemed capable of stimulating erythropoiesis and reducing anemia associated with blood loss in humans.

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CA002458924A CA2458924A1 (en) 2001-08-30 2002-08-29 Casein derived peptides and uses thereof in therapy
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PCT/IL2002/000720 WO2003018606A2 (en) 2001-08-30 2002-08-29 Casein derived peptides and uses thereof in therapy
EA200400376A EA007814B1 (ru) 2000-03-01 2002-08-29 Пептиды, полученные из казеина, и их использование в терапии
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