EP0563212A1 - Peptides immunoactifs synthetiques presentant une activite immunomodulante et therapeutique - Google Patents

Peptides immunoactifs synthetiques presentant une activite immunomodulante et therapeutique

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Publication number
EP0563212A1
EP0563212A1 EP19920902085 EP92902085A EP0563212A1 EP 0563212 A1 EP0563212 A1 EP 0563212A1 EP 19920902085 EP19920902085 EP 19920902085 EP 92902085 A EP92902085 A EP 92902085A EP 0563212 A1 EP0563212 A1 EP 0563212A1
Authority
EP
European Patent Office
Prior art keywords
arg
lys
glu
tyr
asp
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP19920902085
Other languages
German (de)
English (en)
Other versions
EP0563212A4 (fr
Inventor
Andrew Atkin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
IMMUNODYNAMICS Inc
Original Assignee
IMMUNODYNAMICS Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by IMMUNODYNAMICS Inc filed Critical IMMUNODYNAMICS Inc
Publication of EP0563212A1 publication Critical patent/EP0563212A1/fr
Publication of EP0563212A4 publication Critical patent/EP0563212A4/en
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • C07K14/575—Hormones
    • C07K14/57581—Thymosin; Related peptides
    • 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
    • C07K14/575—Hormones
    • C07K14/66—Thymopoietins
    • C07K14/662—Thymopoietins at least 1 amino acid in D-form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates, generally, to synthetic immunoactive peptides having immunodulating and therapeutic activities and use of such peptides in pharmaceuticals. More particularly, the present invention relates to chemically synthesized immunoactive peptides useful in immunotherapy for
  • Fraction V the uncharacterized mixture of polypeptides from calf thymus extract, having relatively high amounts of alpha-, beta- and gamma-thymosins and related polypeptides, has proven to be useful from immunomodulation in in vitro and in vivo tests, as summarized in Aiuti, F. and Wigzell, H., Thymus.
  • Pentapeptide sequences with thymopoietin-like activity and increased resistance to enzymatic degradation in biological fluids were created and disclosed in G. Goldstein et al., U.S. Patent No. 4,505,853, issued March 19th, 1985, however, their biological activity was comparable only with activity of parental peptide sequences.
  • an object of the present invention to provide a series of synthetic peptides which are effective in the therapy of immunodeficiencies, immunosuppression and T-cell subset deviations, and related ailments.
  • X is a hydrophobic or neutral amino acid
  • a 1 through A 12 are, independently, neutral or positively-side-chain-charged amino acids independently selected from the group consisting of Ala, D-Ala, Arg , D-Arg, Asp, D-Asp, Glu, D-Glu , Gly, D-Gly, His, D-His, Ile, D-Ile, Leu, D-Leu, Met, D-Met, Phe, D-Phe, Pro, D-Pro, dehydro Pro, Sar, D-Sar, Ser, D-Ser, Tre, D-Tre, Trp, D-Trp, Val and D-Val; and, B 1 through B12 are, independently, neutral or
  • negatively-side-chain-charged amino acids independently selected from the group consisting of Ala, D-Ala , Asp, D-Asp, Glu, D-Glu, Gly, D-Gly, Ile, D-Ile, Leu, D-Leu, Met, D-Met.
  • D-2-aminopimelyl may be acylated and/or amidated.
  • the foregoing generic formula includes the following sequences of amino acids in accordance with the foregoing definitions for "A,” “B” and "X";
  • compositions to be administered to a patient in the treatment of immunodeficiencies, immunosuppression, T-cell subset deviations and for the enhancement of vaccinations, etc. is to include one or more of the foregoing peptides in combination with an appropriate solubilizer.
  • Suitable additives known to those skilled in the art e.g., carriers, preservatives and viscosity modifiers, may be added to the compounds of the invention as required.
  • the synthetic immunologically-active peptides of the present invention are, for example, for
  • parenteral use direct intranasal, ear, eye, intravaginal or rectal instillation and application to intact or injured conjunctive, mucosa or skin, in order to accomplish the normalization of immune responses.
  • the preparations are to be used either locally or systemically in order to induce immunomodulation, enhance the effect of vaccination and achieve other goals of immunotherapy.
  • Preferred peptides of the present invention are those wherein: A 1 through An are, independently, Arg, Asn, Gin, Lys, Phe or Val; B 1 through B n are, independently, Asp, Glu, Tyr, Phe or Val;
  • X is Ala, Gly, Ile, Leu, Phe or Val.
  • Most preferred peptides coming within the scope of the present invention contain either balanced side chain charges of the sequences which are symmetical relative to X or uncompensated opposite side chain charges relative to X.
  • peptides may be acylated, amidated or cyclized during synthesis.
  • peptides falling within the scope of the present invention, which have been found to be particularly effective include:
  • Examples of peptides synthesized in accordance with the present invention include: Arg-Asp-Lys-Asp-Val-Tyr-Arg
  • peptides synthesized in accordance with the present invention which have been found to be most effective in immunotherapy, include:
  • Cyclized peptides synthesized in accordance with the present invention include:
  • peptides encompassed within the scope of the present invention and which have effective levels of immunotherapeutic activity, though not as great as those peptides listed above, further include:
  • Linear peptides of the present invention may be synthesized via procedures generally known to those skilled in the art and which are of wide use at present. M. Bodanszky and A. Bodanszky, Peptide Chemistry: A Practical Textbook. Springer-Verlag, N.Y. (1988); M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis. Springer-Verlag. N.Y. (1989). All linear peptides of the present
  • inventions may be synthesized by the solid phase method utilizing peptide synthesizers which are commercially available through, for example, Applied Biosystems, Inc., Foster City, California, U.S.A., and t-Boc chemistry.
  • Dicarbonic amino acids were attached to a resin via estification of a side chain carboxyl group and deprotected, Aminoacid-O-nitrophenol esters and aminoacid-O-succinimide esters were coupled directly to the deprotected alpha-amino groups of the growth peptide in the desired sequence to produce C-terminal and N-terminal deprotected peptide-resin.
  • resin-bounded peptides were cyclized using dicyclohexyl carbodiimide, cleaved and side chain
  • Figures 1 - 5 (i.e., Tables 1 - 5) present experimental data illustrating the use and effectiveness of the peptides of the present invention. Detailed Description of the Preferred Embodiments
  • Phytohemagglutinin is a non-specific stimulator of T-lymphocyte activation, which does not induce 3 H-thymidine uptake by peripheral blood lymphocytes in sub-optimal amounts.
  • Peptides of the present invention were added in a wide range of concentrations to lymphocyte cultures and caused a dramatic increase of 3 H-thymidine incorporation into cell DNA. As shown in Table 1, the peptides of the
  • Peripheral blood lymphocytes were purified by isopicnic centrifugation, washed and diluted in complete RPMI 1640 medium, supplemented with human AB sera. 10 5 cells were added into the wells of 96 well plates, which contain 100 ⁇ l of tested substances, diluted in RPMI 1640 culture medium as above, and a suboptimal amount of PHA. Cells were cultured for 4 days and 3 H-thymidine was added into each well for 24 hours. Cells were harvested and incorporation of 3H-thymidine was measured by scintillation counting. All experiments were conducted in quadruplicate.
  • Thymosin alpha-1 fragment N23-27 in culture medium for either 1 hour or 24 hours.
  • Expression of CD4, CD8 and NK markers was detected by immunofluorescene as being the number of positive cells in cultures.
  • vaccinia virus partially protects the mouse from infection with Ectromelia virus.
  • the latter infection is lethal in most cases in inbred mice.
  • Mice BALB/c received peptides of the present invention in doses of from 0.1 mcg to 1 mcg per kg of body weight, one day prior to exposure to vaccinia virus. A month later, they were injected with Ectromelia virus in an extract from the spleen and liver of spontaneously infected animals. The clinical signs of infection on record were
  • mice C57BL/6 with Influenza A virus strain WSN saved a significant number of animals. (See, Table 5.)
  • the peptide had the amino acid sequence of Tyr-Arg-Lys-Glu-Leu-Glu-Lys-Lys-Glu. Mortality was recorded during a two-week period. P was calculated using the "F" distribution of Fischer.
  • Peptides of the present invention injected in doses of from 0.1 meg to 1 meg per kg of mouse body weight, normalized the depleted T-cell immunity of thymectomized animals.
  • toxicity There were no significant changes in arterial blood pressure, heart rate, respiration or body temperature between the placebo group and animals injected with peptides during acute or chronic toxicity studies.
  • the peptides of the invention did not cause any morphological changes in the brain, heart, lung, kidney and liver tissues.
  • Complete blood counts on the experimental animals revealed an elevation of white blood cells to high normal levels. Hyperplasia of the thymus and thymusdependent zones of lymph nodes was recorded.
  • inventions preferably include an effective amount of one or more peptides and a solubilizer, with the possible inclusion of additional carriers and
  • preservatives as determined by the specifics of the different product formulations so desired by the skilled artisan.
  • Solubilizers useful in combination with the peptides of the present invention include any solubilizer which is compatible with bodily fluids.
  • solubilizers are water, solvents such as dimethylsulfoxide, propylene glycol, dimethylformamide and mixtures thereof, and surface active agents, such as non-ionic alkylene oxide block copolymers.
  • surface active agents such as non-ionic alkylene oxide block copolymers.
  • additives can be selected from, for example, sodium chloride and potassium chloride, sodium and potassium phosphate salts, sucrose, glucose, protein hydrolysate, dextran, polyvinylpyrrolidone and polyethylene glycol, among others.
  • peptides are included in medical treatment
  • composition of the present invention in order to provide doses ranging from 0.0001 mg to about 5 mg per kg of body weight for parenteral use, as well as concentrations ranging from about 0.0001% to about 5% for topical use.
  • a preferred composition of the present invention for parenteral usage is a 0.01% solution of peptides in 1 ml of 0.85 wt-% sodium chloride containing 0.1 wt-% of ascorbic acid; it can be lyophilized in the presence of 100 mg glucose.
  • a preferred composition of the present invention for eye and ear drops is a composition comprising a 0.0001 wt-% solution of peptides in a 0.85% sodium chloride solution.
  • peptides of the present invention may be used for immunomodulation of various immunodeficiencies and immunosuppressed conditions, T-cell subset and lymphocyte deviations, enhancement of a vaccine's efficacy, as well as for immunotherapy, including infections, local or systemic complications of non-infectious diseases, postoperatives inflammations, wounds and burns. While only several embodiments of the present invention have been described, it will be obvious to those of ordinary skill in the art that many

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Toxicology (AREA)
  • Endocrinology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Peptides synthétiques qui sont efficaces dans la thérapie des déficits immunitaires, de la suppression immunitaire, des déviations de sous-ensembles de lymphocytes T et des pathologies apparentées.
EP19920902085 1990-11-23 1991-11-22 Peptides immunoactifs synthetiques presentant une activite immunomodulante et therapeutique Withdrawn EP0563212A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US61749490A 1990-11-23 1990-11-23
US617494 1990-11-23

Publications (2)

Publication Number Publication Date
EP0563212A1 true EP0563212A1 (fr) 1993-10-06
EP0563212A4 EP0563212A4 (fr) 1994-04-27

Family

ID=24473862

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19920902085 Withdrawn EP0563212A1 (fr) 1990-11-23 1991-11-22 Peptides immunoactifs synthetiques presentant une activite immunomodulante et therapeutique

Country Status (3)

Country Link
EP (1) EP0563212A1 (fr)
AU (1) AU9140891A (fr)
WO (1) WO1992009628A1 (fr)

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5215964A (en) * 1991-06-03 1993-06-01 Immunobiology Research Institute, Inc. Peptides useful in regulating the immune and nervous systems
US5589458A (en) * 1992-11-13 1996-12-31 Thomas Jefferson University Compounds that inhibit T cell proliferation and methods for using the same
US6017719A (en) * 1994-06-14 2000-01-25 Nexell Therapeutics, Inc. Positive and positive/negative cell selection mediated by peptide release
GB9421180D0 (en) * 1994-10-20 1994-12-07 Peptide Therapeutics Ltd Immunomodulatory Polypeptides
GB9425582D0 (en) * 1994-12-19 1995-02-15 Iaf Biochem Int Peptides having immunomodulatory activity
RU2107691C1 (ru) * 1995-03-02 1998-03-27 Дейгин Владислав Исакович Пептид и способ его получения
US6103699A (en) 1996-06-07 2000-08-15 Immunotech Developments Inc. Peptide, a method for its preparation and a pharmaceutical composition containing the peptide
US6159940A (en) * 1996-02-28 2000-12-12 Immunotech Developments Inc. Method for modulating hemopoiesis
US6046167A (en) * 1998-03-25 2000-04-04 University Of Cincinnati Peptide YY analogs
US6734287B1 (en) 1998-04-09 2004-05-11 Idexx Laboratories, Inc. Specific binding proteins for treating canine allergy
EP0955311A3 (fr) * 1998-04-09 2000-08-16 Idexx Laboratories, Inc. Vaccin peptidique contre l'allergie des chiens
EP1082346A1 (fr) * 1999-03-30 2001-03-14 Idexx Laboratories, Inc. Proteines de liaison specifiques pour le traitement d'allergies
CA2329152A1 (fr) * 1999-03-30 2000-10-05 Idexx Laboratories, Inc. Vaccin peptidique pour allergie canine
US7129052B1 (en) 2000-07-12 2006-10-31 The United States Of America As Represented By The Department Of Health And Human Services Peptides and their utility in modulation of behavior of cells expressing α3β1 integrins
US20050084967A1 (en) 2002-06-28 2005-04-21 Xcyte Therapies, Inc. Compositions and methods for eliminating undesired subpopulations of T cells in patients with immunological defects related to autoimmunity and organ or hematopoietic stem cell transplantation
US20220183950A1 (en) * 2019-02-08 2022-06-16 Lubrizol Advanced Materials, Inc. Compounds useful for the treatment and/or care of the skin, hair, nails and/or mucous membranes

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4547489A (en) * 1984-06-11 1985-10-15 Ortho Pharmaceutical Corporation Conformationally restricted thymopentin-like compounds
EP0353565A1 (fr) * 1988-07-29 1990-02-07 ELLEM INDUSTRIA FARMACEUTICA S.p.A. Peptides immunostimulants, leurs procédé de préparation, et compositions pharmaceutiques les contenant

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4002740A (en) * 1975-08-21 1977-01-11 Gideon Goldstein Tridecapeptide compositions and methods
DE3100974A1 (de) * 1980-01-18 1982-01-21 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V., 3400 Göttingen Thymosin(alpha)(pfeil abwaerts)1(pfeil abwaerts)-fragmente enthaltende arzneimittel mit immunregulierender wirkung, und thymosin(alpha)(pfeil abwaerts)1(pfeil abwaerts)-fragmente
US4397842A (en) * 1980-03-13 1983-08-09 Ortho Pharmaceutical Corporation Peptides having thymopoietin-like activity
US4659694A (en) * 1983-10-27 1987-04-21 Hoffmann-La Roche Inc. Prothymosin alpha

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4547489A (en) * 1984-06-11 1985-10-15 Ortho Pharmaceutical Corporation Conformationally restricted thymopentin-like compounds
EP0353565A1 (fr) * 1988-07-29 1990-02-07 ELLEM INDUSTRIA FARMACEUTICA S.p.A. Peptides immunostimulants, leurs procédé de préparation, et compositions pharmaceutiques les contenant

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ARCH.BIOCHEM.BIOPHYS. vol. 242, no. 1 , October 1985 pages 248 - 254 G.A.HEAVNER ET AL 'Structural requirements for the biological activity of thymopentin analogs' *
JOURNAL OF MEDICINAL CHEMISTRY. vol. 33, no. 1 , January 1990 , WASHINGTON US pages 354 - 360 M.MOKOTOFF ET AL 'Thymosin-like peptides as potential immunostimulants' *
See also references of WO9209628A1 *

Also Published As

Publication number Publication date
AU9140891A (en) 1992-06-25
WO1992009628A1 (fr) 1992-06-11
EP0563212A4 (fr) 1994-04-27

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