U.S. patent application number 12/667192 was filed with the patent office on 2011-08-18 for use of tight junction antagonists in the treatment of acute lung injury and acute respiratory distress.
Invention is credited to Alessio Fasano, Blake Paterson, Peter Ward.
Application Number | 20110201543 12/667192 |
Document ID | / |
Family ID | 40226478 |
Filed Date | 2011-08-18 |
United States Patent
Application |
20110201543 |
Kind Code |
A1 |
Paterson; Blake ; et
al. |
August 18, 2011 |
USE OF TIGHT JUNCTION ANTAGONISTS IN THE TREATMENT OF ACUTE LUNG
INJURY AND ACUTE RESPIRATORY DISTRESS
Abstract
The present application provides compositions and methods for
treating acute lung injury and acute respiratory distress syndrome.
The methods include administering one or more tight junction
antagonists to the lung of a subject in need thereof.
Inventors: |
Paterson; Blake; (Baltimore,
MD) ; Ward; Peter; (Baltimore, MD) ; Fasano;
Alessio; (West Friendship, MD) |
Family ID: |
40226478 |
Appl. No.: |
12/667192 |
Filed: |
June 27, 2008 |
PCT Filed: |
June 27, 2008 |
PCT NO: |
PCT/US2008/068465 |
371 Date: |
April 25, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60947228 |
Jun 29, 2007 |
|
|
|
Current U.S.
Class: |
514/1.5 |
Current CPC
Class: |
A61K 38/00 20130101;
A61K 45/06 20130101; C07K 7/06 20130101; A61K 38/08 20130101; A61K
9/007 20130101; A61P 11/00 20180101 |
Class at
Publication: |
514/1.5 |
International
Class: |
A61K 38/08 20060101
A61K038/08; A61P 11/00 20060101 A61P011/00 |
Claims
1. A method of treating an excessive or undesirable permeability of
lung tissue containing tight junctions comprising: administering to
a subject in need thereof a composition comprising a tight junction
antagonist.
2. A method according to claim 1, wherein the subject is a
human.
3. A method according to claim 1, wherein the tight junction
antagonist is a peptide.
4. A method according to claim 3, wherein the peptide comprises
GGVLVQPG (SEQ ID NO: 15).
5. A method according to claim 3, wherein the peptide consists of
GGVLVQPG (SEQ ID NO: 15).
6. A method according to claim 1, wherein the composition is
administered in conjunction with an additional therapeutic
agent.
7. A method according to claim 7, wherein the composition and the
additional therapeutic agent are administered simultaneously.
8. A method according to claim 7, wherein the composition and the
additional therapeutic agent are not administered
simultaneously.
9. A method according to claim 6, wherein the composition further
comprises the additional therapeutic agent.
10. A method according to claim 6, wherein the additional
therapeutic agent is selected from the group consisting of
aminosalicylates, corticosteroids, immunomodulators, antibiotics,
cytokines, chemokines and biologic therapeutics.
11. A method according to claim 1, wherein the composition is
formulated for pulmonary delivery.
12. A method of treating acute respiratory distress syndrome,
comprising: administering to a subject in need thereof a
composition comprising a tight junction antagonist.
13-22. (canceled)
23. A method of treating acute lung injury, comprising:
administering to a subject in need thereof a composition comprising
a tight junction antagonist.
24-33. (canceled)
34. A composition formulated for pulmonary delivery comprising a
tight junction antagonist.
35.-39. (canceled)
Description
BACKGROUND
[0001] Acute Respiratory Distress Syndrome (ARDS) presents in about
150,000 individuals in the US annually, with a mortality rate of
30-50%. ARDS occurs in response to diverse forms of severe injury,
in which lung edema results in respiratory failure. The current
standard of care for ARDS is limited to the management of the
disease through supportive mechanical ventilation. The loss of
endothelial barrier integrity is central to the pulmonary edema
that occurs in ARDS.
[0002] Triggering causes for Acute Lung Injury (ALI) including ARDS
can, for example, be diffuse pulmonary infections (e.g. due to
viruses, bacteria, fungi), aspiration of liquids (e.g. gastric
juice or water), inhalation of toxins or irritants (e.g. chlorine
gas, nitrogen oxides, smoke), direct or indirect trauma (e.g.
multiple fractures or pulmonary contusion), systemic reactions to
inflammations outside the lung (e.g. hemorrhagic pancreatitis,
gram-negative septicemia), transfusions of high blood volumes or
alternatively after cardiopulmonary bypass.
[0003] The pulmonary vascular endothelium lines the intravascular
space and presents a selective barrier that actively regulates
paracellular movement of circulating fluid, macromolecules, and
cells, into extravascular tissues and compartments. Loss of this
endothelial barrier integrity is the central defect found in ALI
and ARDS. The host response to a wide range of injurious stimuli
includes the biosynthesis and release of endogenous mediators, some
of which can open the paracellular pathway in lung microvascular
endothelia. Several of these mediators have been identified,
including tumor necrosis factor .alpha., interleukin-1,
thrombospondin-1, and SPARC/osteonectin, and these mediators have
been established as factors that disrupt endothelial barrier
integrity. In recent preliminary studies, we found that .DELTA.G,
the active domain of zonula occludens toxin (ZOT) of Vibrio
cholerae, increases paracellular permeability across human lung
microvascular endothelial cells (HMVEC-Ls).
[0004] ZOT and .DELTA.G have been previously identified as tight
junction agonists, i.e., compounds that mediate or facilitate or
augment the physiological, transient opening of tight junctions
that form a barrier between adjacent epithelial cells. The ability
of ZOT and .DELTA.G to open tight junctions has been used to
facilitate the transfer of macromolecule across epithelial barriers
(see U.S. Pat. No. 5,665,389 and Salama et al. J. Pharmacology and
Experimental Therapeutics 312(1):199-205, 2005). ZOT has been shown
to act as a tight junction agonist that allows opening of tight
junctions between adjacent mucosal epithelial cells. Compounds that
antagonize the opening of tight junctions have been identified (see
U.S. Pat. Nos. 6,458,925, 6,670,448, 6,936,689 and 7,189,696). One
such antagonist is currently in Phase II clinical trials for the
treatment of celiac disease where it protects against loss of gut
mucosal barrier function.
[0005] There remains a need in the art for compositions and methods
for the treatment of ALI and ARDS. These and other needs are met by
the present invention.
SUMMARY OF THE INVENTION
[0006] The present invention provides compositions and methods for
the treatment of an excessive or undesirable permeability of lung
tissue containing tight junctions. Methods of the invention may
include administering to a subject in need thereof a composition
comprising a tight junction antagonist. In some embodiments, a
subject is any mammal, for example, a human. In some embodiments, a
tight junction antagonist may be a peptide, for example, a peptide
comprising a sequence selected from the group consisting of SEQ ID
NOs:1-24. In some embodiments, a tight junction antagonist may be a
peptide, for example, a peptide comprising the sequence
G-G-V-L-V-Q-P-G (SEQ ID NO:15). In some embodiments, a tight
junction antagonist may consist of the sequence G-G-V-L-V-Q-P-G
(SEQ ID NO:15).
[0007] In some embodiments, the present invention provides
compositions and methods for the treatment of acute lung injury.
Such methods may comprise administering to a subject in need
thereof a composition comprising a tight junction antagonist. In
some embodiments, a subject is any mammal, for example, a human. In
some embodiments, a tight junction antagonist may be a peptide, for
example, a peptide comprising a sequence selected from the group
consisting of SEQ ID NOs:1-24. In some embodiments, a tight
junction antagonist may be a peptide, for example, a peptide
comprising the sequence G-G-V-L-V-Q-P-G (SEQ ID NO:15). In some
embodiments, a tight junction antagonist may consist of the
sequence G-G-V-L-V-Q-P-G (SEQ ID NO:15).
[0008] In some embodiments, the present invention provides
materials and method for the treatment of acute respiratory
distress syndrome. Such methods may include administering to a
subject in need thereof a composition comprising a tight junction
antagonist. In some embodiments, a subject is any mammal, for
example, a human. In some embodiments, a tight junction antagonist
may be a peptide, for example, a peptide comprising a sequence
selected from the group consisting of SEQ ID NOs:1-24. In some
embodiments, a tight junction antagonist may be a peptide, for
example, a peptide comprising the sequence G-G-V-L-V-Q-P-G (SEQ ID
NO:15). In some embodiments, a tight junction antagonist may
consist of the sequence G-G-V-L-V-Q-P-G (SEQ ID NO:15).
Compositions for use in the methods of the invention may also
comprise one or more additional components. Examples of additional
components include, but are not limited to, aminosalicylates,
corticosteroids, immunomodulators, antibiotics, cytokines,
chemokines and biologic therapeutics. Compositions for use in the
methods of the invention may be formulated in any manner known to
those skilled in the art, for example, the compositions may be
formulated for pulmonary delivery.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1 is a schematic representation of the experimental
protocol used in the examples.
[0010] FIG. 2 is a bar graph showing lung permeability as a
function of the treatment regimen comparing IV versus IT
administration of tight junction antagonist.
[0011] FIG. 3 is a bar graph showing lung permeability as a
function of the amount of tight junction antagonist applied with
anti-BSA antibody intratracheally.
DETAILED DESCRIPTION OF THE INVENTION
[0012] Antagonists of Tight Junction Opening
[0013] As used herein, tight junction antagonists prevent, inhibit
or reduce the opening of tight junctions, for example, the opening
of tight junctions induced by a tight junction agonist. A tight
junction antagonist may bind to the receptor that mediates tight
junction agonist induced opening of tight junctions. For example, a
tight junction antagonist may bind to the ZOT receptor and prevent,
inhibit, reduce or reverse the tight junction opening triggered by
the tight junction agonist ZOT.
[0014] As used herein a subject is any animal, e.g., mammal, upon
which methods of the invention may be practiced and/or to which
materials of the present invention may be administered. Subjects
include, but are not limited to, humans.
[0015] Any antagonist of tight junction opening may be used in the
practice of the present invention. For example, antagonists of the
invention may comprise peptide antagonists. Examples of peptide
antagonists include, but are not limited to, peptides that comprise
an amino acid sequence selected from the group consisting of
TABLE-US-00001 Gly Arg Val Cys Val Gln Pro Gly, (SEQ ID NO: 1) Gly
Arg Val Cys Val Gln Asp Gly, (SEQ ID NO: 2) Gly Arg Val Leu Val Gln
Pro Gly, (SEQ ID NO: 3) Gly Arg Val Leu Val Gln Asp Gly, (SEQ ID
NO: 4) Gly Arg Leu Cys Val Gln Pro Gly, (SEQ ID NO: 5) Gly Arg Leu
Cys Val Gln Asp Gly, (SEQ ID NO: 6) Gly Arg Leu Leu Val Gln Pro
Gly, (SEQ ID NO: 7) Gly Arg Leu Leu Val Gln Asp Gly, (SEQ ID NO: 8)
Gly Arg Gly Cys Val Gln Pro Gly, (SEQ ID NO: 9) Gly Arg Gly Cys Val
Gln Asp Gly, (SEQ ID NO: 10) Gly Arg Gly Leu Val Gln Pro Gly, (SEQ
ID NO: 11) Gly Arg Gly Leu Val Gln Asp Gly, (SEQ ID NO: 12) Gly Gly
Val Cys Val Gln Pro Gly, (SEQ ID NO: 13) Gly Gly Val Cys Val Gln
Asp Gly, (SEQ ID NO: 14) Gly Gly Val Leu Val Gln Pro Gly, (SEQ ID
NO: 15) Gly Gly Val Leu Val Gln Asp Gly, (SEQ ID NO: 16) Gly Gly
Leu Cys Val Gln Pro Gly, (SEQ ID NO: 17) Gly Gly Leu Cys Val Gln
Asp Gly, (SEQ ID NO: 18) Gly Gly Leu Leu Val Gln Pro Gly, (SEQ ID
NO: 19) Gly Gly Leu Leu Val Gln Asp Gly, (SEQ ID NO: 20) Gly Gly
Gly Cys Val Gln Pro Gly, (SEQ ID NO: 21) Gly Gly Gly Cys Val Gln
Asp Gly, (SEQ ID NO: 22) Gly Gly Gly Leu Val Gln Pro Gly, (SEQ ID
NO: 23) and Gly Gly Gly Leu Val Gln Asp Gly (SEQ ID NO: 24)
[0016] Examples of peptide antagonists include, but are not limited
to, peptides that consist of an amino acid sequence selected from
the group consisting of SEQ ID NOs:1-24. Examples of peptide
antagonists of tight junctions can be found in U.S. Pat. Nos.
6,458,925, 6,670,448, 6,936,689, and 7,189,696 the entire contents
of which are specifically incorporate herein by reference.
[0017] When the antagonist is a peptide, any length of peptide may
be used.
[0018] Generally, the size of the peptide antagonist will range
from about 6 to about 100, from about 6 to about 90, from about 6
to about 80, from about 6 to about 70, from about 6 to about 60,
from about 6 to about 50, from about 6 to about 40, from about 6 to
about 30, from about 6 to about 25, from about 6 to about 20, from
about 6 to about 15, from about 6 to about 14, from about 6 to
about 13, from about 6 to about 12, from about 6 to about 11, from
about 6 to about 10, from about 6 to about 9, or from about 6 to
about 8 amino acids in length. Peptide antagonists of the invention
may be from about 8 to about 100, from about 8 to about 90, from
about 8 to about 80, from about 8 to about 70, from about 8 to
about 60, from about 8 to about 50, from about 8 to about 40, from
about 8 to about 30, from about 8 to about 25, from about 8 to
about 20, from about 8 to about 15, from about 8 to about 14, from
about 8 to about 13, from about 8 to about 12, from about 8 to
about 11, or from about 8 to about 10 amino acids in length.
Peptide antagonists of the invention may be from about 10 to about
100, from about 10 to about 90, from about 10 to about 80, from
about 10 to about 70, from about 10 to about 60, from about 10 to
about 50, from about 10 to about 40, from about 10 to about 30,
from about 10 to about 25, from about 10 to about 20, from about 10
to about 15, from about 10 to about 14, from about 10 to about 13,
or from about 10 to about 12 amino acids in length. Peptide
antagonists of the invention may be from about 12 to about 100,
from about 12 to about 90, from about 12 to about 80, from about 12
to about 70, from about 12 to about 60, from about 12 to about 50,
from about 12 to about 40, from about 12 to about 30, from about 12
to about 25, from about 12 to about 20, from about 12 to about 15,
or from about 12 to about 14 amino acids in length. Peptide
antagonists of the invention may be from about 15 to about 100,
from about 15 to about 90, from about 15 to about 80, from about 15
to about 70, from about 15 to about 60, from about 15 to about 50,
from about 15 to about 40, from about 15 to about 30, from about 15
to about 25, from about 15 to about 20, from about 19 to about 15,
from about 15 to about 18, or from about 17 to about 15 amino acids
in length.
[0019] The peptide antagonists 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 therefrom using well-known techniques.
[0020] Compositions
[0021] Typically, compositions, such as pharmaceutical
compositions, comprising a tight junction antagonist (e.g., peptide
tight junction antagonist) comprise a pharmaceutically effective
amount of the antagonist. The pharmaceutically effective amount of
antagonist (e.g., peptide tight junction antagonist) employed in
any given composition 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.
[0022] Generally, the amount of antagonist used for preventing,
ameliorating and/or treating a disease in a subject will be in the
range of about 1.0 .mu.g to 1 g, preferably about 1 mg to about
1000 mg, or from about 10 mg to about 100 mg, or from about 10 mg
to about 50 mg, or from about 10 mg to about 25 mg of antagonist
per dose.
[0023] Compositions of the invention may comprise one or more tight
junction antagonists at a level of from about 0.1 wt % to about 20
wt %, from about 0.1 wt % to about 18 wt %, from about 0.1 wt % to
about 16 wt %, from about 0.1 wt % to about 14 wt %, from about 0.1
wt % to about 12 wt %, from about 0.1 wt % to about 10 wt %, from
about 0.1 wt % to about 8 wt %, from about 0.1 wt % to about 6 wt
%, from about 0.1 wt % to about 4 wt %, from about 0.1 wt % to
about 2 wt %, from about 0.1 wt % to about 1 wt %, from about 0.1
wt % to about 0.9 wt %, from about 0.1 wt % to about 0.8 wt %, from
about 0.1 wt % to about 0.7 wt %, from about 0.1 wt % to about 0.6
wt %, from about 0.1 wt % to about 0.5 wt %, from about 0.1 wt % to
about 0.4 wt %, from about 0.1 wt % to about 0.3 wt %, or from
about 0.1 wt % to about 0.2 wt % of the total weight of the
composition. Compositions of the invention may comprise one or more
tight junction antagonists at a level of about 0.1 wt %, about 0.2
wt %, about 0.3 wt %, about 0.4 wt %, about 0.5 wt %, about 0.6 wt
%, about 0.7 wt %, about 0.8 wt %, or about 0.9 wt % based on the
total weight of the composition.
[0024] Compositions of the invention may comprise one or more tight
junction antagonists at a level of from about 1 wt % to about 20 wt
%, from about 1 wt % to about 18 wt %, from about 1 wt % to about
16 wt %, from about 1 wt % to about 14 wt %, from about 1 wt % to
about 12 wt %, from about 1 wt % to about 10 wt %, from about 1 wt
% to about 9 wt %, from about 1 wt % to about 8 wt %, from about 1
wt % to about 7 wt %, from about 1 wt % to about 6 wt %, from about
1 wt % to about 5 wt %, from about 1 wt % to about 4 wt %, from
about 1 wt % to about 3 wt %, or from about 1 wt % to about 2 wt %
of the total weight of the composition. Compositions of the
invention may comprise one or more tight junction effectors at a
level of about 1 wt %, about 2 wt %, about 3 wt %, about 4 wt %,
about 5 wt %, about 6 wt %, about 7 wt %, about 8 wt %, or about 9
wt % based on the total weight of the composition.
[0025] Compositions of the invention may be formulated for
pulmonary delivery (e.g., may be pulmonary dosage forms). Typically
such compositions may be provided as pharmaceutical aerosols, e.g.,
solution aerosols or powder aerosols. Those of skill in the art are
aware of many different methods and devices for the formation of
pharmaceutical aerosols, for example, those disclosed by Sciarra
and Sciarra, Aerosols, in Remington: The Science and Practice of
Pharmacy, 20th Ed., Chapter 50, Gennaro et al. Eds., Lippincott,
Williams and Wilkins Publishing Co., (2000).
[0026] In one embodiment, the dosage forms are in the form of a
powder aerosol (i.e, comprise particles). These are particularly
suitable for use in inhalation delivery systems. Powders may
comprise particles of any size suitable for administration to the
lung.
[0027] Powder formulations may optionally contain at least one
particulate pharmaceutically acceptable carrier known to those of
skill in the art. Examples of suitable pharmaceutical carriers
include, but are not limited to, saccharides, including
monosaccharides, disaccharides, polysaccharides and sugar alcohols
such as arabinose, glucose, fructose, ribose, mannose, sucrose,
trehalose, lactose, maltose, starches, dextran, mannitol or
sorbitol. In one embodiment, a powder formulation may comprise
lactose as a carrier.
[0028] Powder formulations may be contained in any container known
to those in the art. Containers may be capsules of, for example,
gelatin or plastic, or in blisters (e.g. of aluminum or plastic),
for use in a dry powder inhalation device. In some embodiments, the
total weight of the formulation in the container may be from about
5 mg to about 50 mg. In other embodiments, powder formulations may
be contained in a reservoir in a multi-dose dry powder inhalation
device adapted to deliver a suitable amount per actuation.
[0029] Powder formulations typically comprise small particles.
Suitable particles can be prepared using any means known in the
art, for example, by grinding in an airjet mill, ball mill or
vibrator mill, sieving, microprecipitation, spray-drying,
lyophilisation or controlled crystallisation. Typically, particles
will be about 10 microns or less in diameter. Particles for use in
the compositions of the invention may have a diameter of from about
0.1 microns to about 10 microns, from about 0.1 microns to about 9
microns, from about 0.1 microns to about 8 microns, from about 0.1
microns to about 7 microns, from about 0.1 microns to about 6
microns, from about 0.1 microns to about 5 microns, from about 0.1
microns to about 4 microns, from about 0.1 microns to about 3
microns, from about 0.1 microns to about 2 microns, from about 0.1
microns to about 1 micron, from about 0.1 microns to about 0.5
microns, from about 1 micron to about 10 microns, from about 1
micron to about 9 microns, from about 1 micron to about 8 microns,
from about 1 micron to about'7 microns, from about 1 micron to
about 6 microns, from about 1 micron to about 5 microns, from about
1 micron to about 4 microns, from about 1 micron to about 3
microns, from about 1 micron to about 2 microns, from about 2
microns to about 10 microns, from about 2 microns to about 9
microns, from about 2 microns to about 8 microns, from about 2
microns to about 7 microns, from about 2 microns to about 6
microns, from about 2 microns to about 5 microns, from about 2
microns to about 4 microns, or from about 2 microns to about 3
microns. In some embodiments, particles for use in the invention
may be about 1 micron, about 2 microns, about 3 microns, about 4
microns, about 5 microns, about 6 microns, about 7 microns, about 8
microns, about 9 microns, or about 10 microns in diameter.
[0030] In one embodiment, the dosage forms are in the form of a
solution aerosol (i.e., comprise droplets). Typically, droplets
will be about 10 microns or less in diameter. Droplets for use in
the compositions of the invention may have a diameter of from about
0.1 microns to about 10 microns, from about 0.1 microns to about 9
microns, from about 0.1 microns to about 8 microns, from about 0.1
microns to about 7 microns, from about 0.1 microns to about 6
microns, from about 0.1 microns to about 5 microns, from about 0.1
microns to about 4 microns, from about 0.1 microns to about 3
microns, from about 0.1 microns to about 2 microns, from about 0.1
microns to about 1 micron, from about 0.1 microns to about 0.5
microns, from about 1 micron to about 10 microns, from about 1
micron to about 9 microns, from about 1 micron to about 8 microns,
from about 1 micron to about 7 microns, from about 1 micron to
about 6 microns, from about 1 micron to about 5 microns, from about
1 micron to about 4 microns, from about 1 micron to about 3
microns, from about 1 micron to about 2 microns, from about 2
microns to about 10 microns, from about 2 microns to about 9
microns, from about 2 microns to about 8 microns, from about 2
microns to about 7 microns, from about 2 microns to about 6
microns, from about 2 microns to about 5 microns, from about 2
microns to about 4 microns, or from about 2 microns to about 3
microns. In some embodiments, particles and/or droplets for use in
the invention may be about 1 micron, about 2 microns, about 3
microns, about 4 microns, about 5 microns, about 6 microns, about 7
microns, about 8 microns, about 9 microns, or about 10 microns in
diameter.
[0031] In addition to a tight junction antagonist, compositions of
the invention may further comprise one or more additional
therapeutic agents, particularly therapeutic agents conventionally
used for treating lung conditions such as ALI and ARDS. Such
additional therapeutic agents include, but are not limited to,
steroids and other anti-inflammatory compounds. Suitable
therapeutic agents may include one or more of aminosalicylates,
corticosteroids, immunomodulators, antibiotics, cytokines,
chemokines and biologic therapies.
[0032] Compositions of the invention may also comprise one or more
pharmaceutically acceptable excipients. Suitable excipients
include, but are not limited to, buffers, buffer salts, bulking
agents, salts, surface active agents, acids, bases, sugars, and
binders.
[0033] Methods of Use
[0034] The compositions of the invention can be used for
preventing, slowing the onset of, ameliorating and/or treating ALI
and ARDS. Typically, compositions may be administered one or more
times each day in an amount suitable to prevent, reduce the
likelihood of an attack of, or reduce the severity of an attack of
the underlying disease condition.
[0035] In some embodiments, compositions of the invention may be
given repeatedly over a protracted period, i.e., may be chronically
administered. Typically, compositions may be administered one or
more times each day in an amount suitable to treat ALI and
ARDS.
[0036] In some embodiments, compositions of the invention may be
used to treat acute symptoms of ALI and ARDS. Typically,
embodiments of this type will require administration of the
compositions of the invention to a subject undergoing an acute
episode in an amount suitable to reduce the severity of the
symptoms. One or more administration may be used.
[0037] A composition according to the present invention may be
pre-mixed prior to administration, or can be formed in vivo when
two or more components (e.g., a tight junction antagonist and an
additional therapeutic agent) are administered within 24 hours of
each other. When administered separately, the components may be
administered in either order (e.g. tight junction antagonist first
followed by additional therapeutic agent or additional therapeutic
agent first followed by tight junction antagonist). The components
can be administered within a time span of about 12 hours, about 8
hours, about 4 hours, about 2 hours, about 1 hour, about 0.5 hour,
about 0.25 hour, about 0.1 hour, about 1 minute, about 0.5 minute,
or about 0.1 minute.
[0038] Administration of the compositions described above, e.g.,
compositions comprising one or more tight junction antagonists and
optionally comprising one or more additional therapeutic agents,
may be by inhalation. For example, one or more tight junction
antagonists and one or more additional therapeutic agents or a
mixture thereof; may be in inhalable form. An example of an
inhalable form is an atomizable composition such as an aerosol
comprising the tight junction antagonist, either alone or in
combination with one or more additional therapeutic agents, in
solution or dispersion in a propellant, or a nebulizable
composition comprising a solution or dispersion of the active
ingredient in an aqueous, organic or aqueous/organic medium. For
example, the inhalable form of the compositions of the invention
may be an aerosol comprising a mixture of one or more tight
junction antagonists and one or more additional therapeutic agents
in solution or dispersion in a propellant, or a combination of an
aerosol containing one or more tight junction antagonists in
solution or dispersion in a propellant with an aerosol containing
one or more therapeutic agents in solution or dispersion in a
propellant. In another example, the inhalable form of the
compositions of the invention my be a nebulizable composition
comprising a dispersion of one or more tight junction antagonists
and one or more additional therapeutic agents in an aqueous,
organic or aqueous/organic medium, or a combination of a dispersion
of one or more tight junction antagonists with a dispersion of one
or more additional therapeutic agents in such a medium.
[0039] Compositions of the invention may be administered in
conjunction with one or more additional therapeutic agents,
particularly therapeutic agents used conventionally for treating
lung conditions such as ALI and ARDS. Such additional therapeutic
agents include, but are not limited to, steroids and other
anti-inflammatory compounds. Suitable therapeutic agents may
include one or more of aminosalicylates, corticosteroids,
immunomodulators, antibiotics, cytokines, chemokines and biologic
therapies.
[0040] Compositions of the invention and one or more additional
therapeutic agents may be administered simultaneously, or
alternatively compositions of the invention and one or more
additional therapeutic agents may not be administered
simultaneously. Furthermore, compositions of the invention may be
administered prior to administration of one or more additional
therapeutic agents, or alternatively compositions of the invention
may be administered subsequent to administration of one or more
additional therapeutic agents.
[0041] The following examples are provided for illustrative
purposes only, and are in no way intended to limit the scope of the
present invention.
EXAMPLES
[0042] The IgG immune complex model is a well established model of
lung injury and is shown schematically in FIG. 1. Briefly, a
heterologous antibody mix containing antibodies to a known antigen
are injected into an animal intravenously (IV) or intratracheally
(IT). The known antigen and a small amount of radiolabelled known
antigen are injected into the animal IV. This results in immune
complex (IC) formation between the antigen and the cognate
antibodies in the heterologous antibody mix. The immune complex
binds to binds to the Fc gamma receptor (Fc.gamma.R) and this
initiates an inflammatory cascade and leads to injury. One of the
results of the inflammatory cascade is an increase in lung
permeability that increases with extent of injury. The increase in
lung permeability is quantified by measuring the radiolabelled
antigen present in lung versus blood where radiolabel in the lung
versus blood increases with permeability. (See Johnson and Ward, J.
Clin. Investigation 54:349-357, 1974).
[0043] FIG. 2 shows the results of an experiment where 4-5 mice per
arm were treated as described above where the known antigen was
bovine serum albumin (BSA) the heterologous antibody mix included
antibody to bovine serum albumin (anti-BSA) and the treatment was
carried out in the presence and absence of tight junction
antagonist SEQ ID NO:15.
[0044] FIG. 2 shows a comparison of the change in lung permeability
resulting from IC formation in response to the treatment described
above in the presence and absence of tight junction antagonist as
well as a comparison of the effects of IV versus IT administration
of tight junction antagonist.
[0045] FIG. 3 shows the results of varying the dose of SEQ ID NO:15
administered with the anti-BSA antibodies delivered IT.
[0046] All publications, patents and patent applications mentioned
in this specification are indicative of the level of skill of those
skilled in the art to which this invention pertains, and are herein
incorporated by reference to the same extent as if each individual
publication, patent or patent application was specifically and
individually indicated to be incorporated by reference.
Sequence CWU 1
1
2418PRTArtificial SequenceTight junction antagonist 1Gly Arg Val
Cys Val Gln Pro Gly1 528PRTArtificial SequenceTight junction
antagonist 2Gly Arg Val Cys Val Gln Asp Gly1 538PRTArtificial
SequenceTight junction antagonist 3Gly Arg Val Leu Val Gln Pro Gly1
548PRTArtificial SequenceTight junction antagonist 4Gly Arg Val Leu
Val Gln Asp Gly1 558PRTArtificial SequenceTight junction antagonist
5Gly Arg Leu Cys Val Gln Pro Gly1 568PRTArtificial SequenceTight
junction antagonist 6Gly Arg Leu Cys Val Gln Asp Gly1
578PRTArtificial SequenceTight junction antagonist 7Gly Arg Leu Leu
Val Gln Pro Gly1 588PRTArtificial SequenceTight junction antagonist
8Gly Arg Leu Leu Val Gln Asp Gly1 598PRTArtificial SequenceTight
junction antagonist 9Gly Arg Gly Cys Val Gln Pro Gly1
5108PRTArtificial SequenceTight junction antagonist 10Gly Arg Gly
Cys Val Gln Asp Gly1 5118PRTArtificial SequenceTight junction
antagonist 11Gly Arg Gly Leu Val Gln Pro Gly1 5128PRTArtificial
SequenceTight junction antagonist 12Gly Arg Gly Leu Val Gln Asp
Gly1 5138PRTArtificial SequenceTight junction antagonist 13Gly Gly
Val Cys Val Gln Pro Gly1 5148PRTArtificial SequenceTight junction
antagonist 14Gly Gly Val Cys Val Gln Asp Gly1 5158PRTArtificial
SequenceTight junction antagonist 15Gly Gly Val Leu Val Gln Pro
Gly1 5168PRTArtificial SequenceTight junction antagonist 16Gly Gly
Val Leu Val Gln Asp Gly1 5178PRTArtificial SequenceTight junction
antagonist 17Gly Gly Leu Cys Val Gln Pro Gly1 5188PRTArtificial
SequenceTight junction antagonist 18Gly Gly Leu Cys Val Gln Asp
Gly1 5198PRTArtificial SequenceTight junction antagonist 19Gly Gly
Leu Leu Val Gln Pro Gly1 5208PRTArtificial SequenceTight junction
antagonist 20Gly Gly Leu Leu Val Gln Asp Gly1 5218PRTArtificial
SequenceTight junction antagonist 21Gly Gly Gly Cys Val Gln Pro
Gly1 5228PRTArtificial SequenceTight junction antagonist 22Gly Gly
Gly Cys Val Gln Asp Gly1 5238PRTArtificial SequenceTight junction
antagonist 23Gly Gly Gly Leu Val Gln Pro Gly1 5248PRTArtificial
SequenceTight junction antagonist 24Gly Gly Gly Leu Val Gln Asp
Gly1 5
* * * * *