WO1998052415B1 - Substantially pure zonulin, a physiological modulator of mammalian tight junctions - Google Patents
Substantially pure zonulin, a physiological modulator of mammalian tight junctionsInfo
- Publication number
- WO1998052415B1 WO1998052415B1 PCT/US1998/007636 US9807636W WO9852415B1 WO 1998052415 B1 WO1998052415 B1 WO 1998052415B1 US 9807636 W US9807636 W US 9807636W WO 9852415 B1 WO9852415 B1 WO 9852415B1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- zonulin
- therapeutic agent
- pharmaceutical composition
- composition
- group
- Prior art date
Links
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Abstract
A substantially pure mammalian protein, hereinafter 'zonulin', that is a physiological modulator of mammalian tight junctions is disclosed, as well as methods for the use of the same.
Claims
AMENDED CLAIMS
[received by the International Bureau on 11 December 1998 (11.12.98); original claims 1-42 cancelled; new claims 43-107 added (10 pages)]
Claim 43. Substantially pure zonulin having an apparent molecular weight of about 47 kDa, as determined by SDS-polyacrylamide gel electrophoresis, which is recognized by both anti-tau polyclonal antibody and by anti-ZOT polyclonal antibody, and is capable of reversibly opening mammalian tight junctions, and wherein said zonulin has an N-terminal amino acid sequence selected from the group consisting of:
(1) Asn Gin Arg Pro Pro Pro Ala Gly Val Thr Ala Tyr Asp Tyr Leu Val lie Gin (SEQ ID NO:l);
(2) Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu (SEQ ID NO: 2);
(3) Val Thr Phe Tyr Thr Asp Ala Val Ser (SEQ ID NO: 3) ;
(4) Met Leu Gin Lys Ala Glu Ser Gly Gly Val Leu Val Gin Pro Gly Xaa Ser Asn Arg Leu (SEQ ID NO: 4) ; and
(5) Glu Val Gin Leu Val Glu Ser Gly Gly Xaa Leu (SEQ ID NO:7) .
Claim 44. A pharmaceutical composition for delivery of a therapeutic agent to the intestine comprising:
(A) a therapeutic agent; and
(B) an intestinal absorption enhancing effective amount of purified zonulin, wherein said zonulin has an apparent molecular weight of about 47 kDa, as determined by SDS-polyacrylamide gel electrophoresis, which is recognized by both anti-tau polyclonal antibody and by anti-ZOT polyclonal antibody, and is capable of reversibly opening mammalian tight junctions, and wherein said zonulin has an N-terminal amino acid sequence selected from the group consisting of:
(1) Asn Gin Arg Pro Pro Pro Ala Gly Val Thr Ala Tyr Asp Tyr Leu Val lie Gin (SEQ ID N0:l) ;
(2) Glu Val Gin Leu Val Glu Ser Gly Gly Xaa Leu (SEQ ID NO: 7) ; and
(3) Met Leu Gin Lys Ala Glu Ser Gly Gly Val Leu Val Gin Pro Gly Xaa Ser Asn Arg Leu (SEQ ID NO:4).
Claim 45. The pharmaceutical composition of Claim 44, wherein said therapeutic agent is selected from the group consisting of a drug compound, biologically active peptide and vaccine.
Claim 46. The pharmaceutical composition of Claim 45, wherein said drug compound is selected from the group consisting of an antineoplastic drug and antibiotics.
Claim 47. The pharmaceutical composition of Claim 46, wherein said antineoplastic drug is selected from the group consisting of cytarabine, mitomycin, doxorubicin, vincristine and vinblastine.
Claim 48. The pharmaceutical composition of Claim 46, wherein said antibiotic is selected from the group consisting of methicillin, mezlocillin, piperacillin, cetoxitin, cefonicid, cefmetazole and aztreonam.
Claim 49. The pharmaceutical composition of Claim 45, wherein said biologically active peptide is selected from the group consisting of a hormone, lymphokine, globulin and albumin.
Claim 50. The pharmaceutical composition of Claim 49, wherein said hormone is selected from the group consisting of testosterone, nandrolene, menotropins, insulin and urofolltropin.
Claim 51. The pharmaceutical composition of Claim 49, wherein said lymphokine is selected from the group consisting of interferon-α, interferon-β, interferon-γ, interleukin-1 , interleukin-2 , interleukin-4 and interleukin-8.
Claim 52. The pharmaceutical composition of Claim 49, wherein said globulin is an immunoglobulin selected from the group consisting of polyvalent IgG, and specific IgG, IgA or IgM.
Claim 53. The pharmaceutical composition of Claim 44, wherein the ratio of therapeutic agent to zonulin is in the range of about 1:10 to 3:1.
Claim 54. The pharmaceutical composition of Claim 53 , wherein the ratio of therapeutic agent to zonulin is in the range of about 1:5 to 2:1.
Claim 55. The pharmaceutical composition of Claim 44, wherein zonulin is present in the composition in an amount of from about 40 ng to 1000 ng.
Claim 56. The pharmaceutical composition of Claim 55, wherein zonulin is present in the composition in an amount of from about 400 ng to 800 ng.
Claim 57. The pharmaceutical composition of Claim 44, wherein said composition is an oral dosage composition for intestinal delivery of said therapeutic agent.
Claim 58. A pharmaceutical composition for delivery of a therapeutic agent to the heart comprising:
(A) a therapeutic agent; and
(B) a heart absorption enhancing effective amount of purified zonulin, wherein said zonulin has an apparent molecular weight of about 47 kDa, as determined by SDS-polyacrylamide gel electrophoresis, which is recognized by both anti-tau polyclonal antibody and by anti-ZOT polyclonal antibody, and is capable of reversibly opening mammalian tight junctions, and wherein said zonulin has an N-terminal amino acid sequence Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu (SEQ ID NO: 2) .
Claim 59. The pharmaceutical composition of Claim 58, wherein said therapeutic agent is a drug which acts on the cardiovascular system.
Claim 60. The pharmaceutical composition of Claim 59, wherein said drug which acts on the cardiovascular system is selected from the group consisting of lidocaine, adenosine, dobutamine, dopamine, epinephrine, norepinephrine and phentolamine.
Claim 61. The pharmaceutical composition of Claim 58, wherein the ratio of therapeutic agent to zonulin is in the range of about 1:10 to 3:1.
Claim 62. The pharmaceutical composition of Claim 61, wherein the ratio of therapeutic agent to zonulin is in the range of about 1:5 to 2:1.
Claim 63. The pharmaceutical composition of Claim 58 , wherein zonulin is present in the composition in an amount of from about 40 ng to 1000 ng.
Claim 64. The pharmaceutical composition of Claim 63, wherein zonulin is present in the composition in an amount of from about 400 ng to 800 ng.
Claim 65. A pharmaceutical composition for delivery of a therapeutic agent to the brain comprising:
(A) a therapeutic agent; and
(B) a brain absorption enhancing effective amount of purified zonulin, wherein said zonulin has an apparent molecular weight of about 47 kDa, as determined by SDS-polyacrylamide gel electrophoresis, which is recognized by both anti-tau polyclonal antibody and by anti-ZOT polyclonal antibody, and is capable of reversibly opening mammalian tight junctions, and wherein said zonulin has an N-terminal amino acid sequence Val Thr Phe Tyr Thr Asp Ala Val Ser (SEQ ID NO: 3) .
Claim 66. The pharmaceutical composition of Claim 65, wherein said therapeutic agent is a drug which acts on the central nervous system.
AMENDED SHEET (ARTICLE 1fi)
Claim 67. The pharmaceutical composition of Claim 66, wherein said drug which acts on the central nervous system is selected from the group consisting of doxapram, alfentanil, dezocin, nalbuphine, buprenorphine, naloxone, ketorolac, midazolam, propofol, metacurine, mivacurium and succinylcholine.
Claim 68. The pharmaceutical composition of Claim 65, wherein the ratio of therapeutic agent to zonulin is in the range of about 1:10 to 3:1.
Claim 69. The pharmaceutical composition of Claim 68, wherein the ratio of therapeutic agent to zonulin is in the range of about 1:5 to 2:1.
Claim 70. The pharmaceutical composition of Claim 65, wherein zonulin is present in the composition in an amount of from about 40 ng to 1000 ng.
Claim 71. The pharmaceutical composition of Claim 70, wherein zonulin is present in the composition in an amount of from about 400 ng to 800 ng.
Claim 72. The pharmaceutical composition of Claim 65, wherein said composition is an intravenous dosage composition for delivery of said therapeutic agent through the blood-brain barrier.
Claim 73. A method for delivery of a therapeutic agent comprising administering, to a subject in need thereof, a pharmaceutical composition comprising:
(A) a therapeutic agent; and
(B) an intestinal absorption enhancing effective amount of purified zonulin, wherein said zonulin has an apparent molecular weight of about 47 kDa, as determined by SDS-polyacrylamide gel electrophoresis, which is recognized by both anti-tau polyclonal antibody and by anti-ZOT polyclonal antibody, and is capable of reversibly opening mammalian tight junctions, and wherein said zonulin has an N-terminal amino acid sequence selected from the group consisting, of
(1) Asn Gin Arg Pro Pro Pro Ala Gly Val Thr Ala Tyr Asp Tyr Leu Val lie Gin (SEQ ID NO:l) ;
(2) Glu Val Gin Leu Val Glu Ser Gly Gly Xaa Leu (SEQ ID NO: 7) ; and
(3) Met Leu Gin Lys Ala Glu Ser Gly Gly Val Leu Val Gin Pro Gly Xaa Ser Asn Arg Leu (SEQ ID NO: 4).
Claim 74. The method of Claim 73, wherein said therapeutic agent is selected from the group consisting of a drug compound, biologically active peptide and vaccine.
Claim 75. The method of Claim 74, wherein said drug compound is selected from the group consisting an antineoplastic drug and antibiotics.
Claim 76. The method of Claim 75, wherein said antineoplastic drug is selected from the group consisting of cytarabine, mitomycin, doxorubicin, vincristine and vinblastine.
Claim 77. The method of Claim 75, wherein said antibiotic is selected from the group consisting of methicillin, mezlocillin, piperacillin, cetoxitin, cefonicid, cefmetazole and aztreonam.
Claim 78. The method of Claim 74, wherein said biologically active peptide is selected from the group consisting of a hormone, lymphokine, globulin and albumin.
Claim 79. The method of Claim 78, wherein said hormone is selected from the group consisting of testosterone, nandrolene, menotropins, insulin and urofolltropin.
Claim 80. The method of Claim 78, wherein said lymphokine is selected from the group consisting of interferon-α, interferon-β, interferon-γ, interleukin-1, interleukin-2 , interleukin-4 and interleukin-8.
Claim 81. The method of Claim 78, wherein said globulin is an immunoglobulin selected from the group consisting of polyvalent IgG, and specific IgG, IgA or IgM.
Claim 82. The method of Claim 73, wherein the ratio of therapeutic agent to zonulin is in the range of about 1:10 to 3:1.
Claim 83. The method of Claim 82 , wherein the ratio of therapeutic agent to zonulin is in the range of about 1:5 to 2:1.
Claim 84. The method of Claim 73, wherein zonulin is present in the composition in an amount of from about 40 ng to 1000 ng.
Claim 85. The method of Claim 84, wherein zonulin is present in the composition in an amount of from about 400 ng to 800 ng.
Claim 86. The method of Claim 73, wherein the zonulin is administered in an amount such that the final concentration is in the range of about 10~5 M to 10"14 M.
Claim 87. The method of Claim 86, wherein the zonulin is administered in an amount such that the final concentration is in the range of about 10"6 M to 5.0 x 10"8 M.
Claim 88. The method of Claim 73, wherein said composition is an oral dosage composition for intestinal delivery of said therapeutic agent, and said administering is by oral administration.
Claim 89. A method for delivery of a therapeutic agent comprising administering, to a subject in need thereof, a pharmaceutical composition comprising:
(A) a therapeutic agent; and
(B) a heart absorption enhancing effective amount of purified zonulin, wherein said zonulin has an apparent molecular weight of about 47 kDa, as determined by SDS-polyacrylamide gel electrophoresis, which is recognized by both anti-tau polyclonal antibody and by anti-ZOT polyclonal antibody, and is capable of reversibly opening mammalian tight junctions, and wherein said zonulin has an N-terminal amino. acid sequence Glu Val Gin Leu Val Glu Ser Gly
60
Gly Gly Leu Val Gin Pro Gly Gly Ser Leu Arg Leu (SEQ ID NO:2) .
Claim 90. The method of Claim 89, wherein said therapeutic agent is a drug which acts on the cardiovascular system.
Claim 91. The method of Claim 90, wherein said drug which acts on the cardiovascular system is selected from the group consisting of lidocaine, adenosine, dobutamine, dopamine, epinephrine, norepinephrine and phentolamine.
Claim 92. The method of Claim 89, wherein the ratio of therapeutic agent to zonulin is in the range of about 1:10 to 3:1.
Claim 93. The method of Claim 92 , wherein the ratio of therapeutic agent to zonulin is in the range of about 1:5 to 2:1.
Claim 94. The method of Claim 89, wherein zonulin is present in the composition in an amount of from about 40 ng to 1000 ng.
Claim 95. The method of Claim 94, wherein zonulin is present in the composition in an amount of from about 400 ng to 800 ng.
Claim 96. The method of Claim 89, wherein the zonulin is administered in an amount such that the final concentration is in the range of about 10"5 M to 10"14 M.
Claim 97. The method of Claim 96, wherein the zonulin is administered in an amount such that the final concentration is in the range of about 10"6 M to 5.0 x 10~8 M.
61
Claim 98. A method for delivery of a therapeutic agent comprising administering, to a subject in need thereof, a pharmaceutical composition comprising:
(A) a therapeutic agent; and
(B) a brain absorption enhancing effective amount of purified zonulin, wherein said zonulin has an apparent molecular weight of about 47 kDa, as determined by SDS-polyacrylamide gel electrophoresis, which is recognized by both anti-tau polyclonal antibody and by anti-ZOT polyclonal antibody, and is capable of reversibly opening mammalian tight junctions, and wherein said zonulin has an N-terminal amino acid sequence Val Thr Phe Tyr Thr Asp Ala Val Ser (SEQ ID NO: 3) .
Claim 99. The method of Claim 98, wherein said therapeutic agent is a drug which acts on the central nervous system.
Claim 100. The method of Claim 99, wherein said drug which acts on the central nervous system is selected from the group consisting of doxapram, alfentanil, dezocin, nalbuphine, buprenorphine, naloxone, ketorolac, midazolam, propofol, metacurine, mivacurium and succinylcholine.
Claim 101. The method of Claim 98, wherein the ratio of therapeutic agent to zonulin is in the range of about 1:10 to 3:1.
Claim 102. The method of Claim 101, wherein the ratio of therapeutic agent to zonulin is in the range of about 1:5 to 2:1.
Claim 103. The method of Claim 98, wherein zonulin is present in the composition in an amount of from about 40 ng to 1000 ng.
Claim 104. The method of Claim 103 , wherein zonulin is present in the composition in an amount of from about 400 ng to 800 ng.
62
Claim 105. The method of Claim 98, wherein the zonulin is administered in an amount such that the final concentration is in the range of about 10~5 M to 10"14 M.
Claim 106. The method of Claim 105, wherein the zonulin is administered in an amount such that the final concentration is in the range of about 10"6 M to 5.0 x 10~8 M.
Claim 107. The method of Claim 98, wherein said composition is an intravenous dosage composition for delivery of said therapeutic agent through the blood-brain barrier, and said administering is by intravenous administration.
63
STATEMENT UNDER ARTICLE 19(1)
Claims 1-42 are pending in the International application.
Claims 1-42 are being cancelled. Claims 43-107 are added.
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT98919778T ATE250625T1 (en) | 1997-05-21 | 1998-04-28 | ESSENTIALLY PURE ZONULIN AS A PHYSIOLOGICAL MODULATOR OF ßTIGHT JUNCTIONSß IN MAMMALS |
| JP55036098A JP2001527572A (en) | 1997-05-21 | 1998-04-28 | Substantially pure zonulin, a physiological regulator of mammalian tight junctions |
| DE69818450T DE69818450T2 (en) | 1997-05-21 | 1998-04-28 | IN KEY PURE ZONULIN AS A PHYSIOLOGICAL MODULATOR OF "TIGHT JUNCTIONS" IN MAMMALS |
| DK98919778T DK0982988T3 (en) | 1997-05-21 | 1998-04-28 | Essentially pure zonulin, a physiological modulator of mammalian tight junctions |
| AU72491/98A AU7249198A (en) | 1997-05-21 | 1998-04-28 | Substantially pure zonulin, a physiological modulator of mammalian tight junctions |
| CA002290459A CA2290459A1 (en) | 1997-05-21 | 1998-04-28 | Substantially pure zonulin, a physiological modulator of mammalian tight junctions |
| EP98919778A EP0982988B1 (en) | 1997-05-21 | 1998-04-28 | Substantially pure zonulin, a physiological modulator of mammalian tight junctions |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/859,931 | 1997-05-21 | ||
| US08/859,931 US5945510A (en) | 1997-05-21 | 1997-05-21 | Substantially pure zonulin, a physiological modulator of mammalian tight junctions |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO1998052415A1 WO1998052415A1 (en) | 1998-11-26 |
| WO1998052415B1 true WO1998052415B1 (en) | 1999-02-11 |
Family
ID=25332088
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1998/007636 WO1998052415A1 (en) | 1997-05-21 | 1998-04-28 | Substantially pure zonulin, a physiological modulator of mammalian tight junctions |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US5945510A (en) |
| EP (1) | EP0982988B1 (en) |
| JP (2) | JP2001527572A (en) |
| AT (1) | ATE250625T1 (en) |
| AU (1) | AU7249198A (en) |
| CA (1) | CA2290459A1 (en) |
| DE (1) | DE69818450T2 (en) |
| DK (1) | DK0982988T3 (en) |
| ES (1) | ES2209133T3 (en) |
| WO (1) | WO1998052415A1 (en) |
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| US5908825A (en) * | 1997-01-09 | 1999-06-01 | University Of Maryland At Baltimore | Dosage composition for nasal delivery and method of use of the same |
| US6458925B1 (en) * | 1998-08-03 | 2002-10-01 | University Of Maryland, Baltimore | Peptide antagonists of zonulin and methods for use of the same |
| US6733762B1 (en) | 1998-09-14 | 2004-05-11 | University Of Maryland, Baltimore | Method of using Zot to inhibit lymphocyte proliferation in an antigen-specific manner |
| RU2214271C2 (en) * | 1998-09-14 | 2003-10-20 | Юниверсити Оф Мэриленд, Балтимор | Method for application of zot and zonulin for inhibition of antigen-specific proliferation of lymphocytes |
| KR100619612B1 (en) | 1999-10-04 | 2006-09-01 | 넥타르 테라퓨틱스 에이엘, 코포레이션 | Polymer stabilized neuropeptides |
| US7026294B2 (en) * | 2000-05-19 | 2006-04-11 | University Of Maryland | Method of use of peptide antagonists of zonulin to prevent or delay the onset of diabetes |
| US7034036B2 (en) * | 2000-10-30 | 2006-04-25 | Pain Therapeutics, Inc. | Inhibitors of ABC drug transporters at the blood-brain barrier |
| EP1384469A1 (en) * | 2002-07-25 | 2004-01-28 | Cognis France S.A. | Method for protecting and for modulating tight junctions |
| EP1384468A1 (en) * | 2002-07-25 | 2004-01-28 | Cognis France S.A. | Method for protecting and for modulating tight junctions |
| AU2004259705B2 (en) * | 2003-07-15 | 2009-04-23 | University Of Maryland, Baltimore | Agonist polypeptide of receptor for zot and zonulin |
| US20080038843A1 (en) * | 2006-08-11 | 2008-02-14 | University Of Maryland - Baltimore | Method of diagnosing celiac disease |
| AR053661A1 (en) * | 2005-01-14 | 2007-05-16 | Univ Maryland | PEPTIDE TO DELIVER VACCINES VIA MUCOSAS |
| TW200716159A (en) * | 2005-06-09 | 2007-05-01 | Univ Maryland | Method of use of antagonists of zonulin to prevent the loss of or to regenerate pancreatic cells |
| CA2638914C (en) | 2006-02-09 | 2014-04-08 | Alba Therapeutics Corporation | Formulations for a tight junction effector |
| US20070239520A1 (en) * | 2006-03-31 | 2007-10-11 | Devin Collins | Motivational apparatus and method of motivation |
| US20090069247A1 (en) * | 2006-10-06 | 2009-03-12 | Blake Paterson | Use of tight junction antagonists to treat inflammatory bowel disease |
| US8034776B2 (en) * | 2006-10-26 | 2011-10-11 | Alba Therapeutics Corporation | Materials and methods for the treatment of celiac disease |
| EP2091551B1 (en) * | 2006-11-03 | 2020-01-15 | Alba Therapeutics Corporation | Method of treating asthma |
| US8728491B2 (en) * | 2007-05-07 | 2014-05-20 | Alba Therapeutics Corporation | Transcutaneous delivery of therapeutic agents |
| US20110201543A1 (en) * | 2007-06-29 | 2011-08-18 | Blake Paterson | Use of tight junction antagonists in the treatment of acute lung injury and acute respiratory distress |
| US8198233B2 (en) | 2007-07-26 | 2012-06-12 | Alba Therapeutics Corporation | Synthetic peptides that enhance tight junction permeability |
| KR102061486B1 (en) | 2012-03-19 | 2020-01-03 | 시다라 세라퓨틱스, 인코포레이티드 | Dosing regimens for echinocandin class compounds |
| WO2016190310A1 (en) * | 2015-05-26 | 2016-12-01 | 国立大学法人名古屋大学 | Tight junction mitigator, drug absorption auxiliary comprising same, and medicinal composition comprising same |
| EP3579863A4 (en) | 2017-02-10 | 2020-11-11 | 9 Meters Biopharma, Inc. | Compositions and methods for treating or preventing environmental enteropathy |
| WO2019165346A1 (en) | 2018-02-23 | 2019-08-29 | Innovate Biopharmaceuticals, Inc. | Compounds and methods for treating tight junction permeability |
Family Cites Families (1)
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| US5665389A (en) * | 1995-05-24 | 1997-09-09 | University Of Maryland At Baltimore | Oral dosage composition for intestinal delivery and method of treating diabetes |
-
1997
- 1997-05-21 US US08/859,931 patent/US5945510A/en not_active Expired - Lifetime
-
1998
- 1998-04-28 CA CA002290459A patent/CA2290459A1/en not_active Abandoned
- 1998-04-28 AU AU72491/98A patent/AU7249198A/en not_active Abandoned
- 1998-04-28 EP EP98919778A patent/EP0982988B1/en not_active Expired - Lifetime
- 1998-04-28 JP JP55036098A patent/JP2001527572A/en not_active Ceased
- 1998-04-28 WO PCT/US1998/007636 patent/WO1998052415A1/en active IP Right Grant
- 1998-04-28 AT AT98919778T patent/ATE250625T1/en not_active IP Right Cessation
- 1998-04-28 DE DE69818450T patent/DE69818450T2/en not_active Expired - Lifetime
- 1998-04-28 ES ES98919778T patent/ES2209133T3/en not_active Expired - Lifetime
- 1998-04-28 DK DK98919778T patent/DK0982988T3/en active
-
2005
- 2005-04-27 JP JP2005130614A patent/JP2005290008A/en not_active Withdrawn
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