WO1992009628A1 - Synthetic immunoactive peptides having immunomodulating and therapeutic activities - Google Patents

Synthetic immunoactive peptides having immunomodulating and therapeutic activities Download PDF

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Publication number
WO1992009628A1
WO1992009628A1 PCT/US1991/008795 US9108795W WO9209628A1 WO 1992009628 A1 WO1992009628 A1 WO 1992009628A1 US 9108795 W US9108795 W US 9108795W WO 9209628 A1 WO9209628 A1 WO 9209628A1
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Prior art keywords
arg
lys
glu
tyr
asp
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PCT/US1991/008795
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French (fr)
Inventor
Andrew Atkin
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Immunodynamics, Inc.
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Application filed by Immunodynamics, Inc. filed Critical Immunodynamics, Inc.
Publication of WO1992009628A1 publication Critical patent/WO1992009628A1/en

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    • 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";
  • 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
  • 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.
  • 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

Abstract

Synthetic peptides which are effective in the therapy of immunodeficiencies, immunosuppression and T-cell subset deviations, and related ailments.

Description

Description
Synthetic Immunoactive Peptides Having
Immunomodulating and Therapeutic Activities
Technical Field 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
regulation of T-cell dependent immunity.
Background Art
It is generally known in the prior art that a great number of disorders in humans, as well as animals, are associated with decreased immunity or immunodeficiency. Various degrees of altered levels of immunity are found in oncologic and hematalogic diseases, aging, etc. As a result of immunological dysfunction, various infections, neoplasias and accerated metastasizing may be observed in persons suffering from such disorders. The crucial role of thymus-dependent immunity in the function of the immune system is well- established. Recently, a number of biologically active polypeptides have been isolated from the thymus and, at least partially, characterized. Among such polypeptides are various thymosins,
thymopoietins and thymic serum factor. These results are detailed in Cardarelli, Nate P., The Thymus in Health and Senescence. CRC Press (1989); Goldstein, Allan L., Thymic Hormones and Lymphokines: Basic
Chemistry and Clinical Applications. NY, Plenum Press (1989); and, Gideon Goldstein et al., NY Liss (1987).
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.
Thymic Hormones, and T-Lymphocytes, Proceedings of the Serono Symposium, V. 38 (Academic Press 1989.) The potential effectiveness of Fraction V as an immunomodulating drug has been disclosed in H.
Strausser, U.S. Patent No. 4,444,757, issued April 24th, 1984. The clinical use of the foregoing preparations has been limited by:
1. The impossibility of obtaining an adequate quantity for studies, as well as the need for using a significant amount of autological material of
thymuses of newborn children:
2. The impossibility of precise biochemical identification of extracts; and,
3. An immune response to the xenogenic or allogenic proteins from thymic extracts.
In summary, the use of purified natural or
recombinant polypeptides for immunotherapy is limited by the limited source of biologically active
components, as well as the immunological and biochemical difficulties in their purification.
Synthetic peptides avoid these drawbacks.
Different immunologically active synthetic peptides, related to either natural thymosins alpha 1, beta 3 and beta 4, as modified sequences, have been disclosed in, for example, S. Wang, U.S. Patent No. 4,116,951, issued September 26th, 1978; T. Low et al., U.S. Patent No. 4,395,404, issued July 26th, 1983; and, C. Birr et al., U.S. Patent No. 4,612,365, issued September 16th, 1986. Additionally, the active synthetic peptide of thymopoietin has been described in G. Goldstein et al., Science. 1979, 204. p. 1309. This peptide sequence has been disclosed in G. Goldstein et al., U.S. Patent No. 4,190,646, issued February 1980, and modified sequences having similar activity were disclosed in G. Goldstein et al., U.S. Patent No. 4,201,886, issued April 14th,
1981. These peptide sequences induce differentiation of lymphocytes into mature T-cells expressing
specific markers, support the delicate equilibrium of helper and suppressor T-cells, stimulate the
previously-diminished immune response and suppress excessive autoimmune activity to various auto-antigens.
Nevertheless, the overall biological activities of presently known synthetic peptides have proven to be insufficient for clinical use, as detailed, for example, in B. K. Kantharia et al., "Thymopentin
(TP-5) in the treatment of Rhumatoid arthritis," Br. J. Rheumatol. 1989, 28(2), pp. 118-123; J. A. Hansen, J. E. Sanders, R. Stuart, "Use of thymic grafts of thymic factors to augment immunologic recovery after bone marrow transplantation: brief report with 2 - 12 years follow-up. Bone marrow transplant. 1980, pp. 424-436.
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.
In order to overcome the weak activities of the thymopoietin-derived peptide to the #32-36 sequence, an additional peptide from alpha-1 thymosin was added. This further procedure, however, failed to increase the biological activity of the parent sequences, as detailed in M. Mokotoff et al.,
"Thymosin-like peptides as potential immunostimulants. Synthesis via the polymeric-reagent method," J. Med. Chem.. 1990, 33(1), pp. 354-360.
Additional prior art known to the inventor, but which has failed to overcome the difficulties encountered in the production of immunotherapeutically active peptides, includes G. Goldstein et al., U.S. Patent No. 4,002,740, issued January 11th, 1977; W. McGregor, U.S. Patent No. 4,082,737, issued April 4th, 1978; G. Goldstein, U.S. Patent No.
4,124,700, issued November 7th, 1978; A. Goldstein et al., U.S. Patent No. 4,297,276, issued October 27th, 1981; C. Birr et al., U.S. Patent No. 4,353,821, issued October 12th, 1982; G. Heavner, U.S. Patent No. 4,369,137, issued January 18th, 1983; B.
Horecker, U.S. Patent No. 4,374,197, issued February 15th, 1983; G. Goldstein et al. , U.S. Patent No.
4,397,842, issued August 9th, 1983; C. Birr et al., U.S. Patent No. 4,466,918, issued August 21st, 1984; C. Birr et al., U.S. Patent No. 4,470,926, issued September 11th, 1984; A. Felix et al., U.S. Patent No. 4,504,415, issued March 12th, 1985; A. Felix et al., U.S. Patent No. 4,517,119, issued May 14th, 1985; B. Horecker, U.S. Patent No. 4,659,694, issued April 21st, 1987; B. Horecker, U.S. Patent No.
4,716,148, issued December 29th, 1987; and, C. Birr et al., U.S. Patent No. 4,910,296, issued March 20th, 1990. It is clear that if the difficulties encountered in the production of immunotherapeutically active peptides could be overcome, a major advancement in the treatment of various diseases would be achieved. Thus, a great need exists for the creation of
biologically active peptides which can be used for the clinically effective correction of immunodeficiencies and immunosuppressions associated with different pathological conditions. Disclosure of Invention
It is, therefore, 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.
It is an additional object of the present invention to provide a series of synthetic peptides which have a biological activity which is several hundred times more effective than presently known immunologically-active sequences.
It is, yet, a further object of the present invention to provide synthetic peptides which are non-toxic to humans, even when administered in doses which are several thousand times higher than
effective dose levels.
It is an additional object of the present invention to provide a series of synthetic peptides which overcome the disadvantages inherent in the prior art and with similar substances found in nature.
The foregoing and related objects are achieved by linear and cyclized peptide compounds constructed by combination and/or overlapping of the sequences:
A1 B1 X B2 A2 , A3 B3 X A4 B4 , B5 A5 X A6 B6 ,
B7 A7 X B8 A8 , A9 B9 , A10 A1 1 ,
B1 0 A1 2 and/or B1 1 B1 2 , wherein,
X is a hydrophobic or neutral amino acid
independently selected from the group
consisting of Ala, D-Ala, Gly, D-Gly, Ile, D-Ile, Leu, D-Leu, Met, D-Met, Phe, D-Phe, Pro, D-Pro, Sar, D-Sar, Ser, D-Ser, Tre, D-Tre, Trp,
D-Trp, Val and D-Val; A1 through A12 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, B1 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. Phe, D-Phe, Pro, D-Pro, dehydro Pro, Sar, D-Sar, Tre, D-Tre, Tyr, D-Tyr, Val, P-Val, L-2- aminoglutaryl, D-2-aminoglutaryl, L-2-aminoadiphyl, D-2-aminoadiphyl, L-2-aminopimelyl and
D-2-aminopimelyl. The foregoing peptides, in accordance with the present invention, 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";
1. A1A2B2XA3B3 2. A1A2XB2A2A3
3. A1B1XB2A2A3 4. B1A1XB2A2A3
5. B1B2A2XA3B3 6. B1B2A2XB3A3
7. A1B1XA2B2B3 8. B1A1XA2B2B3
9. A1B2A2XA3B3 10. A1B2A2XB3A3
11. A1B1XB2A2B3 12. B1A1XB2A2B3
13. B1A2B2XB3A3 14. B1A2B2XA3B3
15. A1B1XA2B2A3 16. B1A1XA2B2A3
17. A1A2A3B3XB4 A4 18. A1 A2 A3 B3 XA4 B4
19. A1 A2 B3 A3 XA4 B4 20. A1 A2 B3 A3 XB4 A4
21. A1 B1 XB2 A2 A3 A4 22. A1 B1 XA2 B2 A3 A4
23. B1A1XA2B2A3A4 24. B1A1XB2A2A3A4
25. B1 B2 A3 B3 XB4 A4 26. B1 B2 A3 B3 XA4 B4
27. B1 B2 B3 A3 XA4 B4 28. B1 B2 B3 A3 XB4 A4
29. A1 B1 XB2 A2 B3 B3 30. A1B1XAB2B3B4
31. B1A1XA2B2B3B4 32. B1A1XB2A2B3B4
33. A1 B1 A2 B2 XB3 A3 34. A1 B1 A2 B2 XA3 B3
35. A1 B1 B2 A2 XA3 B3 36. A1 B1 B2 A2 XB3 A3
37. A1B1XB2A2A3B3 39. A1 B1 XA2 B2 A3 B3
39. B1A1XA2B2A3B3 40. B1 A1 XB2 A2 A3 B3 41. B1 A1 A2 B2 XB3 A3 42. B1 Al A2 B2 XA3 B3
43. B1 A1 B2 A2 XA3 B3 44. B1 A1 B2 A2 XB3 A3
45. A1 B1 XB2 A2 B3 A3 46. A1 B1 XA2 B2 B3 A3
47. B1 A1 XA2 B2 B3 A3 48. B1 A1 XB2 A2 B3 A3 49. B1 A1 A2 B2 XB3 A3 A4 B4 50. A1 B1 A2 B2 XB3 A3 B4 A4
51. B1 A1 A2 B2 XA3 B3 A4 B4 53. B1 A1 B2 A2 XA3 B3 A4 B4
53. A1 B1 B2 A2 XA3 B3 B4 A4 54. A1 B1 A2 B2 XA3 B3 B4 A4
55. B1 A1 B2 A2 XB3 A3 A4 B4 56. A1 B1 B2 A2 XB3 A3 B4 A4
57. B1 A1 A2 B2 XB3 A3 B4 A4 58. A1 B1 A2 B2 XB3 A3 A4 B4 59. B1 A1 A2 B2 XA3 B3 B4 A4 60. A1 B1 A2 B2 XA3 B3 A4 B4
61. B1 A1 B2 A2 XA3 B3 B4 A4 62. A1 B1 B2 A2 XA3 B3 A4 B4
63. B1 A1 B2 A2 XB3 A3 B4 A4 64. A1 B1 B2 A2 XB3 A3 A4 B4
65. A1 B2 XA2 A2 XA3 B3 66. A1 B1 XB2 A2 XB3 A3
67. A1 B1 XA2 B2 XB3 A3 68. B1 A1 XA2 B2 XB3 A3 69. B1 A1 XA2 B2 XA3 B3 70. B1 A1 XB2 A2 XA3 B3
71. A1 B1 XB2 A2 A3 B3 XB4 A4 72. A1 B1 XA2 B2 A3 B3 XA4 B4
73. B1 A1 XA2 B2 B3 A3 XA4 B4 74. B1 A1 XB2 A2 B3 A3 XB4 A4
75. A1 B1 XB2 A2 A3 B3 XA4 B4 76. A1 B1 XA2 B2 A3 B3 XB4 A4
77. A1 B1 XB2 A2 B3 A3 XA4 B4 78. B1 A1 XA2 B2 A3 B3 XB4 A4 79. A1 B1 XB2 A2 B3 A3 XB4 A4 80. B1 A1 XB2 A2 A3 B3 XB4 A4
81. A1 B1 XA2 B2 B3 A3 XB4 A4 82. B1 A1 XB2 A2 A3 B3 XA4 B4
83. A1 B1 XA2 B2 B3 A3 XA4 B4 84. B1 Al XA2 B2 A3 B3 XA4 B4
85. B1 A1 XA2 B2 B3 A3 XB4 A4 86. B1 A1 XB2 A2 B3 A3 XA4 B4 The present invention should be understood as encompassing pharmaceutically acceptable acid or base salts, as well as the free peptides generically described above and which are detailed hereinafter. For the purposes of achieving the objects of the present invention, amino acid sequence No. 41
provides the most effective peptides. Amino acid sequences Nos. 49 and 59 have also been found to be very effective. It was surprisingly discovered that the peptides of the invention, as defined above, express immunomodulating activity, with many such peptides
expressing a more powerful immunodulating activity than known natural, or naturally modified, amino acid sequences. The 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: A1 through An are, independently, Arg, Asn, Gin, Lys, Phe or Val; B1 through Bn 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.
For protection against amino- and carboxypeptidases, peptides may be acylated, amidated or cyclized during synthesis. Examples of peptides falling within the scope of the present invention, which have been found to be particularly effective include:
Arg-Asp-Lys-Asp-Val-Tyr-Arg
Lys-Asp-Lys-Asp-Val-Tyr-Lys
Lys-Glu-Lys-Asp-Val-Tyr-Lys
Arg-Glu-Arg-Asp-Val-Tyr-Arg
Lys-Glu-Leu-Tyr-Arg-Lys-Glu
Lys-Glu-Leu-Glu-Lys-Lys-Glu
Arg-Glu-Leu-Glu-Arg-Arg-Glu
Lys-Asp-Val-Asp-Lys-Lys-Asp
Lys-Asp-Leu-Glu-Lys-Lys-Glu
Tyr-Arg-Lys-Asp-Val-Tyr-Arg-Lys-Glu
Tyr-Arg-Lys-Glu-Leu-Glu-Lys-Lys-Glu
Glu-Lys-Lys-Glu-Leu-Tyr-Arg-Lys-Glu
Tyr-Arg-Lys-Glu-Leu-Tyr-Arg-Glu-Lys
Tyr-Arg-Lys-Asp-Val-Tyr-Arg-Lys-Asp-Val-Tyr-Arg
Glu-Lys-Lys-Glu-Leu-Tyr-Arg-Lys-Glu-Leu-Tyr-Arg Glu-Arg-Lys-Glu-Leu-Tyr-Arg-Lys-Glu-Leu-Tyr-Arg
Examples of peptides synthesized in accordance with the present invention, which have been found to be most effective in immunotherapy, include: Arg-Asp-Lys-Asp-Val-Tyr-Arg
Lys-Asp-Lys-Asp-Val-Tyr-Lys
Lys-Glu-Lys-Asp-Val-Tyr-Lys
Arg-Glu-Arg-Asp-Val-Tyr-Arg
Lys-Glu-Leu-Tyr-Arg-Lys-Glu
Lys-Glu-Leu-Glu-Lys-Lys-Glu
Arg-Glu-Leu-Glu-Arg-Arg-Glu
Lys-Asp-Val-Asp-Lys-Lys-Asp
Lys-Asp-Leu-Glu-Lys-Lys-Glu
Tyr-Arg-Lys-Asp-Val-Tyr-Arg-Lys-Glu
Tyr-Arg-Lys-Glu-Leu-Glu-Lys-Lys-Glu
Glu-Lys-Lys-Glu-Leu-Tyr-Arg-Lys-Glu
Tyr-Arg-Lys-Glu-Leu-Tyr-Arg-Glu-Lys
Tyr-Arg-Lys-Asp-Val-Tyr-Arg-Lys-Asp-Val-Tyr-Arg
Glu-Lys-Lys-Glu-Leu-Tyr-Arg-Lys-Glu-Leu-Tyr-Arg Glu-Arg-Lys-Glu-Leu-Tyr-Arg-Lys-Glu-Leu-Tyr-Arg
Examples of peptides synthesized in accordance with the present invention, which have been found to be most effective in immunotherapy, include:
Glu-Arg-Lys-Glu-Leu-Tyr-Arg
Tyr-Arg-Lys-Asp-Val-Tyr-Arg
Tyr-Arg-Lys-Glu-Leu-Tyr-Arg
Glu-Arg-Lys-Asp-Val-Tyr-Arg
Cyclized peptides synthesized in accordance with the present invention, and which are preferred for their effective in immunotherapy, include:
Figure imgf000018_0001
Figure imgf000019_0001
Other 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:
Arg-Lys-Asp-Val-Lys-Tyr; Arg-Lys-Asp-Val-Arg-Tyr; Arg-Lys-Asp-Val-Phe-Glu; Arg-Glu-Glu-Val-Phe-Glu; Arg-Lys-Asp-Val-Tyr-Arg; Arg-Asn-Asp-Val-Tyr-Arg; Arg-Lys-Glu-Leu-Tyr-Arg; Arg-Gln-Glu-Leu-Tyr-Arg; Arg-Lys-Asp-Val-Tyr-Lys; Arg-Asn-Asp-Val-Tyr-Lys; Arg-Lys-Glu-Leu-Tyr-Lys; Arg-Gln-Glu-Leu-Tyr-Lys; Arg-Lys-Asp-Val-Glu-Arg; Arg-Lys-Glu-Leu-Glu-Arg; Arg-Lys-Glu-Val-Glu-Arg; Arg-Phe-Leu-Tyr-Arg-Asp; Phe-Tyr-Arg-Leu-Arg-Tyr; Glu-Tyr-Arg-Leu-Arg-Tyr; Glu-Tyr Arg-Leu-Tyr-Arg; Lys-Glu-Leu-Gln-Glu-Glu; Lys-Asp-Val-Arg-Tyr-Tyr; Lys-Asp-Val-Lys-Phe-Glu; Lys-Asp-Val-Arg-Phe-Glu; Lys-Asp-Val-Arg-Tyr-Asp; Arg-Tyr-Asn-Val-Tyr-Arg; Arg-Tyr-Gln-Leu-Tyr-Arg; Arg-Tyr-Asn-Val-Tyr-Lys; Arg-Tyr-Gln-Leu-Tyr-Lys; Arg-Glu-Lys-Leu-Tyr-Arg; Gln-Glu-Lys-Leu-Tyr-Arg; Gln-Asp-Lys-Leu-Tyr-Arg; Asn-Asp-Lys-Leu-Tyr-Arg; Lys-Tyr-Val-Tyr-Arg-Asp; Tyr-Arg-Asp-Val-Tyr-Arg; Tyr-Lys-Asp-Val-Tyr-Lys; Tyr-Lys-Glu-Leu-Tyr-Arg; Asp-Asn-Tyr-Val-Tyr-Arg; Asp-Asn-Tyr-Leu-Glu-Arg; Asp-Asn-Tyr-Leu-Glu-Gln; Arg-Asn-Lys-Asp-Val-Tyr-Arg;
Arg-Gln-Arg-Glu-Leu-Tyr-Arg;
Arg-Asn-Arg-Tyr-Leu-Tyr-Arg;
Arg-Asp-Val-Tyr-Arg-Gln-Asn;
Lys-Asp-Val-Tyr-Arg-Gln-Asn;
Arg-Asp-Val-Tyr-Lys-Gln-Asn;
Asp-Glu-Lys-Glu-Leu-Tyr-Arg;
Glu-Glu-Lys-Asp-Val-Tyr-Arg;
Asp-Glu-Gln-Glu-Leu-Phe-Arg;
Gln-Asp-Val-Tyr-Arg-Glu-Asp;
Gln-Glu-Asn-Asp-Val-Glu-Gln;
Asn-Asp-Gln-Glu-Leu-Glu-Gln;
Asn-Asp-Lys-Asp-Val-Asp-Lys;
Gln-Glu-Asp-Lys-Leu-Tyr-Arg;
Arg-Glu-Asp-Lys-Leu-Tyr-Arg;
Arg-Glu-Asp-Arg-Leu-Tyr-Arg; Arg-Asp-Glu-Arg-Leu-Tyr-Arg;
Arg-Glu-Tyr-Arg-Leu-Tyr-Arg:
Lys'-Glu-Tyr-Arg-Leu-Tyr-Arg
Lys-Asp-Val-Tyr Arg-Arg-Tyr;
Lys-Asp-Val-Tyr-Arg-Lys-Tyr;
Lys-Asp-Val-Tyr-Arg-Lys-Asp;
Lys-Glu-Leu-Glu-Arg-Lys-Glu;
Arg-Asp-Val-Asp-Lys-Lys-Asp;
Lys-Asp-Leu-Glu-Lys-Lys-Asp;
Lys-Glu-Leu-Lys-Glu-Lys-Glu:
Lys-Asp-Leu-Lys Glu-Lys-Asp;
Glu-Arg-Lys-Asp Val-Tyr-Arg:
Glu-Lys-Lys-Asp-Val-Tyr-Arg;
Asp-Arg-Lys-Asp Val-Tyr-Arg:
Lys-Glu-Leu-Lys-Glu-Tyr-Arg
Lys -Asp-Val-Lys-Glu-Tyr-Lys:
Glu-Lys-Lys-Glu-Leu-Glu-Lys-Lys-Glu;
Glu-Lys-Lys-Glu-Leu-Tyr-Arg-Arg-Tyr;
Glu-Lys-Lys-Glu-Leu-Arg-Tyr-Tyr-Arg;
Tyr-Arg-Lys-Asp-Val-Lys-Tyr-Tyr-Arg;
Glu-Lys-Lys-Glu-Leu-Tyr-Arg-Tyr-Arg;
Glu-Lys-Lys-Glu-Leu-Tyr-Arg-Glu-Arg;
Glu-Lys-Lys-Glu-Leu-Tyr-Arg-Glu-Arg; Glu-Lys-Lys-Glu-Leu-Glu-Gln-Tyr-Arg ;
Glu-Lys-Lys-Glu-Leu-Glu-Gln-Asp-Asn;
Lys-Glu-Glu-Lys-Leu-Glu-Lys-Lys-Glu;
Lys-Asp-Asp-Lys-Leu-Tyr-Arg-Gln-Glu;
Gln-Glu-Asp-Lys-Leu-Tyr-Arg-Gln-Glu;
Gln-Glu-Asp-Lys-Leu-Tyr-Arg-Gln-Glu;
Arg-Tyr-Leu-Arg-Tyr-Leu-Tyr-Arg ;
Arg-Tyr-Leu-Lys-Glu-Leu-Tyr-Arg ;
Tyr-Arg-Gly-Lys-Glu-Leu-Tyr-Arg ;
Arg-Tyr-Leu-Tyr-Arg-Lys-Asp-Val-Tyr-Arg ; and,
Arg-Tyr-Leu-Glu-Lys-Lys-Glu-Leu-Tyr-Arg .
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
invention, for example, 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.
In practice, crude preparations of peptides were purified by low pressure column ion-exchange
chromatography following preparative ion-exchange as reverse phase HPLC . Purity of the final products had been analyzed by analytical reverse phase HPLC using ODS-columns and structure was verified by amino acid analysis. Purity of peptides synthesized varied from 94.2% to 99.2%. Cyclized peptides synthesized in accordance with the present invention may be synthesized in
accordance with the following:
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. These resin-bounded peptides were cyclized using dicyclohexyl carbodiimide, cleaved and side chain
deprotected following purification. Aminoacidic analysis or NMR spectra may be utilized to confirm that the desired cyclized peptide has been produced.
Other objects and features of the present invention will be described in connection with the accompanying drawing figures and tables, which further illustrate the invention. It should, however, be recognized that the accompanying figures and tables are intended solely to illustrate the invention and are not intended as a means for defining the scope of the invention.
Brief Description of the Drawing Figures/Tables
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
Turning now, in detail, to an analysis of the preferred embodiments and experimental data,
conducted by the inventor, which illustrates the immunotherapeutic activity of the peptide compounds of the present invention.
Initially, a suboptimal amount of phyto- hemagglutinin from Phaseolus vulgaris was utilized in experimentation. Phytohemagglutinin is a non-specific stimulator of T-lymphocyte activation, which does not induce 3H-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 3H-thymidine incorporation into cell DNA. As shown in Table 1, the peptides of the
invention are over 100 to 1000 times more active than other known immunologically-active sequences. The peptides tested in Table 1 were as follows:
Peptides Amino Acid Sequence
Thymopoietin NN32-36 Arg-Lys-Asp-Val-Tyr
Thymosin alpha-1 N23-27 Val-Glu-Glu-Ala-Glu
Peptide (a) Arg-Lys-Asp-Val-Tyr-Arg
Peptide (b) Arg-Lys-Asp-Val-Tyr-Lys
Peptide (c) Glu-Arg-Lys-Asp-Val-Tyr-Arg Peptide (d) Tyr-Arg-Lys-Asp-Val-Tyr-Arg
Peripheral blood lymphocytes (PBL) were purified by isopicnic centrifugation, washed and diluted in complete RPMI 1640 medium, supplemented with human AB sera. 105 cells were added into the wells of 96 well plates, which contain 100 μl of tested substances, diluted in RPMI 1640 culture medium as above, and a suboptimal amount of PHA. Cells were cultured for 4 days and 3H-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. The addition of peptides to the peripheral blood lymphocytes of patients with depressed immunity, as reflected by decreased expression of T-cell subset markers and lymphocyte deviations, normalizes these characteristics. Positive results were achieved within one hour of incubation, while no normalization was seen after such time when any presently known sequence was added. By contrast, previously known sequences led to limited normalization, but only after 18 - 24 hours of incubation. The experimental data of such comparative testing is set forth in Table 2.
With respect to the data set forth in Table 2, the PBL of normal persons and patients were treated by the peptide Glu-Lys-Lys-Asp-Val-Tyr-Arg or
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.
All experiments were conducted in triplicate. P was calculated by using the t distribution of Student.
As measured by 3H-thymidine uptake, the peptides of the invention were able to restore normal response to phytohemagglutinin, while the amino acid sequences of peptides known to the prior art failed to do so. The experimental results are presented in Table 3. (Such comparative testing was performed in a manner similar to that described above for the test results set forth in Table 1. PBL of patients with signs of immunodeficiency were tested for PHA-induced
3H-thymidine uptake in the presence of tested
substances in culture medium.)
It is known that 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
hepatosplenomegaly, mucosal inflammation and necrosis of extremities and tail. The potentiating effect of peptides following vaccination with viccinia virus was evident. The test results are presented in Table 4 for the peptide Tyr-Arg-Lys-Glu-Leu-Tyr-Arg versus a placebo. (In Table 4, P was calculated using the "F" distribution of Fischer, also known as Fischer's exact test.)
A single injection of a peptide one day prior to intranasal application in 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.
In toxicity studies, no toxicity was observed for the peptides of the invention in doses of up to 1 g per kg of mouse body weight; 20 subcutaneous or intraperitoneal injections every other day of the same dose also failed to produce any signs of
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.
The medical formulations of the present
invention 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. Examples of 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. When the solubilizer used is water, additional additives can be used to achieve physiological concentrations of inorganic salts, normal osmotic pressure and effective lyophilization. Such
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.
In accordance with a preferred embodiment, 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, for example, is a composition comprising a 0.0001 wt-% solution of peptides in a 0.85% sodium chloride solution.
The medicinal compositions utilizing the
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
modifications may be made to the present invention without departing from the spirit and scope thereof.

Claims

Claims
1. A peptide compound, or an acid or base salt thereof, constructed by combination and/or overlapping of the amino acid sequences: A1 B1 X B2 A2, A3 B3 X A4 B4, B5 A5 X A6 B6, B7A7 X B8 A8, A9 B9, A10 A11,
B10 A12 and/or B11 B12, wherein,
X is a hydrophobic or neutral amino acid
independently selected from the group
consisting of Ala, D-Ala, Gly, D-Gly, Ile,
D-Ile, Leu, D-Leu, Met, D-Met, Phe, D-Phe, Pro, D-Pro, Sar, D-Sar, Ser, D-Ser, Tre, D-Tre, Trp, D-Trp, Val and D-Val; A1 through A12 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, B1 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. Phe, D-Phe, Pro, D-Pro, dehydro Pro, Sar, D-Sar, Tre, D-Tre, Tyr, D-Tyr, Val, D-Val, L-2- aminoglutaryl, D-2-aminoglutaryl, L-2-aminoadiphyl, D-2-aminoadiphyl, L-2-aminopimelyl and
D-2-aminopimelyl.
2. The peptide compound according to Claim 1, wherein,
X is an amino acid selected from the group
consisting of Ala, Gly, Ile, Leu, Phe and Val; A1 through An are amino acids independently
selected from the group consisting of Arg, Asn, Gin, Lys, Phe and Val; and, i through Bn are amino acids independently
selected from the group consisting, of Asp, Glu, Tyr, Phe and Val.
3. The peptide compound according to Claim 1, wherein said peptide compound has balanced side chain charges of amino acid sequences which are symmetrical to X.
4. The peptide compound according to Claim 1, wherein said peptide compound has uncompensated opposite side chain charges of amino acid sequences relative to X.
5. The peptide compound according to Claim 1, wherein said peptide compound is Glu-Arg-Lys-Glu-Leu-Tyr-Arg.
6. The peptide compound according to Claim 1, wherein said peptide compound is Tyr-Arg-Lys-Asp-Val-Tyr-Arg.
7. The peptide compound according to Claim 1, wherein said peptide compound is Tyr-Arg-Lys-Glu-Leu-Tyr-Arg.
8. The peptide compound according to Claim 1, wherein said peptide compound is Glu-Arg-Lys-Asp-Val-Tyr-Arg.
9. The peptide compound according to Claim 1 , wherein said peptide compound is a member selected from the group consisting of :
Arg-Asp-Lys-Asp-Val -Tyr-Arg;
Lys-Asp-Lys-Asp-Val-Tyr-Lys;
Lys-Glu-Lys-Asp-Val-Tyr-Lys;
Arg-Glu-Arg-Asp-Val-Tyr-Arg;
Lys-Glu-Leu-Tyr-Arg--Lys-Glu;
Lys-Glu-Leu-Glu-Lys-Lys-Glu;
Arg-Glu-Leu-Glu-Arg-Arg-Glu;
Lys-Asp-Val-Asp-Lys-Lys-Asp;
Lys-Asp-Leu-Glu-Lys-Lys-Glu;
Tyr-Arg-Lys-Asp-Val-Tyr-Arg-Lys-Glu;
Tyr-Arg-Lys-Glu-Leu-Glu-Lys-Lys-Glu;
Glu-Lys-Lys-Glu-Leu-Tyr-Arg-Lys-Glu;
Tyr-Arg-Lys-Glu-Leu-Tyr-Arg-Glu-Lys;
Tyr-Arg-Lys-Asp-Val-Tyr-Arg-Lys-Asp-Val-Tyr-Arg;
Glu-Lys-Lys-Glu-Leu-Tyr-Arg-Lys-Glu-Leu-Tyr-Arg;
Glu-Arg-Lys-Glu-Leu-Tyr-Arg-Lys-Glu-Leu-Tyr-Arg;
Figure imgf000036_0001
Figure imgf000037_0001
10. The peptide compound according to Claim 1, wherein said peptide compound is a member selected from the group consisting of:
Arg-Lys-Asp-Val-Lys-Tyr; Arg-Lys-Asp-Val-Arg-Tyr; Arg-Lys-Asp-Val-Phe-Glu; Arg-Glu-Glu-Val-Phe-Glu; Arg-Lys-Asp-Val-Tyr-Arg; Arg-Asn-Asp-Val-Tyr-Arg; Arg-Lys-Glu-Leu-Tyr-Arg; Arg-Gln-Glu-Leu-Tyr-Arg; Arg-Lys-Asp-Val-Tyr-Lys; Arg-Asn-Asp-Val-Tyr-Lys; Arg-Lys-Glu-Leu-Tyr-Lys; Arg-Gln-Glu-Leu-Tyr-Lys; Arg-Lys-Asp-Val-Glu-Arg; Arg-Lys-Glu-Leu-Glu-Arg; Arg-Lys-Glu-Val-Glu-Arg; Arg-Phe-Leu-Tyr-Arg-Asp; Phe-Tyr-Arg-Leu-Arg-Tyr; Glu-Tyr-Arg-Leu-Arg-Tyr; Glu-Tyr-Arg-Leu-Tyr-Arg; Lys-Glu-Leu-Gln-Glu-Glu; Lys-Asp-Val-Arg-Tyr-Tyr; Lys-Asp-Val-Lys-Phe-Glu; Lys-Asp-Val-Arg-Phe-Glu; Lys-Asp-Val-Arg-Tyr-Asp; Arg-Tyr-Asn-Val-Tyr-Arg; Arg-Tyr-Gln-Leu-Tyr-Arg; Arg-Tyr-Asn-Val-Tyr-Lys; Arg-Tyr-Gln-Leu-Tyr-Lys; Arg-Glu-Lys-Leu-Tyr-Arg; Gln-Glu-Lys-Leu-Tyr-Arg; Gln-Asp-Lys-Leu-Tyr-Arg; Asn-Asp-Lys-Leu-Tyr-Arg; Lys-Tyr-Val-Tyr-Arg-Asp; Tyr-Arg-Asp-Val-Tyr-Arg; Tyr-Lys-Asp-Val-Tyr-Lys; Tyr-Lys-Glu-Leu-Tyr-Arg; Asp-Asn-Tyr-Val-Tyr-Arg; Asp-Asn-Tyr-Leu-Glu-Arg;
Asp-Asn-Tyr-Leu-Glu-Gln; Arg-Asn-Lys-Asp-Val-Tyr-Arg;
Arg-Gln-Arg-Glu-Leu-Tyr-Arg;
Arg-Asn-Arg-Tyr-Leu-Tyr-Arg;
Arg-Asp-Val-Tyr-Arg-Gln-Asn;
Lys-Asp-Val-Tyr-Arg-Gln-Asn;
Arg-Asp-Val-Tyr-Lys-Gln-Asn;
Asp-Glu-Lys-Glu-Leu-Tyr-Arg; Glu-Glu--Lys-Asp-Val-Tyr-Arg; Asp-Glu-Gln-Glu-Leu-Phe-Arg Gin-Asp-Val-Tyr-Arg-Glu-Asp Gln-Glu-Asn-Asp-Val-Glu-Gln Asn-Asp-Gln-Glu-Leu-Glu-Gln Asn-Asp-Lys-Asp-Val-Asp-Lys Gln-Glu-Asp-Lys-Leu-Tyr-Arg Arg-Glu-Asp-Lys-Leu-Tyr-Arg Arg-Glu-Asp-Arg-Leu-Tyr-Arg Arg-Asp-Glu-Arg-Leu-Tyr-Arg Arg-Glu-Tyr-Arg-Leu-Tyr-Arg Lys-Glu-Tyr-Arg-Leu-Tyr-Arg Lys-Asp-Val-Tyr-Arg-Arg-Tyr Lys-Asp-Val-Tyr-Arg-Lys-Tyr Lys-Asp-Val-Tyr-Arg-Lys-Asp Lys-Glu-Leu-Glu-Arg-Lys-Glu Arg-Asp-Val-Asp-Lys-Lys-Asp Lys-Asp-Leu-Glu-Lys-Lys-Asp Lys-Glu-Leu-Lys-Glu-Lys-Glu Lys-Asp-Leu-Lys-Glu-Lys-Asp Glu-Arg-Lys-Asp-Val-Tyr-Arg Glu-Lys-Lys-Asp-Val-Tyr-Arg Asp-Arg-Lys-Asp-Val-Tyr-Arg Lys-Glu-Leu-Lys-Glu-Tyr-Arg Lys-Asp-Val-Lys-Glu-Tyr-Lys ;
Glu-Lys-Lys-Glu-Leu-Glu-Lys-Lys-Glu;
Glu-Lys-Lys-Glu-Leu-Tyr-Arg-Arg-Tyr ;
Glu-Lys-Lys-Glu-Leu-Arg-Tyr-Tyr-Arg ;
Tyr-Arg-Lys-Asp-Val-Lys-Tyr-Tyr-Arg ;
Glu-Lys-Lys-Glu-Leu-Tyr-Arg-Tyr-Arg ;
Glu-Lys-Lys-Glu-Leu-Tyr-Arg-Glu-Arg ;
Glu-Lys-Lys-Glu-Leu-Tyr-Arg-Glu-Arg ;
Glu-Lys-Lys-Glu-Leu-Glu-Gln-Tyr-Arg ;
Glu-Lys-Lys-Glu-Leu-Glu-Gln-Asp-Asn;
Lys-Glu-Glu-Lys-Leu-Glu-Lys-Lys-Glu ;
Lys-Asp-Asp-Lys-Leu-Tyr-Arg-Gln-Glu ;
Gln-Glu-Asp-Lys-Leu-Tyr-Arg-Gln-Glu;
Gln-Glu-Asp-Lys-Leu-Tyr-Arg-Gln-Glu ;
Arg-Tyr-Leu-Arg-Tyr-Leu-Tyr-Arg ;
Arg-Tyr-Leu-Lys-Glu-Leu-Tyr-Arg ;
Tyr-Arg-Gly-Lys-Glu-Leu-Tyr-Arg ;
Arg-Tyr-Leu-Tyr-Arg-Lys-Asp-Val-Tyr-Arg ; and , Arg-Tyr-Leu-Glu-Lys-Lys-Glu-Leu-Tyr-Arg .
11. A composition having immunotheapeutic activity, comprising:
a peptide compound, or an acid or "base salt thereof, constructed by combination and/or overlap ping of the amino acid sequences : A1 B1 X B2 A2 , A3 B3 X A4 B4 , Bs As X A6 B6 ,
B7 A7 X B8 A8 , A9 B9 , A1 o A1 1 ,
B1 0 A1 2 and/or B1 1 B1 2 , wherein , X is a hydrophobic or neutral amino acid
independently selected from the group
consisting of Ala, D-Ala, Gly, D-Gly, Ile, D-Ile, Leu, D-Leu, Met, D-Met, Phe, D-Phe, Pro, D-Pro, Sar, D-Sar, Ser, D-Ser, Tre, D-Tre, Trp, D-Trp, Val and D-Val; A1 through A12 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, B1 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. Phe, D-Phe, Pro, D-Pro, dehydro Pro, Sar, D-Sar, Tre, D-Tre, Tyr, D-Tyr, Val, D-Val, L-2- aminoglutaryl, D-2-aminoglutaryl, L-2-aminoadiphyl, D-2-aminoadiphyl, L-2-aminopimelyl and
D-2-aminopimelyl; and, a solubilizer for said peptide compound.
12. The composition having immunotherapeutic activity according to Claim 11, wherein said peptide compound is Glu-Arg-Lys-Glu-Leu-Tyr-Arg.
13. The composition having immunotherapeutic activity according to Claim 11, wherein said peptide compound is Tyr-Arg-Lys-Asp-Val-Tyr-Arg.
14. The composition having immunotherapeutic activity according to Claim 11, wherein said peptide compound is Tyr-Arg-Lys-Glu-Leu-Tyr-Arg.
15. The composition having immunotherapeutic activity according to Claim 11, wherein said peptide compound is Glu-Arg-Lys-Asp-Val-Tyr-Arg.
16. The composition having immunotherapeutic activity according to Claim 11, wherein said peptide compound is a member selected from the group
consisting of: Arg-Asp-Lys-Asp-Val-Tyr-Arg;
Lys-Asp-Lys-Asp-Val-Tyr-Lys;
Lys-Glu-Lys-Asp-Val-Tyr-Lys;
Arg-Glu-Arg-Asp-Val-Tyr-Arg;
Lys-Glu-Leu-Tyr-Arg-Lys-Glu;
Lys-Glu-Leu-Glu-Lys-Lys-Glu;
Arg-Glu-Leu-Glu-Arg-Arg-Glu;
Lys-Asp-Val-Asp-Lys-Lys-Asp;
Lys-Asp-Leu-Glu-Lys-Lys-Glu;
Tyr-Arg-Lys-Asp-Val-Tyr-Arg-Lys-Glu;
Tyr-Arg-Lys-Glu-Leu-Glu-Lys-Lys-Glu;
Glu-Lys-Lys-Glu-Leu-Tyr-Arg-Lys-Glu;
Tyr-Arg-Lys-Glu-Leu-Tyr-Arg-Glu-Lys;
Tyr-Arg-Lys-Asp-Val-Tyr-Arg-Lys-Asp-Val-Tyr-Arg;
Glu-Lys-Lys-Glu-Leu-Tyr-Arg-Lys-Glu-Leu-Tyr-Arg; Glu-Arg-Lys-Glu-Leu-Tyr-Arg-Lys-Glu-Leu-Tyr-Arg ;
Figure imgf000044_0001
17. The composition having immunotherapeutic activity according to Claim 11, wherein said peptide compound is a member selected from the group
consisting of: Arg-Lys-Asp-Val-Lys-Tyr; Arg-Lys-Asp-Val-Arg-Tyr; Arg-Lys-Asp-Val-Phe-Glu; Arg-Glu-Glu-Val-Phe-Glu; Arg-Lys-Asp-Val-Tyr-Arg; Arg-Asn-Asp-Val-Tyr-Arg; Arg-Lys-Glu-Leu-Tyr-Arg; Arg-Gln-Glu-Leu-Tyr-Arg Arg-Lys-Asp-Val-Tyr-Lys; Arg-Asn-Asp-Val-Tyr-Lys; Arg-Lys-Glu-Leu-T;yr-Lys; Arg-Gln-Glu-Leu-Tyr-Lys Arg-Lys-Asp-Val-Glu-Arg; Arg-Lys-Glu-Leu-Glu-Arg; Arg-Lys-Glu-Val-Glu-Arg; Arg-Phe-Leu-Tyr-Arg-Asp; Phe-Tyr-Arg-Leu-Arg-Tyr; Glu-Tyr-Arg-Leu-Arg-Tyr; Glu-Tyr-Arg-Leu-Tyr-Arg; Lys-Glu-Leu-Gln-Glu-Glu; Lys-Asp-Val-Arg-Tyr-Tyr; Lys-Asp-Val-Lys-Phe-Glu; Lys-Asp-Val-Arg-Phe-Glu; Lys-Asp-Val-Arg-Tyr-Asp; Arg-Tyr-Asn-Val-Tyr-Arg; Arg-Tyr-Gln-Leu-Tyr-Arg; Arg-Tyr-Asn-Val-Tyr-Lys; Arg-Tyr-Gln-Leu-Tyr-Lys; Arg-Glu-Lys-Leu-Tyr-Arg; Gln-Glu-Lys-Leu-Tyr-Arg; Gln-Asp-Lys-Leu-Tyr-Arg; Asn-Asp-Lys-Leu-Tyr-Arg: Lys-Tyr-Val-Tyr-Arg-Asp; Tyr-Arg-Asp-Val-Tyr-Arg; Tyr-Lys-Asp-Val-Tyr-Lys; Tyr-Lys-Glu-Leu-Tyr-Arg: Asp-Asn-Tyr-Val-Tyr-Arg; Asp-Asn-Tyr-Leu-Glu-Arg Asp-Asn-Tyr-Leu-Glu-Gln; Arg-Asn-Lys-Asp-Val-Tyr-Arg;
Arg-Gln-Arg-Glu-Leu-Tyr-Arg; Arg-Asn-Arg-Tyr-Leu-Tyr-Arg; Arg-Asp-Val-Tyr-Arg-Gln-Asn; Lys-Asp-Val-Tyr-Arg-Gln-Asn; Arg-Asp-Val-Tyr-Lys-Gln-Asn; Asp-Glu-Lys-Glu-Leu-Tyr-Arg; Glu-Glu-Lys-Asp-Val-Tyr-Arg; Asp-Glu-Gln-Glu-Leu-Phe-Arg; Gln-Asp-Val-Tyr-Arg-Glu-Asp; Gln-Glu-Asn-Asp-Val-Glu-Gln; Asn-Asp-Gln-Glu-Leu-Glu-Gln; Asn-Asp-Lys-Asp-Val-Asp-Lys; Gln-Glu-Asp-Lys-Leu-Tyr-Arg; Arg-Glu-Asp-Lys-Leu-Tyr-Arg; Arg-Glu-Asp-Arg-Leu-Tyr-Arg; Arg-Asp-Glu-Arg-Leu-Tyr-Arg; Arg-Glu-Tyr-Arg-Leu-Tyr-Arg; Lys-Glu-Tyr-Arg-Leu-Tyr-Arg; Lys-Asp-Val-Tyr-Arg-Arg-Tyr; Lys-Asp-Val-Tyr-Arg-Lys-Tyr; Lys-Asp-Val-Tyr-Arg-Lys-Asp; Lys-Glu-Leu-Glu-Arg-Lys-Glu; Arg-Asp-Val-Asp-Lys-Lys-Asp; Lys-Asp-Leu-Glu-Lys-Lys-Asp; Lys-Glu-Leu-Lys-Glu-Lys-Glu; Lys-Asp-Leu-Lys-Glu-Lys-Asp;
Glu-Arg-Lys-Asp-Val-Tyr-Arg;
Glu-Lys-Lys-Asp-Val-Tyr-Arg;
Asp-Arg-Lys-Asp-Val-Tyr-Arg;
Lys-Glu-Leu-Lys-Glu-Tyr-Arg;
Lys-Asp-Val-Lys-Glu-Tyr-Lys;
Glu-Lys-Lys-Glu-Leu-Glu-Lys-Lys-Glu;
Glu-Lys-Lys-Glu-Leu-Tyr-Arg-Arg-Tyr;
Glu-Lys-Lys-Glu-Leu-Arg-Tyr-Tyr-Arg:
Tyr-Arg-Lys-Asp-Val-Lys-Tyr-Tyr-Arg;
Glu-Lys-Lys-Glu-Leu-Tyr-Arg-Tyr-Arg:
Glu-Lys-Lys-Glu-Leu-Tyr-Arg-Glu-Arg;
Glu-Lys-Lys-Glu-Leu-Tyr-Arg-Glu-Arg
Glu-Lys-Lys-Glu-Leu-Glu-Gln-Tyr-Arg;
Glu-Lys-Lys-Glu-Leu-Glu-Gln-Asp-Asn;
Lys-Glu-Glu-Lys-Leu-Glu-Lys-Lys-Glu:
Lys-Asp-Asp-Lys-Leu-Tyr-Arg-Gln-Glu;
Gln-Glu-Asp-Lys-Leu-Tyr-Arg-Gln-Glu;
Gln-Glu-Asp-Lys-Leu-Tyr-Arg-Gln-Glu;
Arg-Tyr-Leu-Arg-Tyr-Leu-Tyr-Arg;
Arg-Tyr-Leu-Lys-Glu-Leu-Tyr-Arg;
Tyr-Arg-Gly-Lys-Glu-Leu-Tyr-Arg;
Arg-Tyr-Leu-Tyr-Arg-Lys-Asp-Val-Tyr-Arg; and,
Arg-Tyr-Leu-Glu-Lys-Lys-Glu-Leu-Tyr-Arg.
18. The composition having immunotherapeutic activity according to Claim 11, wherein said peptide compound is incorporated into a polymeric matrix selected from the group consisting of a polyanhydride copolymer, ethylen-vinyl acetate copolymer, lactic acid-glycolic acid copolymer, polyhydroxymethylmetacrilate, polyvinyl alcohol and a combination thereof.
19. The composition having immunotherapeutic activity according to Claim 11, wherein said
solubilizer is a member selected from the group consisting of water, dimethylsulfoxide, propylene glycol, dimethylformamide and a combination thereof.
20. The composition having immunotherapeutic activity according to Claim 11, wherein said
solubilizer is a non-ionic alkylene oxide block copolymer.
21. The composition having immunotherapeutic activity according to Claim 11, further comprising an additive selected from the group consisting of a stabilizer, a viscosifier, a preservative and a combination thereof.
PCT/US1991/008795 1990-11-23 1991-11-22 Synthetic immunoactive peptides having immunomodulating and therapeutic activities WO1992009628A1 (en)

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0670727A1 (en) * 1992-11-13 1995-09-13 Thomas Jefferson University Compounds that inhibit t cell proliferation and methods using the same
WO1996012739A1 (en) * 1994-10-20 1996-05-02 Peptide Therapeutics Limited Immunomodulatory polypeptides
WO1996019494A1 (en) * 1994-12-19 1996-06-27 Biochem Pharma Inc. Peptides having immunomodulatory activity
EP0955311A2 (en) * 1998-04-09 1999-11-10 Idexx Laboratories, Inc. Peptide vaccine for canine allergy
US6017719A (en) * 1994-06-14 2000-01-25 Nexell Therapeutics, Inc. Positive and positive/negative cell selection mediated by peptide release
US6046167A (en) * 1998-03-25 2000-04-04 University Of Cincinnati Peptide YY analogs
US6051683A (en) * 1995-03-02 2000-04-18 Immunotech Developments Inc. Immune regulating peptides and method of obtaining them
US6103699A (en) * 1996-06-07 2000-08-15 Immunotech Developments Inc. Peptide, a method for its preparation and a pharmaceutical composition containing the peptide
WO2000058365A1 (en) * 1999-03-30 2000-10-05 Idexx Laboratories, Inc. Specific binding proteins for treating canine allergy
WO2000058349A1 (en) * 1999-03-30 2000-10-05 Idexx Laboratories, Inc. Peptide vaccine for canine allergy
US6159940A (en) * 1996-02-28 2000-12-12 Immunotech Developments Inc. Method for modulating hemopoiesis
US6734287B1 (en) 1998-04-09 2004-05-11 Idexx Laboratories, Inc. Specific binding proteins for treating canine allergy
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
US9528088B2 (en) 2002-06-28 2016-12-27 Life Technologies Corporation Methods for eliminating at least a substantial portion of a clonal antigen-specific memory T cell subpopulation
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Families Citing this family (1)

* 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

Citations (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
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
US4910296A (en) * 1980-01-18 1990-03-20 Max-Planck-Gesellschaft Zur Foederung Der Wissenschaften E.V. Medicaments containing alpha 1 thymosin fragments and having an immunostimulant action, and fragments of alpha 1 thymosin

Family Cites Families (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
IT1226552B (en) * 1988-07-29 1991-01-24 Ellem Ind Farmaceutica IMMUNOSTIMULANT PEPTIDES.

Patent Citations (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
US4910296A (en) * 1980-01-18 1990-03-20 Max-Planck-Gesellschaft Zur Foederung Der Wissenschaften E.V. Medicaments containing alpha 1 thymosin fragments and having an immunostimulant action, and fragments of alpha 1 thymosin
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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0563212A4 *

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5958882A (en) * 1992-11-13 1999-09-28 Thomas Jefferson University Compounds that inhibit T cell proliferation and methods using the same
EP0670727A1 (en) * 1992-11-13 1995-09-13 Thomas Jefferson University Compounds that inhibit t cell proliferation and methods using the same
EP0670727A4 (en) * 1992-11-13 1997-07-30 Univ Jefferson Compounds that inhibit t cell proliferation and methods using the same.
US6017719A (en) * 1994-06-14 2000-01-25 Nexell Therapeutics, Inc. Positive and positive/negative cell selection mediated by peptide release
WO1996012739A1 (en) * 1994-10-20 1996-05-02 Peptide Therapeutics Limited Immunomodulatory polypeptides
US5980913A (en) * 1994-12-19 1999-11-09 Biochem Pharma, Inc. Peptides having immunomodulatory activity
AU705418B2 (en) * 1994-12-19 1999-05-20 Shire Canada Inc. Peptides having immunomodulatory activity
WO1996019494A1 (en) * 1994-12-19 1996-06-27 Biochem Pharma Inc. Peptides having immunomodulatory activity
US6051683A (en) * 1995-03-02 2000-04-18 Immunotech Developments Inc. Immune regulating peptides and method of obtaining them
US6410515B1 (en) 1995-06-07 2002-06-25 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
US6103699A (en) * 1996-06-07 2000-08-15 Immunotech Developments Inc. Peptide, a method for its preparation and a pharmaceutical composition containing the peptide
US6046167A (en) * 1998-03-25 2000-04-04 University Of Cincinnati Peptide YY analogs
EP0955311A3 (en) * 1998-04-09 2000-08-16 Idexx Laboratories, Inc. Peptide vaccine for canine allergy
EP0955311A2 (en) * 1998-04-09 1999-11-10 Idexx Laboratories, Inc. Peptide vaccine for canine allergy
US6734287B1 (en) 1998-04-09 2004-05-11 Idexx Laboratories, Inc. Specific binding proteins for treating canine allergy
WO2000058349A1 (en) * 1999-03-30 2000-10-05 Idexx Laboratories, Inc. Peptide vaccine for canine allergy
WO2000058365A1 (en) * 1999-03-30 2000-10-05 Idexx Laboratories, Inc. Specific binding proteins for treating canine allergy
US7745144B2 (en) 1999-07-15 2010-06-29 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
US8114406B2 (en) 1999-07-15 2012-02-14 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Peptides and their utility in modulation of behavior of cells expressing α3β1 integrins
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
US9528088B2 (en) 2002-06-28 2016-12-27 Life Technologies Corporation Methods for eliminating at least a substantial portion of a clonal antigen-specific memory T cell subpopulation
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