U.S. patent application number 14/243681 was filed with the patent office on 2014-10-02 for transcutaneous delivery of therapeutic agents.
This patent application is currently assigned to Alba Therapeutics Corporation. The applicant listed for this patent is Alba Therapeutics Corporation. Invention is credited to Blake Paterson, Dorothea Sesardic.
Application Number | 20140294894 14/243681 |
Document ID | / |
Family ID | 40351379 |
Filed Date | 2014-10-02 |
United States Patent
Application |
20140294894 |
Kind Code |
A1 |
Sesardic; Dorothea ; et
al. |
October 2, 2014 |
TRANSCUTANEOUS DELIVERY OF THERAPEUTIC AGENTS
Abstract
The present invention provides materials and methods to
facilitate the transcutaneous delivery of therapeutic agents. In
some embodiments, agonists of tight junctions are used in
compositions to facilitate the uptake of therapeutic agents from
the skin. In a particular embodiment, the present invention
provides immunogenic compositions comprising a tight junction
agonist and an antigen. In a particular embodiment, the present
invention provides vaccine compositions comprising a tight junction
agonist and an antigen.
Inventors: |
Sesardic; Dorothea; (London,
GB) ; Paterson; Blake; (Baltimore, MD) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Alba Therapeutics Corporation |
Baltimore |
MD |
US |
|
|
Assignee: |
Alba Therapeutics
Corporation
Baltimore
MD
|
Family ID: |
40351379 |
Appl. No.: |
14/243681 |
Filed: |
April 2, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12599430 |
Jan 11, 2011 |
8728491 |
|
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PCT/US08/62894 |
May 7, 2008 |
|
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14243681 |
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60991058 |
Nov 29, 2007 |
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60916503 |
May 7, 2007 |
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Current U.S.
Class: |
424/209.1 ;
424/184.1; 424/212.1; 424/219.1; 424/232.1; 424/245.1; 424/246.1;
424/247.1; 424/254.1; 424/256.1; 514/21.6; 514/21.7; 514/21.8;
514/5.9 |
Current CPC
Class: |
A61K 39/145 20130101;
A61K 39/07 20130101; A61K 2039/54 20130101; A61P 31/20 20180101;
A61K 39/295 20130101; C07K 4/04 20130101; A61K 39/08 20130101; A61P
3/10 20180101; A61K 39/05 20130101; A61K 2039/55516 20130101; A61K
39/165 20130101; A61P 37/04 20180101; A61K 39/102 20130101; C07K
7/06 20130101; A61K 39/099 20130101; A61K 38/03 20130101; A61K
39/285 20130101; A61P 31/04 20180101; A61K 39/20 20130101; A61P
31/14 20180101; A61K 38/28 20130101; A61P 31/16 20180101; A61K
39/39 20130101; A61K 38/00 20130101; C07K 4/00 20130101; A61K 38/08
20130101; A61P 31/12 20180101; C07K 4/06 20130101 |
Class at
Publication: |
424/209.1 ;
514/5.9; 424/212.1; 424/219.1; 424/245.1; 424/254.1; 424/247.1;
424/246.1; 424/256.1; 424/232.1; 514/21.8; 514/21.7; 514/21.6;
424/184.1 |
International
Class: |
C07K 7/06 20060101
C07K007/06; A61K 39/165 20060101 A61K039/165; A61K 39/20 20060101
A61K039/20; A61K 39/05 20060101 A61K039/05; A61K 39/02 20060101
A61K039/02; A61K 38/08 20060101 A61K038/08; A61K 39/07 20060101
A61K039/07; A61K 39/102 20060101 A61K039/102; A61K 39/285 20060101
A61K039/285; A61K 39/145 20060101 A61K039/145; C07K 4/00 20060101
C07K004/00; A61K 38/03 20060101 A61K038/03; A61K 38/28 20060101
A61K038/28; A61K 39/08 20060101 A61K039/08 |
Claims
1. A transcutaneous dosage composition comprising a therapeutic
agent and a transcutaneous absorption enhancing amount of a tight
junction agonist, wherein the tight junction agonist is a peptide
comprising an amino acid sequence selected from the group
consisting of: TABLE-US-00003 (a) (SEQ ID NO: 1) Phe Cys Ile Gly
Arg Leu; (b) (SEQ ID NO: 2) Xaa1 Cys Ile Gly Arg Leu; (c) (SEQ ID
NO: 3) Phe Xaa2 Ile Gly Arg Leu; (d) (SEQ ID NO: 4) Phe Cys Xaa3
Gly Arg Leu; (e) (SEQ ID NO: 5) Phe Cys Ile Xaa4 Arg Leu; (f) (SEQ
ID NO: 6) Phe Cys Ile Gly Xaa5 Leu; (g) (SEQ ID NO: 7) Phe Cys Ile
Gly Arg Xaa6; (h) (SEQ ID NO: 8) Xaa1 Xaa2 Ile Gly Arg Leu; (i)
(SEQ ID NO: 9) Xaa1 Cys Xaa3 Gly Arg Leu; (j) (SEQ ID NO: 10) Xaa1
Cys Ile Xaa4 Arg Leu; (k) (SEQ ID NO: 11) Xaa1 Cys Ile Gly Xaa5
Leu; (l) (SEQ ID NO: 12) Xaa1 Cys Ile Gly Arg Xaa6; (m) (SEQ ID NO:
13) Phe Xaa2 Xaa3 Gly Arg Leu; (n) (SEQ ID NO: 14) Phe Xaa2 Ile
Xaa4 Arg Leu; (o) (SEQ ID NO: 15) Phe Xaa2 Ile Gly Xaa5 Leu; (p)
(SEQ ID NO: 16) Phe Xaa2 Ile Gly Arg Xaa6; (q) (SEQ ID NO: 17) Phe
Cys Xaa3 Xaa4 Arg Leu; (r) (SEQ ID NO: 18) Phe Cys Xaa3 Gly Xaa5
Leu; (s) (SEQ ID NO: 19) Phe Cys Xaa3 Gly Arg Xaa6; (t) (SEQ ID NO:
20) Phe Cys Ile Xaa4 Xaa5 Leu; (u) (SEQ ID NO: 21) Phe Cys Ile Xaa4
Arg Xaa6; and (v) (SEQ ID NO: 22) Phe Cys Ile Gly Xaa5 Xaa6,
wherein Xaa1 is selected from the group consisting of Ala, Val,
Leu, Ile, Pro, Trp, Tyr, and Met; Xaa2 is selected from the group
consisting of Gly, Ser, Thr, Tyr, Asn, and Gln; Xaa3 is selected
from the group consisting of Ala, Val, Leu, Ile, Pro, Trp, and Met;
Xaa4 is selected from the group consisting of Gly, Ser, Thr, Tyr,
Asn, Ala, and Gln: Xaa5 is selected from the group consisting of
Lys and His; Xaa6 is selected from the group consisting of Ala,
Val, Leu, Ile, Pro, Trp, and Met.
2. The dosage composition of claim 1, wherein the peptide comprises
from about 6 to about 10 amino acid residues.
3. The dosage composition of claim 1, wherein the therapeutic agent
is selected from the group consisting of antibiotics,
anti-inflammatories, analgesics, insulin, vaccines, small
molecules, peptides, proteins, lipids, carbohydrates, and
combinations thereof.
4. The dosage composition of claim 1, wherein the composition is in
a form selected form the group consisting of an aqueous solution
and a saline solution.
5. The dosage composition of claim 1, wherein the composition
further comprises one or more pharmaceutically acceptable
excipients.
6. The dosage composition of claim 1, wherein the therapeutic agent
is an antigen.
7. The dosage composition of claim 6, wherein the antigen is
selected from the group consisting of measles virus antigens, mumps
virus antigens, rubella virus antigens, Corynebacterium diphtherias
antigens, Bordetella pertussis antigens, Clostridium tetani
antigens, Bacillus anthracis antigens, Haemophilus influenzae
antigens, smallpox virus antigens, and influenza virus
antigens.
8. The dosage composition of claim 6 further comprising an
adjuvant.
9. A method of treating an animal, comprising: administering to the
animal's skin the dosage composition of claim 1.
10. The method of claim 8, wherein the animal is human.
11. A method of treating diabetes in an animal in need thereof,
comprising: administering to the animal's skin the dosage
composition of claim 1, wherein said therapeutic agent is insulin
and/or a derivative thereof.
12. The method of claim 11, wherein the animal is human.
13. A method of inducing an immune response in an animal in need
thereof, comprising: administering to the animal's skin the dosage
composition of claim 6.
14. The method of claim 13, wherein the animal is human.
15. A method of inducing a protective immune response in an animal
in need thereof, comprising: administering to the animal's skin the
dosage composition of claim 6.
16. The method of claim 15, wherein the animal is human.
Description
STATEMENT CONCERNING RELATED APPLICATIONS
[0001] This application claims benefit of 35 U.S.C. section 119(e)
based on copending U.S. Provisional Applications Ser. No.
60/916,503, and 60/991,058, filed May 7, 2007, and Nov. 29, 2007
respectively, and herein incorporated by reference in their
entireties.
FIELD OF THE INVENTION
[0002] The present invention provides materials and methods to
facilitate the transcutaneous delivery of therapeutic agents. In
some embodiments, agonists of biological pathways responsible for
opening and closing tight junctions (e.g., tight junction agonists,
zonulin agonists, ZOT agonists) are used in compositions to
facilitate the uptake of therapeutic agents across the skin.
BACKGROUND OF THE INVENTION
[0003] The skin provides a protective barrier against deleterious
materials present in the environment. Since the skin has a large
surface area and is readily accessible, it has been used as the
site of therapeutic delivery. Administration to the skin avoids the
difficulties of other routes of administration, for example, the
acid environment of the stomach encountered when oral
administration is used or the pain associated with piercing the
skin in parenteral administration. Numerous examples of
transcutaneous delivery systems are known in the art, for example,
U.S. Pat. Nos. 7,201,919, 7,097,853, and 6,946,144 all disclose
various compositions and devices for transcutaneous administration
of agents. There remains a need in the art for methods and
compositions to improve the uptake of therapeutic agents from the
skin. This need and others are met by the present invention.
SUMMARY OF THE INVENTION
[0004] In one embodiment, the present invention provides
transcutaneous dosage compositions. Such compositions may comprise
one or more therapeutic agents and a transcutaneous absorption
enhancing amount of one or more tight junction agonists. As used
herein, a "tight junction agonist" is a compound that mediates or
facilitates or augments the physiological, transient opening of
tight junctions, for example, the tight junctions between adjacent
epithelial cells. An example of a tight junction agonist is zonula
occludens toxin (ZOT), which is produced by Vibrio cholerae. A ZOT
receptor agonist is a compound which is believed to mediate tight
junction opening through the same receptor utilized by ZOT. In
another embodiment, a tight junction agonist may comprise zonulin.
In some embodiments, a tight junction agonist may comprise a
peptide. In some embodiments, a tight junction agonist may be a
fragment of ZOT and/or zonulin. In some embodiments, a tight
junction agonist comprising a peptide may comprise the amino acid
sequence FCIGRL (SEQ ID NO:1). A tight junction agonist comprising
a peptide may comprise from about 6 to about 50 amino acids, from
about 6 to about 25 amino acids, or from about 6 to about 10 amino
acids.
[0005] A transcutaneous dosage composition according to the
invention may comprise one or more therapeutic agents. Examples of
suitable therapeutic agents include, but are not limited to,
antibiotics, anti-inflammatories, analgesics, insulin and vaccines.
Therapeutic agents for use in the invention may be of any type
known to those of skill in the art, for example, small molecules,
peptides, proteins, lipids, carbohydrates, and combinations
thereof.
[0006] Transcutaneous dosage compositions of the invention may be
liquids (e.g., aqueous solutions, emulsions, suspensions and the
like). In some embodiments, a transcutaneous dosage composition may
be an aqueous solution, for example, a saline solution.
[0007] Transcutaneous dosage compositions of the invention may also
comprise one or more pharmaceutically acceptable excipients.
Typical excipients that may be included in the compositions of the
invention include, but are not limited to, sugars, salts, buffer
salts, stabilizers, surfactants, polymers, preservatives and the
like. Any pharmaceutically acceptable excipient known to those of
skill in the art may be used.
[0008] An example of a transcutaneous dosage composition of the
invention is an aqueous solution comprising a tight junction
agonist comprising a peptide comprising the sequence FCIGRL and
also comprising at least one antigen.
[0009] The present invention also provides methods for treating
animals (e.g., mammals including humans) by administering to the
animal's skin a composition comprising one or more therapeutic
agents and a transcutaneous absorption enhancing amount of one or
more tight junction agonist. An example of a method of treating an
animal is a method treating diabetes in an animal (e.g., a mammal
such as a human) in need thereof, comprising administering to the
animal's skin a composition comprising insulin and/or an insulin
derivative and a transcutaneous absorption enhancing amount of one
or more tight junction agonist. Compositions for use in methods of
the invention may be liquids or aqueous solutions and may comprise
one or more pharmaceutically acceptable excipients as described
above.
[0010] In one embodiment, the present invention provides a method
of inducing an immune response against an antigen in a mammal
comprising administering a peptide having amino acid sequence
FCIGRL (SEQ ID NO: 1) or a functional derivative thereof and the
antigen to the skin of the animal, wherein the mammal raises the
immune response against the antigen. Compositions for use in
methods of inducing an immune response may further comprise one or
more adjuvants (i.e., compounds that promote an enhanced immune
response).
[0011] The present invention also provides immunogenic
compositions. Such compositions may comprise one or more antigens
and a transcutaneous absorption enhancing amount of one or more
tight junction agonists. Examples of antigens that may be included
in immunogenic compositions of the invention include, but are not
limited to, measles virus antigens, mumps virus antigens, rubella
virus antigens, Corynebacterium diphtheriae antigens, Bordetella
pertussis antigens, Clostridium tetani antigens, Bacillus anthracis
antigens, Haemophilus influenzae antigens, smallpox virus antigens,
and influenza virus antigens. Such compositions may further
comprise one or more adjuvants. Immunogenic compositions of the
invention may be liquids and may comprise one or more
pharmaceutically acceptable excipients as described above.
[0012] In another embodiment, the present invention provides
compositions and methods for the transcutaneous delivery of
vaccines. Vaccines of the invention may be formulated for
transcutaneous delivery. Such vaccines may comprise one or more
antigens and a transcutaneous absorption enhancing amount of one or
more tight junction agonists (e.g., a ZOT receptor agonist). Any
antigen capable of inducing a protective immune response may be
used in the vaccines of the invention. Examples of suitable
antigens include, but are not limited to, measles virus antigens,
mumps virus antigens, rubella virus antigens, Corynebacterium
diphtheriae antigens, Bordetella pertussis antigens, Clostridium
tetani antigens, Bacillus anthracis antigens, Haemophilus
influenzae antigens, smallpox virus antigens, and influenza virus
antigens. Such vaccines may further comprise one or more adjuvants.
Vaccines of the invention may be liquids and may comprise one or
more pharmaceutically acceptable excipients as described above.
[0013] In particular embodiments the present invention
provides:
[0014] A transcutaneous dosage composition, comprising: one or more
therapeutic agents; and a transcutaneous absorption enhancing
amount of one or more tight junction agonists.
[0015] A transcutaneous dosage composition, comprising: one or more
therapeutic agents; and a transcutaneous absorption enhancing
amount of one or more tight junction agonists, wherein at least one
agonist comprises a peptide.
[0016] A transcutaneous dosage composition, comprising: one or more
therapeutic agents; and a transcutaneous absorption enhancing
amount of one or more tight junction agonists, wherein at least one
agonist comprises a peptide comprising the sequence FCIGRL.
[0017] A transcutaneous dosage composition, comprising: one or more
therapeutic agents; and a transcutaneous absorption enhancing
amount of one or more tight junction agonists, wherein at least one
agonist comprises a peptide comprising a sequence selected from the
group consisting of Xaa1 Cys Ile Gly Arg Leu (SEQ ID NO: 2), Phe
Xaa2 Ile Gly Arg Leu (SEQ ID NO: 3), Phe Cys Xaa3 Gly Arg Leu (SEQ
ID NO: 4), Phe Cys Ile Xaa4 Arg Leu (SEQ ID NO: 5), Phe Cys Ile Gly
Xaa5 Leu (SEQ ID NO: 6), and Phe Cys Ile Gly Arg Xaa6 (SEQ ID NO:
7), wherein Xaa1 is selected from the group consisting of Ala, Val,
Leu, Ile, Pro, Trp, Tyr, and Met; Xaa2 is selected from the group
consisting of Gly, Ser, Thr, Tyr, Asn, and Gln; Xaa3 is selected
from the group consisting of Ala, Val, Leu, Ile, Pro, Trp, and Met;
Xaa4 is selected from the group consisting of Gly, Ser, Thr, Tyr,
Asn, Ala, and Gln; Xaa5 is selected from the group consisting of
Lys and His; Xaa6 is selected from the group consisting of Ala,
Val, Leu, Ile, Pro, Trp, and Met.
[0018] A transcutaneous dosage composition, comprising: one or more
therapeutic agents; and a transcutaneous absorption enhancing
amount of one or more tight junction agonists, wherein at least one
agonist comprises a peptide comprising a sequence selected from the
group consisting of Xaa1 Xaa2 Ile Gly Arg Leu (SEQ ID NO: 8), Xaa1
Cys Xaa3 Gly Arg Leu (SEQ ID NO: 9), Xaa1 Cys Ile Xaa4 Arg Leu (SEQ
ID NO: 10), Xaa1 Cys Ile Gly Xaa5 Leu (SEQ ID NO: 11), Xaa1 Cys Ile
Gly Arg Xaa6 (SEQ ID NO: 12), Phe Xaa2 Xaa3 Gly Arg Leu (SEQ ID NO:
13), Phe Xaa2 Ile Xaa4 Arg Leu (SEQ ID NO: 14), Phe Xaa2 Ile Gly
Xaa5 Leu (SEQ ID NO: 15), Phe Xaa2 Ile Gly Arg Xaa6 (SEQ ID NO:
16), Phe Cys Xaa3 Xaa4 Arg Leu (SEQ ID NO: 17), Phe Cys Xaa3 Gly
Xaa5 Leu (SEQ ID NO: 18), Phe Cys Xaa3 Gly Arg Xaa6 (SEQ ID NO:
19), Phe Cys Ile Xaa4 Xaa5 Leu (SEQ ID NO: 20), Phe Cys Ile Xaa4
Arg Xaa6 (SEQ ID NO: 21), and Phe Cys Ile Gly Xaa5 Xaa6 (SEQ ID NO:
22), wherein Xaa1 is selected from the group consisting of Ala,
Val, Leu, Ile, Pro, Trp, Tyr, and Met; Xaa2 is selected from the
group consisting of Gly, Ser, Thr, Tyr, Asn, and Gln; Xaa3 is
selected from the group consisting of Ala, Val, Leu, Ile, Pro, Trp,
and Met; Xaa4 is selected from the group consisting of Gly, Ser,
Thr, Tyr, Asn, Ala, and Gln; Xaa5 is selected from the group
consisting of Lys and His; Xaa6 is selected from the group
consisting of Ala, Val, Leu, Ile, Pro, Trp, and Met.
[0019] A transcutaneous dosage composition, comprising: one or more
therapeutic agents; and a transcutaneous absorption enhancing
amount of one or more tight junction agonists, wherein at least one
agonist comprises a peptide comprising from about 6 to about 10
amino acids.
[0020] A transcutaneous dosage composition, comprising: one or more
therapeutic agents; and a transcutaneous absorption enhancing
amount of one or more tight junction agonists, wherein at least one
therapeutic agent is selected from the group consisting of
antibiotics, anti-inflammatories, analgesics, insulin and
vaccines.
[0021] A transcutaneous dosage composition, comprising: one or more
therapeutic agents; and a transcutaneous absorption enhancing
amount of one or more tight junction agonists, wherein at least one
therapeutic agent is selected from the group consisting of small
molecules, peptides, proteins, lipids, carbohydrates, and
combinations thereof.
[0022] A transcutaneous dosage composition, comprising: one or more
therapeutic agents; and a transcutaneous absorption enhancing
amount of one or more tight junction agonists, wherein the
composition is in aqueous solution.
[0023] A transcutaneous dosage composition, comprising: one or more
therapeutic agents; and a transcutaneous absorption enhancing
amount of one or more tight junction agonists, wherein the
composition is in a saline solution.
[0024] A transcutaneous dosage composition, comprising: one or more
therapeutic agents; and a transcutaneous absorption enhancing
amount of one or more tight junction agonists, wherein the
composition further comprises one or more pharmaceutically
acceptable excipients.
[0025] A transcutaneous dosage composition, comprising: one or more
therapeutic agents; and a transcutaneous absorption enhancing
amount of one or more tight junction agonists, wherein the tight
junction agonist is a peptide comprising the sequence FCIGRL and
the composition is in aqueous solution and the composition
comprises one or more therapeutic agents selected from the group
consisting of small molecules, peptides, proteins, lipids, and
carbohydrates and combinations thereof.
[0026] A method of treating an animal, comprising: administering to
the animal's skin a composition comprising one or more therapeutic
agents and a transcutaneous absorption enhancing amount of a tight
junction agonist.
[0027] A method of treating an animal, comprising: administering to
the animal's skin a composition comprising one or more therapeutic
agents and a transcutaneous absorption enhancing amount of a tight
junction agonist, wherein the animal is a mammal.
[0028] A method of treating an animal, comprising: administering to
the animal's skin a composition comprising one or more therapeutic
agents and a transcutaneous absorption enhancing amount of a tight
junction agonist, wherein the animal is a human.
[0029] A method of treating an animal, comprising: administering to
the animal's skin a composition comprising one or more therapeutic
agents and a transcutaneous absorption enhancing amount of a tight
junction agonist, wherein at least one agonist comprises a
peptide.
[0030] A method of treating an animal, comprising: administering to
the animal's skin a composition comprising one or more therapeutic
agents and a transcutaneous absorption enhancing amount of a tight
junction agonist, wherein at least one agonist comprises a peptide
comprising the sequence FCIGRL.
[0031] A method of treating an animal, comprising: administering to
the animal's skin a composition comprising one or more therapeutic
agents and a transcutaneous absorption enhancing amount of a tight
junction agonist, wherein at least one agonist comprises a peptide
comprising a sequence selected from the group consisting of Xaa1
Cys Ile Gly Arg Leu (SEQ ID NO: 2), Phe Xaa2 Ile Gly Arg Leu (SEQ
ID NO: 3), Phe Cys Xaa3 Gly Arg Leu (SEQ ID NO: 4), Phe Cys Ile
Xaa4 Arg Leu (SEQ ID NO: 5), Phe Cys Ile Gly Xaa5 Leu (SEQ ID NO:
6), and Phe Cys Ile Gly Arg Xaa6 (SEQ ID NO: 7), wherein Xaa1 is
selected from the group consisting of Ala, Val, Leu, Ile, Pro, Trp,
Tyr, and Met; Xaa2 is selected from the group consisting of Gly,
Ser, Thr, Tyr, Asn, and Gln; Xaa3 is selected from the group
consisting of Ala, Val, Leu, Ile, Pro, Trp, and Met; Xaa4 is
selected from the group consisting of Gly, Ser, Thr, Tyr, Asn, Ala,
and Gln; Xaa5 is selected from the group consisting of Lys and His;
Xaa6 is selected from the group consisting of Ala, Val, Leu, Ile,
Pro, Trp, and Met.
[0032] A method of treating an animal, comprising: administering to
the animal's skin a composition comprising one or more therapeutic
agents and a transcutaneous absorption enhancing amount of a tight
junction agonist, wherein at least one agonist comprises a peptide
comprising a sequence selected from the group consisting of Xaa1
Xaa2 Ile Gly Arg Leu (SEQ ID NO: 8), Xaa1 Cys Xaa3 Gly Arg Leu (SEQ
ID NO: 9), Xaa1 Cys Ile Xaa4 Arg Leu (SEQ ID NO: 10), Xaa1 Cys Ile
Gly Xaa5 Leu (SEQ ID NO: 11), Xaa1 Cys Ile Gly Arg Xaa6 (SEQ ID NO:
12), Phe Xaa2 Xaa3 Gly Arg Leu (SEQ ID NO: 13), Phe Xaa2 Ile Xaa4
Arg Leu (SEQ ID NO: 14), Phe Xaa2 Ile Gly Xaa5 Leu (SEQ ID NO: 15),
Phe Xaa2 Ile Gly Arg Xaa6 (SEQ ID NO: 16), Phe Cys Xaa3 Xaa4 Arg
Leu (SEQ ID NO: 17), Phe Cys Xaa3 Gly Xaa5 Leu (SEQ ID NO: 18), Phe
Cys Xaa3 Gly Arg Xaa6 (SEQ ID NO: 19), Phe Cys Ile Xaa4 Xaa5 Leu
(SEQ ID NO: 20), Phe Cys Ile Xaa4 Arg Xaa6 (SEQ ID NO: 21), and Phe
Cys Ile Gly Xaa5 Xaa6 (SEQ ID NO: 22), wherein Xaa1 is selected
from the group consisting of Ala, Val, Leu, Ile, Pro, Trp, Tyr, and
Met; Xaa2 is selected from the group consisting of Gly, Ser, Thr,
Tyr, Asn, and Gln; Xaa3 is selected from the group consisting of
Ala, Val, Leu, Ile, Pro, Trp, and Met; Xaa4 is selected from the
group consisting of Gly, Ser, Thr, Tyr, Asn, Ala, and Gln; Xaa5 is
selected from the group consisting of Lys and His; Xaa6 is selected
from the group consisting of Ala, Val, Leu, Ile, Pro, Trp, and
Met.
[0033] A method of treating an animal, comprising: administering to
the animal's skin a composition comprising one or more therapeutic
agents and a transcutaneous absorption enhancing amount of a tight
junction agonist, wherein at least one agonist comprises a peptide
comprising from about 6 to about 10 amino acids.
[0034] A method of treating an animal, comprising: administering to
the animal's skin a composition comprising one or more therapeutic
agents and a transcutaneous absorption enhancing amount of a tight
junction agonist, wherein at least one therapeutic agent is
selected from the group consisting of antibiotics,
anti-inflammatories, analgesics, insulin and vaccines.
[0035] A method of treating an animal, comprising: administering to
the animal's skin a composition comprising one or more therapeutic
agents and a transcutaneous absorption enhancing amount of a tight
junction agonist, wherein at least one therapeutic agent is
selected from the group consisting of small molecules, peptides,
proteins, lipids, carbohydrates, and combinations thereof.
[0036] A method of treating an animal, comprising: administering to
the animal's skin a composition comprising one or more therapeutic
agents and a transcutaneous absorption enhancing amount of a tight
junction agonist, wherein the composition is in aqueous
solution.
[0037] A method of treating an animal, comprising: administering to
the animal's skin a composition comprising one or more therapeutic
agents and a transcutaneous absorption enhancing amount of a tight
junction agonist, wherein the composition is in a saline
solution.
[0038] A method of treating an animal, comprising: administering to
the animal's skin a composition comprising one or more therapeutic
agents and a transcutaneous absorption enhancing amount of a tight
junction agonist, wherein the composition further comprises one or
more pharmaceutically acceptable excipients.
[0039] A method of treating an animal, comprising: administering to
the animal's skin a composition comprising one or more therapeutic
agents and a transcutaneous absorption enhancing amount of a tight
junction agonist, wherein the tight junction agonist is a peptide
comprising the sequence FCIGRL and the composition is in aqueous
solution and the composition comprises one or more therapeutic
agents selected from the group consisting of small molecules,
peptides, proteins, lipids, carbohydrates, and combinations
thereof.
[0040] A method of treating diabetes in an animal in need thereof,
comprising: administering to the animal's skin a composition
comprising insulin and/or a derivative thereof and a transcutaneous
absorption enhancing amount of a tight junction agonist.
[0041] A method of treating diabetes in an animal in need thereof,
comprising: administering to the animal's skin a composition
comprising insulin and/or a derivative thereof and a transcutaneous
absorption enhancing amount of a tight junction agonist, wherein
the animal is a mammal.
[0042] A method of treating diabetes in an animal in need thereof,
comprising: administering to the animal's skin a composition
comprising insulin and/or a derivative thereof and a transcutaneous
absorption enhancing amount of a tight junction agonist, wherein
the animal is a human.
[0043] A method of treating diabetes in an animal in need thereof,
comprising: administering to the animal's skin a composition
comprising insulin and/or a derivative thereof and a transcutaneous
absorption enhancing amount of a tight junction agonist, wherein at
least one agonist comprises a peptide.
[0044] A method of treating diabetes in an animal in need thereof,
comprising: administering to the animal's skin a composition
comprising insulin and/or a derivative thereof and a transcutaneous
absorption enhancing amount of a tight junction agonist, wherein at
least one agonist comprises a peptide comprising the sequence
FCIGRL.
[0045] A method of treating diabetes in an animal in need thereof,
comprising: administering to the animal's skin a composition
comprising insulin and/or a derivative thereof and a transcutaneous
absorption enhancing amount of a tight junction agonist, wherein at
least one agonist comprises a peptide comprising a sequence
selected from the group consisting of Xaa1 Cys Ile Gly Arg Leu (SEQ
ID NO: 2), Phe Xaa2 Ile Gly Arg Leu (SEQ ID NO: 3), Phe Cys Xaa3
Gly Arg Leu (SEQ ID NO: 4), Phe Cys Ile Xaa4 Arg Leu (SEQ ID NO:
5), Phe Cys Ile Gly Xaa5 Leu (SEQ ID NO: 6), and Phe Cys Ile Gly
Arg Xaa6 (SEQ ID NO: 7), wherein Xaa1 is selected from the group
consisting of Ala, Val, Leu, Ile, Pro, Trp, Tyr, and Met; Xaa2 is
selected from the group consisting of Gly, Ser, Thr, Tyr, Asn, and
Gln; Xaa3 is selected from the group consisting of Ala, Val, Leu,
Ile, Pro, Trp, and Met; Xaa4 is selected from the group consisting
of Gly, Ser, Thr, Tyr, Asn, Ala, and Gln; Xaa5 is selected from the
group consisting of Lys and His; Xaa6 is selected from the group
consisting of Ala, Val, Leu, Ile, Pro, Trp, and Met.
[0046] A method of treating diabetes in an animal in need thereof,
comprising: administering to the animal's skin a composition
comprising insulin and/or a derivative thereof and a transcutaneous
absorption enhancing amount of a tight junction agonist, wherein at
least one agonist comprises a peptide comprising a sequence
selected from the group consisting of Xaa1 Xaa2 Ile Gly Arg Leu
(SEQ ID NO: 8), Xaa1 Cys Xaa3 Gly Arg Leu (SEQ ID NO: 9), Xaa1 Cys
Ile Xaa4 Arg Leu (SEQ ID NO: 10), Xaa1 Cys Ile Gly Xaa5 Leu (SEQ ID
NO: 11), Xaa1 Cys Ile Gly Arg Xaa6 (SEQ ID NO: 12), Phe Xaa2 Xaa3
Gly Arg Leu (SEQ ID NO: 13), Phe Xaa2 Ile Xaa4 Arg Leu (SEQ ID NO:
14), Phe Xaa2 Ile Gly Xaa5 Leu (SEQ ID NO: 15), Phe Xaa2 Ile Gly
Arg Xaa6 (SEQ ID NO: 16), Phe Cys Xaa3 Xaa4 Arg Leu (SEQ ID NO:
17), Phe Cys Xaa3 Gly Xaa5 Leu (SEQ ID NO: 18), Phe Cys Xaa3 Gly
Arg Xaa6 (SEQ ID NO: 19), Phe Cys Ile Xaa4 Xaa5 Leu (SEQ ID NO:
20), Phe Cys Ile Xaa4 Arg Xaa6 (SEQ ID NO: 21), and Phe Cys Ile Gly
Xaa5 Xaa6 (SEQ ID NO: 22); wherein Xaa1 is selected from the group
consisting of Ala, Val, Leu, Ile, Pro, Trp, Tyr, and Met; Xaa2 is
selected from the group consisting of Gly, Ser, Thr, Tyr, Asn, and
Gln; Xaa3 is selected from the group consisting of Ala, Val, Leu,
Ile, Pro, Trp, and Met; Xaa4 is selected from the group consisting
of Gly, Ser, Thr, Tyr, Asn, Ala, and Gln; Xaa5 is selected from the
group consisting of Lys and His; Xaa6 is selected from the group
consisting of Ala, Val, Leu, Ile, Pro, Trp, and Met.
[0047] A method of treating diabetes in an animal in need thereof,
comprising: administering to the animal's skin a composition
comprising insulin and/or a derivative thereof and a transcutaneous
absorption enhancing amount of a tight junction agonist, wherein at
least one agonist comprises a peptide comprising from about 6 to
about 10 amino acids.
[0048] A method of treating diabetes in an animal in need thereof,
comprising: administering to the animal's skin a composition
comprising insulin and/or a derivative thereof and a transcutaneous
absorption enhancing amount of a tight junction agonist, wherein
the composition is in aqueous solution.
[0049] A method of treating diabetes in an animal in need thereof,
comprising: administering to the animal's skin a composition
comprising insulin and/or a derivative thereof and a transcutaneous
absorption enhancing amount of a tight junction agonist, wherein
the composition is in a saline solution.
[0050] A method of treating diabetes in an animal in need thereof,
comprising: administering to the animal's skin a composition
comprising insulin and/or a derivative thereof and a transcutaneous
absorption enhancing amount of a tight junction agonist, wherein
the composition further comprises one or more pharmaceutically
acceptable excipients.
[0051] A method of treating diabetes in an animal in need thereof,
comprising: administering to the animal's skin a composition
comprising insulin and/or a derivative thereof and a transcutaneous
absorption enhancing amount of a tight junction agonist, wherein
the tight junction agonist is a peptide comprising the sequence
FCIGRL and the composition is in aqueous solution and the
composition comprises human insulin and/or a pharmaceutically
acceptable derivative thereof.
[0052] A method of inducing an immune response in an animal,
comprising: administering to the animal's skin a composition
comprising one or more antigens and a transcutaneous absorption
enhancing amount of a tight junction agonist.
[0053] A method of inducing an immune response in an animal,
comprising: administering to the animal's skin a composition
comprising one or more antigens and a transcutaneous absorption
enhancing amount of a tight junction agonist, further comprising
administering an adjuvant.
[0054] A method of inducing an immune response in an animal,
comprising: administering to the animal's skin a composition
comprising one or more antigens and a transcutaneous absorption
enhancing amount of a tight junction agonist, wherein the
composition further comprises an adjuvant.
[0055] A method of inducing an immune response in an animal,
comprising: administering to the animal's skin a composition
comprising one or more antigens and a transcutaneous absorption
enhancing amount of a tight junction agonist, wherein the animal is
a mammal.
[0056] A method of inducing an immune response in an animal,
comprising: administering to the animal's skin a composition
comprising one or more antigens and a transcutaneous absorption
enhancing amount of a tight junction agonist, wherein the animal is
a human.
[0057] A method of inducing an immune response in an animal,
comprising: administering to the animal's skin a composition
comprising one or more antigens and a transcutaneous absorption
enhancing amount of a tight junction agonist, wherein at least one
agonist comprises a peptide.
[0058] A method of inducing an immune response in an animal,
comprising: administering to the animal's skin a composition
comprising one or more antigens and a transcutaneous absorption
enhancing amount of a tight junction agonist, wherein at least one
agonist comprises a peptide comprising the sequence FCIGRL.
[0059] A method of inducing an immune response in an animal,
comprising: administering to the animal's skin a composition
comprising one or more antigens and a transcutaneous absorption
enhancing amount of a tight junction agonist, wherein at least one
agonist comprises a peptide comprising a sequence selected from the
group consisting of Xaa1 Cys Ile Gly Arg Leu (SEQ ID NO: 2), Phe
Xaa2 Ile Gly Arg Leu (SEQ ID NO: 3), Phe Cys Xaa3 Gly Arg Leu (SEQ
ID NO: 4), Phe Cys Ile Xaa4 Arg Leu (SEQ ID NO: 5), Phe Cys Ile Gly
Xaa5 Leu (SEQ ID NO: 6), and Phe Cys Ile Gly Arg Xaa6 (SEQ ID NO:
7), wherein Xaa1 is selected from the group consisting of Ala, Val,
Leu, Ile, Pro, Trp, Tyr, and Met; Xaa2 is selected from the group
consisting of Gly, Ser, Thr, Tyr, Asn, and Gln; Xaa3 is selected
from the group consisting of Ala, Val, Leu, Ile, Pro, Trp, and Met;
Xaa4 is selected from the group consisting of Gly, Ser, Thr, Tyr,
Asn, Ala, and Gln; Xaa5 is selected from the group consisting of
Lys and His; Xaa6 is selected from the group consisting of Ala,
Val, Leu, Ile, Pro, Trp, and Met.)
[0060] A method of inducing an immune response in an animal,
comprising: administering to the animal's skin a composition
comprising one or more antigens and a transcutaneous absorption
enhancing amount of a tight junction agonist, wherein at least one
agonist comprises a peptide comprising a sequence selected from the
group consisting of Xaa1 Xaa2 Ile Gly Arg Leu (SEQ ID NO: 8), Xaa1
Cys Xaa3 Gly Arg Leu (SEQ ID NO: 9), Xaa1 Cys Ile Xaa4 Arg Leu (SEQ
ID NO: 10), Xaa1 Cys Ile Gly Xaa5 Leu (SEQ ID NO: 11), Xaa1 Cys Ile
Gly Arg Xaa6 (SEQ ID NO: 12), Phe Xaa2 Xaa3 Gly Arg Leu (SEQ ID NO:
13), Phe Xaa2 Ile Xaa4 Arg Leu (SEQ ID NO: 14), Phe Xaa2 Ile Gly
Xaa5 Leu (SEQ ID NO: 15), Phe Xaa2 Ile Gly Arg Xaa6 (SEQ ID NO:
16), Phe Cys Xaa3 Xaa4 Arg Leu (SEQ ID NO: 17), Phe Cys Xaa3 Gly
Xaa5 Leu (SEQ ID NO: 18), Phe Cys Xaa3 Gly Arg Xaa6 (SEQ ID NO:
19), Phe Cys Ile Xaa4 Xaa5 Leu (SEQ ID NO: 20), Phe Cys Ile Xaa4
Arg Xaa6 (SEQ ID NO: 21), and Phe Cys Ile Gly Xaa5 Xaa6 (SEQ ID NO:
22), wherein Xaa1 is selected from the group consisting of Ala,
Val, Leu, Ile, Pro, Trp, Tyr, and Met; Xaa2 is selected from the
group consisting of Gly, Ser, Thr, Tyr, Asn, and Gln; Xaa3 is
selected from the group consisting of Ala, Val, Leu, Ile, Pro, Trp,
and Met; Xaa4 is selected from the group consisting of Gly, Ser,
Thr, Tyr, Asn, Ala, and Gln; Xaa5 is selected from the group
consisting of Lys and His; Xaa6 is selected from the group
consisting of Ala, Val, Leu, Ile, Pro, Trp, and Met.
[0061] A method of inducing an immune response in an animal,
comprising: administering to the animal's skin a composition
comprising one or more antigens and a transcutaneous absorption
enhancing amount of a tight junction agonist, wherein at least one
agonist comprises a peptide comprising from about 6 to about 10
amino acids.
[0062] A method of inducing an immune response in an animal,
comprising: administering to the animal's skin a composition
comprising one or more antigens and a transcutaneous absorption
enhancing amount of a tight junction agonist, wherein at least one
antigen is selected from the group consisting of measles virus
antigens, mumps virus antigens, rubella virus antigens,
Corynebacterium diphtheriae antigens, Bordetella pertussis
antigens, Clostridium tetani antigens, Bacillus anthracis antigens,
Haemophilus influenzae antigens, smallpox virus antigens, and
influenza virus antigens.
[0063] A method of inducing an immune response in an animal,
comprising: administering to the animal's skin a composition
comprising one or more antigens and a transcutaneous absorption
enhancing amount of a tight junction agonist, wherein the
composition is in aqueous solution.
[0064] A method of inducing an immune response in an animal,
comprising: administering to the animal's skin a composition
comprising one or more antigens and a transcutaneous absorption
enhancing amount of a tight junction agonist, wherein the
composition is in a saline solution.
[0065] A method of inducing an immune response in an animal,
comprising: administering to the animal's skin a composition
comprising one or more antigens and a transcutaneous absorption
enhancing amount of a tight junction agonist, wherein the
composition further comprises one or more pharmaceutically
acceptable excipients.
[0066] A method of inducing an immune response in an animal,
comprising: administering to the animal's skin a composition
comprising one or more antigens and a transcutaneous absorption
enhancing amount of a tight junction agonist, wherein the tight
junction agonist is a peptide comprising the sequence FCIGRL and
the composition is in aqueous solution and the composition
comprises one or more antigens selected from the group consisting
of measles virus antigens, mumps virus antigens, rubella virus
antigens, Corynebacterium diphtheriae antigens, Bordetella
pertussis antigens, Clostridium letuni antigens, Bacillus anthracis
antigens, Haemophilus influenzae antigens, smallpox virus antigens,
and influenza virus antigens.
[0067] An immunogenic composition comprising one or more antigens
and a transcutaneous absorption enhancing amount of a tight
junction agonist.
[0068] An immunogenic composition comprising one or more antigens
and a transcutaneous absorption enhancing amount of a tight
junction agonist, wherein at least one antigen is selected from the
group consisting of measles virus antigens, mumps virus antigens,
rubella virus antigens, Corynebacterium diphtheriae antigens,
Bordetella pertussis antigens, Clostridium tetani antigens,
Bacillus anthracis antigens, Haemophilus influenzae antigens,
smallpox virus antigens, and influenza virus antigens.
[0069] An immunogenic composition comprising one or more antigens
and a transcutaneous absorption enhancing amount of a tight
junction agonist, wherein at least one agonist comprises a
peptide.
[0070] An immunogenic composition comprising one or more antigens
and a transcutaneous absorption enhancing amount of a tight
junction agonist, wherein at least one agonist comprises a peptide
comprising the sequence FCIGRL.
[0071] An immunogenic composition comprising one or more antigens
and a transcutaneous absorption enhancing amount of a tight
junction agonist, wherein at least one agonist comprises a peptide
comprising a sequence selected from the group consisting of Xaa1
Cys Ile Gly Arg Leu (SEQ ID NO: 2), Phe Xaa2 Ile Gly Arg Leu (SEQ
ID NO: 3), Phe Cys Xaa3 Gly Arg Leu (SEQ ID NO: 4), Phe Cys Ile
Xaa4 Arg Leu (SEQ ID NO: 5). Phe Cys Ile Gly Xaa5 Leu (SEQ ID NO:
6), and Phe Cys Ile Gly Arg Xaa6 (SEQ ID NO: 7), wherein Xaa1 is
selected from the group consisting of Ala, Val, Leu, Ile, Pro, Trp,
Tyr, and Met; Xaa2 is selected from the group consisting of Gly,
Ser, Thr, Tyr, Asn, and Gln; Xaa3 is selected from the group
consisting of Ala, Val, Leu, Ile, Pro, Trp, and Met; Xaa4 is
selected from the group consisting of Gly, Ser, Thr, Tyr, Asn, Ala,
and Gln; Xaa5 is selected from the group consisting of Lys and His;
Xaa6 is selected from the group consisting of Ala, Val, Leu, Ile,
Pro, Trp, and Met.
[0072] An immunogenic composition comprising one or more antigens
and a transcutaneous absorption enhancing amount of a tight
junction agonist, wherein at least one agonist comprises a peptide
comprising a sequence selected from the group consisting of Xaa1
Xaa2 Ile Gly Arg Leu (SEQ ID NO: 8), Xaa1 Cys Xaa3 Gly Arg Leu (SEQ
ID NO: 9), Xaa1 Cys Ile Xaa4 Arg Leu (SEQ ID NO: 10), Xaa1 Cys Ile
Gly Xaa5 Leu (SEQ ID NO: 11), Xaa1 Cys Ile Gly Arg Xaa6 (SEQ ID NO:
12), Phe Xaa2 Xaa3 Gly Arg Leu (SEQ ID NO: 13), Phe Xaa2 Ile Xaa4
Arg Leu (SEQ ID NO: 14), Phe Xaa2 Ile Gly Xaa5 Leu (SEQ ID NO: 15),
Phe Xaa2 Ile Gly Arg Xaa6 (SEQ ID NO: 16), Phe Cys Xaa3 Xaa4 Arg
Leu (SEQ ID NO: 17), Phe Cys Xaa3 Gly Xaa5 Leu (SEQ ID NO: 18), Phe
Cys Xaa3 Gly Arg Xaa6 (SEQ ID NO: 19), Phe Cys Ile Xaa4 Xaa5 Leu
(SEQ ID NO: 20), Phe Cys Ile Xaa4 Arg Xaa6 (SEQ ID NO: 21), and Phe
Cys Ile Gly Xaa5 Xaa6 (SEQ ID NO: 22), wherein Xaa1 is selected
from the group consisting of Ala, Val, Leu, Ile, Pro, Trp, Tyr, and
Met; Xaa2 is selected from the group consisting of Gly, Ser, Thr,
Tyr, Asn, and Gln: Xaa3 is selected from the group consisting of
Ala, Val, Leu, Ile, Pro, Trp, and Met; Xaa4 is selected from the
group consisting of Gly, Ser, Thr, Tyr, Asn, Ala, and Gln; Xaa5 is
selected from the group consisting of Lys and His; Xaa6 is selected
from the group consisting of Ala, Val, Leu, Ile, Pro, Trp, and
Met.
[0073] An immunogenic composition comprising one or more antigens
and a transcutaneous absorption enhancing amount of a tight
junction agonist, wherein at least one agonist comprises a peptide
comprising from about 6 to about 10 amino acids.
[0074] An immunogenic composition comprising one or more antigens
and a transcutaneous absorption enhancing amount of a tight
junction agonist, wherein the composition is in aqueous
solution.
[0075] An immunogenic composition comprising one or more antigens
and a transcutaneous absorption enhancing amount of a tight
junction agonist, wherein the composition is in a saline
solution.
[0076] An immunogenic composition comprising one or more antigens
and a transcutaneous absorption enhancing amount of a tight
junction agonist, wherein the composition further comprises one or
more pharmaceutically acceptable excipients.
[0077] An immunogenic composition comprising one or more antigens
and a transcutaneous absorption enhancing amount of a tight
junction agonist, wherein the tight junction agonist is a peptide
comprising the sequence FCIGRL and the composition is in aqueous
solution and the composition comprises at least one antigen
selected from the group consisting of measles virus antigens, mumps
virus antigens, rubella virus antigens, Corynebacterium diphtheriae
antigens, Bordetella pertussis antigens, Clostridium tetani
antigens, Bacillus anthracis antigens, Haemophilus influenzae
antigens, smallpox virus antigens, and influenza virus
antigens.
[0078] A vaccine comprising one or more antigens and a
transcutaneous absorption enhancing amount of a tight junction
agonist.
[0079] A vaccine comprising one or more antigens and a
transcutaneous absorption enhancing amount of a tight junction
agonist, wherein at least one antigen is selected from the group
consisting of measles virus antigens, mumps virus antigens, rubella
virus antigens, Corynebacterium diphtheriae antigens, Bordetella
pertussis antigens, Clostridium tetani antigens, Bacillus anthracis
antigens, Haemophilus influenzae antigens, smallpox virus antigens,
and influenza virus antigens.
[0080] A vaccine comprising one or more antigens and a
transcutaneous absorption enhancing amount of a tight junction
agonist, wherein at least one agonist comprises a peptide.
[0081] A vaccine comprising one or more antigens and a
transcutaneous absorption enhancing amount of a tight junction
agonist, wherein at least one agonist comprises a peptide
comprising the sequence FCIGRL.
[0082] A vaccine comprising one or more antigens and a
transcutaneous absorption enhancing amount of a tight junction
agonist, wherein at least one agonist comprises a peptide
comprising a sequence selected from the group consisting of Xaa1
Cys Ile Gly Arg Leu (SEQ ID NO: 2), Phe Xaa2 Ile Gly Arg Leu (SEQ
ID NO: 3), Phe Cys Xaa3 Gly Arg Leu (SEQ ID NO: 4), Phe Cys Ile
Xaa4 Arg Leu (SEQ ID NO: 5), Phe Cys Ile Gly Xaa5 Leu (SEQ ID NO:
6), and Phe Cys Ile Gly Arg Xaa6 (SEQ ID NO: 7), wherein Xaa1 is
selected from the group consisting of Ala, Val, Leu, Ile, Pro, Trp,
Tyr, and Met; Xaa2 is selected from the group consisting of Gly,
Ser, Thr, Tyr, Asn, and Gln; Xaa3 is selected from the group
consisting of Ala, Val, Leu, Ile, Pro, Trp, and Met; Xaa4 is
selected from the group consisting of Gly, Ser, Thr, Tyr, Asn, Ala,
and Gln; Xaa5 is selected from the group consisting of Lys and His;
Xaa6 is selected from the group consisting of Ala, Val, Leu, Ile,
Pro, Trp, and Met.
[0083] A vaccine comprising one or more antigens and a
transcutaneous absorption enhancing amount of a tight junction
agonist, wherein at least one agonist comprises a peptide
comprising a sequence selected from the group consisting of Xaa1
Xaa2 Ile Gly Arg Leu (SEQ ID NO: 8), Xaa1 Cys Xaa3 Gly Arg Leu (SEQ
ID NO: 9), Xaa1 Cys Ile Xaa4 Arg Leu (SEQ ID NO: 10), Xaa1 Cys Ile
Gly Xaa5 Leu (SEQ ID NO: 11), Xaa1 Cys Ile Gly Arg Xaa6 (SEQ ID NO:
12), Phe Xaa2 Xaa3 Gly Arg Leu (SEQ ID NO: 13), Phe Xaa2 Ile Xaa4
Arg Leu (SEQ ID NO: 14), Phe Xaa2 Ile Gly Xaa5 Leu (SEQ ID NO: 15),
Phe Xaa2 Ile Gly Arg Xaa6 (SEQ ID NO: 16), Phe Cys Xaa3 Xaa4 Arg
Leu (SEQ ID NO: 17), Phe Cys Xaa3 Gly Xaa5 Leu (SEQ ID NO: 18), Phe
Cys Xaa3 Gly Arg Xaa6 (SEQ ID NO: 19), Phe Cys Ile Xaa4 Xaa5 Leu
(SEQ ID NO: 20), Phe Cys Ile Xaa4 Arg Xaa6 (SEQ ID NO: 21), and Phe
Cys Ile Gly Xaa5 Xaa6 (SEQ ID NO: 22), wherein Xaa1 is selected
from the group consisting of Ala, Val, Leu, Ile, Pro, Trp, Tyr, and
Met; Xaa2 is selected from the group consisting of Gly, Ser, Thr,
Tyr, Asn, and Gln; Xaa3 is selected from the group consisting of
Ala, Val, Leu, Ile, Pro, Trp, and Met; Xaa4 is selected from the
group consisting of Gly, Ser, Thr, Tyr, Asn, Ala, and Gln; Xaa5 is
selected from the group consisting of Lys and His: Xaa6 is selected
from the group consisting of Ala, Val, Leu, Ile, Pro, Trp, and
Met.
[0084] A vaccine comprising one or more antigens and a
transcutaneous absorption enhancing amount of a tight junction
agonist, wherein at least one agonist comprises a peptide
comprising from about 6 to about 15 amino acids.
[0085] A vaccine comprising one or more antigens and a
transcutaneous absorption enhancing amount of a tight junction
agonist, wherein the vaccine is an aqueous solution.
[0086] A vaccine comprising one or more antigens and a
transcutaneous absorption enhancing amount of a tight junction
agonist, wherein the vaccine is a saline solution.
[0087] A vaccine comprising one or more antigens and a
transcutaneous absorption enhancing amount of a tight junction
agonist, wherein the vaccine further comprises one or more
pharmaceutically acceptable excipients.
[0088] A vaccine comprising one or more antigens and a
transcutaneous absorption enhancing amount of a tight junction
agonist, wherein the tight junction agonist is a peptide comprising
the sequence FCIGRL and the vaccine is an aqueous solution and the
vaccine comprises at least one antigen selected from the group
consisting of measles virus antigens, mumps virus antigens, rubella
virus antigens, Corynebacterium diphtheriae antigens, Bordetella
pertussis antigens, Clostridium tetani antigens, Bacillus anthracis
antigens, Haemophilus influenzae antigens, smallpox virus antigens,
and influenza virus antigens.
BRIEF DESCRIPTION OF THE DRAWINGS
[0089] FIG. 1 describes the immunization protocol used in
experiments 1 and 2. Animals were immunized with tetanus toxoid
02/126 (TT; 25 .mu.g), cholera toxin (CT; 25 .mu.g); and/or AT-1002
(25 .mu.g or 75 .mu.g). The ten week schedule that included a
primary immunization, a first and second boost after 4 and 8 weeks
respectively, and a test bleed at 6 weeks. Terminal bleed and
spleen harvesting was carried out at ten weeks, and samples were
processed as indicated.
[0090] FIG. 2 provides a summary of the characteristics of the
AT1002 peptide (Phe-Cys-Ile-Gly-Arg-Leu) used in experiment 1.
[0091] FIG. 3 shows the immunization procedure as described in
Example 1.
[0092] FIG. 4A shows experiment 1 tetanus IgG titers measured by
ELISA in test bleeds taken from individual animal at week 6.
[0093] FIG. 4B shows experiment 1 tetanus IgG titers measured by
ELISA in terminal bleeds taken from individual animal at week
10.
[0094] FIG. 5 shows a summary of the experiment 1 tetanus IgG titer
measurements in different treatment groups 6 and 10 weeks after the
primary immunization. Data represent the mean.+-.s.e.m. (n=5 for
each group). *p<0.05 vesus TT at the same time point. Peptide
AT1002 significantly enhances the anti-tetanus response compared to
tetanus toxoid alone. Higher dose of AT1002 peptide does not
increaser the anti-tetanus response.
[0095] FIG. 6 shows the experiment 1 anti-tetanus IgG subclass
titer measurements in treatment groups 10 weeks after the primary
immunization. Data represent the mean.+-.s.e.m. (n=5 for each
group). No indication of a shift toward a Th1 response using AT1002
as an adjuvant. Serum IgA was also measured in the same samples,
and no measurable level was observed in any of the groups in this
experiment.
[0096] FIG. 7 shows the summarized proliferation of spleen cells
isolated from immunized mice after restimulation with tetanus
toxoid 02/126 (0-100 .mu.g/ml) in experiment I. Data represent the
mean.+-.s.e.m. (n=3 for each group), and they are expressed as a
Stimulation Index relative to proliferation of cells grown in RPMI
medium without restimulation. Results show a lack of proliferation
in TT restimulated spleen cells from mice immunized with TT+AT1002
(25 .mu.g) indicating a potential technical problem with this
assay.
[0097] FIG. 8A shows the summarized production of Interleukin-6
(IL-6) by spleen cells isolated from immunized mice after
restimulation with tetanus toxoid 02/126 (0-100 .mu.g/ml) in
experiment 1. Data represent the mean.+-.s.e.m. (n=3 for each
group). AT1002 does increase IL-6 production compared to groups
immunized with toxoid (TT) alone.
[0098] FIG. 8B shows the summarized production of Interferon-gamma
(IFN-.gamma.) by spleen cells isolated from immunized mice after
restimulation with tetanus toxoid 02/126 (0-100 .mu.g/ml) in
experiment 1. Data represent the mean.+-.s.e.m. (n=3 for each
group). AT1002 does not increase IFN-.gamma. production compared to
groups immunized with toxoid (TT) alone. Levels of IL-5 and IL-10
were also measured following restimulation, and AT1002 does not
increase production of either one compared to groups immunized with
toxoid (TT) alone.
[0099] FIG. 9 summarizes the conclusions from Experiment 1.
[0100] FIG. 10 provides a summary of the characteristics of the
AT1002 peptide (FCIGRL) used in experiment 2.
[0101] FIG. 11A shows experiment 2 tetanus IgG titers measured by
ELISA in test bleeds taken from individual animal at week 6.
[0102] FIG. 11B shows experiment 2 tetanus IgG titers measured by
ELISA in test bleeds taken from individual animal at week 10.
[0103] FIG. 12 shows a summary of the experiment 2 tetanus IgG
titer measurements in different treatment groups 6 and 10 weeks
after the primary immunization. Data represent the mean.+-.s.e.m.
(n=5 for each group). *p<0.05 vesus TT at the same time point.
Peptide AT1002 significantly enhances the anti-tetanus response in
a dose-dependent manner compared to tetanus toxoid alone. There was
high variability within each group.
[0104] FIG. 13 shows the summarized proliferation of spleen cells
isolated from immunized mice after restimulation with tetanus
toxoid 02/126 (0-100 .mu.g/ml) in experiment 2. Data represent the
mean.+-.s.e.m. (n=3 for each group), and they are expressed as a
Stimulation Index relative to proliferation of cells grown in RPMI
medium without restimulation. *p<0.05 versus AT1002 3 .mu.g and
AT1002 300 .mu.g at the same tetanus toxin dosage. Results show
that AT1002 (30 .mu.g) induces the strongest cell proliferation
response on restimulation with immunizing antigen.
[0105] FIG. 14A shows the summarized production of Interleukin-6
(IL-6) by spleen cells isolated from immunized mice after
restimulation with tetanus toxoid 02/126 (0-100 .mu.g/ml) in
experiment 2. Data represent the mean.+-.s.e.m. (n=3 for each
group). AT1002 does increase IL-6 production compared to groups
immunized with toxoid (TT) alone.
[0106] FIG. 14B shows the summarized production of Interferon-gamma
(IFN-.gamma.) by spleen cells isolated from immunized mice after
restimulation with tetanus toxoid 02/126 (0-100 .mu.g/ml) in
experiment 2. Data represent the mean.+-.s.e.m. (n=3 for each
group).
[0107] FIG. 15 summarizes the conclusions derived from Experiment
2.
[0108] FIG. 16 shows anti-tetanus IgG titers after 6 and 10 weeks.
Data represent the mean.+-.SEM (n=5 per group).
[0109] FIG. 17 shows spleen cell proliferation following
re-stimulation with TT (0-100 .mu.g/ml). Data represent the
mean.+-.SEM from three spleen cell cultures per group.
[0110] FIG. 18A shows production of IL-6 in splenocytes following
re-stimulation with TT (0-100 .mu.g/ml). Data represent the
mean.+-.SEM from three spleen cell cultures per group. *p<0.05,
**p<0.01 vs TT alone.
[0111] FIG. 18B shows production of IFN-.gamma. in splenocytes
following re-stimulation with TT (0-100 .mu.g/ml). Data represent
the mean.+-.SEM from three spleen cell cultures per group.
[0112] FIG. 19A shows experiment 3 tetanus IgG titers measured by
ELISA in test bleeds taken from individual animals at week 6.
Animals were immunized transcutaneously with tetanus toxoid 02/126
(25 .mu.g) alone or in combination with peptide AT1002 (30 .mu.g);
Phe-Allyl(Gly)-Ile-Gly-Arg-Leu (FaGIGRL (SEQ ID NO:144); 30 .mu.g)
or Phe-Gly-Ile-Gly-Arg-Leu (FGIGRL (SEQ ID NO:169); 30 .mu.g). Mice
received 3 doses of antigen.+-.adjuvant at weeks 0, 4 and 8,
animals were bled at weeks 6 and 10, and spleens were harbested at
week 10 to measure proliferative responses on restimulatin with
immunizing antigen (tetanus toxoid). Anti-tetanus IgG responses
were measured by ELISA as described. n=6 for all immunization
groups except: Ti group n=5 (one animal excluded due to cut on
abdomen after shaving); and FaGIGRL group n=3 (three animals
excluded due to non-response to anesthesia).
[0113] FIG. 19B shows experiment 3 tetanus IgG titers measured by
ELISA in terminal bleeds taken from individual animal at week 10.
Animals were immunized and samples were gathered as described above
(FIG. 21). Anti-tetanus IgG responses were measured by ELISA as
described. n=6 for all immunization groups except: TT group n=5
(one animal excluded due to cut on abdomen after shaving); and
FaGIGRL group n=3 (three animals excluded due to non-response to
anesthesia).
[0114] FIG. 20 shows a summary of the experiment 3 tetanus IgG
titer measurements in different treatment groups 6 and 10 weeks
after the primary immunization. Data represent the mean.+-.s.e.m.
(n=6 for each group except as noted in FIG. 21). *p<0.05 vesus
test bleed titerin the same group (paired T-test). ANOVA analysis
did not reveal any significant differences between immunization
groups at either time point.
[0115] FIG. 21 shows the summarized proliferation of spleen cells
isolated from immunized mice after restimulation with tetanus
toxoid 02/126 (1 or 100 .mu.g/ml) in experiment 3. Data represent
the mean.+-.s.e.m. (n=3 for each group), and they are expressed as
a Stimulation Index relative to proliferation of cells grown in
RPMI medium without restimulation.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0116] As used herein, "a" or "an" may mean one or more. As used
herein in the claim(s), when used in conjunction with the word
"comprising", the words "a" or "an" may mean one or more than one.
As used herein "another" may mean at least a second or more.
[0117] As used herein, "adjuvant" refers to a compound that
induces, enhances, and/or augments an immune response to an
antigen.
[0118] As used herein, "antigen" refers to any compound that can
elicit an immune response, for example, which can elicit production
of an antibody that specifically binds to the antigen.
[0119] As used herein, "immunogenic composition" refers to any
composition comprising an antigen.
[0120] As used herein, "vaccine" refers to an immunogenic
composition capable of eliciting a protective immune response when
administered to a subject. A protective immune response is one that
reduces the severity of disease when a vaccinated subject is
contacted with the disease causing agent (e.g., virus, bacterium,
etc). Examples of a reduction in severity of a disease include,
prevention of disease, delay in onset of disease, decreased
severity of symptoms, decreased morbidity, and delayed
mortality.
[0121] As used herein, a "tight junction agonist" is a compound
that mediates or facilitates or augments the physiological,
transient opening of tight junctions. Tight junctions are
structures that form a barrier between adjacent epithelial cells
(Johnson and Quay, Expert Opin Drug Deliv. 2005 March;
2(2):281-98). An example of a tight junction agonist is zonula
occludens toxin (ZOT), which is produced by Vibrio cholerae. A ZOT
receptor agonist is a tight junction agonist which is believed to
mediate tight junction opening through the same receptor utilized
by ZOT. Tight junction agonists also include zonulin.
Tight Junction Agonists
[0122] Compositions of the invention typically comprise one or more
tight junction agonists. A tight junction agonist facilitates
absorption of a therapeutic agent. Further, the absorption occurs
through the skin. Thus, a tight junction agonist as used herein is
a compound that mediates the physiological, transient opening of
tight junctions. In some embodiments, a tight junction agonist may
operate by binding to the ZOT receptor, i.e., may be a ZOT receptor
agonist.
[0123] In some embodiments, a tight junction agonist may comprise a
peptide comprising the amino acid sequence FCIGRL and/or functional
derivatives of this sequence. Functional derivatives of peptide
FCIGRL include, for example, Xaa1 Cys Ile Gly Arg Leu (SEQ ID NO:
2), Phe Xaa2 Ile Gly Arg Leu (SEQ ID NO: 3), Phe Cys Xaa3 Gly Arg
Leu (SEQ ID NO: 4), Phe Cys Ile Xaa4 Arg Leu (SEQ ID NO: 5), Phe
Cys Ile Gly Xaa5 Leu (SEQ ID NO: 6), and Phe Cys Ile Gly Arg Xaa6
(SEQ ID NO: 7). Xaa1 is selected from the group consisting of Ala,
Val, Leu, Ile, Pro, Trp, Tyr, and Met; Xaa2 is selected from the
group consisting of Gly, Ser, Thr, Tyr, Asn, and Gln; Xaa3 is
selected from the group consisting of Ala, Val, Leu, Ile, Pro, Trp,
and Met; Xaa4 is selected from the group consisting of Gly, Ser,
Thr, Tyr, Asn, Ala, and Gln; Xaa5 is selected from the group
consisting of Lys and His; Xaa6 is selected from the group
consisting of Ala, Val, Leu, Ile, Pro, Trp, and Met. In some
embodiments, a tight junction agonist may consist of a peptide
having the sequence FCIGRL and/or functional derivatives of this
sequence as described herein.
[0124] Further, functional derivatives of peptide FCIGRL include:
Xaa1 Xaa2 Ile Gly Arg Leu (SEQ ID NO: 8), Xaa1 Cys Xaa3 Gly Arg Leu
(SEQ ID NO: 9), Xaa1 Cys Ile Xaa4 Arg Leu (SEQ ID NO: 10), Xaa1 Cys
Ile Gly Xaa5 Leu (SEQ ID NO: 11), Xaa1 Cys Ile Gly Arg Xaa6 (SEQ
NO: 12), Phe Xaa2 Xaa3 Gly Arg Leu (SEQ ID NO: 13), Phe Xaa2 Ile
Xaa4 Arg Leu (SEQ ID NO: 14), Phe Xaa2 Ile Gly Xaa5 Leu (SEQ ID NO:
15), Phe Xaa2 Ile Gly Arg Xaa6 (SEQ ID NO: 16), Phe Cys Xaa3 Xaa4
Arg Leu(SEQ ID NO: 17), Phe Cys Xaa3 Gly Xaa5 Leu (SEQ ID NO: 18),
Phe Cys Xaa3 Gly Arg Xaa6 (SEQ ID NO: 19), Phe Cys Ile Xaa4 Xaa5
Leu (SEQ ID NO: 20), Phe Cys Ile Xaa4 Arg Xaa6 (SEQ ID NO: 21), and
Phe Cys Ile Gly Xaa5 Xaa6 (SEQ ID NO: 22). Xaa1 is selected from
the group consisting of Ala, Val, Leu, Ile, Pro, Trp, Tyr, and Met;
Xaa2 is selected from the group consisting of Gly, Ser, Thr, Tyr,
Asn, and Gln; Xaa3 is selected from the group consisting of Ala,
Val, Leu, Ile, Pro, Trp, and Met; Xaa4 is selected from the group
consisting of Gly, Ser, Thr, Tyr, Asn, Ala, and Gln; Xaa5 is
selected from the group consisting of Lys and His; Xaa6 is selected
from the group consisting of Ala, Val, Leu, Ile, Pro, Trp, and
Met.
[0125] In further specific embodiments, a tight junction agonist
may comprise a peptide comprising an amino acid sequence selected
from the group consisting of Cys Ile Gly Arg Leu (SEQ ID NO:23);
Ile Gly Arg Let, (SEQ ID NO:24); Phe Cys Ile Gly Arg (SEQ ID
NO:25); Phe Cys Ile Gly (SEQ ID NO:26): Ala Cys Ile Gly Arg Leu
(SEQ ID NO:27); Phe Ala Ile Gly Arg Leu (SEQ ID NO:28); Phe Cys Ala
Gly Arg Leu (SEQ ID NO:29); Phe Cys Ile Ala Are Leu (SEQ ID NO:30);
Phe Cys Ile Gly Ala Leu (SEQ ID NO:31); Phe Cys Ile Gly Arg Ala
(SEQ ID NO:32); Phe Cys Ile Gly Arg Leu (SEQ ID NO:33); Pro Cys Ile
Gly Arg Leu (SEQ ID NO:34); Gln Cys Ile Gly Arg Leu (SEQ ID NO:35);
Gly Cys Ile Gly Arg Leu (SEQ ID NO:36); Thr Cys Ile Gly Arg Leu
(SEQ ID NO:37); Ser Cys Ile Gly Arg Leu (SEQ ID NO:38); Sar Cys Ile
Gly Arg Leu (SEQ ID NO:39); Asn Cys Ile Gly Arg Leu (SEQ ID NO:40);
Arg Cys Ile Gly Arg Leu (SEQ ID NO:41); Cha Cys Ile Gly Arg Leu
(SEQ ID NO:42); Aib Cys Ile Gly Arg Leu (SEQ ID NO:43); (t-Bu)Gly
Cys Ile Gly Arg Leu (SEQ ID NO:44); Phe Thi Ile Gly Arg Leu (SEQ ID
NO:45); Phe Hse Ile Gly Are Leu (SEQ ID NO:46); Phe Thr Ile Gly Arg
Leu (SEQ ID NO:47); Phe Abu Ile Gly Arg Leu (SEQ ID NO:48); Phe Ser
Ile Gly Arg Leu (SEQ ID NO:49); Phe Met(O) Ile Gly Arg Leu (SEQ ID
NO:50); Phe Met(O)2 Ile Gly Arg Leu (SEQ ID NO:51); Phe (d)Cys Ile
Gly Arg Leu (SEQ ID NO:52): Phe Met Ile Gly Arg Leu (SEQ ID NO:53);
Nva Cys Ile Gly Arg Leu (SEQ ID NO:54); Val Cys Ile Gly Arg Leu
(SEQ ID NO:55); Hse Cys Ile Gly Arg Leu (SEQ ID NO:56); Phe Cys Ile
Gly Arg Gly (SEQ ID NO:57); (d)Ala Cys Ile Gly Arg Gly (SEQ ID
NO:58); Ala Cys Ile Gly Arg Gly (SEQ ID NO:59); Phe Cys Ile Gly Arg
Gly (SEQ ID NO:60); (d)Phe Cys Ile Gly Arg Gly (SEQ ID NO:61); Phe
Cys Ile Gly Arg Ser (SEQ ID NO:62); Phe Cys Ile Gly Arg Gln (SEQ ID
NO:63); Phe Cys Ile Gly Arg (d)Leu (SEQ ID NO:64); Phe Cys Ile Gly
Arg Lys (SEQ ID NO:65); Phe Cys Ile Gly Arg (d)Ala (SEQ ID NO:66);
Phe Cys Ile Gly Arg Ile (SEQ ID NO:67); Phe Cys Ile Gly Arg Gly
(SEQ ID NO:68); Phe Cys Ile Gly Arg Nva (SEQ ID NO:69); Phe Cys Ile
Gly Arg betaAla (SEQ ID NO:70); Phe Cys Ile Gly Arg Tle (SEQ ID
NO:71); Phe Cys Ile Gly Arg Asp (SEQ ID NO:72); Phe Cys Ile Gly Arg
MeAla (SEQ ID NO:73); Phe Cys Ile Gly Arg Abu (SEQ ID NO:74); Phe
Cys Ile Gly Arg Glu (SEQ ID NO:75); Phe Cys Ile Gly Arg Aib (SEQ ID
NO:76); Phe Cys Ile Gly Arg Phe (SEQ ID NO:77); Phe Cys Ile Gly Arg
Asn (SEQ ID NO:78); Phe Cys Ile Gly Arg Pro (SEQ ID NO:79); Glu Cys
Ile Gly Arg Leu (SEQ ID NO:80); Asp Cys Ile Gly Arg Leu (SEQ ID
NO:81); Phe Cys Ile Gly Arg Cha (SEQ ID NO:82); Abu Cys Ile Gly Arg
Leu (SEQ ID NO:83); Lys Cys Ile Gly Arg Leu (SEQ ID NO:84); Orn Cys
Ile Gly Arg Leu (SEQ ID NO:85); Phe Cys Ile Gly Arg Leu Cys (SEQ ID
NO:86); Leu Gly Gln Gln Gln Pro Phe Pro Pro Gln Gln Pro Tyr (SEQ ID
NO:87); Phe Nva Ile Gly Arg Leu (SEQ ID NO:88); Phe Nle Ile Gly Arg
Leu (SEQ ID NO:89); Pro Gly Pro Gly Arg Leu (SEQ ID NO:90); Phe Cys
Ile Pro Gly Pro (SEQ ID NO:91); Phe Cys Leu Gly Arg Leu (SEQ ID
NO:92); Phe Cys Ile Gly Gly Val Leu Val Gln Pro Gly (SEQ ID NO:93);
Gly Cys Ile Gly Arg Gly (SEQ ID NO:94); Tyr Cys Ile Gly Arg Leu
(SEQ ID NO:95); Phe Cys Ile Gly Cit Leu (SEQ ID NO:96); Ac Ala Cys
Ile Gly Arg Leu (SEQ ID NO:97); Trp Cys Ile Gly Arg Leu (SEQ ID
NO:98); Ac Ala Cys Ile Gly Arg Ser (SEQ ID NO:99); Ac Ala Cys Ile
Gly Arg Ala (SEQ ID NO:100); Phe(4-NO2) Cys Ile Gly Arg Leu (SEQ ID
NO:101); Phe(4-Cl) Cys Ile Gly Arg Leu (SEQ ID NO:102). Phe Cys Ile
Gly Arg Phe(4-Cl) (SEQ ID NO:103); Phe Cys Ile Gly Arg Phe(4-NO2)
(SEQ ID NO:104); Ac Phe Cys Ile Gly Arg Phe (SEQ ID NO:105); Tic
Cys Ile Gly Arg Leu (SEQ ID NO:106); Ser Leu Ile Gly Arg Leu (SEQ
ID NO:107); Leu Arg Gly Ile Cys Phe (SEQ ID NO:108); Leu Arg Gly
Ile (d)Cys Phe (SEQ ID NO:109); (d)Leu Arg Gly Ile Cys Phe (SEQ ID
NO:110); Leu (d)Arg Gly Ile Cys Phe (SEQ ID NO:111); Phe Cys Ile
Gly (d)Arg Leu (SEQ ID NO:112); Phe Cys Ile(nMe) Gly Arg Leu (SEQ
ID NO:113); Phe Cys Ile Gly Arg Thi (SEQ ID NO:114); Thi Cys Ile
Gly Arg Leu (SEQ ID NO:115); (d)Leu (d)Arg Gly (d)Ile (d)Cys (d)Phe
(SEQ ID NO:116); (d)Phe (d)Cys Ile Gly (d)Arg (d)Leu (SEQ ID
NO:117); (d)Phe (d)Cys (d)Ile Gly Arg (d)Leu (SEQ ID NO:118); Phe
Cys (d)Ile Gly Arg Leu (SEQ ID NO:119); Phe (d)Cys (d)Ile Gly
(d)Arg (d)Leu (SEQ ID NO:120); (d)Phe Cys (d)Ile Gly (d)Arg (d)Leu
(SEQ ID NO:121); Leu Arg Gly Ile Cys (d)Phe (SEQ ID NO:122); (d)Leu
(d)Arg Gly (d)Ile Cys (d)Phe (SEQ ID NO:123); Leu (d)Arg Gly (d)Ile
(d)Cys (d)Phe (SEQ ID NO:124); Leu Arg Gly (d)Ile Cys Phe (SEQ ID
NO:125); (d)Phe (d)Cys (d)Ile Gly (d)Arg Leu (SEQ ID NO:126);
(d)Leu (d)Arg Gly Ile (d)Cys (d)Phe (SEQ ID NO:127); (d)Leu Arg Gly
(d)Ile (d)Cys (d)Phe (SEQ ID NO:128); (d)Leu (d)Arg Gly (d)Ile
(d)Cys Phe (SEQ ID NO:129); Ac Phe Hse Ile Gly Arg Ala (SEQ ID
NO:130); Ac Phe Hse Ile Gly Arg Ser (SEQ ID NO:131); Ac Phe Use Ile
Gly Arg Phe (SEQ ID NO:132); Phe Cys Ile Gly Arg Tic (SEQ ID
NO:133); Phe Hse Ile Gly Arg Phe (SEQ ID NO:134); Phe Cys(S-benzyl)
Ile Gly Arg Leu (SEQ ID NO:135); Phe Cys(t-buthiol) Ile Gly Arg Leu
(SEQ ID NO:136); Phe Leu Ile Gly Arg Leu (SEQ ID NO:137); Phe Phe
Leu Ile Gly Arg Leu (SEQ ID NO:138); Phe Phe Ile Gly Arg Leu (SEQ
ID NO:139); Phe Phg Ile Gly Arg Leu (SEQ ID NO:140); Phe Pro Ile
Gly Arg Leu (SEQ ID NO:141): Phe (d)Val Ile Gly Arg Leu (SEQ ID
NO:142); Phe Cha Ile Gly Arg Leu (SEQ ID NO:143); Phe Allyl(Gly)
Ile Gly Arg Leu (SEQ ID NO:144); Phe tBu(Gly) Ile Gly Arg Leu (SEQ
ID NO:145); Phe Cys Ala Gly (SEQ ID NO:146); Phe Cys Gly Gly (SEQ
ID NO:147); Phe Trp Ile Gly Arg Leu (SEQ ID NO:148); Phe His Ile
Gly Arg Leu (SEQ ID NO:149); Phe Pro Ile Gly Arg Leu (SEQ ID
NO:150); Phe Asp Ile Gly Arg Leu (SEQ ID NO:151); Phe Dab Ile Gly
Arg Leu (SEQ ID NO:152); Phe (d)Cys Ile Gly (d)Arg Leu (SEQ ID
NO:153); (d)Leu Arg Gly Ile Cys Phe (SEQ ID NO:154); (d)Leu (d)Arg
Gly Ile Cys Phe (SEQ ID NO:155); (d)Leu (d)Arg Gly Ile Cys (d)Phe
(SEQ ID NO:156); (d)Leu (d)Arg Gly Ile (d)Cys Phe (SEQ ID NO:157);
Gly Phe Cys Ile Gly Arg Leu (SEQ ID NO:158); Phe Leu Ile Gly Arg
Leu (SEQ ID NO:159); Ac Phe Cys Ile Gly Arg Leu (SEQ ID NO:160);
Phe Phe Ile Gly Arg Leu (SEQ ID NO:161); Phe (cyclopropane)Pro Ile
Gly Arg Leu (SEQ ID NO162:); Phe Dpr Ile Gly Arg Leu (SEQ ID
NO:163); Phe Pen(Acm) Ile Gly Arg Leu (SEQ ID NO:164); Leu Arg Gly
Gly Arg Leu (SEQ ID NO:165); (d)Phe Cys Ile Gly Arg Leu (SEQ ID
NO:166); (d)Phe (d)Cys (d)Ile Gly (d)Arg (d)Leu (SEQ ID NO:167);
Phe Arg Ile Gly Arg Leu (SEQ ID NO:168); Phe Gly Ile Gly Arg Leu
(SEQ ID NO:169); Phe Gln Ile Gly Arg Leu (SEQ ID NO:170); Phe Glu
Ile Gly Arg Leu (SEQ ID NO:171); Phe Lys Ile Gly Arg Leu (SEQ ID
NO:172); Phe Asn Ile Gly Arg Leu (SEQ ID NO:173); Phe Tyr Ile Gly
Arg Leu (SEQ ID NO:174); Phe Leu Ile Gly Arg Leu (SEQ ID NO:175);
Phe Val Ile Gly Arg Leu (SEQ ID NO:176); Phe Ile Ile Gly Arg Leu
(SEQ ID NO:177); Phe Hey Ile Gly Arg Leu (SEQ ID NO:178); Ser Leu
Ile Gly Arg Leu (SEQ ID NO:179); Phe Cys Ala Gly Met Ser (SEQ ID
NO:180); Phe Cys Val Gly Met Ser (SEQ ID NO:181); Phe
(2-pyridiyl)Ala Ile Gly Arg Leu (SEQ ID NO:182); Phe Leu (d)Ile Gly
Arg Leu (SEQ ID NO:183); Ac Phe Leu Ile Gly Arg Leu (SEQ ID
NO:184); Phe (d)Leu Ile Gly Arg Leu (SEQ ID NO:185); Leu Arg Gly
(d)Ile Leu Phe (SEQ ID NO:186); Phe Abu(dimer) Ile Gly Arg Leu (SEQ
ID NO:187); Phe (Dehydro)Leu Ile Gly Arg Leu (SEQ ID NO:188); Leu
Arg Gly Ile Leu Phe (SEQ ID NO:189); Ac Phe Hse Ile Gly Arg (SEQ ID
NO:190); Phe Hse (d)Ile Gly Arg (SEQ ID NO:191); Ac Phe Hse Ile Gly
Arg Leu (SEQ ID NO:192); Phe Leu Ile Gly Arg (SEQ ID NO:193); Phe
Hse (d)Ile Gly Arg Leu (SEQ ID NO:194); Phe (4-CN) Phe Ile Gly Arg
Leu (SEQ ID NO:195); Phe (3-Me) Phe Ile Gly Arg Leu (SEQ ID
NO:196); Phe Cyclopropyl(Ala) Ile Gly Arg Leu (SEQ ID NO:197); Phe
Allyl(Gly) Ile Gly Arg (SEQ ID NO:198); Phe (d)Allyl(Gly) Ile Gly
Arg (SEQ ID NO:199); Phe Pra Ile Gly Arg (SEQ ID NO:200); Phe
Allyl(Gly) Ile Thr Arg Leu (SEQ ID NO:201); Phe Allyl(Gly) Ile Leu
Arg Leu (SEQ ID NO:202); Phe Allyl(Gly) Ile Ile Arg Leu (SEQ ID
NO:203); Phe Allyl(Gly) Ile Ala Arg Leu (SEQ ID NO:204); Phe
Allyl(Gly) Ile Pro Arg Leu (SEQ ID NO:205); Phe Allyl(Gly) Pro Gly
Arg Leu (SEQ ID NO:206); Phe Allyl(Gly) Phe Gly Arg Leu (SEQ ID
NO:207); Phe Allyl(Gly) Thr Gly Are Leu (SEQ ID NO:208); Phe
Allyl(Gly) Leu Gly Arg Leu (SEQ ID NO:209); Phe Allyl(Gly) Ser Gly
Arg Leu (SEQ ID NO:210); Phe Allyl(Gly) Phe Gly Arg Leu (SEQ ID
NO:211); Phe Allyl(Gly) Val Gly Arg Leu (SEQ ID NO:212); Phe
Allyl(Gly) Gly Gly Arg Leu (SEQ ID NO:213); Phe Allyl(Gly) Ala Gly
Arg Leu (SEQ ID NO:214); Met Allyl(Gly) Ile Gly Arg Leu (SEQ ID
NO:215); Gln Allyl(Gly) Ile Gly Arg Leu (SEQ ID NO:216); Leu
Allyl(Gly) Ile Gly Arg Leu (SEQ ID NO:217); Ser Allyl(Gly) Ile Gly
Arg Leu (SEQ ID NO:218); Thr Allyl(Gly) Ile Gly Arg Leu (SEQ ID
NO:219); Glu Allyl(Gly) Ile Gly Arg Leu (SEQ ID NO:220); Val
Allyl(Gly) Ile Gly Arg Leu (SEQ ID NO:221); Tyr Allyl(Gly) Ile Gly
Arg Leu (SEQ ID NO:222); Gly Allyl(Gly) Ile Gly Arg Leu (SEQ ID
NO:223); Asp Allyl(Gly) Ile Gly Arg Leu (SEQ ID NO:224); Trp
Allyl(Gly) Ile Gly Arg Leu (SEQ ID NO:225); Lys Allyl(Gly) Ile Gly
Arg Leu (SEQ ID NO:226); Ala Allyl(Gly) Ile Gly Arg Leu (SEQ ID
NO:227); His Allyl(Gly) Ile Gly Arg Leu (SEQ ID NO:228); Pro
Allyl(Gly) Ile Gly Arg Leu (SEQ ID NO:229); Arg Allyl(Gly) Ile Gly
Arg Leu (SEQ ID NO:230); Ile Allyl(Gly) Ile Gly Arg Leu (SEQ ID
NO:231); Met Allyl(Gly) Ile Gly Arg Leu (SEQ ID NO:232); Tyr Ile
Gly Ser Arg (SEQ ID NO:233); Phe (2-furyl)Ala Ile Gly Arg (SEQ ID
NO:234); Phe Thr Ile Gly Arg (SEQ ID NO:235); Phe StyrylGly Ile Gly
Arg Leu (SEQ ID NO:236); Phe HOCit Ile Gly Arg Leu (SEQ ID NO:237);
Phe Thr Ile Gly Arg Leu (SEQ ID NO:238); Phe (2-furyl)Ala Ile Gly
Arg Leu (SEQ ID NO:239); Phe Ile Gly Arg Leu (SEQ ID NO:240); Phe
Allyl(Gly) Ile Gly Arg Leu (SEQ ID NO:241); Arg Gly Ile Leu Phe
(SEQ ID NO:242); Gly Ile Leu Phe (SEQ ID NO:243); Leu Arg Gly Ile
Leu (SEQ ID NO:244); Leu Arg Gly (d)Ile Leu Phe (SEQ ID NO:245);
Leu Arg Gly Phe Leu Phe (SEQ ID NO:246); Leu Arg Gly Leu Leu Phe
(SEQ ID NO:247); Leu Arg Gly Ile Leu (d)Phe (SEQ ID NO:248); Leu
Arg Gly Ile (d)Leu Phe (SEQ ID NO:249); Leu (d)Arg Gly Ile Leu Phe
(SEQ ID NO:250); (d)Leu Arg Gly Ile Leu Phe (SEQ ID NO:251); Phe
Arg Gly Ile Leu Phe (SEQ ID NO:252); Leu Arg Gly Ile AllyGly Phe
(SEQ ID NO:253); Phe Allyl(Gly) Ile Gly Arg His (SEQ ID NO:254);
Phe Allyl(Gly) Ile Gly Arg Asp (SEQ ID NO:255); Phe Allyl(Gly) Ile
Gly Arg Arg (SEQ ID NO:256); Phe Allyl(Gly) Ile Gly Arg Phe (SEQ ID
NO:257); Phe Allyl(Gly) Ile Gly Arg Ala (SEQ ID NO:258); Phe
Allyl(Gly) Ile Gly Arg Gly (SEQ ID NO:259); Phe Allyl(Gly) Ile Gly
Arg Gln (SEQ ID NO:260); Phe Allyl(Gly) Ile Gly Arg Glu (SEQ ID
NO:261); Phe Allyl(Gly) Ile Gly Arg Thr (SEQ ID NO:262); Phe
Allyl(Gly) Ile Gly Arg Tyr (SEQ ID NO:263); Phe Allyl(Gly) Ile Gly
Arg Ser (SEQ ID NO:264); Phe Allyl(Gly) Ile Gly Arg Asn (SEQ ID
NO:265); Phe Allyl(Gly) Ile Gly Arg Met (SEQ ID NO:266); Phe
Allyl(Gly) Ile Gly Arg Lys (SEQ ID NO:267); Phe Allyl(Gly) Ile Gly
Arg Ile (SEQ ID NO:268); Phe Allyl(Gly) Ile Gly Arg Trp (SEQ ID
NO:269); Phe Allyl(Gly) Ile Gly Arg Pro (SEQ ID NO:270); Phe
Allyl(Gly) Ile Gly Arg Val (SEQ ID NO:271); Phe Allyl(Gly) Ile Gly
His Leu (SEQ ID NO:272); Phe Allyl(Gly) Ile Gly Asp Leu (SEQ ID
NO:273); Phe Allyl(Gly) Ile Gly Glu Leu (SEQ ID NO:274); Phe
Allyl(Gly) Ile Gly Gln Leu (SEQ ID NO:275); Phe Allyl(Gly) Ile Gly
Gly Leu (SEQ ID NO:276); Phe Allyl(Gly) Ile Gly Ala Leu (SEQ ID
NO:277); Phe Allyl(Gly) Ile Gly Phe Leu (SEQ ID NO:278); Phe
Allyl(Gly) Ile Gly Lys Leu (SEQ ID NO:279); Phe Allyl(Gly) Ile Gly
Leu Leu (SEQ ID NO:280); Phe Allyl(Gly) Ile Gly Met Leu (SEQ ID
NO:281); Phe Allyl(Gly) Ile Gly Asn Leu (SEQ ID NO:282); Phe
Allyl(Gly) Ile Gly Ser Leu (SEQ ID NO:283); Phe Allyl(Gly) Ile Gly
Tyr Leu (SEQ ID NO:284); Phe Allyl(Gly) Ile Gly Thr Leu (SEQ ID
NO:285); Phe Allyl(Gly) Ile Gly Ile Leu (SEQ ID NO:286); Phe
Allyl(Gly) Ile Gly Trp Leu (SEQ ID NO:287); Phe Allyl(Gly) Ile Gly
Pro Leu (SEQ ID NO:288); Phe Allyl(Gly) Ile Gly Val Leu (SEQ ID
NO:289); Phe N-Allyl(Gly) Ile Gly Arg Leu (SEQ ID NO:290); Phe
Allyl(Gly) Tyr Gly Arg Leu (SEQ ID NO:291); Phe Allyl(Gly) His Gly
Arg Leu (SEQ ID NO:292); Phe Allyl(Gly) Asn Gly Arg Leu (SEQ ID
NO:293); Phe Allyl(Gly) Asp Gly Arg Leu (SEQ ID NO:294); Phe
Allyl(Gly) Gln Gly Arg Leu (SEQ ID NO:295); Phe Allyl(Gly) Glu Gly
Arg Leu (SEQ ID NO:296); Phe Allyl(Gly) Lys Gly Arg Leu (SEQ ID
NO:297); Phe Allyl(Gly) Arg Gly Arg Leu (SEQ ID NO:298); Phe
Allyl(Gly) Ile Arg Arg Leu (SEQ ID NO:299); Phe Allyl(Gly) Ile Asn
Arg Leu (SEQ ID NO:300); Phe Allyl(Gly) Ile His Arg Leu (SEQ ID
NO:301); Phe Allyl(Gly) Ile Lys Arg Leu (SEQ ID NO:302); Phe
Allyl(Gly) Ile Gln Arg Leu (SEQ ID NO:303); Phe Allyl(Gly) Ile Phe
Arg Leu (SEQ ID NO:304); Phe Allyl(Gly) Ile Ser Arg Leu (SEQ ID
NO:305); Phe Allyl(Gly) Ile Val Arg Leu (SEQ ID NO:306); Phe
Allyl(Gly) Ile Asp Arg Leu (SEQ ID NO:307); Phe Allyl(Gly) Ile Glu
Arg Leu (SEQ ID NO:308); Phe N-Allyl(Gly) Ile Gly Arg (SEQ ID
NO:309); Phe N-Allyl(Gly) Ile Gly Arg Leu (SEQ ID NO:310); Benzyl
Allyl(Gly) Ile Gly Arg Leu (SEQ ID NO:311); c(Phe Allyl(Gly) Ile
Gly Arg Leu) (SEQ ID NO:312); Gly Phe Gly Ile Leu Arg (SEQ ID
NO:313); and Ile Gly Phe Leu Arg Gly (SEQ ID NO:314).
[0126] In further particular embodiments, a tight junction agonist
may consist of a peptide having an amino acid sequence selected
from the group consisting of: Cys Ile Gly Arg Leu (SEQ ID NO:23);
Ile Gly Arg Leu (SEQ ID NO:24); Phe Cys Ile Gly Arg (SEQ ID NO:25);
Phe Cys Ile Gly (SEQ ID NO:26); Ala Cys Ile Gly Arg Leu (SEQ ID
NO:27); Phe Ala Ile Gly Arg Leu (SEQ ID NO:28); Phe Cys Ala Gly Arg
Leu (SEQ ID NO:29); Phe Cys Ile Ala Arg Leu (SEQ ID NO:30); Phe Cys
Ile Gly Ala Leu (SEQ ID NO:31); Phe Cys Ile Gly Arg Ala (SEQ ID
NO:32); Phe Cys Ile Gly Arg Leu (SEQ ID NO:33); Pro Cys Ile Gly Arg
Leu (SEQ ID NO:34); Gln Cys Ile Gly Arg Leu (SEQ ID NO:35); Gly Cys
Ile Gly Arg Leu (SEQ ID NO:36); Thr Cys Ile Gly Arg Leu (SEQ ID
NO:37); Ser Cys Ile Gly Arg Leu (SEQ ID NO:38); Sar Cys Ile Gly Arg
Leu (SEQ ID NO:39); Asn Cys Ile Gly Arg Leu (SEQ ID NO:40); Arg Cys
Ile Gly Arg Leu (SEQ ID NO:41); Cha Cys Ile Gly Arg Leu (SEQ ID
NO:42); Aib Cys Ile Gly Arg Leu (SEQ ID NO:43); (t-Bu)Gly Cys Ile
Gly Arg Leu (SEQ ID NO:44); Phe Thi Ile Gly Arg Leu (SEQ ID NO:45);
Phe Hse Ile Gly Arg Leu (SEQ ID NO:46); Phe Thr Ile Gly Arg Leu
(SEQ ID NO:47); Phe Abu Ile Gly Arg Leu (SEQ ID NO:48); Phe Ser Ile
Gly Arg Leu (SEQ ID NO:49); Phe Met(O) Ile Gly Arg Leu (SEQ ID
NO:50); Phe Met(O)2 Ile Gly Arg Leu (SEQ ID NO:51); Phe (d)Cys Ile
Gly Arg Leu (SEQ ID NO:52); Phe Met Ile Gly Arg Leu (SEQ ID NO:53);
Nva Cys Ile Gly Arg Leu (SEQ ID NO:54); Val Cys Ile Gly Arg Leu
(SEQ ID NO:55); Hse Cys Ile Gly Arg Leu (SEQ ID NO:56); Phe Cys Ile
Gly Arg Gly (SEQ ID NO:57); (d)Ala Cys Ile Gly Arg Gly (SEQ ID
NO:58); Ala Cys Ile Gly Arg Gly (SEQ ID NO:59); Phe Cys Ile Gly Arg
Gly (SEQ ID NO:60); (d)Phe Cys Ile Gly Arg Gly (SEQ ID NO:61); Phe
Cys Ile Gly Arg Ser (SEQ ID NO:62); Phe Cys Ile Gly Arg Gln (SEQ ID
NO:63); Phe Cys Ile Gly Arg (d)Leu (SEQ ID NO:64); Phe Cys Ile Gly
Arg Lys (SEQ ID NO:65); Phe Cys Ile Gly Arg (d)Ala (SEQ ID NO:66);
Phe Cys Ile Gly Arg Ile (SEQ ID NO:67); Phe Cys Ile Gly Arg Gly
(SEQ ID NO:68); Phe Cys Ile Gly Arg Nva (SEQ ID NO:69); Phe Cys Ile
Gly Arg betaAla (SEQ ID NO:70); Phe Cys Ile Gly Arg Tle (SEQ ID
NO:71); Phe Cys Ile Gly Arg Asp (SEQ ID NO:72); Phe Cys Ile Gly Arg
MeAla (SEQ ID NO:73); Phe Cys Ile Gly Arg Abu (SEQ ID NO:74); Phe
Cys Ile Gly Arg Glu (SEQ ID NO:75); Phe Cys Ile Gly Arg Aib (SEQ ID
NO:76); Phe Cys Ile Gly Arg Phe (SEQ ID NO:77); Phe Cys Ile Gly Arg
Asn (SEQ ID NO:78); Phe Cys Ile Gly Arg Pro (SEQ ID NO:79); Glu Cys
Ile Gly Arg Leu (SEQ ID NO:80); Asp Cys Ile Gly Arg Leu (SEQ ID
NO:81); Phe Cys Ile Gly Arg Cha (SEQ ID NO:82); Abu Cys Ile Gly Arg
Leu (SEQ ID NO:83); Lys Cys Ile Gly Arg Leu (SEQ ID NO:84); Orn Cys
Ile Gly Arg Leu (SEQ ID NO:85); Phe Cys Ile Gly Arg Leu Cys (SEQ ID
NO:86); Leu Gly Gln Gln Gln Pro Phe Pro Pro Gln Gln Pro Tyr (SEQ ID
NO:87); Phe Nva Ile Gly Arg Leu (SEQ ID NO:88); Phe Nle Ile Gly Arg
Leu (SEQ ID NO:89); Pro Gly Pro Gly Arg Leu (SEQ ID NO:90); Phe Cys
Ile Pro Gly Pro (SEQ ID NO:91); Phe Cys Leu Gly Arg Leu (SEQ ID
NO:92); Phe Cys Ile Gly Gly Val Leu Val Gln Pro Gly (SEQ ID NO:93);
Gly Cys Ile Gly Arg Gly (SEQ ID NO:94); Tyr Cys Ile Gly Arg Leu
(SEQ ID NO:95); Phe Cys Ile Gly Cit Leu (SEQ ID NO:96); Ac Ala Cys
Ile Gly Arg Leu (SEQ ID NO:97); Trp Cys Ile Gly Arg Leu (SEQ ID
NO:98); Ac Ala Cys Ile Gly Arg Ser (SEQ ID NO:99); Ac Ala Cys Ile
Gly Arg Ala (SEQ ID NO:100); Phe(4-NO2) Cys Ile Gly Arg Leu (SEQ ID
NO:101); Phe(4-Cl) Cys Ile Gly Arg Leu (SEQ ID NO:102); Phe Cys Ile
Gly Arg Phe(4-Cl) (SEQ ID NO:103); Phe Cys Ile Gly Arg Phe(4-NO2)
(SEQ ID NO:104); Ac Phe Cys Ile Gly Arg Phe (SEQ ID NO:105); Tic
Cys Ile Gly Arg Leu (SEQ ID NO:106); Ser Leu Ile Gly Arg Leu (SEQ
ID NO:107); Leu Arg Gly Ile Cys Phe (SEQ ID NO:108); Leu Arg Gly
Ile (d)Cys Phe (SEQ ID NO:109); (d)Leu Arg Gly Ile Cys Phe (SEQ ID
NO:110); Leu (d)Arg Gly Ile Cys Phe (SEQ ID NO:111); Phe Cys Ile
Gly (d)Arg Leu (SEQ II) NO:112): Phe Cys Ile(nMe) Gly Arg Leu (SEQ
ID NO:113); Phe Cys Ile Gly Arg Thi (SEQ ID NO:114); Thi Cys Ile
Gly Arg Leu (SEQ ID NO:115); (d)Leu (d)Arg Gly (d)Ile (d)Cys (d)Phe
(SEQ ID NO:116); (d)Phe (d)Cys Ile Gly (d)Arg (d)Leu (SEQ ID
NO:117); (d)Phe (d)Cys (d)Ile Gly Arg (d)Leu (SEQ ID NO:118); Phe
Cys (d)Ile Gly Arg Leu (SEQ ID NO:119); Phe (d)Cys (d)Ile Gly
(d)Arg (d)Leu (SEQ ID NO:120); (d)Phe Cys (d)Ile Gly (d)Arg (d)Leu
(SEQ ID NO:121); Leu Arg Gly Ile Cys (d)Phe (SEQ ID NO:122); (d)Leu
(d)Arg Gly (d)Ile Cys (d)Phe (SEQ ID NO:123); Leu (d)Arg Gly (d)Ile
(d)Cys (d)Phe (SEQ ID NO:124); Leu Arg Gly (d)Ile Cys Phe (SEQ ID
NO:125); (d)Phe (d)Cys (d)Ile Gly (d)Arg Leu (SEQ ID NO:126);
(d)Leu (d)Arg Gly Ile (d)Cys (d)Phe (SEQ ID NO:127); (d)Leu Arg Gly
(d)Ile (d)Cys (d)Phe (SEQ ID NO:128); (d)Leu (d)Arg Gly (d)Ile
(d)Cys Phe (SEQ ID NO:129); Ac Phe Hse Ile Gly Arg Ala (SEQ ID
NO:130); Ac Phe Hse Ile Gly Arg Ser (SEQ ID NO:131); Ac Phe Hse Ile
Gly Arg Phe (SEQ ID NO:132); Phe Cys Ile Gly Arg Tic (SEQ ID
NO:133); Phe Hse Ile Gly Arg Phe (SEQ ID NO:134); Phe Cys(S-benzyl)
Ile Gly Arg Leu (SEQ ID NO:135); Phe Cys(t-buthiol) Ile Gly Arg Leu
(SEQ ID NO:136): Phe Leu Ile Gly Arg Leu (SEQ ID NO:137); Phe Phe
Leu Ile Gly Arg Leu (SEQ ID NO:138); Phe Phe Ile Gly Arg Leu (SEQ
ID NO:139); Phe Phg Ile Gly Arg Leu (SEQ ID NO:140); Phe Pro Ile
Gly Arg Leu (SEQ ID NO:141); Phe (d)Val Ile Gly Arg Leu (SEQ ID
NO:142); Phe Cha Ile Gly Arg Leu (SEQ ID NO:143); Phe Allyl(Gly)
Ile Gly Arg Leu (SEQ ID NO:144); Phe tBu(Gly) Ile Gly Arg Leu (SEQ
ID NO:145); Phe Cys Ala Gly (SEQ ID NO:146); Phe Cys Gly Gly (SEQ
ID NO:147); Phe Trp Ile Gly Arg Leu (SEQ ID NO:148); Phe His Ile
Gly Arg Leu (SEQ ID NO:149); Phe Pro Ile Gly Arg Leu (SEQ ID
NO:150); Phe Asp Ile Gly Arg Leu (SEQ ID NO:151); Phe Dab Ile Gly
Arg Leu (SEQ ID NO:152); Phe (d)Cys Ile Gly (d)Arg Leu (SEQ ID
NO:153); (d)Leu Arg Gly Ile Cys Phe (SEQ ID NO:154); (d)Leu (d)Arg
Gly Ile Cys Phe (SEQ ID NO:155); (d)Leu (d)Arg Gly Ile Cys (d)Phe
(SEQ ID NO:156); (d)Leu (d)Arg Gly Ile (d)Cys Phe (SEQ ID NO:157);
Gly Phe Cys Ile Gly Arg Leu (SEQ ID NO:158); Phe Leu Ile Gly Arg
Leu (SEQ ID NO:159); Ac Phe Cys Ile Gly Arg Leu (SEQ ID NO:160);
Phe Phe Ile Gly Arg Leu (SEQ ID NO:161); Phe (cyclopropane)Pro Ile
Gly Arg Leu (SEQ ID NO162:): Phe Dpr Ile Gly Arg Leu (SEQ ID
NO:163); Phe Pen(Acm) Ile Gly Arg Leu (SEQ ID NO:164); Leu Arg Gly
Gly Arg Leu (SEQ ID NO:165); (d)Phe Cys Ile Gly Arg Leu (SEQ ID
NO:166); (d)Phe (d)Cys (d)Ile Gly (d)Arg (d)Leu (SEQ ID NO:167);
Phe Arg Ile Gly Arg Leu (SEQ ID NO:168); Phe Gly Ile Gly Arg Leu
(SEQ ID NO:169); Phe Gln Ile Gly Arg Leu (SEQ ID NO:170); Phe Glu
Ile Gly Arg Leu (SEQ ID NO:171); Phe Lys Ile Gly Arg Leu (SEQ ID
NO:172); Phe Asn Ile Gly Arg Leu (SEQ ID NO:173); Phe Tyr Ile Gly
Arg Leu (SEQ ID NO:174); Phe Leu Ile Gly Arg Leu (SEQ ID NO:175);
Phe Val Ile Gly Arg Leu (SEQ ID NO:176); Phe Ile Ile Gly Arg Leu
(SEQ ID NO:177); Phe Hcy Ile Gly Arg Leu (SEQ ID NO:178); Ser Leu
Ile Gly Arg Leu (SEQ ID NO:179); Phe Cys Ala Gly Met Ser (SEQ ID
NO:180): Phe Cys Val Gly Met Ser (SEQ ID NO:181); Phe
(2-pyridiyl)Ala Ile Gly Arg Leu (SEQ ID NO:182): Phe Leu (d)Ile Gly
Arg Leu (SEQ ID NO:183); Ac Phe Leu Ile Gly Arg Leu (SEQ ID
NO:184); Phe (d)Leu Ile Gly Arg Leu (SEQ ID NO:185); Leu Arg Gly
(d)Ile Leu Phe (SEQ ID NO:186); Phe Abu(dimer) Ile Gly Arg Leu (SEQ
ID NO:187); Phe (Dehydro)Leu Ile Gly Arg Leu (SEQ ID NO:188); Leu
Arg Gly Ile Leu Phe (SEQ ID NO:189); Ac Phe Hse Ile Gly Arg (SEQ ID
NO:190); Phe Hse (d)Ile Gly Arg (SEQ ID NO:191); Ac Phe Hse Ile Gly
Arg Leu (SEQ ID NO:192); Phe Leu Ile Gly Arg (SEQ ID NO:193); Phe
Hse (d)Ile Gly Arg Leu (SEQ ID NO:194); Phe (4-CN) Phe Ile Gly Arg
Leu (SEQ ID NO:195); Phe (3-Me) Phe Ile Gly Arg Leu (SEQ ID
NO:196); Phe Cyclopropyl(Ala) Ile Gly Arg Leu (SEQ ID NO:197); Phe
Allyl(Gly) Ile Gly Arg (SEQ ID NO:198); Phe (d)Allyl(Gly) Ile Gly
Arg (SEQ ID NO:199); Phe Pra Ile Gly Arg (SEQ ID NO:200); Phe
Allyl(Gly) Ile Thr Arg Leu (SEQ ID NO:201); Phe Allyl(Gly) Ile Leu
Arg Leu (SEQ ID NO:202); Phe Allyl(Gly) Ile Ile Arg Leu (SEQ ID
NO:203); Phe Allyl(Gly) Ile Ala Arg Leu (SEQ ID NO:204); Phe
Allyl(Gly) Ile Pro Arg Leu (SEQ ID NO:205); Phe Allyl(Gly) Pro Gly
Arg Leu (SEQ ID NO:206); Phe Allyl(Gly) Phe Gly Arg Leu (SEQ ID
NO:207); Phe Allyl(Gly) Thr Gly Arg Leu (SEQ ID NO:208); Phe
Allyl(Gly) Leu Gly Arg Leu (SEQ ID NO:209); Phe Allyl(Gly) Ser Gly
Arg Leu (SEQ ID NO:210); Phe Allyl(Gly) Phe Gly Arg Leu (SEQ ID
NO:211); Phe Allyl(Gly) Val Gly Arg Leu (SEQ ID NO:212); Phe
Allyl(Gly) Gly Gly Arg Leu (SEQ ID NO:213); Phe Allyl(Gly) Ala Gly
Arg Leu (SEQ ID NO:214); Met Allyl(Gly) Ile Gly Arg Leu (SEQ ID
NO:215); Gln Allyl(Gly) Ile Gly Arg Leu (SEQ ID NO:216); Leu
Allyl(Gly) Ile Gly Arg Leu (SEQ ID NO:217); Ser Allyl(Gly) Ile Gly
Arg Leu (SEQ ID NO:218); Thr Allyl(Gly) Ile Gly Arg Leu (SEQ ID
NO:219); Glu Allyl(Gly) Ile Gly Arg Leu (SEQ ID NO:220); Val
Allyl(Gly) Ile Gly Arg Leu (SEQ ID NO:221); Tyr Allyl(Gly) Ile Gly
Arg Leu (SEQ ID NO:222); Gly Allyl(Gly) Ile Gly Arg Leu (SEQ ID
NO:223); Asp Allyl(Gly) Ile Gly Arg Leu (SEQ ID NO:224); Trp
Allyl(Gly) Ile Gly Arg Leu (SEQ ID NO:225); Lys Allyl(Gly) Ile Gly
Arg Leu (SEQ ID NO:226); Ala Allyl(Gly) Ile Gly Arg Leu (SEQ ID
NO:227); His Allyl(Gly) Ile Gly Arg Leu (SEQ ID NO:228): Pro
Allyl(Gly) Ile Gly Arg Leu (SEQ ID NO:229); Arg Allyl(Gly) Ile Gly
Arg Leu (SEQ ID NO:230); Ile Allyl(Gly) Ile Gly Arg Leu (SEQ ID
NO:231); Met Allyl(Gly) Ile Gly Arg Leu (SEQ ID NO:232); Tyr Ile
Gly Ser Arg (SEQ ID NO:233); Phe (2-furyl)Ala Ile Gly Arg (SEQ ID
NO:234); Phe Thr Ile Gly Arg (SEQ ID NO:235); Phe StyrylGly Ile Gly
Arg Leu (SEQ ID NO:236); Phe HOCit Ile Gly Arg Leu (SEQ ID NO:237);
Phe Thr Ile Gly Arg Leu (SEQ ID NO:238); Phe (2-furyl)Ala Ile Gly
Arg Leu (SEQ ID NO:239); Phe Ile Gly Arg Leu (SEQ ID NO:240); Phe
Allyl(Gly) Ile Gly Arg Leu (SEQ ID NO:241); Arg Gly Ile Leu Phe
(SEQ ID NO:242); Gly Ile Leu Phe (SEQ ID NO:243); Leu Arg Gly Ile
Leu (SEQ ID NO:244); Leu Arg Gly (d)Ile Leu Phe (SEQ ID NO:245);
Leu Arg Gly Phe Leu Phe (SEQ ID NO:246); Leu Arg Gly Leu Leu Phe
(SEQ ID NO:247); Leu Arg Gly Ile Leu (d)Phe (SEQ ID NO:248); Leu
Arg Gly Ile (d)Leu Phe (SEQ ID NO:249); Leu (d)Arg Gly Ile Leu Phe
(SEQ ID NO:250); (d)Leu Arg Gly Ile Leu Phe (SEQ ID NO:251); Phe
Arg Gly Ile Leu Phe (SEQ ID NO:252); Leu Arg Gly Ile AllyGly Phe
(SEQ ID NO:253); Phe Allyl(Gly) Ile Gly Arg His (SEQ ID NO:254);
Phe Allyl(Gly) Ile Gly Arg Asp (SEQ ID NO:255); Phe Allyl(Gly) Ile
Gly Arg Arg (SEQ ID NO:256); Phe Allyl(Gly) Ile Gly Arg Phe (SEQ ID
NO:257); Phe Allyl(Gly) Ile Gly Arg Ala (SEQ ID NO:258); Phe
Allyl(Gly) Ile Gly Arg Gly (SEQ ID NO:259); Phe Allyl(Gly) Ile Gly
Arg Gln (SEQ ID NO:260); Phe Allyl(Gly) Ile Gly Arg Glu (SEQ ID
NO:261); Phe Allyl(Gly) Ile Gly Arg Thr (SEQ ID NO:262); Phe
Allyl(Gly) Ile Gly Arg Tyr (SEQ ID NO:263); Phe Allyl(Gly) Ile Gly
Arg Ser (SEQ ID NO:264); Phe Allyl(Gly) Ile Gly Arg Asn (SEQ ID
NO:265); Phe Allyl(Gly) Ile Gly Arg Met (SEQ ID NO:266); Phe
Allyl(Gly) Ile Gly Arg Lys (SEQ ID NO:267); Phe Allyl(Gly) Ile Gly
Arg Ile (SEQ ID NO:268); Phe Allyl(Gly) Ile Gly Arg Trp (SEQ ID
NO:269); Phe Allyl(Gly) Ile Gly Arg Pro (SEQ ID NO:270); Phe
Allyl(Gly) Ile Gly Arg Val (SEQ ID NO:271); Phe Allyl(Gly) Ile Gly
His Leu (SEQ ID NO:272); Phe Allyl(Gly) Ile Gly Asp Leu (SEQ ID
NO:273); Phe Allyl(Gly) Ile Gly Glu Leu (SEQ ID NO:274); Phe
Allyl(Gly) Ile Gly Gln Leu (SEQ ID NO:275); Phe Allyl(Gly) Ile Gly
Gly Leu (SEQ ID NO:276); Phe Allyl(Gly) Ile Gly Ala Leu (SEQ ID
NO:277); Phe Allyl(Gly) Ile Gly Phe Leu (SEQ ID NO:278); Phe
Allyl(Gly) Ile Gly Lys Leu (SEQ ID NO:279); Phe Allyl(Gly) Ile Gly
Leu Leu (SEQ ID NO:280); Phe Allyl(Gly) Ile Gly Met Leu (SEQ ID
NO:281); Phe Allyl(Gly) Ile Gly Asn Leu (SEQ ID NO:282); Phe
Allyl(Gly) Ile Gly Ser Leu (SEQ ID NO:283); Phe Allyl(Gly) Ile Gly
Tyr Leu (SEQ ID NO:284); Phe Allyl(Gly) Ile Gly Thr Leu (SEQ ID
NO:285); Phe Allyl(Gly) Ile Gly Ile Leu (SEQ ID NO:286); Phe
Allyl(Gly) Ile Gly Trp Leu (SEQ ID NO:287); Phe Allyl(Gly) Ile Gly
Pro Leu (SEQ ID NO:288); Phe Allyl(Gly) Ile Gly Val Leu (SEQ ID
NO:289); Phe N-Allyl(Gly) Ile Gly Arg Leu (SEQ ID NO:290); Phe
Allyl(Gly) Tyr Gly Arg Leu (SEQ ID NO:291); Phe Allyl(Gly) His Gly
Arg Leu (SEQ ID NO:292); Phe Allyl(Gly) Asn Gly Arg Leu (SEQ ID
NO:293); Phe Allyl(Gly) Asp Gly Arg Leu (SEQ ID NO:294); Phe
Allyl(Gly) Gln Gly Arg Leu (SEQ ID NO:295); Phe Allyl(Gly) Glu Gly
Arg Leu (SEQ ID NO:296); Phe Allyl(Gly) Lys Gly Arg Leu (SEQ ID
NO:297); Phe Allyl(Gly) Arg Gly Arg Leu (SEQ ID NO:298); Phe
Allyl(Gly) Ile Arg Arg Leu (SEQ ID NO:299); Phe Allyl(Gly) Ile Asn
Arg Leu (SEQ ID NO:300); Phe Allyl(Gly) Ile His Arg Leu (SEQ ID
NO:301); Phe Allyl(Gly) Ile Lys Arg Leu (SEQ ID NO:302); Phe
Allyl(Gly) Ile Gln Arg Leu (SEQ ID NO:303); Phe Allyl(Gly) Ile Phe
Arg Leu (SEQ ID NO:304); Phe Allyl(Gly) Ile Ser Arg Leu (SEQ ID
NO:305); Phe Allyl(Gly) Ile Val Arg Leu (SEQ ID NO:306); Phe
Allyl(Gly) Ile Asp Arg Leu (SEQ ID NO:307); Phe Allyl(Gly) Ile Glu
Arg Leu (SEQ ID NO:308); Phe N-Allyl(Gly) Ile Gly Arg (SEQ ID
NO:309); Phe N-Allyl(Gly) Ile Gly Arg Leu (SEQ ID NO:310); Benzyl
Allyl(Gly) Ile Gly Arg Leu (SEQ ID NO:311); c(Phe Allyl(Gly) Ile
Gly Arg Leu) (SEQ ID NO:312); Gly Phe Gly Ile Leu Arg (SEQ ID
NO:313); and Ile Gly Phe Leu Arg Gly (SEQ ID NO:314).
[0127] When the tight junction agonist is a peptide, any length of
peptide may be used. For example, an agonist may be about 3, about
4, about 5, about 6, about 7, about 8, about 9, about 10, about 11,
about 12, about 13, about 14 or about 15 amino acids in length. In
some embodiments, a peptide tight junction agonist may be from
about 3 to about 12, from about 4 to about 12, from about 5 to
about 12, from about 6 to about 12, from about 7 to about 12, from
about 8 to about 12, from about 9 to about 12, from about 10 to
about 12, from about 3 to about 10, from about 4 to about 10, from
about 5 to about 10, from about 6 to about 10, from about 7 to
about 10, from about 8 to about 10, from about 9 to about 10 amino
acids in length. In some embodiments, a peptide tight junction
agonist may be 9 amino acids or less in length. In some embodiments
of the invention, peptides do not encompass full length ZOT or
zonulin.
[0128] Peptide agonists can be chemically synthesized and purified
using well-known techniques, such as described in High Performance
Liquid Chromatography of Peptides and Proteins: Separation Analysis
and Conformation, Eds. Mant et al., C.R.C. Press (1991), and a
peptide synthesizer, such as Symphony (Protein Technologies, Inc.);
or by using recombinant DNA techniques, i.e., where the nucleotide
sequence encoding the peptide is inserted in an appropriate
expression vector, e.g., an E. coli or yeast expression vector,
expressed in the respective host cell, and purified from the cells
using well-known techniques.
Therapeutic Agents
[0129] Compositions of the invention typically comprise one or more
therapeutic agents and/or immunogenic agents. Therapeutic agents
that can be used in the compositions include agents that act on any
organ of the body, such as heart, brain, intestine, or kidneys.
Examples of suitable therapeutic agents include, but are not
limited to, glucose metabolism agents (e.g., insulin), antibiotics,
antineoplastics, antihypertensives, antiepileptics, central nervous
system agents, and immune system suppressants.
[0130] The particular therapeutic and/or immunogenic agent used in
the compositions of the invention can be any small molecule
compound, biologically active peptide, vaccine, or any other
moiety. In some embodiments, therapeutic agents for use in the
invention may be those that, in the absence of a tight junction
agonist, are not adequately absorbed into the bloodstream through
the skin.
[0131] Examples of drug compounds which can be employed as
therapeutic agents in the present invention include, but are not
limited to, drugs which act on the cardiovascular system, drugs
which act on the central nervous system, antineoplastic drugs and
antibiotics. Examples of drugs which act on the cardiovascular
system include, but are not limited to, antihypertensives, statins,
adenosine, dobutamine, dopamine, epinephrine, norepinephrine, and
phentolamine. Others as are known in the art can also be used.
[0132] Examples of drugs which act on the central nervous system
include, but are not limited to, doxapram, alfentanil, dezocin,
nalbuphine, buprenorphine, naloxone, ketorolac, midazolam, and
propofol. Other examples include, but are not limited to,
antipsychotics, antidepressents, antiepileptics, and drugs used to
treat Alzheimers disease. Others as are known in the art can also
be used.
[0133] Examples of antineoplastic drugs include, but are not
limited to, cytarabine, mitomycin, doxorubicin, vincristine and
vinblastine, carboplatin, cisplatin, oxaloplatin, vinorelbine,
docetaxel, paclitaxel, taxane, 5-fluorouridine related drugs,
xeloda, genncitabine, and anthracline. Additional examples include,
but are not limited to, Erbitux, Herceptin.RTM., Avastin.TM., and
estrogen receptor antagonists and agonists. Others as are known in
the art can also be used.
[0134] Examples of antibiotics include, but are not limited to,
methicillin, mezlocillin, piperacillin, cetoxitin, cefonicid,
cefinetazole and aztreonam. Others as are known in the art can also
be used.
[0135] Any type of therapeutic and/or immunogenic agent can be used
in the practice of the invention. Examples of specific types of
agents include, but are not limited to, RNAi, treatment aptamers,
antivirals amantadine, rimantadine, zanamavir and oseltamivir),
immune suppressants (e.g., cyclosporine A), HIV fusion inhibitors
(e.g., enfuvirtide), and HIV protease inhibitors, (e.g., ritonavir,
saquinavir, indinavir, amprenavir, nelfinavir, lopinavir,
atazanavir, entricitabine, and fosamprenavir calcium).
[0136] Examples of biologically active peptides that may be used as
therapeutic agents in the practice of the present invention
include, but are not limited to, hormones, lymphokines, globulins,
and albumins. Examples of hormones which can be employed in the
present invention include: testosterone, nandrolene, menotropins,
insulin and urofolltropin. Other examples of biologically active
peptides include: insulin modified by chemical or enzymatic means
(including mutations introduced using recombinant DNA technology),
parathyroid hormone, parathyroid hormone antagonist, calcitonin,
vasopressin, renin, prolactin, growth hormone, thyroid stimulating
hormone, corticotropin, corticotropin-releasing factor, follicle
stimulating hormone, luteinizing hormone, chorionic gonadotropin,
atrial peptides, interferon, tissue plasminogen activator,
gammaglobulins, Factor VII, Factor VIII, growth hormone releasing
hormone, luteinizing hormone releasing hormone, somatostatin and
cholecystokinins. Others as are known in the art can also be used.
If the biologically active ingredient is insulin and/or an insulin
derivative, the transcutaneous dosage composition is useful for the
treatment of diabetes.
[0137] Examples of lymphokines which can be employed in the present
invention include interferon-.alpha., interferon-.beta.,
interferon-.gamma., interleukin-1, interleukin-2, interleukin-4 and
interleukin-8.
[0138] Examples of globulins include .alpha.-globulins,
.beta.-globulins and .gamma.-globulins (immunoglobulin). Examples
of immunoglobulins which can be employed in the present invention
include polyvalent IgG or specific IgG, IgA and IgM, e.g.,
anti-tetanus antibodies. An example of albumin which can be used is
human serum albumin. Others as are known in the art can also be
used.
[0139] Examples of antigens that can be used in the compositions of
the invention (e.g., immunogenic and/or vaccine compositions)
include peptides, proteins, microorganisms (e.g., attenuated and/or
recombinant microorganisms), cells (e.g., cancer cells and/or
recombinant cells) and viruses (e.g., attenuated and/or recombinant
viruses). Examples of peptide antigens include the B subunit of the
heat labile enterotoxin of enterotoxigenic E. coli, the B subunit
of cholera toxin, capsular antigens of enteric pathogens, fimbriae
or pili of enteric pathogens, HIV surface antigens, cancer antigens
(e.g., cancer cells comprising antigens, isolated antigens, etc.),
dust allergens, and acari allergens. Other immunogenic compounds as
are known in the art can also be used.
[0140] Examples of attenuated microorganisms and viruses that can
be used in the compositions of the invention (e.g., vaccine
compositions) include those of enterotoxigenic Escherichia coli,
enteropathogenic Escherichia coli, Vibrio cholerae, Shigella
flexneri, Salmonella typhi and rotavirus (Fasano et al, In: Le
Vaccinazioni in Pediatria, Eds. Vierucci et al, CSH, Milan, pages
109-121 (1991); Guandalini et al, In: Management of Digestive and
Liver Disorders in Infants and Children, Elsevior, Eds. Butz et al,
Amsterdam, Chapter 25 (1993): Levine et al, Sem. Fed. Infect. Dis.,
5.243-250 (1994); and Kaper et al, Clin. Micrbiol. Rev., 8:48-86
(1995), each of which is incorporated by reference herein in its
entirety).
[0141] Any antigen capable of inducing a protective immune response
may be used in the vaccines of the invention. Examples of suitable
antigens include, but are not limited to, measles virus antigens,
mumps virus antigens, rubella virus antigens, Corynebacterium
diphtheriae antigens, Bordetella pertussis antigens, Clostridium
tetani antigens, Bacillus anthracis antigens, Haemophilus
influenzae antigens, smallpox virus antigens, and influenza virus
antigens.
Formulations
[0142] Compositions of the invention may formulated for
transcutaneous delivery (e.g., may be transcutaneous dosage forms).
Typically such compositions may be provided as topical solutions
and/or gels. Those of skill in the art are aware of many different
methods and devices for the formation of topical medications, for
example, those disclosed by Block, Medicated Topicals, in
Remington: The Science and Practice of Pharmacy, 20th Ed., Chapter
44, Gennaro et al. Eds., Lippincott, Williams and Wilkins
Publishing Co., (2000).
[0143] Typically, compositions comprising a tight junction agonist
(e.g., peptide agonist) comprise a pharmaceutically effective
amount of the agonist. The pharmaceutically effective amount of
agonist (e.g., peptide agonist) employed may vary according to
factors such as the disease state, age, sex, and weight of the
individual. Dosage regimens may be adjusted to provide the optimum
therapeutic response. For example, a single bolus may be
administered, several divided doses may be administered over time
or the dose may be proportionally reduced or increased as indicated
by the exigencies of the therapeutic situation.
[0144] Compositions of the invention may comprise one or tight
junction agonist at a level of from about 0.000001 wt % to about 50
wt %, from about 0.000001 wt % to about 45 wt %, from about
0.000001 wt % to about 40 wt %, from about 0.000001 wt % to about
35 wt %, from about 0.000001 wt % to about 30 wt %, from about
0.000001 wt % to about 25 wt %, from about 0.000001 wt % to about
20 wt %, from about 0.000001 wt % to about 15 wt %, from about
0.000001 wt % to about 10 wt %, from about 0.000001 wt % to about 5
wt %, from about 0.000001 wt % to about 2.5 wt %, from about
0.000001 wt % to about 1 wt %, from about 0.000001 wt % to about
0.1 wt %, from about 0.000001 wt % to about 0.01 wt %, from about
0.000001 wt % to about 0.001 wt %, from about 0.000001 wt % to
about 0.0001 wt %, from about 0.000001 wt % to about 0.00005 wt %,
from about 0.0001 wt % to about 50 wt %, from about 0.0001 wt % to
about 45 wt %, from about 0.0001 wt % to about 40 wt %, from about
0.0001 wt % to about 35 wt %, from about 0.0001 wt % to about 30 wt
%, from about 0.0001 wt % to about 25 wt %, from about 0.0001 wt %
to about 20 wt %, from about 0.0001 wt % to about 15 wt %, from
about 0.0001 wt % to about 10 wt %, from about 0.0001 wt % to about
5 wt %, from about 0.0001 wt % to about 2.5 wt %, from about 0.0001
wt % to about 1 wt %. from about 0.0001 wt % to about 0.1 wt %,
from about 0.0001 wt % to about 0.01 wt %, from about 0.0001 wt %
to about 0.001 wt %, from about 0.0001 wt % to about 0.0005 wt %,
from about 0.1 wt % to about 50 wt %, from about 0.1 wt % to about
45 wt %, from about 0.1 wt % to about 40 wt %, from about 0.1 wt %
to about 35 wt %, from about 0.1 wt % to about 30 wt %, from about
0.1 wt % to about 25 wt %, from about 0.1 wt % to about 20 wt %,
from about 0.1 wt % to about 15 wt %, from about 0.1 wt % to about
10 wt %, from about 0.1 wt % to about 5 wt %, from about 0.1 wt %
to about 2.5 wt %, from about 0.1 wt % to about 1 wt %, from about
0.1 wt % to about 0.5 wt %, from about 0.1 wt % to about 0.2 wt %,
from about 1 wt % to about 50 wt %, from about 1 wt % to about 45
wt %, from about 1 wt % to about 40 wt %. from about 1 wt % to
about 35 wt %, from about 1 wt % to about 30 wt %, from about 1 wt
% to about 25 wt %, from about 1 wt % to about 20 wt %, from about
1 wt % to about 15 wt %, from about 1 wt % to about 10 wt %, from
about 1 wt % to about 5 wt %, from about 1 wt % to about 2.5 wt %,
from about 5 wt % to about 50 wt %, from about 5 wt % to about 45
wt %, from about 5 wt % to about 40 wt %, from about 5 wt % to
about 35 wt %, from about 5 wt % to about 30 wt %, from about 5 wt
% to about 25 wt %, from about 5 wt % to about 20 wt %, from about
5 wt % to about 15 wt %, from about 5 wt % to about 10 wt %, from
about 5 wt % to about 9 wt %, from about 5 wt % to about 8 wt %,
from about 5 wt % to about 7 wt %, or from about 5 wt % to about 6
wt % of the total weight of the composition. Compositions of the
invention may comprise one or more tight junction agonists at a
level of about 0.00001 wt %, about 0.00005 wt %, about 0.0001 wt %,
about 0.0005 wt %, about 0.001 wt %, about 0.005 wt %, about 0.01
wt %, about 0.05 wt %, about 0.1 wt %, about 0.5 wt %, about 1 wt
%, about 5 wt %, about 10 wt %, about 15 wt %, about 20 wt %, about
25 wt %, about 30 wt %, about 35 wt %, about 40 wt %, about 45 wt
%, or about 50 wt % based on the total weight of the
composition.
[0145] Compositions of the invention may comprise one or more
therapeutic agents and/or immunogenic agents at a concentration
sufficient to cause the desired biological response (e.g., at a
pharmaceutically effective concentration). Compositions of the
invention may comprise one or therapeutic and/or immunogenic agents
at a level of from about 0.1 wt % to about 50 wt %, from about 0.1
wt % to about 45 wt %, from about 0.1 wt % to about 40 wt %, from
about wt % to about 35 wt %, from about 0.1 wt % to about 30 wt %,
from about 0.1 wt % to about 25 wt %, from about 0.1 wt % to about
20 wt %, from about 0.1 wt % to about 15 wt %, from about 0.1 wt %
to about 10 wt %, from about 0.1 wt % to about 5 wt %, from about
0.1 wt % to about 2.5 wt %, from about 0.1 wt % to about 1 wt %,
from about 0.1 wt % to about 0.5 wt %, from about 0.1 wt % to about
0.2 wt %, from about 1 wt % to about 50 wt %. from about 1 wt % to
about 45 wt %, from about 1 wt % to about 40 wt %, from about 1 wt
% to about 35 wt %, from about 1 wt % to about 30 wt %, from about
1 wt % to about 25 wt %, from about 1 wt % to about 20 wt %. from
about 1 wt % to about 15 wt %, from about 1 wt % to about 10 wt %,
from about 1 wt % to about 5 wt %, from about 1 wt % to about 2.5
wt %, from about 5 wt % to about 50 wt %, from about 5 wt % to
about 45 wt %, from about 5 wt % to about 40 wt %, from about 5 wt
% to about 35 wt %, from about 5 wt % to about 30 wt %, from about
5 wt % to about 25 wt %, from about 5 wt % to about 20 wt %, from
about 5 wt % to about 15 wt %, from about 5 wt % to about 10 wt %,
from about 5 wt % to about 9 wt %, from about 5 wt % to about 8 wt
%, from about 5 wt % to about 7 wt %, or from about 5 wt % to about
6 wt % of the total weight of the composition. Compositions of the
invention may comprise one or more therapeutic and/or immunogenic
agents at a level of about 0.1 wt %, about 1 wt %, about 5 wt %,
about 10 wt %, about 15 wt %, about 20 wt %, about 25 wt %, about
30 wt %, about 35 wt %, about 40 wt %. about 45 wt %. or about 50
wt % based on the total weight of the composition.
[0146] Compositions of the invention may comprise one or
pharmaceutically acceptable excipients at a level of from about 0.1
wt % to about 50 wt %, from about 0.1 wt % to about 45 wt %, from
about 0.1 wt % to about 40 wt %, from about wt % to about 35 wt %,
from about 0.1 wt % to about 30 wt %, from about 0.1 wt % to about
25 wt %, from about 0.1 wt % to about 20 wt %, from about 0.1 wt %
to about 15 wt %, from about 0.1 wt % to about 10 wt %. from about
0.1 wt % to about 5 wt %, from about 0.1 wt % to about 2.5 wt %,
from about 0.1 wt % to about 1 wt %, from about 0.1 wt % to about
0.5 wt %, from about 0.1 wt % to about 0.2 wt %, from about 1 wt %
to about 50 wt %, from about 1 wt % to about 45 wt %, from about 1
wt % to about 40 wt %, from about 1 wt % to about 35 wt %, from
about 1 wt % to about 30 wt %, from about 1 wt % to about 25 wt %,
from about I wt % to about 20 wt %, from about 1 wt % to about 15
wt %, from about 1 wt % to about 10 wt %, from about 1 wt % to
about 5 wt %, from about 1 wt % to about 2.5 wt %, from about 5 wt
% to about 50 wt %, from about 5 wt % to about 45 wt %, from about
5 wt % to about 40 wt %, from about 5 wt % to about 35 wt %, from
about 5 wt % to about 30 wt %, from about 5 wt % to about 25 wt %,
from about 5 wt % to about 20 wt %, from about 5 wt % to about 15
wt %, from about 5 wt % to about 10 wt %, from about 5 wt % to
about 9 wt %, from about 5 wt % to about 8 wt %, from about 5 wt %
to about 7 wt %, or from about 5 wt % to about 6 wt % of the total
weight of the composition. Compositions of the invention may
comprise one or more pharmaceutically acceptable excipients at a
level of about 0.1 wt %, about 1 wt %, about 5 wt %, about 10 wt %,
about 15 wt %, about 20 wt %, about 25 wt %, about 30 wt %, about
35 wt %, about 40 wt %, about 45 wt %, or about 50 wt % based on
the total weight of the composition.
Methods of Use
[0147] The pharmaceutical compositions of the invention can be used
for treating, ameliorating, and/or preventing a disease. Any
disease may be treated using the compositions of the invention by
selection of an appropriate therapeutic and/or immunogenic agent.
In one embodiment, the present invention provides a method of
treating diabetes by administering a composition comprising one or
more tight junction agonist and one or more insulin and/or
derivative thereof to the skin of a subject in need of the
treatment.
[0148] Examples of diseases that can be treated using the
compositions of the invention include, but are not limited to,
cancer, autoimmune diseases, vascular disease, bacterial
infections, gastritis, gastric cancer, collagnenous colitis,
inflammatory bowel disease, osteoporosis, systemic lupus
erythematosus, food allergy, asthma, and irritable bowel syndrome.
For example, to treat cancer of the colon or rectal area, a
composition comprising a therapeutically effective amount of
Erbitux (Cetuximab) and an absorption enhancing amount of one or
more tight junction agonists may be administered to the skin of a
patient in need thereof, to treat breast cancer, a composition
comprising a therapeutically effective amount of Herceptin
(Trastuzumab) and an absorption enhancing amount of one or more
tight junction agonists may be administered to the skin of a
patient in need thereof, and to treat various types of cancer, a
composition comprising a therapeutically effective amount of
Avastin (Bevacizumab) and an absorption enhancing amount of one or
more tight junction agonist may be administered to the skin of a
patient in need thereof. Further examples include treatment of
osteoporosis using a composition comprising one or more tight
junction agonists and a therapeutically effective amount of Fosamax
(Alendronate) administered to the skin of a subject in need
thereof, treatment of transplant rejection using a composition
comprising one or more tight junction agonists and a
therapeutically effective amount of Cyclosporin A administered to
the skin of a subject in need thereof, treatment of anemia using a
composition comprising one or more tight junction agonists and a
therapeutically effective amount of erythropoietin administered to
the skin of a subject in need thereof, and treatment of hemophilia
using a composition comprising one or more tight junction agonists
and a therapeutically effective amount of Factor VIII administered
to the skin of a subject in need thereof.
[0149] The following examples are provided for illustrative
purposes only, and are in no way intended to limit the scope of the
present invention.
EXAMPLES
[0150] The experiments described in the attached figures were
performed with tight junction agonist peptide FCIGRL also known as
AT1002.
Example 1
[0151] Transcutaneous Immunization (TCl)
[0152] Groups of 5 female Balbc mice (8-10 weeks) were immunized
transcutaneously at 0, 4 and 8 weeks with TT alone (25 .mu.g/dose)
or together with AT-1002 (0.03-300 .mu.g/dose). For TCI, mice were
anesthetized intraperitoneally, for approximately 1 hour, with a
ketamine-xylazine mixture to prevent self grooming. A small surface
area of the abdomen was shaved and the hair was then completely
removed by application of a depilatory cream (Nair) for 2 minutes.
The cream was removed with cotton wool soaked in warm water and the
prepared skin surface was hydrated with PBS for 5 minutes. 50-100
.mu.l of immunizing solution was applied evenly over the exposed
skin and left for up to 1 hr to absorb through the skin. The mice
were then washed thoroughly with lukewarm water and patted dry.
Example 2
[0153] Antibody Assay
[0154] Total IgG antibody levels against TT were determined using
an in-house Enzyme-Linked Immunosorbent assay. Results were
analyzed using parallel-line analysis and antibody levels were
expressed in IU/ml against in-house standard 98572 (Tetanus potency
3.5 IU/ml). FIGS. 4A and 4B show anti-tetanus IgG titers in
individual animals in experiment 1 after 6 and 10 weeks
respectively. FIG. 5 shows anti-tetanus IgG titers of pooled sera
for each immunization group after 6 and 10 weeks in experiment 1.
Data represent the mean.+-.SEM (n=5 per group). IgG1 and IgG2a
subclasses were measured in a similar manner by comparison with
appropriate purified mouse immunoglobulins, and their levels were
expressed as .mu.gml. FIG. 6 shows anti-tetanus IgG1 and IgG2a
titers of pooled sera for each immunization group after 6 and 10
weeks in experiment 1. FIGS. 11A and 11B show anti-tetanus IgG
titers in individual animals in experiment 2 after 6 and 10 weeks
respectively. FIG. 12 shows anti-tetanus IgG titres of pooled sera
for each immunization group after 6 and 10 weeks in experiment 2.
Data represent the mean.+-.SEM (n=5 per group).
[0155] FIGS. 19A and 19B shows anti-tetanus IgG titers in
individual animals in experiment 1 after 6 and 10 weeks
respectively. FIG. 20 shows anti-tetanus IgG titres of pooled sera
for each immunization group after 6 and 10 weeks in experiment 3.
Data represent the mean.+-.SEM (n=6 per group except for TT group
(n=5)).
Example 3
[0156] In Vivo Toxin Neutralization (TNT) Assay
[0157] The neutralizing capacity of anti-TT antibodies in pooled
sera was measured in mice, using onset of paralysis as an endpoint.
The neutralizing potency of the serum samples was expressed in
IU/ml, measured against the WHO International Standard TE-3
antitoxin. The results from experiemtns 1 and 2 are shown in Tables
1 and 2 respectively.
TABLE-US-00001 TABLE 1 In vivo toxin neutralization assay -
Experiment 1 Tetanus Tetanus IgG Neutralizing Ab (ELISA, IU/ml)
Group Immunization Details (IU/ml) Pooled sera A TT 02/126 0.31
0.31 B TT + CT 15.7 13.81 C TT + AT1002 (25 .mu.g) 1.85 2.08 D TT +
AT1002 (75 .mu.g) ND 0.80 I AT1002 (75 .mu.g) <0.07 <0.01 J
PBS <0.07 <0.01
[0158] Neutralizing antibody titers were determined by challenge
with tetanus toxin in vivo as descroibed above. Each data point
rerpresents the measurement for the pooled sera from the terminal
bleed samples (week 10) obtained for each immunization treatment
group. Mouse model of paralysis was used with International
Standards of IU.
[0159] (Immunization with TT in combination with AT1002 (25 .mu.g)
increased the protective antibody levels six-fold compared to TF
treatment alone. This response was approximately 200-fold higher
than the minimal protective level (0.01 IU/ml is considered
protective).
TABLE-US-00002 TABLE 2 In vivo toxin neutralization assay -
Experiment 2 Tetanus Tetanus IgG Neutralizing Ab (ELISA, IU/ml)
Group Immunization Details (IU/ml) Pooled sera A TT + AT1002 (300
.mu.g) 1.10 2.38 B TT + AT1002 (30 .mu.g) <0.55 0.96 C TT +
AT1002 (3 .mu.g) 0.25 0.61 D TT + AT1002 (0.3 .mu.g) <0.13* 0.26
E TT + AT1002 (0.03 .mu.g) 0.07 0.10 F TT 02/126 <0.18 0.23 G
PBS <0.02 0.003 H AT1002 (300 .mu.g) <0.02 0.003 *End point
not established.
[0160] AT-1002 (top dose) increased protective antibody levels
compared to immunization with TT alone. Response to immunization
with TT+AT1002 (300 .mu.g) .about.100 fold higher than minimum
protctive level (0.01 IU/ml considered protective).
Example 4
[0161] Spleen Cell Proliferation Assay
[0162] Single cell suspensions were prepared from spleens of
individual mice and viable splenocytes (2.times.10.sup.5 per well,
96 well plate) were re-stimulated with TT (0.1-100 .mu.g/ml). After
4 days, cells were pulsed with 0.5 mCi/well [.sup.3H]-thymidine and
harvested onto glass fibre filter mats. Antigen-specific
proliferation was determined by measuring the radioactivity
incorporated into cellular DNA. Results were expressed as
stimulation indices (SI) of the mean cpm obtained from triplicate
cultures in the presence of specific antigen divided by the mean
cpm of triplicate cultures incubated in medium only. A SI>2 is
considered positive. FIGS. 7, 13, 17 and 21 shows spleen cell
proliferation following re-stimulation with TT in experiemtns 1, 2
and 3. Data represent the mean.+-.SEM from three spleen cell
cultures per group.
Example 5
[0163] Cytokine Assay
[0164] Spleen cells (2.times.10.sup.6 per well, 24 well plate) were
cultured overnight prior to re-stimulation with TT for a further 72
hrs. Concentrations of IFN-.gamma. and IL-6 in culture supernatants
were measured using ELISA kits (BD Biosciences), as per the
manufactures instructions. Cytokine levels were expressed as pg/ml
as measured against relevant cytokine standards. FIGS. 8A, 14A and
18A show production of IL-6 in splenocytes following re-stimulation
with TT (0-100 .mu.g/ml). Data represent the mean.+-.SEM from three
spleen cell cultures per group. *p<0.05, **p<0.01 vs TT
alone. FIGS. 8B, 14B and 18B show production of IFN-.gamma. in
splenocytes following re-stimulation with TT (0-100 .mu.g/ml) after
immunization of mice with TT in the presence and absence of
adjuvant. Data represent the mean.+-.SEM from three spleen cell
cultures per group.
[0165] While the invention has been described in detail, and with
reference to specific embodiments thereof, it will be apparent to
one of ordinary skill in the art that various changes and
modifications can be made therein without departing from the spirit
and scope thereof and such changes and modifications may be
practiced within the scope of the appended claims. All patents and
publications herein are incorporated by reference to the same
extent as if each individual publication was specifically and
individually indicated to be incorporated by reference in their
entirety.
Sequence CWU 1
1
31416PRTUnknownTight junction agonist peptide 1Phe Cys Ile Gly Arg
Leu 1 5 26PRTUnknownTight junction agonist peptide 2Xaa Cys Ile Gly
Arg Leu 1 5 36PRTUnknownTight junction agonist peptide 3Phe Xaa Ile
Gly Arg Leu 1 5 46PRTUnknownTight junction agonist peptide 4Phe Cys
Xaa Gly Arg Leu 1 5 56PRTUnknownTight junction agonist peptide 5Phe
Cys Ile Xaa Arg Leu 1 5 66PRTUnknownTight junction agonist peptide
6Phe Cys Ile Gly Xaa Leu 1 5 76PRTUnknownTight junction agonist
peptide 7Phe Cys Ile Gly Arg Xaa 1 5 86PRTUnknownTight junction
agonist peptide 8Xaa Xaa Ile Gly Arg Leu 1 5 96PRTUnknownTight
junction agonist peptide 9Xaa Cys Xaa Gly Arg Leu 1 5
106PRTUnknownTight junction agonist peptide 10Xaa Cys Ile Xaa Arg
Leu 1 5 116PRTUnknownTight junction agonist peptide 11Xaa Cys Ile
Gly Xaa Leu 1 5 126PRTUnknownTight junction agonist peptide 12Xaa
Cys Ile Gly Arg Xaa 1 5 136PRTUnknownTight junction agonist peptide
13Phe Xaa Xaa Gly Arg Leu 1 5 146PRTUnknownTight junction agonist
peptide 14Phe Xaa Ile Xaa Arg Leu 1 5 156PRTUnknownTight junction
agonist peptide 15Phe Xaa Ile Gly Xaa Leu 1 5 166PRTUnknownTight
junction agonist peptide 16Phe Xaa Ile Gly Arg Xaa 1 5
176PRTUnknownTight junction agonist peptide 17Phe Cys Xaa Xaa Arg
Leu 1 5 186PRTUnknownTight junction agonist peptide 18Phe Cys Xaa
Gly Xaa Leu 1 5 196PRTUnknownTight junction agonist peptide 19Phe
Cys Xaa Gly Arg Xaa 1 5 206PRTUnknownTight junction agonist peptide
20Phe Cys Ile Xaa Xaa Leu 1 5 216PRTUnknownTight junction agonist
peptide 21Phe Cys Ile Xaa Arg Xaa 1 5 226PRTUnknownTight junction
agonist peptide 22Phe Cys Ile Gly Xaa Xaa 1 5 235PRTUnknownTight
junction agonist peptide 23Cys Ile Gly Arg Leu 1 5
244PRTUnknownTight junction agonist peptide 24Ile Gly Arg Leu 1
255PRTUnknownTight junction agonist peptide 25Phe Cys Ile Gly Arg 1
5 264PRTUnknownTight junction agonist peptide 26Phe Cys Ile Gly 1
276PRTUnknownTight junction agonist peptide 27Ala Cys Ile Gly Arg
Leu 1 5 286PRTUnknownTight junction agonist peptide 28Phe Ala Ile
Gly Arg Leu 1 5 296PRTUnknownTight junction agonist peptide 29Phe
Cys Ala Gly Arg Leu 1 5 306PRTUnknownTight junction agonist peptide
30Phe Cys Ile Ala Arg Leu 1 5 316PRTUnknownTight junction agonist
peptide 31Phe Cys Ile Gly Ala Leu 1 5 326PRTUnknownTight junction
agonist peptide 32Phe Cys Ile Gly Arg Ala 1 5 336PRTUnknownTight
junction agonist peptide 33Phe Cys Ile Gly Arg Leu 1 5
346PRTUnknownTight junction agonist peptide 34Pro Cys Ile Gly Arg
Leu 1 5 356PRTUnknownTight junction agonist peptide 35Gln Cys Ile
Gly Arg Leu 1 5 366PRTUnknownTight junction agonist peptide 36Gly
Cys Ile Gly Arg Leu 1 5 376PRTUnknownTight junction agonist peptide
37Thr Cys Ile Gly Arg Leu 1 5 386PRTUnknownTight junction agonist
peptide 38Ser Cys Ile Gly Arg Leu 1 5 396PRTUnknownTight junction
agonist peptide 39Xaa Cys Ile Gly Arg Leu 1 5 406PRTUnknownTight
junction agonist peptide 40Asn Cys Ile Gly Arg Leu 1 5
416PRTUnknownTight junction agonist peptide 41Arg Cys Ile Gly Arg
Leu 1 5 426PRTUnknownTight junction agonist peptide 42Xaa Cys Ile
Gly Arg Leu 1 5 436PRTUnknownTight junction agonist peptide 43Xaa
Cys Ile Gly Arg Leu 1 5 446PRTUnknownTight junction agonist peptide
44Xaa Cys Ile Gly Arg Leu 1 5 456PRTUnknownTight junction agonist
peptide 45Phe Xaa Ile Gly Arg Leu 1 5 466PRTUnknownTight junction
agonist peptide 46Phe Xaa Ile Gly Arg Leu 1 5 476PRTUnknownTight
junction agonist peptide 47Phe Thr Ile Gly Arg Leu 1 5
486PRTUnknownTight junction agonist peptide 48Phe Xaa Ile Gly Arg
Leu 1 5 496PRTUnknownTight junction agonist peptide 49Phe Ser Ile
Gly Arg Leu 1 5 506PRTUnknownTight junction agonist peptide 50Phe
Xaa Ile Gly Arg Leu 1 5 516PRTUnknownTight junction agonist peptide
51Phe Xaa Ile Gly Arg Leu 1 5 526PRTUnknownTight junction agonist
peptide 52Phe Cys Ile Gly Arg Leu 1 5 536PRTUnknownTight junction
agonist peptide 53Phe Met Ile Gly Arg Leu 1 5 546PRTUnknownTight
junction agonist peptide 54Xaa Cys Ile Gly Arg Leu 1 5
556PRTUnknownTight junction agonist peptide 55Val Cys Ile Gly Arg
Leu 1 5 566PRTUnknownTight junction agonist peptide 56Xaa Cys Ile
Gly Arg Leu 1 5 576PRTUnknownTight junction agonist peptide 57Phe
Cys Ile Gly Arg Gly 1 5 586PRTUnknownTight junction agonist peptide
58Ala Cys Ile Gly Arg Gly 1 5 596PRTUnknownTight junction agonist
peptide 59Ala Cys Ile Gly Arg Gly 1 5 606PRTUnknownTight junction
agonist peptide 60Phe Cys Ile Gly Arg Gly 1 5 616PRTUnknownTight
junction agonist peptide 61Phe Cys Ile Gly Arg Gly 1 5
626PRTUnknownTight junction agonist peptide 62Phe Cys Ile Gly Arg
Ser 1 5 636PRTUnknownTight junction agonist peptide 63Phe Cys Ile
Gly Arg Gln 1 5 646PRTUnknownTight junction agonist peptide 64Phe
Cys Ile Gly Arg Leu 1 5 656PRTUnknownTight junction agonist peptide
65Phe Cys Ile Gly Arg Lys 1 5 666PRTUnknownTight junction agonist
peptide 66Phe Cys Ile Gly Arg Ala 1 5 676PRTUnknownTight junction
agonist peptide 67Phe Cys Ile Gly Arg Ile 1 5 686PRTUnknownTight
junction agonist peptide 68Phe Cys Ile Gly Arg Gly 1 5
696PRTUnknownTight junction agonist peptide 69Phe Cys Ile Gly Arg
Xaa 1 5 706PRTUnknownTight junction agonist peptide 70Phe Cys Ile
Gly Arg Xaa 1 5 716PRTUnknownTight junction agonist peptide 71Phe
Cys Ile Gly Arg Xaa 1 5 726PRTUnknownTight junction agonist peptide
72Phe Cys Ile Gly Arg Asp 1 5 736PRTUnknownTight junction agonist
peptide 73Phe Cys Ile Gly Arg Xaa 1 5 746PRTUnknownTight junction
agonist peptide 74Phe Cys Ile Gly Arg Xaa 1 5 756PRTUnknownTight
junction agonist peptide 75Phe Cys Ile Gly Arg Glu 1 5
766PRTUnknownTight junction agonist peptide 76Phe Cys Ile Gly Arg
Xaa 1 5 776PRTUnknownTight junction agonist peptide 77Phe Cys Ile
Gly Arg Phe 1 5 786PRTUnknownTight junction agonist peptide 78Phe
Cys Ile Gly Arg Asn 1 5 796PRTUnknownTight junction agonist peptide
79Phe Cys Ile Gly Arg Pro 1 5 806PRTUnknownTight junction agonist
peptide 80Glu Cys Ile Gly Arg Leu 1 5 816PRTUnknownTight junction
agonist peptide 81Asp Cys Ile Gly Arg Leu 1 5 826PRTUnknownTight
junction agonist peptide 82Phe Cys Ile Gly Arg Xaa 1 5
836PRTUnknownTight junction agonist peptide 83Xaa Cys Ile Gly Arg
Leu 1 5 846PRTUnknownTight junction agonist peptide 84Lys Cys Ile
Gly Arg Leu 1 5 856PRTUnknownTight junction agonist peptide 85Xaa
Cys Ile Gly Arg Leu 1 5 867PRTUnknownTight junction agonist peptide
86Phe Cys Ile Gly Arg Leu Cys 1 5 8713PRTUnknownTight junction
agonist peptide 87Leu Gly Gln Gln Gln Pro Phe Pro Pro Gln Gln Pro
Tyr 1 5 10 886PRTUnknownTight junction agonist peptide 88Phe Xaa
Ile Gly Arg Leu 1 5 896PRTUnknownTight junction agonist peptide
89Phe Xaa Ile Gly Arg Leu 1 5 906PRTUnknownTight junction agonist
peptide 90Pro Gly Pro Gly Arg Leu 1 5 916PRTUnknownTight junction
agonist peptide 91Phe Cys Ile Pro Gly Pro 1 5 926PRTUnknownTight
junction agonist peptide 92Phe Cys Leu Gly Arg Leu 1 5
9311PRTUnknownTight junction agonist peptide 93Phe Cys Ile Gly Gly
Val Leu Val Gln Pro Gly 1 5 10 946PRTUnknownTight junction agonist
peptide 94Gly Cys Ile Gly Arg Gly 1 5 956PRTUnknownTight junction
agonist peptide 95Tyr Cys Ile Gly Arg Leu 1 5 966PRTUnknownTight
junction agonist peptide 96Phe Cys Ile Gly Xaa Leu 1 5
976PRTUnknownTight junction agonist peptide 97Ala Cys Ile Gly Arg
Leu 1 5 986PRTUnknownTight junction agonist peptide 98Trp Cys Ile
Gly Arg Leu 1 5 996PRTUnknownTight junction agonist peptide 99Ala
Cys Ile Gly Arg Ser 1 5 1006PRTUnknownTight junction agonist
peptide 100Ala Cys Ile Gly Arg Ala 1 5 1016PRTUnknownTight junction
agonist peptide 101Xaa Cys Ile Gly Arg Leu 1 5 1026PRTUnknownTight
junction agonist peptide 102Xaa Cys Ile Gly Arg Leu 1 5
1036PRTUnknownTight junction agonist peptide 103Phe Cys Ile Gly Arg
Xaa 1 5 1046PRTUnknownTight junction agonist peptide 104Phe Cys Ile
Gly Arg Xaa 1 5 1056PRTUnknownTight junction agonist peptide 105Phe
Cys Ile Gly Arg Phe 1 5 1066PRTUnknownTight junction agonist
peptide 106Xaa Cys Ile Gly Arg Leu 1 5 1076PRTUnknownTight junction
agonist peptide 107Ser Leu Ile Gly Arg Leu 1 5 1086PRTUnknownTight
junction agonist peptide 108Leu Arg Gly Ile Cys Phe 1 5
1096PRTUnknownTight junction agonist peptide 109Leu Arg Gly Ile Cys
Phe 1 5 1106PRTUnknownTight junction agonist peptide 110Leu Arg Gly
Ile Cys Phe 1 5 1116PRTUnknownTight junction agonist peptide 111Leu
Arg Gly Ile Cys Phe 1 5 1126PRTUnknownTight junction agonist
peptide 112Phe Cys Ile Gly Arg Leu 1 5 1136PRTUnknownTight junction
agonist peptide 113Phe Cys Xaa Gly Arg Leu 1 5 1146PRTUnknownTight
junction agonist peptide 114Phe Cys Ile Gly Arg Xaa 1 5
1156PRTUnknownTight junction agonist peptide 115Xaa Cys Ile Gly Arg
Leu 1 5 1166PRTUnknownTight junction agonist peptide 116Leu Arg Gly
Ile Cys Phe 1 5 1176PRTUnknownTight junction agonist peptide 117Phe
Cys Ile Gly Arg Leu 1 5 1186PRTUnknownTight junction agonist
peptide 118Phe Cys Ile Gly Arg Leu 1 5 1196PRTUnknownTight junction
agonist peptide 119Phe Cys Ile Gly Arg Leu 1 5 1206PRTUnknownTight
junction agonist peptide 120Phe Cys Ile Gly Arg Leu 1 5
1216PRTUnknownTight junction agonist peptide 121Phe Cys Ile Gly Arg
Leu 1 5 1226PRTUnknownTight junction agonist peptide 122Leu Arg Gly
Ile Cys Phe 1 5 1236PRTUnknownTight junction agonist peptide 123Leu
Arg Gly Ile Cys Phe 1 5 1246PRTUnknownTight junction agonist
peptide 124Leu Arg Gly Ile Cys Phe 1 5 1256PRTUnknownTight junction
agonist peptide 125Leu Arg Gly Ile Cys Phe 1 5 1266PRTUnknownTight
junction agonist peptide 126Phe Cys Ile Gly Arg Leu 1 5
1276PRTUnknownTight junction agonist peptide 127Leu Arg Gly Ile Cys
Phe 1 5 1286PRTUnknownTight junction agonist peptide 128Leu Arg Gly
Ile Cys Phe 1 5 1296PRTUnknownTight junction agonist peptide 129Leu
Arg Gly Ile Cys Phe 1 5 1306PRTUnknownTight junction agonist
peptide 130Phe Xaa Ile Gly Arg Ala 1 5 1316PRTUnknownTight junction
agonist peptide 131Phe Xaa Ile Gly Arg Ser 1 5 1326PRTUnknownTight
junction agonist peptide 132Phe Xaa Ile Gly Arg Phe 1 5
1336PRTUnknownTight junction agonist peptide 133Phe Cys Ile Gly Arg
Xaa 1 5 1346PRTUnknownTight junction agonist peptide 134Phe Xaa Ile
Gly Arg Phe 1 5 1356PRTUnknownTight junction agonist peptide 135Phe
Xaa Ile Gly Arg Leu 1 5 1366PRTUnknownTight junction agonist
peptide 136Phe Xaa Ile Gly Arg Leu 1 5 1376PRTUnknownTight junction
agonist peptide 137Phe Leu Ile Gly Arg Leu 1 5 1387PRTUnknownTight
junction agonist peptide 138Phe Phe Leu Ile Gly Arg Leu 1 5
1396PRTUnknownTight junction agonist peptide 139Phe Phe Ile Gly Arg
Leu 1 5 1406PRTUnknownTight junction agonist peptide 140Phe Xaa Ile
Gly Arg Leu 1 5 1416PRTUnknownTight junction agonist peptide 141Phe
Pro Ile Gly Arg Leu 1 5 1426PRTUnknownTight junction agonist
peptide 142Phe Val Ile Gly Arg Leu 1 5 1436PRTUnknownTight junction
agonist peptide 143Phe Xaa Ile Gly Arg Leu 1 5 1446PRTUnknownTight
junction agonist peptide 144Phe Xaa Ile Gly Arg Leu 1 5
1456PRTUnknownTight junction agonist peptide 145Phe Xaa Ile Gly Arg
Leu 1 5 1464PRTUnknownTight junction agonist peptide 146Phe Cys Ala
Gly 1 1474PRTUnknownTight junction agonist peptide 147Phe Cys Gly
Gly 1 1486PRTUnknownTight junction agonist peptide 148Phe Trp Ile
Gly Arg Leu 1 5 1496PRTUnknownTight junction agonist peptide 149Phe
His Ile Gly Arg Leu 1 5 1506PRTUnknownTight junction agonist
peptide 150Phe Pro Ile Gly Arg Leu 1 5 1516PRTUnknownTight junction
agonist peptide 151Phe Asp Ile Gly Arg Leu 1 5 1526PRTUnknownTight
junction agonist peptide 152Phe Xaa Ile Gly Arg Leu 1 5
1536PRTUnknownTight junction agonist peptide 153Phe Cys Ile Gly Arg
Leu 1 5 1546PRTUnknownTight junction agonist peptide 154Leu Arg Gly
Ile Cys Phe 1 5 1556PRTUnknownTight junction agonist peptide 155Leu
Arg Gly Ile Cys Phe 1 5 1566PRTUnknownTight junction agonist
peptide 156Leu Arg Gly Ile Cys Phe 1 5 1576PRTUnknownTight junction
agonist peptide 157Leu Arg Gly Ile Cys Phe 1 5 1587PRTUnknownTight
junction agonist peptide 158Gly Phe Cys Ile Gly Arg Leu 1 5
1596PRTUnknownTight junction agonist peptide 159Phe Leu Ile Gly Arg
Leu 1 5 1606PRTUnknownTight junction agonist peptide 160Phe Cys Ile
Gly Arg Leu 1 5 1616PRTUnknownTight junction agonist peptide 161Phe
Phe Ile Gly Arg Leu 1 5 1626PRTUnknownTight junction agonist
peptide 162Phe Xaa Ile Gly Arg Leu 1 5 1636PRTUnknownTight junction
agonist peptide 163Phe Xaa Ile Gly Arg Leu 1 5 1646PRTUnknownTight
junction agonist peptide 164Phe Xaa Ile Gly Arg Leu 1 5
1656PRTUnknownTight junction agonist peptide 165Leu Arg Gly Gly Arg
Leu 1 5 1666PRTUnknownTight junction agonist peptide 166Phe Cys Ile
Gly Arg Leu 1 5 1676PRTUnknownTight junction agonist peptide 167Phe
Cys Ile Gly Arg Leu 1 5 1686PRTUnknownTight junction agonist
peptide 168Phe Arg Ile Gly Arg Leu 1 5 1696PRTUnknownTight junction
agonist peptide 169Phe Gly Ile Gly Arg Leu 1 5 1706PRTUnknownTight
junction agonist peptide 170Phe Gln Ile Gly Arg Leu 1 5
1716PRTUnknownTight junction agonist peptide 171Phe Glu Ile Gly Arg
Leu 1 5 1726PRTUnknownTight junction agonist peptide 172Phe Lys Ile
Gly Arg Leu 1 5 1736PRTUnknownTight junction agonist peptide 173Phe
Asn Ile Gly Arg Leu 1 5 1746PRTUnknownTight junction agonist
peptide 174Phe Tyr Ile Gly Arg Leu 1 5 1756PRTUnknownTight junction
agonist peptide 175Phe Leu Ile Gly Arg Leu 1 5 1766PRTUnknownTight
junction agonist peptide 176Phe Val Ile Gly Arg Leu 1 5
1776PRTUnknownTight junction agonist peptide 177Phe Ile Ile Gly Arg
Leu 1 5 1786PRTUnknownTight junction agonist peptide 178Phe Xaa Ile
Gly Arg Leu 1 5 1796PRTUnknownTight junction agonist peptide 179Ser
Leu Ile Gly Arg Leu 1 5 1806PRTUnknownTight junction agonist
peptide 180Phe Cys Ala Gly Met Ser 1 5 1816PRTUnknownTight junction
agonist peptide 181Phe Cys Val Gly Met Ser 1 5 1826PRTUnknownTight
junction agonist peptide 182Phe Xaa Ile Gly Arg Leu 1 5
1836PRTUnknownTight junction agonist peptide 183Phe Leu Ile Gly Arg
Leu 1 5 1846PRTUnknownTight junction agonist peptide 184Phe Leu Ile
Gly Arg Leu 1 5 1856PRTUnknownTight junction agonist peptide 185Phe
Leu Ile Gly Arg Leu 1 5 1866PRTUnknownTight junction agonist
peptide 186Leu Arg Gly Ile Leu Phe 1 5 1876PRTUnknownTight junction
agonist peptide 187Phe Xaa Ile Gly Arg Leu 1 5 1886PRTUnknownTight
junction agonist peptide 188Phe Xaa Ile Gly Arg Leu 1 5
1896PRTUnknownTight junction agonist peptide 189Leu Arg Gly Ile Leu
Phe 1 5 1905PRTUnknownTight junction agonist peptide 190Phe Xaa Ile
Gly Arg 1 5 1915PRTUnknownTight junction agonist peptide 191Phe Xaa
Ile Gly Arg 1 5 1926PRTUnknownTight junction agonist peptide 192Phe
Xaa Ile Gly Arg Leu 1 5 1935PRTUnknownTight junction agonist
peptide 193Phe Leu Ile Gly Arg 1 5 1946PRTUnknownTight junction
agonist peptide 194Phe Xaa Ile Gly Arg Leu 1 5 1956PRTUnknownTight
junction agonist peptide 195Xaa Phe Ile Gly Arg Leu 1 5
1966PRTUnknownTight junction agonist peptide 196Xaa Phe Ile Gly Arg
Leu 1 5 1976PRTUnknownTight junction agonist peptide 197Phe Xaa Ile
Gly Arg Leu 1 5 1985PRTUnknownTight junction agonist peptide 198Phe
Xaa Ile Gly Arg 1 5 1995PRTUnknownTight junction agonist peptide
199Phe Xaa Ile Gly Arg 1 5 2005PRTUnknownTight junction agonist
peptide 200Phe Xaa Ile Gly Arg 1 5 2016PRTUnknownTight junction
agonist peptide 201Phe Xaa Ile Thr Arg Leu 1 5 2026PRTUnknownTight
junction agonist peptide 202Phe Xaa Ile Leu Arg Leu 1 5
2036PRTUnknownTight junction agonist peptide 203Phe Xaa Ile Ile Arg
Leu 1 5 2046PRTUnknownTight junction agonist peptide 204Phe Xaa Ile
Ala Arg Leu 1 5 2056PRTUnknownTight junction agonist peptide 205Phe
Xaa Ile Pro Arg Leu 1 5 2066PRTUnknownTight junction agonist
peptide 206Phe Xaa Pro Gly Arg Leu 1 5 2076PRTUnknownTight junction
agonist peptide 207Phe Xaa Phe Gly Arg Leu 1 5 2086PRTUnknownTight
junction agonist peptide 208Phe Xaa Thr Gly Arg Leu 1 5
2096PRTUnknownTight junction agonist peptide 209Phe Xaa Leu Gly Arg
Leu 1 5 2106PRTUnknownTight junction agonist peptide 210Phe Xaa Ser
Gly Arg Leu 1 5 2116PRTUnknownTight junction agonist peptide 211Phe
Xaa Phe Gly Arg Leu 1 5 2126PRTUnknownTight junction agonist
peptide 212Phe Xaa Val Gly Arg Leu 1 5 2136PRTUnknownTight junction
agonist peptide 213Phe Xaa Gly Gly Arg Leu 1 5 2146PRTUnknownTight
junction agonist peptide 214Phe Xaa Ala Gly Arg Leu 1 5
2156PRTUnknownTight junction agonist peptide 215Met Xaa Ile Gly Arg
Leu 1 5 2166PRTUnknownTight junction agonist peptide 216Gln Xaa Ile
Gly Arg Leu 1 5 2176PRTUnknownTight junction agonist peptide 217Leu
Xaa Ile Gly Arg Leu 1 5 2186PRTUnknownTight junction agonist
peptide 218Ser Xaa Ile Gly Arg Leu 1 5 2196PRTUnknownTight junction
agonist peptide 219Thr Xaa Ile Gly Arg Leu 1 5 2206PRTUnknownTight
junction agonist peptide 220Glu Xaa Ile Gly Arg Leu 1 5
2216PRTUnknownTight junction agonist peptide 221Val Xaa Ile Gly Arg
Leu 1 5 2226PRTUnknownTight junction agonist peptide 222Tyr Xaa Ile
Gly Arg Leu 1 5 2236PRTUnknownTight junction agonist peptide 223Gly
Xaa Ile Gly Arg Leu 1 5 2246PRTUnknownTight junction agonist
peptide 224Asp Xaa Ile Gly Arg Leu 1 5 2256PRTUnknownTight junction
agonist peptide 225Trp Xaa Ile Gly Arg Leu 1 5 2266PRTUnknownTight
junction agonist peptide 226Lys Xaa Ile Gly Arg Leu 1 5
2276PRTUnknownTight junction agonist peptide 227Ala Xaa Ile Gly Arg
Leu 1 5 2286PRTUnknownTight junction agonist peptide 228His Xaa Ile
Gly Arg Leu 1 5 2296PRTUnknownTight junction agonist peptide 229Pro
Xaa Ile Gly Arg Leu 1 5 2306PRTUnknownTight junction agonist
peptide 230Arg Xaa Ile Gly Arg Leu 1 5 2316PRTUnknownTight junction
agonist peptide 231Ile Xaa Ile Gly Arg Leu 1 5 2326PRTUnknownTight
junction agonist peptide 232Met Xaa Ile Gly Arg Leu 1 5
2335PRTUnknownTight junction agonist peptide 233Tyr Ile Gly Ser Arg
1 5 2345PRTUnknownTight junction agonist peptide 234Phe Xaa Ile Gly
Arg 1 5 2355PRTUnknownTight junction agonist peptide 235Phe Thr Ile
Gly Arg 1 5 2366PRTUnknownTight junction agonist peptide 236Phe Xaa
Ile Gly Arg Leu 1 5 2376PRTUnknownTight junction agonist peptide
237Phe Xaa Ile Gly Arg Leu 1 5 2386PRTUnknownTight junction agonist
peptide 238Phe Thr Ile Gly Arg Leu 1 5 2396PRTUnknownTight junction
agonist peptide 239Phe Xaa Ile Gly Arg Leu 1 5 2405PRTUnknownTight
junction agonist peptide 240Phe Ile Gly Arg Leu 1 5
2416PRTUnknownTight junction agonist peptide 241Phe Xaa Ile Gly Arg
Leu 1 5 2425PRTUnknownTight junction agonist peptide 242Arg Gly Ile
Leu Phe 1 5 2434PRTUnknownTight junction agonist peptide 243Gly Ile
Leu Phe 1 2445PRTUnknownTight junction agonist peptide 244Leu Arg
Gly Ile Leu 1 5 2456PRTUnknownTight junction agonist peptide 245Leu
Arg Gly Ile Leu Phe 1 5 2466PRTUnknownTight junction agonist
peptide 246Leu Arg Gly Phe Leu Phe 1 5 2476PRTUnknownTight junction
agonist peptide 247Leu Arg Gly Leu Leu Phe 1 5 2486PRTUnknownTight
junction agonist peptide 248Leu Arg Gly Ile Leu Phe 1 5
2496PRTUnknownTight junction agonist peptide 249Leu Arg Gly Ile Leu
Phe 1 5 2506PRTUnknownTight junction agonist peptide 250Leu Arg Gly
Ile Leu Phe 1 5 2516PRTUnknownTight junction agonist peptide 251Leu
Arg Gly Ile Leu Phe 1 5 2526PRTUnknownTight junction agonist
peptide 252Phe Arg Gly Ile Leu Phe 1 5 2536PRTUnknownTight junction
agonist peptide 253Leu Arg Gly Ile Xaa Phe 1 5 2546PRTUnknownTight
junction agonist peptide 254Phe Xaa Ile Gly Arg His 1 5
2556PRTUnknownTight junction agonist peptide 255Phe Xaa Ile Gly Arg
Asp 1 5 2566PRTUnknownTight junction agonist peptide 256Phe Xaa Ile
Gly Arg Arg 1 5 2576PRTUnknownTight junction agonist peptide 257Phe
Xaa Ile Gly Arg Phe 1 5 2586PRTUnknownTight junction agonist
peptide 258Phe Xaa Ile Gly Arg Ala 1 5 2596PRTUnknownTight junction
agonist peptide 259Phe Xaa Ile Gly Arg Gly 1 5 2606PRTUnknownTight
junction agonist peptide 260Phe Xaa Ile Gly Arg Gln 1 5
2616PRTUnknownTight junction agonist peptide 261Phe Xaa Ile Gly Arg
Glu 1 5 2626PRTUnknownTight junction agonist peptide 262Phe Xaa Ile
Gly Arg Thr 1 5 2636PRTUnknownTight junction agonist peptide 263Phe
Xaa Ile Gly Arg Tyr 1 5 2646PRTUnknownTight junction agonist
peptide 264Phe Xaa Ile Gly Arg Ser 1 5 2656PRTUnknownTight junction
agonist peptide 265Phe Xaa Ile Gly Arg Asn 1 5 2666PRTUnknownTight
junction agonist peptide 266Phe Xaa Ile Gly Arg Met 1 5
2676PRTUnknownTight junction agonist peptide 267Phe Xaa Ile Gly Arg
Lys 1 5 2686PRTUnknownTight junction agonist peptide 268Phe Xaa Ile
Gly Arg Ile 1 5 2696PRTUnknownTight junction agonist peptide 269Phe
Xaa Ile Gly Arg Trp 1 5 2706PRTUnknownTight junction agonist
peptide 270Phe Xaa Ile Gly Arg Pro 1 5 2716PRTUnknownTight junction
agonist peptide 271Phe Xaa Ile Gly Arg Val 1 5 2726PRTUnknownTight
junction agonist peptide 272Phe Xaa Ile Gly His Leu 1 5
2736PRTUnknownTight junction agonist peptide 273Phe Xaa Ile Gly Asp
Leu 1 5 2746PRTUnknownTight junction agonist peptide 274Phe Xaa Ile
Gly Glu Leu 1 5 2756PRTUnknownTight junction agonist peptide 275Phe
Xaa Ile Gly Gln Leu 1 5 2766PRTUnknownTight junction agonist
peptide 276Phe Xaa Ile Gly Gly Leu 1 5 2776PRTUnknownTight junction
agonist peptide 277Phe Xaa Ile Gly Ala Leu 1 5 2786PRTUnknownTight
junction agonist peptide 278Phe Xaa Ile Gly Phe Leu 1 5
2796PRTUnknownTight junction agonist peptide 279Phe Xaa Ile Gly Lys
Leu 1 5 2806PRTUnknownTight junction agonist peptide 280Phe Xaa Ile
Gly Leu Leu 1 5 2816PRTUnknownTight junction agonist peptide 281Phe
Xaa Ile Gly Met Leu 1 5 2826PRTUnknownTight junction agonist
peptide 282Phe Xaa Ile Gly Asn Leu 1 5 2836PRTUnknownTight junction
agonist peptide 283Phe Xaa Ile Gly Ser Leu 1 5 2846PRTUnknownTight
junction agonist peptide 284Phe Xaa Ile Gly Tyr Leu 1 5
2856PRTUnknownTight junction agonist peptide 285Phe Xaa Ile Gly Thr
Leu 1 5 2866PRTUnknownTight junction agonist peptide 286Phe Xaa Ile
Gly Ile Leu 1 5 2876PRTUnknownTight junction agonist peptide 287Phe
Xaa Ile Gly Trp Leu 1 5 2886PRTUnknownTight junction agonist
peptide 288Phe Xaa Ile Gly Pro Leu 1 5 2896PRTUnknownTight junction
agonist peptide 289Phe Xaa Ile Gly Val Leu 1 5 2906PRTUnknownTight
junction agonist peptide 290Phe Xaa Ile Gly Arg Leu 1 5
2916PRTUnknownTight junction agonist peptide 291Phe Xaa Tyr Gly Arg
Leu 1 5 2926PRTUnknownTight junction agonist peptide 292Phe Xaa His
Gly Arg Leu 1 5 2936PRTUnknownTight junction agonist peptide 293Phe
Xaa Asn Gly Arg Leu 1 5 2946PRTUnknownTight junction agonist
peptide 294Phe Xaa Asp Gly Arg Leu 1 5 2956PRTUnknownTight junction
agonist peptide 295Phe Xaa Gln Gly Arg Leu 1 5 2966PRTUnknownTight
junction agonist peptide 296Phe Xaa Glu Gly Arg Leu 1 5
2976PRTUnknownTight junction agonist peptide 297Phe Xaa Lys Gly Arg
Leu 1 5 2986PRTUnknownTight junction agonist peptide 298Phe Xaa Arg
Gly Arg Leu 1 5 2996PRTUnknownTight junction agonist peptide 299Phe
Xaa Ile Arg Arg Leu 1 5 3006PRTUnknownTight junction agonist
peptide 300Phe Xaa Ile Asn Arg Leu 1 5 3016PRTUnknownTight junction
agonist peptide 301Phe Xaa Ile His Arg Leu 1 5 3026PRTUnknownTight
junction agonist peptide 302Phe Xaa Ile Lys Arg Leu 1 5
3036PRTUnknownTight junction agonist peptide 303Phe Xaa Ile Gln Arg
Leu 1 5 3046PRTUnknownTight junction agonist peptide 304Phe Xaa Ile
Phe Arg Leu 1 5 3056PRTUnknownTight junction agonist peptide 305Phe
Xaa Ile Ser Arg Leu 1 5 3066PRTUnknownTight junction agonist
peptide 306Phe Xaa Ile Val Arg Leu 1 5 3076PRTUnknownTight junction
agonist peptide 307Phe Xaa Ile Asp Arg Leu 1 5 3086PRTUnknownTight
junction agonist peptide 308Phe Xaa Ile Glu Arg Leu 1 5
3095PRTUnknownTight junction agonist peptide 309Phe Xaa Ile Gly Arg
1 5 3106PRTUnknownTight junction agonist peptide 310Phe Xaa Ile Gly
Arg Leu 1 5 3115PRTUnknownTight junction agonist peptide 311Xaa Ile
Gly Arg Leu 1 5 3126PRTUnknownTight junction agonist peptide 312Phe
Xaa Ile Gly Arg Leu 1 5 3136PRTUnknownTight junction agonist
peptide 313Gly Phe Gly Ile Leu Arg 1 5 3146PRTUnknownTight junction
agonist peptide 314Ile Gly Phe Leu Arg Gly 1 5
* * * * *