U.S. patent application number 13/855596 was filed with the patent office on 2014-03-13 for glue composition for lung volume reduction.
This patent application is currently assigned to PneumRx, Inc.. The applicant listed for this patent is PneumRx, Inc.. Invention is credited to Ronald Dieck, Glen Gong.
Application Number | 20140073588 13/855596 |
Document ID | / |
Family ID | 35480826 |
Filed Date | 2014-03-13 |
United States Patent
Application |
20140073588 |
Kind Code |
A1 |
Gong; Glen ; et al. |
March 13, 2014 |
GLUE COMPOSITION FOR LUNG VOLUME REDUCTION
Abstract
The present invention relates to methods and compositions for
sealing localized regions of damaged lung tissue to reduce overall
lung volume. The glue compositions provide a glue featuring an
adhering moiety coupled to one or more other moieties including,
for example, a cross-linkable moiety and/or one other adhering
moiety. The methods and compositions of the invention find use, for
example, in treating pulmonary conditions, such as emphysema.
Inventors: |
Gong; Glen; (San Francisco,
CA) ; Dieck; Ronald; (Mountain View, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
PneumRx, Inc.; |
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US |
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Assignee: |
PneumRx, Inc.
Mountain View
CA
|
Family ID: |
35480826 |
Appl. No.: |
13/855596 |
Filed: |
April 2, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13089496 |
Apr 19, 2011 |
8431537 |
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13855596 |
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12342657 |
Dec 23, 2008 |
7932225 |
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13089496 |
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11008580 |
Dec 8, 2004 |
7468350 |
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12342657 |
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60580444 |
Jun 16, 2004 |
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60586932 |
Jul 8, 2004 |
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60586950 |
Jul 8, 2004 |
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Current U.S.
Class: |
514/20.4 ;
514/20.3 |
Current CPC
Class: |
A61P 11/00 20180101;
A61K 47/66 20170801; A61K 38/57 20130101; A61K 51/088 20130101;
A61K 38/55 20130101; B82Y 5/00 20130101; A61K 47/6425 20170801 |
Class at
Publication: |
514/20.4 ;
514/20.3 |
International
Class: |
A61K 38/55 20060101
A61K038/55 |
Claims
1. A composition for sealing lung tissue, comprising: a
bifunctional chemical linker; a first adhering moiety connected via
a first amide bond linkage to a first site on the bifunctional
chemical linker; and a second adhering moiety connected via a
second amide bond linkage to a second site on the bifunctional
chemical linker, wherein the first and second adhering moieties
adhere to different sites bearing elastase in a lung, and each
adhering moiety comprises a member selected from the group
consisting of an alpha-1 antitrypsin, an elafin, and a serpin.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 13/089,496, entitled, "Glue Composition for Lung Volume
Reduction", filed Apr. 19, 2011, which is a continuation of U.S.
application Ser. No. 12/342,657, now U.S. Pat. No. 7,932,225,
entitled, "Glue Composition for Lung Volume Reduction," filed Dec.
23, 2008, which is a continuation of U.S. application Ser. No.
11/008,580, now U.S. Pat. No. 7,468,350, entitled, "Glue
Composition for Lung Volume Reduction," filed Dec. 8, 2004, which
claims priority to U.S. provisional applications 60/580,444,
entitled "Targeting Damaged Lung Tissue," filed Jun. 16, 2004; U.S.
60/586,932, entitled "Targeting Damaged Lung Tissue Using Various
Formulations," filed Jul. 8, 2004; and U.S. 60/586,950, entitled
"Lung Volume Reduction Using Glue Composition," filed Jul. 8, 2004,
each of which is incorporated herein in its entirety.
BACKGROUND OF THE INVENTION
[0002] Pulmonary conditions affect millions of Americans and many
more individuals worldwide. Chronic obstructive pulmonary disease
(COPD), for example, including emphysema, asthma, bronchiectais and
chronic bronchitis, is one of the most common chronic conditions
and the fourth leading cause of death in the United States. While
various environmental and genetic factors may contribute to COPD,
cigarette smoking is the primary cause. Cigarette smoke can trigger
inflammatory responses within the lungs, activating elastase,
cathepsin G, and matrix metalloproteinases (MMPs). These enzymes
are proteases that result in progressive destruction of the elastic
tissue of the lungs, reducing the elasticity and lung recoil
required for exhalation. Damaged alveolar walls can eventually
rupture to form inelastic "blebs." Emphysema, for example, is
characterized by abnormal enlargement of alveolar airspaces distal
to terminal bronchioles and destruction of airspace parenchyma
resulting in such "blebs."
[0003] Current treatments are wanting. Treatment of pulmonary
conditions often involves control and management rather than a cure
for the disease. With emphysema, for example, treatment can involve
cessation of smoking, exercise programs, medications that help open
constricted airways, anti-inflammatory medications, oxygen therapy,
placement of one-way valves, and lung volume reduction surgery
(LVRS). LVRS involves surgical removal of damaged, over-inflated
lung tissue to free up space for the expansion of remaining
non-damaged tissue. This technique, however, requires invasive
procedures and benefits tend to decline over time. Further,
treatments using one-way valves have not proved satisfactory. Thus,
there remains a need for improved methods for treating pulmonary
conditions, such as emphysema.
[0004] The present invention provides methods and compositions
directed thereto. Other methods and compositions directed thereto
are provided in U.S. nonprovisional applications entitled
"Targeting Damaged Lung Tissue Using Compositions," filed Dec. 8,
2004; "Targeting Damaged Lung Tissue," filed Dec. 8, 2004;
"Targeting Sites of Damaged Lung Tissue Using Composition," filed
Dec. 8; 2004; "Targeting Sites of Damaged Lung Tissue," filed Dec.
8, 2004; "Imaging Damaged Lung Tissue Using Compositions," filed
Dec. 8, 2004; "Imaging Damaged Lung Tissue," filed Dec. 8, 2004;
"Glue Compositions for Lung Volume Reduction," filed Dec. 8, 2004;
"Lung Volume Reduction Using Glue Compositions," filed Dec. 8,
2004; and "Lung Volume Reduction Using Glue Composition," filed
Dec. 8, 2004, each of which is herein incorporated in its
entirety.
BRIEF SUMMARY OF INVENTION
[0005] One aspect of the invention relates to a glue composition
composing a first adhering moiety and a second adhering moiety
where the adhering moieties are coupled and where the adhering
moieties adhere different sites of lung tissue. In some
embodiments, the lung tissue comprises epithelial lining fluid. In
some embodiments, the different sites comprise different sites
within an enlarged air space. In some embodiments, the first and
second adhering moieties are the same. In some embodiments, the
first and second adhering moieties are different
[0006] In some embodiments, the adhering moieties are coupled via a
chemical linker. In some embodiments, the chemical linker comprises
two functional groups. In some embodiments, at least one of the
functional groups is a hydroxyl group, a carboxyl group, an ester
group, an amine group, or a lysine group. In some embodiments, at
least one of the functional groups is a cyano group, a thiol group,
a cysteine group, a carbonyl group, an aldehyde group or a ketone
group. In some embodiments, the adhering moieties are coupled as a
fusion polypeptide. In some embodiments, the adhering moieties are
coupled via a protein. In some embodiments, the adhering moieties
are coupled via an antibody. In some embodiments, the glue
composition does not comprise a polysaccharide or a carbohydrate
moiety. In some embodiments, the glue composition does not comprise
a mutant plasminogen activator-inhibitor type 1.
[0007] In some embodiments, the adhering moiety adheres a cell
surface marker. In some embodiments, the adhering moiety adheres an
ECM component. In some embodiments, the first and/or second
adhering moiety adheres elastase. In some embodiments, the first
and/or second adhering moiety adheres neutrophil elastase. In some
embodiment, the first and/or second adhering moiety comprises a
protease inhibitor moiety. For example, in some embodiments, the
first and/or second adhering moiety comprises an alpha-1
antitrypsin moiety, for example, a recombinant alpha-1 antitrypsin
moiety. In some embodiments, the first and/or second adhering
moiety comprises an elafin moiety, for example, a recombinant
elafin moiety. In some embodiments, the first and/or second
adhering moiety comprises a serpin moiety, for example, a
recombinant serpin moiety, a secretory leukoprotease inhibitor
(SLP1) moiety, and/or a recombinant secretory leukoprotease
inhibitor (SLP1) moiety. In some embodiments, the first and/or
second adhering moiety adheres at least one matrix
metalloproteinase selected from MMP-1, MMP-2, MMP-3, MMP-4, MMP-5,
MMP-6, MMP-7, MMP-8, and MMP-9. In some embodiments, the glue
composition does not comprise a hyaluronic acid or a salt thereof.
In some embodiments, the first and/or second adhering moiety
adheres desmosine and/or isodesmosine. In some embodiments, the
first and/or second adhering moiety adheres CD8 and/or CD4. In some
embodiments, the first and/or second adhering moiety adheres a
smoke-related moiety.
[0008] In some embodiments, the glue composition is less than 10
microns. In some embodiments, the glue composition is less than 5
microns. In some embodiments, the glue composition is less than 1
micron.
[0009] In another aspect of the invention, the glue composition
further comprises a cross-linkable moiety coupled to the first
and/or second adhering moieties.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] The novel features of the invention are set forth with
particularity in the appended claims. A better understanding of the
features and advantages of the present invention will be obtained
by reference to the following detailed description that sets forth
illustrative embodiments, in which the principles of the invention
are utilized, and the accompanying drawings of which:
[0011] FIGS. 1a-1b illustrate one embodiment of a method to reduce
lung volume using a glue composition comprising a cross-linkable
moiety coupled to an adhering moiety that adheres to lung tissue.
FIG. 1a schematically illustrates a bronchoscope placed in a
bronchus from which a catheter extends to a segmental and
subsegmental bronchus. FIG. 1b schematically illustrates a terminal
bronchiole, terminating in the airspace of an alveolus.
[0012] FIGS. 2a-2b illustrate one embodiment of a method to reduce
lung volume using a glue composition comprising coupled adhering
moieties that adhere to different sites of lung tissue. FIG. 2a
schematically illustrates a bronchoscope placed in a bronchus from
which a catheter extends to a segmental and subsegmental bronchus.
FIG. 2b schematically illustrates a terminal bronchiole,
terminating in the airspace of an alveolus.
DETAILED DESCRIPTION OF THE INVENTION
[0013] One aspect of the present invention provides a glue
composition comprising an adhering moiety that adheres lung tissue,
including lung fluids, such as, for example, epithelial lining
fluid. An adhering moiety may adhere to lung tissue, for example,
sites of non-diseased or normal lung tissue, as well as sites of
diseased and/or non-normal lung tissue that may be affected, have
been affected, or are likely to be affected by a pulmonary
condition. An adhering moiety may bind, attach, or otherwise couple
to lung tissue by covalent and/or non-covalent binding. Examples of
binding forces that may be useful in the present invention include,
but are not limited to, covalent bonds, dipole interactions,
electrostatic forces, hydrogen bonds, hydrophobic interactions,
ionic bonds, and/or van der Waals forces.
[0014] In some preferred embodiments, the adhering moiety adheres
to a protease or other molecule and/or macromolecule present in
lung tissue. For example, the adhering moiety may adhere a molecule
and/or macromolecule found attached, bound, coupled, completed
and/or otherwise associated with lung tissue. Binding, attachment,
coupling, completing and/or association may involve covalent and/or
non-covalent interactions, including, e.g., dipole interactions,
electrostatic forces, hydrogen bonds, hydrophobic interactions,
ionic bonds, and/or van der Waals forces.
[0015] In some embodiments, the adhering moiety may adhere a
molecule and/or macromolecule that is bound, attached, coupled,
complexed and/or otherwise associated with a cell surface of lung
tissue. In some embodiments, the molecule and/or macromolecule may
be bound to a cell wall. In some embodiments, the molecule and/or
macromolecule may be completed with a moiety that is itself bound
to a cell wall. In some embodiments, the molecule and/or
macromolecule may comprise a cell surface marker. In still some
embodiments, the molecule and/or macromolecule may be found
associated with the extra cellular matrix (ECM). For example, the
molecule and/or macromolecule may compose an ECM component or may
be associated with an EMC component of lung tissue.
[0016] In some embodiments, the adhering moiety may adhere a
molecule and/or macromolecule comprising at least one moiety
selected from a protein moiety, a glycoprotein moiety, a
lipoprotein moiety, a lipid moiety, a phospholipid moiety, a
carbohydrate moiety, a nucleic acid moiety, a modified nucleic acid
moiety, and/or a small molecule moiety, including, e.g., a cell
surface marker comprising a glycoprotein moiety and/or an ECM
component comprising a protein moiety.
[0017] In some preferred embodiments, the adhering moiety adheres
to elastase. The elastase may be bound to the cell wall and/or
associated with the extracellular matrix of lung tissue. For
example, elastase causes progressive destruction of elastic fibers
of lung tissues in some pulmonary conditions, e.g., emphysema,
resulting in dilation and rupture of distended alveoli to form
characteristic "blebs." Suki et al., "On the Progressive Nature of
Emphysema, Pulmonary Perspective", American Journal of Respiratory
and Critical Care Medicine, Vol. 168 pgs. 516-520 (2003); Janoff et
al., Am. Rev. Respir. Dis., Vol. 132 pgs. 417-433 (1985); Senior
and Kuhn, in Fishman (ed), Pulmonary Diseases and Disorders, 2d ed.
New York, McGraw-Hill p. 1209-1218 (1988). In some preferred
embodiments, the adhering moiety adheres to neutrophil elastase
and/or neutrophils. In some preferred embodiments, the adhering
moiety adheres pancreatic and/or macrophage elastase. In some
preferred embodiments, the adhering moiety adheres neutrophil
proteinase 3 (Pr3). Pr3 is described, for example, in Duranton et
al., "Inhibition of proteinase 3 by alpha-1 antitrypsin in vitro
predicts very fast inhibition in vivo", Am J Respir Cell Mol Biol.,
Vol. 29 No. 1 pgs 57-61 (2003).
[0018] For example, the adhering moiety may (or may not) comprise
alpha-1 antitrypsin, elafin, thypin (see, e.g., International
Publication. No. WO 02/072769), and/or other serpin, e.g., PAI-1,
PAI-2, SCCA-1, SCCA-2, secretory leukoprotease inhibitor SLP-1
(see, e.g., U.S. Pat. No. 6,753,164), and/or other serpin-related
proteins (e.g., as disclosed in U.S. Publication No. 2004/0126777);
a recombinant form of any of these and/or a moiety of any of these
that retains the ability to adhere to lung tissue. In some
embodiments, the adhering moiety may (or may not) comprise mucous
proteinase inhibitor (MPI) that shows high affinity for binding to
elastase. Belorgey et al., "Effect of polynucleotides on the
inhibition of neutrophil elastase by mucus proteinase inhibitor and
alpha-1 proteinase inhibitor", Biochemistry, Vol. 37 No. 46 pgs
16416-22 (1998). Other adhering moieties that can adhere to
elastase may also be used, such as inhibitors of elastase known in
the art. See, e.g., Janoff et al., Am. Rev. Respir. Dis. Vol. 132
pgs 417-433 (1985); Zimmerman and Powers (1989), In Hornebeck (ed),
Elastin and Elastases, vol II, Boca Raton, CRC Press, pgs 109-123;
and Laurell and Eriksson Scand. J. Clin. Lab. Invest., Vol. 15 pgs
132-140 (1963). Other adhering moieties can include protease
inhibitors of the inter-alpha trypsin inhibitor (ITI) family. The
ITI protein family can be built up from different combinations of
the polypeptides HC1, HC2, HC3 and bikunin, as described, e.g., in
Cuvelier et al., "Proteins of the inter-alpha trypsin inhibitor
(ITI) family. A major role in the biology of the extracellular
matrix", Rev Mal Respir., Vol. 17 No. 2 pgs 437-46 (2000).
[0019] Alpha-1 antitrypsin useful for preparing an adhering moiety
of the present invention may be obtained by any techniques known in
the art and/or disclosed herein. For example, alpha-1 antitrypsin
can be obtained by recombinant methods, as known in the art (e.g.,
recombinant alpha-1 antitrypsin from Novartis). Techniques for
purifying alpha-1 antitrypsin, e.g., from biological natural and/or
recombinant sources are also known in the art. See, e.g.,
International Publication No. WO 00/17227 and U.S. Pat. No.
4,656,254, which describes separating alpha-1 antitrypsin from
plasma.
[0020] In some preferred embodiments, the adhering moiety adheres
to desmosine and/or isodesmosine. Desmosine and/or isodesmosine are
amino acids produced as a result of damage to lung tissues,
particularly damage involving destruction of elastin. Fragmented
elastin, for example, is metabolized to free desmosine or small
peptides; which can be recovered in the urine of the subject. See,
e.g., Starcher B. C., "Lung Elastin and Matrix", Chest, Vol. 117
pgs 229S-234S (2000). In animal models of emphysema, for example,
desmosine urine recovery can serve as a measure of lung damage.
There are several micromethods for measuring desmosine, including,
for example, enzyme-linked immunosorbent assay (see, e.g., Osakabe
T. et al. "Comparison of ELISA and HPLC for the determination of
desmosine and isodesmosine in aortic tissue elastin", J. Clin Lab
Anal Vol. 9 pgs 293-296 (1995)); isotope dilution (see, e.g., Stone
P. J. et al. "Measurement of urinary desmosine by isotope dilution
and high performance liquid chromatography", Am Rev Respir Dis Vol.
144 pgs 284-290 (1991)); high performance liquid chromatography
(see, e.g., Covault H. P. et al. "Liquid-chromatographic
measurement of elastin", Clin Chem Vol. 28 pgs 1465-1468 (1982));
and/or radioimmunoassay (see, e.g., Starcher B. "A role for
neutrophil elastase in the progression of solar elastosis", Connect
Tissue Res Vol. 31 pgs 133-140 (1995)).
[0021] In some preferred embodiments, the adhering moiety adheres
to cathepsin, e.g. cathepsin G, which can be produced by
inflammatory cells in the pathogenesis of COPD. In some
embodiments, the adhering moiety adheres other cysteine
proteinases. In some embodiments the adhering moiety adheres
cathepsins L, S, and K. In some embodiments, the adhering moiety
adheres RGS2, which accumulates at sites of macrophage activation,
e.g., in activated-macrophage-related disorders, including
emphysema. See, e.g., EP 1378518. In some embodiments, the adhering
moiety adheres to alveolar macrophages. In some embodiments, the
adhering moiety adheres to eosinophils. In some embodiments, the
adhering moiety adheres to tumor-necrosis factor-.alpha.. In some
embodiments, the adhering moiety adheres to kallikrenin.
[0022] In some preferred embodiments, the adhering moiety adheres a
collagenase. The presence of collagenase activity may be detected,
for example, by released components, e.g., amino acids, known to
occur in collagen, e.g., hydroxyproline and/or hydroxylysine.
[0023] Examples of collagenases include, e.g., one or more
metalloproteinases. Metalloproteinases include, e.g., MMP-1
(interstitial collagenase or collagenase-1), MMP-2 (gelatinase-A or
72 kD gelatinase), MMP-3 (transin, human fibroblast stromelysin or
stromelysin-I), MMP-4, MMP-5, MMP-6, MMP-7 (matrilysin), MMP-8
(collagenase-2 or neutrophil collagenase), MMP-9 (gelatinase B or
92 kD gelatinase), MMP-10 (stromelysin II), MMP-11 (Stromelysin
III), MMP-12 (macrophase metalloelastase), and/or MMP-13
(collagenase-3) and as well as metalloproteinase ADAM 2222 (see,
e.g., U.S. Publication No. 2003/0194797). Metalloproteinases (also
referred to as metalloproteases in the art) have been described,
e.g., U.S. Publication No. 2003/0199440; U.S. Publication No.
2004/0048302: U.S. Publication No. 2004/0043407; U.S. Publication
No. 2004/0194797; and International Publication No. WO 02/072751.
For example, an adhering moiety comprising an ilomastat moiety may
be used. See, e.g., International Publication No. WO
2004/052236.
[0024] In some embodiments, the glue composition does not comprise
a polysaccharide or carbohydrate moiety, e.g., in some embodiments,
the glue composition does not comprise hyaluronic acid or a salt
thereof; and in some embodiments, the glue composition does not
comprise dextran or glycosaminoglycan. In some embodiments, the
glue composition does not comprise a polysaccharide or carbohydrate
moiety that binds to elastic fibers. In some embodiments, the glue
composition does not comprise an antibody. In some embodiments, the
glue composition does not comprise a lung membrane
dipeptidase-binding molecule, e.g., in some embodiments, the glue
composition may not adhere to lung membrane dipeptidase, and in
some embodiments the glue composition may not comprise GFE-1
peptide. See, e.g., Rajotte et al., "Membrane dipeptidase is the
receptor for a lung-targeting peptide identified by in vivo phage
display", J. Biol Chem Vol. 274 No. 17 pgs 11593-8 (1999) and U.S.
Pat. No. 6,784,153.
[0025] Also, in some preferred embodiments, the adhering moiety
adheres to CD8 and/or CD4, CD8 lymphocytes and/or CD4 lymphocytes,
and/or interleukin 8 (see, e.g, U.S. Publication No. 2003/0232048).
In some embodiments, the adhering moiety adheres to
mitogen-activated protein kinase (International Publication No. WO
03/064639). In some embodiments, the adhering moiety may (or may
not) adhere to CIRL-2 homologs (see, e.g., International
Publication No. WO 2004/031235). In still some embodiments, the
adhering moiety may (or may not) comprise an antibody and/or
binding fragment thereof that adheres to lung tissue. For example,
the adhering moiety may comprise a COPD-related human Ig derived
protein, discussed e.g. in International Publication No. WO
02/072788 and/or U.S. Publication No. 2003/0017150, which can bind
COPD related proteins. In yet another example, the adhering moiety
may comprise an antibody to secreted protein HCEJQ69 (see, e.g.,
U.S. Pat. No. 6,774,216).
[0026] Preferred adhering moieties of the present invention
comprise biological moieties, such as proteins or polypeptides,
which can adhere to lung tissue, and can include
naturally-occurring protease inhibitors, such as alpha-1
antitrypsin and/or mutants thereof and/or fragments thereof, as
well as other protease inhibitor moieties. As well as alpha-1
antitrypsin, other naturally-occurring inhibitors of elastase may
also be used as preferred adhering moieties of the present
invention, including, e.g., monocyte elastase inhibitor and
variants thereof (see, e.g., International Publication No. WO
96/10418; U.S. Pat. No. 5,827,672; and U.S. Pat. No. 5,663,299); as
well as tissue inhibitors of metalloproteinases (TIMPs), such as
TIMP-1, TIMP-2, TIMP-3, and TIMP-4.
[0027] In more preferred embodiments, the adhering moiety is
modified such that it binds to lung tissue irreversibly,
substantially irreversibly, or at least with a high binding
constant, e.g., to resist dissociation for a desired period of
time. Adhering moieties may be selected and/or developed to
increase binding affinity for lung tissue. For example, alpha-1
antitrypsin may be mutated by random and/or directed synthesis, to
engineer mutants with higher binding constants for elastase. For
example, in some preferred embodiments, the adhering moiety has a
K.sub.i value against a component of lung tissue of less than about
200 nM, less than about 150 nM, less than about 100 nM, or less
than about 75 nM. In some preferred embodiments, the adhering
moiety has a K.sub.i value against a component of lung tissue of
more than about 50 nM, more than about 25 nM, more than about 20
nM, more than about 15 nM, more than about 10 nM, more than about 5
nM, more than about 3 nM, or more than bout 1 nM. In some preferred
embodiments, the adhering moiety binds a component of lung tissue
with a K.sub.D less than about 10.sup.-8 M, less than about
10.sup.-9 M, less than about 10.sup.-10 M, less than about
10.sup.-11 M, less than about 10.sup.-12 M, less than about
10.sup.-13 M, or less than about 10.sup.-14 M.
[0028] Other non-naturally occurring protease inhibitors that may
(or may not) be used as an adhering moiety of the present invention
include inhibitors of neutrophil elastase (e.g., methyl ketone
derivatives); inhibitors of macrophage metalloproteinase (e.g.,
RSI13456 and inhibitors discussed in U.S. Publication No.
2003/0199440); Cathepsin G inhibitors (e.g., LEX-032 (Sparta));
various elastase inhibitors (e.g. ABT-491 (Abbot)); inhibiting
compositions (e.g., as disclosed in U.S. Publication No.
2003/0199440 and International Publication No. WO 03/090682,
including lipase inhibitors and phospholipase inhibitors); protease
inhibitor compositions (e.g., as disclosed in International
Publication No. WO 2004/045634); Erdosteine (Edmond Pharma), FK-706
(Fujisawa), GW-311616 (Glaxo-Wellcome), Midesteine (Medea); a
mutant plasminogen activator-inhibitor type 1 (see, e.g., U.S.
Publication. No. 2003/0216321); an N-substituted azetidinone (see,
e.g., EP 0529719); peptidyl carbamates (e.g., U.S. Pat. No.
5,008,245 and/or EP 0367514); SR-268794 (Sanoti) and/or SYN-1134
(Syn. Pharm.); other proteinase inhibitors (e.g., CMP-777
(Dupont)); heteroaryl aminoguanidines and alkoxyguanidines (see,
e.g., U.S. 2004/0106633 and EP 1070049); as well as ON-elastase
inhibitors (e.g., NX-21909 (Gilead)); and several HNE inhibitors
(e.g., CE-1037 (Cortech/United Ther), CE-2000 series (Cortech/Ono),
EPI-HNE-4 (Dyax), EPI-HNE-1 (Protein Engineer), MDL-101146 (HMR),
Ono-5046 (Ono), SPAAT (UAB Res. Found.), WIN-63759 (Sterling
Winthrop), ZD-8321 (AstraZeneca), and/or ZD-0892 (AstraZeneca)).
Adhering moieties may (or may not) also include inhibitors and/or
antibodies of any lung tissue components described herein, as well
as inhibitors and/or antibodies of proteins described in
International Publication No. WO 03/010327; as well as inhibitors
and/or antibodies of eosinophil serine protease 1-like enzymes
described in U.S. Publication No. 2003/0224430 and/or other serine
proteases, e.g., described in International Publication No. WO
2004/053117; as well as inhibitor and/or antibodies of
transmembrane serine proteases, e.g., as discussed in U.S. Pat. No.
6,734,006; as well as inhibitors and/or antibodies of esterase
described in International Publication No. WO 04/020620. As used
herein, "antibodies" includes binding fragments thereof.
[0029] In some preferred embodiments, the adhering moiety comprises
a compound, such as a small molecule compound, that adheres lung
tissue or a component thereof. Such compounds can be obtained, for
example, via ligand screening methods, as known in the art. For
example, a biological sample or a defined candidate moiety can be
brought into contact with a component of lung tissue, for example
purified and/or recombinant elastase, or fragments thereof, as well
as a component isolated and/or purified from epithelial lining
fluid. The candidate moiety may be labeled with a detectable label,
such as a fluorescent, radioactive, and/or an enzymatic tag and
allowed to contact the lung tissue component that may be
immobilized, e.g., under conditions that permit binding. After
removing unbound moieties, bound moiety can be detected using
appropriate methods as known in the art.
[0030] Candidate moieties that can be assayed for adhering lung
tissue for use in the present invention are not limited. For
example, such candidate moieties can be obtained from a wide
variety of sources including libraries of synthetic, semisynthetic
and/or natural substances. Random and/or directed synthesis can be
used, for example, to generate a wide variety of organic compounds
and biomolecules, including randomized oligonucleotides and
oligopeptides. With respect to natural compounds, libraries form
bacterial, fungal, plant and animal extracts are available and/or
can be readily produced. Further, natural, semi-synthetically,
and/or synthetically produced libraries can be modified through
conventional chemical, physical, recombinant, and/or biochemical
techniques to produce combinatorial libraries. Also, known
pharmaceutical or pharmacological agents may be modified by
directed or random chemical modifications, including, for example,
acylation, amidification, alkylation, and/or esterification to
produce structural analogs.
[0031] Candidate moieties may include natural, synthetic and/or
semi-synthetic organic compounds, macromolecules of biological
origin, such as polypeptides, peptides, polysaccharides,
glycoproteins, lipoproteins, fatty acids, and/or fragments thereof;
and/or drugs or small molecules, such as molecules generated
through combinatorial chemistry approaches. Further, when the
candidate moiety comprises a peptide or polypeptide, the candidate
moiety may be expressed by a phage clone belonging to a phage-based
random peptide library (see, e.g., Parmley and Smith, Gene Vol. 73
pgs 305-318 (1988); Oldenburg et al. Proc. Natl. Acad. Sci. USA
Vol. 89 pgs 5393-5397 (1992); Valadon et al., J Mol. Biol., Vol 261
pgs 11-22 (1996); Westerink, Proc. Natl. Acad. Sci USA., Vol. 92
pgs 4021-4025 (1995); and Felici et al., J. Mol. Biol., Vol. 222
pgs 301-310) (1991); and/or the candidate moiety may be expressed
from a cDNA cloned in a vector for performing a two-hybrid
screening assay (U.S. Pat. Nos. 5,667,973 and 5,283,173; Harper et
al., Cell, Vol. 75 pgs 805-816 (1993); Cho et al., Proc. Natl.
Acad. Sci. USA, Vol. 95(7) pgs 3752-3757 (1998); and Fromont-Racine
et al., Nature Genetics, Vol. 16(3) pgs 277-282 (1997).
[0032] The adhering moiety may also adhere to a smoke-related
moiety. For example, the adhering moiety may bind to cigarette
smoke particles, tar, tobacco, and/or other smoke-related residues,
such as Cadmium. Further, it is to be understood that the adhering
moiety may adhere one of more components of lung tissue and/or
smoke-related moieties, including any combination of proteases
disclosed herein, as well as one or more proteases and/or one or
more smoke-related moieties.
[0033] In some embodiments, the adhering moiety may adhere to
modified polypeptides. For example, members of the G-protein
coupled receptor (GPCR) family, e.g., RAI-3 are modified, e.g.,
phosphorylated, and/or associated with tyrosine phosphorylated
activation complexes following exposure to cigarette smoke. See,
e.g., International Publication No. WO 04/001060 and/or U.S.
Publication No. 2004/0121362. In some embodiments of the present
invention, an adhering moiety may be used that adheres to such
modified proteins and/or protein complexes. Such adhering moieties
may (or may not) include modulators of RAI-3, as described in U.S.
Publication No. 2004/0121362. In still some embodiments, an
adhering moiety may (or may not) be used that adheres polypeptides
associated with the NF-.kappa.B pathway that are found in lung
tissue, e.g., as described in U.S. Publication No.
2004/0086896.
[0034] The adhering moiety may also adhere moieties that inhibit
the production of elastic and/or connective tissue proteins. Such
moieties may include, e.g., moieties that inhibit fibroblast
proliferation and/or that inhibit procollagen production and/or
that inhibit proteoglycan, synthesis, preferably moieties that
inhibit synthesis of the major matrix-associated proteoglycans,
such as versican, decorin, and/or large heparan sulfate
proteoglycans. "Inhibiting" and its various grammatical
conjugations can mean reducing a biological process, e.g., reducing
synthesis of a connective tissue component, by an amount compared
with the occurrence of the process in the absence (or in the
presence of lower levels) of the inhibiting moiety. In some
embodiments, the amount may be reduced by at least about 10%, at
least about 20%, at least about 30%, at least about 40%, or at
least about 50%. In some embodiments, the amount may be reduced by
less than about 60%, less than about 70%, less than about 80%, less
than about 90%, or less than about 95%. "Inhibiting" and its
various grammatical conjugations need not mean completely
inhibiting a biological process, e.g., it need not mean inhibiting
synthesis of a connective tissue component to negligible and/or
non-detectable levels. Moieties that can inhibit proteoglycan
synthesis include, for example, Cadmium. See, e.g., Chambers et
al., "Cadmium inhibits proteoglycan and procollagen production by
cultures human lung fibroblasts," Am. J. Respir. Cell Mol. Biol.,
Vol 19 No. 3 pgs 498-506 (1998). Other moieties may include lead,
aldehydes and/or silicates. Fujiwara, "Cell biological study on
abnormal proteoglycan synthesis in vascular cell exposed to heavy
metals," Journal of Health Science, Vol. 50 No. 3 pgs 197-204
(2004). The adhering moiety may also adhere to moieties that impair
the repair of elastic and/or connective tissues of the lungs.
[0035] In some aspects of the present invention, a glue composition
comprising an adhering moiety also comprises a cross-linkable
moiety coupled thereto. The cross-linkable moiety can be any moiety
that facilitates linkage between more than one cross-linkable
moieties, preferably between cross-linkable moieties coupled to
adhering moieties binding to lung tissue at different sites.
Cross-linkable moieties can include, for example, a hydroxyl group,
carboxyl group, ester group, cyano group, thiol group (including
e.g., a cysteine group), carbonyl group, aldehyde group, ketone
group, primary amine group, and/or secondary amine group, as well
as a lysine group.
[0036] In some embodiments, the cross-linkable moiety comprises any
other amine groups, a sulfide group, a carbonyl group (e.g., a
halocarbonyl group and/or .alpha.,.beta.-unsaturated carbonyl
group), a cyanate group (e.g., isothiocyanate group), a carboxylase
group (e.g., an acetate group such as .alpha.-haloacetate group), a
hydrazine group, and/or a biotin group,. See, e.g., US Publication
No. 2002/0071843.
[0037] In some embodiments, the cross-linkable moiety can comprise
fibrinogen and/or fibrin. Fibrinogen can be converted to fibrin,
which is polymerized in a cross-linking reaction. In some
embodiments, the cross-linkable moiety can comprise other protein
and/or proteinaceous materials, e.g., proteinaceous materials
comprising albumin (bovine or human), collagen, PEI, oleic acid,
chitin and/or chitosan, as well as any of those described in U.S.
Pat. No. 5,385,606, U.S. Pat. No. 5,583,114, U.S. Pat. No.
6,310,036, U.S. Pat. No. 5,329,337, and/or U.S. Pat. No. 6,372,229.
In some embodiments, more than one type of cross-linkable moiety
may be coupled to a given adhering moiety or may be coupled to a
number of adhering moieties used in combination, e.g., in one
administration or in a number of successive administrations. Those
of skill in the art will recognize other suitable cross-linkable
moieties that may be used in the practice of the instant invention,
including, for example, any biocompatible cross-linkable moiety
that can form a biocompatible cross-linked product.
[0038] The adhering moiety may be coupled to the cross-linkable
moiety by any techniques and/or approaches known in the art,
described herein, and/or as can be developed by those of skill in
the art. For example, coupling methods include, but are not limited
to the use of bifunctional linkers, amide formation, imine
formation, carbodiimide condensation, disulfide bond formation,
and/or use of a specific binding pair e.g., using a biotin-avidin
interaction. These and other methods known in the art may be found,
e.g., in Hermanson, "Bioconjugate Techniques," Academic Press: San
Diego, 1996; and S. S. Wong, "Chemistry of Protein Conjugation and
Cross-linking," CRC Press, 1993.
[0039] In preferred embodiments, the cross-linkable moiety is
coupled to the adhering moiety in such a way so as not to interfere
with the ability of the adhering moiety to adhere to lung tissue.
For example the cross-linkable moiety can be attached to an alpha-1
antitrypsin moiety at one or more sites that do not modify the
conformation or folding of the alpha-1 antitrypsin, or do not
modify the conformation or folding of regions of alpha-1
antitrypsin necessary and/or involved in adhering to sites of lung
tissue, e.g. adhering to elastase present in lung tissue. For
example, without being limited to a given hypothesis or mode of
action, the active inhibitory site of alpha-1 antitrypsin is found
around Ser358 of the polypeptide, e.g., forming a
pseudo-irreversible equimolar complex with neutrophil elastase.
See, e.g., Sifers et al., "Genetic Control of Human Alpha-1
Antitrypsin", Mol. Biol. Med., Vol. 6 pgs 127-135 (1989). In some
preferred embodiments, a cross-linkable moiety can be attached to
an alpha-1 antitrysin moiety at a site other than around its Ser358
inhibitory site. Similarly, in some embodiments, without being
limited to a given hypothesis or mode of action, a cross-linkable
moiety can be attached to a serpin moiety at a site other than
certain regions known to be involved in attaching to a protease,
which include, for example, the hinge, breach, shutter, and gate
regions of serpins. Irving et al., Genome Res Vol. 10 pgs 1845-64
(2000). Similarly, in some embodiments, without being limited to a
given hypothesis or mode of action, a cross-linkable moiety can be
attached to a monocyte elastase inhibitor moiety at a site other
than a cysteine residue of the inhibitor involved in interacting
with elastase and/or proteinase 3 and/or cathepsin G, See, e.g.,
International Publication WO 96/10418; and U.S. Pat. No.
5,827,672.
[0040] In some embodiments, the cross-linkable moiety may be
chemically bound to the adhering moiety, e.g., a carboxyl group
covalently attached to one or more sites of alpha-1 antitrypsin. In
some embodiments, the cross-linkable moiety may be chemically bound
to a moiety that is itself clinically bound to the adhering moiety,
indirectly coupling the cross-linkable and adhering moieties.
[0041] In preferred embodiments, the size of the glue composition
comprising an adhering moiety coupled to a cross-linkable moiety is
not so large as to prevent access of the glue composition to lung
tissue within enlarged alveoli distal to a terminal bronchiole. For
example, the size of the glue composition comprising an adhering
moiety coupled to a cross-linkable moiety is preferably less than
about 10 microns, less than about 8 microns, less than about 5
microns, less than about 3 microns, less than about 2 microns, or
less than about 1 micron. "Enlarged alveolus" as used herein refers
to an alveolus that is larger than the average alveolus that is not
affected by a pulmonary condition, or that is affected to a lesser
extent. For example, an enlarged alveolus may be at least about 5%,
at least about 10%, at least about 20%, at least about 50%, at
least about 100%, or at least about 150% the size of an average
alveolus.
[0042] Another aspect of the present invention relates to a glue
composition comprising a first adhering moiety and a second
adhering moiety wherein said adhering moieties are coupled and
wherein said adhering moieties adhere to different sites of lung
tissue. In preferred embodiments, the different sites comprise
different sites within an enlarged air space, e.g., within alveolar
walls of an over-inflated alveolus distal to a terminal bronchiole,
as characteristic of some pulmonary conditions, including
emphysema. The first and second adhering moieties may be the same
or different.
[0043] Further, it is to be understood that any plural number of
adhering moieties may be used, i.e., the present invention also
contemplates a glue composition comprising any plural number of
coupled adhering moieties, that may each be the same or different,
or some may be the same while others are different. For example, in
a glue composition comprising three coupled adhering moieties, the
first adhering moiety may be coupled to the second adhering moiety,
which is coupled to a third adhering moiety. The first and third
moieties may or may not be directly coupled to each other. In some
embodiments, the three adhering moieties may be coupled to a moiety
without being directly coupled to each other. The three moieties
may all be the same or different, or two may be the same with the
third is different. Each adhering moiety may adhere to the same of
different components in lung tissue, preferably adhering at
different sites within an enlarged air space, e.g., within alveolar
walls of an over-inflated alveolus distal to a terminal
bronchiole.
[0044] The adhering moieties may be coupled by any techniques
and/or approaches known in the art, described herein, and/or as can
be developed by those of skill in the art. In some embodiments,
coupling may involve covalent bonds, dipole interactions,
electrostatic forces, hydrogen bonds, hydrophobic interactions,
ionic bonds, van der Waals forces, and/or other bonds that can
couple adhering moieties. For example, in some embodiments,
adhering moieties are coupled via a coupling moiety, e.g., a
chemical linker. Any chemical linker may be used, including, e.g.,
an aliphatic group covalently linking the adhering moieties. For
example, a chemical linker useful in this invention may comprise
two (or more) functional groups, where each of the functional
groups can be chemically bonded to an adhering moiety, serving to
couple the adhering moieties. Examples of functional groups
include, e.g., a hydroxyl group, a carboxyl group, an ester group,
a cyano group, a thiol group, a cysteine group, a carbonyl group,
an aldehyde group, a ketone group, and/or amine group, as well as a
lysine group. Other function groups include a cyanate group (e.g.,
isothiocyanate) and/or a carboxylate group (e.g., an acetate group
such as .alpha.-haloacetate).
[0045] Other coupling techniques may also be used. For example,
dimers and/or multimers of adhering moieties may be prepared using
cross-linking techniques so that the adhering moieties are
pre-cross-linked, e.g., forming one or more cross-links between
cysteine residues of peptide and/or polypeptide adhering moieties.
Linker length optimization techniques may also be used (see, e.g.,
U.S. Pat. No. 5,478,925), for use in the present invention.
[0046] In some embodiments, adhering moieties are coupled as a
fusion polypeptide. For example, where the adhering moieties are
peptides and/or polypeptides, two or more adhering moieties may be
joined by a polypeptide linker as the coupling moiety, to form a
fusion polypeptide or fusion protein. A fusion protein may be
generated in various ways, including, e.g., chemical coupling and
co-translation. In some preferred embodiments, adhering moieties
are recombinantly expressed as a fusion product from a recombinant
nucleic acid molecule, where the adhering moieties are linked,
e.g., by one or more intervening amino acids, according to
techniques known in the art. See, e.g., Francis, "Focus on Growth
Factors", Vol. 3 pgs 4-10 (Mediscript, London) (1992). Fusion
proteins may also be made using other techniques known in the art,
e.g., techniques used to create adzymes, which comprise an address
binding site conjugated to a catalytic domain (e.g., as described
in U.S. Publication No. 2004/0081648 and in U.S. Publication No.
2004/0081648); and/or by covalent linking (e.g., via disulfide
bonds) between at least one amino acid of each coupled adhering
moiety (e.g., as descried in U.S. Publication No.
2004/0087778).
[0047] In some embodiments, the adhering moieties are coupled via a
protein, e.g., an antibody and/or a binging fragment thereof. In
some embodiments, liposomes may be prepared that comprise a plural
number of adhering moieties.
[0048] In some preferred embodiments, the adhering moieties are
coupled in such a way so as not to interfere with the ability of
the adhering moiety to adhere lung tissue. For example two (or
more) alpha-1 antitrypsin moieties can be coupled to each other at
sites that do not modify the conformation or folding of the alpha-1
antitrypsin moieties, or do not modify the conformation or folding
of regions of the alpha-1 antitrypsin moieties necessary and/or
involved in adhering to sites of lung tissue, e.g. adhering to
elastase present in lung tissue. For example, without being limited
to a given hypothesis or mode of action, the active inhibitory site
of alpha-1 antitrypsin is found around Ser358 of the polypeptide,
e.g., forming a pseudo-irreversible equimolar complex with
neutrophil elastase. See, e.g., Sifers et al., "Genetic Control of
Human Alpha-1 Antitrypsin", Mol. Biol. Med., Vol. 6 pgs 127-135
(1989). In some preferred embodiments, alpha-1 antitrysin moieties
may be coupled to each other or other adhering moieties at sites
other than around their Ser358 inhibitory sites. Similarly, in some
embodiments, without being limited to a given hypothesis or mode of
action, serpin moieties may be coupled to each other or other
adhering moieties at sites other than certain regions known to be
involved in attaching to protease, which include, for example, the
hinge, breach, shutter, and gate regions of serpins. Irving et al.,
Genome Res Vol. 10 pgs 1845-64 (2000). Some serpins, for example,
contain a reactive center loop (RCL) involved in inhibition where a
stable complex can be formed between the protease and a cleaved
form of the serpin. Attachment via sites other than the RCL regions
of serpin moieties is preferred in some embodiments. Similarly, in
some embodiments, without being limited to a given hypothesis or
mode of action, monocyte elastase inhibitor moieties can be coupled
to each other or other adhering moieties at a site other than a
cysteine residue of the inhibitor involved in interacting with
elastase and/or proteinase 3 and/or cathepsin G. See, e.g.,
International Publication WO 96/10418 and U.S. Pat. No.
5,827,672,
[0049] In preferred embodiments, the size of the glue composition
comprising two (or more) coupled adhering moieties is not so large
as to prevent access of the glue composition to sites of lung
tissue within enlarged air spaces distal to a terminal bronchiole.
For example, the size of the glue composition comprising two (or
more) adhering moieties is preferably less than about 10 microns,
less than about 8 microns, less than about 5 microns, less than
about 3 microns, less than about 2 microns, or less than about 1
micron.
[0050] Coupling of the adhering moieties can keep the adhering
moieties in close or relatively close physical proximity. For
example, in some preferred embodiments a chemical linker may be
used that comprises an aliphatic group of at least about 2 carbon
atoms, at least about 5 carbon atoms, at least about 10 carbon
atoms, or at least about 12 carbon atoms. In some preferred
embodiments, a chemical linker that comprises an aliphatic group of
less than about 30 carbon atoms, less than about 20 carbon atoms,
or less than about 15 carbon atoms can be used. In some preferred
embodiments, a polypeptide linker can be used that comprises at
least about one amino acid, at least about 3 amino acids, or at
least about 5 amino acids. In some preferred embodiments, a
polypeptide linker that comprises less than about 12 amino acids,
less than about 10 amino acids, or less than about 5 amino acids
can be used.
[0051] Further, it is to be understood that a glue composition
comprising two (or more) coupled adhering moieties may further
comprise a coupled or not coupled cross-linkable moiety.
Formulation, Routes of Administration, and Effective Doses
[0052] The glue compositions useful in the practice of the present
invention can be delivered to a subject using a number of routes or
modes of administration. The adhering moieties, cross-linkable
moieties, cross-linking activating moieties, imaging moieties
and/or other moieties and/or agents may be delivered per se or as
pharmaceutically acceptable salts thereof. The term
"pharmaceutically acceptable salt" means those salts which retain
the biological effectiveness and desired properties of the moieties
and/or agents of the present invention, and which are not
biologically or otherwise undesirable. Such salts include salts
with inorganic or organic acids, such as hydrochloric acid,
hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid,
methanesulfonic acid, p-toluenesulfonic acid, acetic acid, fumaric
acid, succinic acid, lactic acid, mandelic acid, malic acid, citric
acid, tartaric acid or maleic acid. In addition, if the moiety
contains a carboxyl group or other acidic group, it may be
converted into a pharmaceutically acceptable addition salt with
inorganic or organic bases. Examples of suitable bases include
sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine,
dicyclohexyl-amine, ethanolamine, diethanolamine and
triethanolamine.
[0053] The adhering, cross-linkable, cross-linking activating,
imaging moieties and/or other moieties and/or agents, or
pharmaceutically acceptable salts thereof can be formulated with a
pharmaceutically acceptable carrier for administration to a subject
in need thereof. "Pharmaceutically acceptable carriers" are well
known in the pharmaceutical art, described, for example, in
Remington's Pharmaceutical Science, Mack Publishing Co. (A. R.
Gennaro edit. 1985). Suitable carriers include, for example,
carriers like alcohol, DMSO, saline solution, and/or water.
Pharmaceutical compositions for use in accordance with the present
invention may be formulated in conventional manner using one or
more physiologically acceptable carriers comprising excipients
and/or auxiliaries, which facilitate processing of the active
moieties into preparations that can be used pharmaceutically.
Proper formulation is dependent upon the route of administration
chosen.
[0054] In some embodiments, the glue compositions of the invention
are dissolved in a suitable solvent, such as sterile water or PBS,
and then dried to remove the solvent and produce a powder. Drying
can be carried out in such as way as to retain the desired
properties of the glue compositions, for example the capability of
an adhering moiety to adhere lung tissue. For example, vacuum
concentration, spray drying, open drying, freeze-drying, and the
like, can be used. The residue obtained can then be ground and/or
further micronized.
[0055] In some preferred embodiments, the adhering, cross-linkable,
cross-linking activating and/or imaging moieties, or
pharmaceutically acceptable salts thereof, as well, as other
moieties and/or agents and/or pharmaceutically acceptable salts
thereof, are formulated as dry powders or aerosolized
physiologically acceptable solutions that may be delivered to the
lungs of a subject. Power and/or liquid formulations can be
prepared to facilitate administration, e.g., to facilitate transfer
from the delivery device into the respiratory tract, preferably
down to the alveoli distal to terminal bronchiles.
[0056] Powder formulations can be prepared in various ways, using
conventional techniques. Powder formulations can be processed to
improve ability to be delivered to a subject, e.g., via inhalation
and/or trans-thoracically. For instance, the way in which the
formulation flows through and/or out of an inhaler device or other
device, can be improved by forming spherical agglomerates by, e.g.,
dry granulation processing. Spherical agglomerate can impart the
glue compositions of this invention with superior handling
characteristics. It is to be understood, however, that the present
invention contemplates the use agglomerates and/or other particles
of all shapes, including both spherical and non-spherical shapes.
Power and/or liquid formulations also preferably have physical
characteristics that help avoid clogging of an aerosol device and
clumping of aerosolized material. For example, additives such as
alcohol, soaps, surfactants, and/or Vitamin E may be use to help
reduce clumping and to facilitate formation of small particles
and/or droplets.
[0057] Liquid formulations may be produced by adding a volume of
sterile delivery solvent to an amount of sterile composition of the
present invention in powder or liquid form. In some embodiments,
formulation temperatures of at least about 0.degree. C., at least
about 4.degree. C., at least about 5.degree. C., at least about
10.degree. C., or at least about 15.degree. C. may be used. In some
embodiments, formulation temperatures of less than about
100.degree. C., less than about 80.degree. C., less than about 60
.degree. C., less than about 37.degree. C., or less than about
30.degree. C. may be used.
[0058] Formulation of the present invention may also be prepared to
provide other suitable physiological parameters for use in the
lungs, including for example, suitable pH. For instance, a pH of at
least about 4, at least about 5, or at least about 6 may be used.
In some embodiments, a pH of less than about 11.0, less than about
10.0, less than about 9.0, less than about 8, or less than about 7
may be used.
[0059] In preferred embodiments, formulation involves selecting
parameters such as concentration, size and/or viscosity of
adhering, cross-linkable, cross-linking activating and/or imaging
moieties, as well as of other moieties and/or agents, and/or
pharmaceutically acceptable salts thereof, e.g., to provide a
rheological profile, such that when aerosolized and/or nebulized,
the formulation produces a range of particle and/or droplet sizes
capable of being delivered to the lungs. A suitable mill, such as a
jet mill, can be used to produce particles in a range of sizes that
facilitates, or preferably maximizes, access to sites of damaged
lung tissue, including sites distal to terminal bronchioles. In
some embodiments, a nozzle comprising tapering pores may be used,
e.g., to increase uniformity of the aerosol generated. See, e.g.,
U.S. Publication No. 2004/0124185.
[0060] In more preferred embodiments, a formulation is prepared
that allows respiratory zone or deep lung delivery. To such
embodiments, the formulation can yield a range of particle and/or
droplet sizes adapted for delivery to the deep lung. In still more
preferred embodiments, formulation involves selecting parameters
such as concentration, size and/or viscosity of adhering,
cross-linkable, cross-linking activating and/or imaging moieties,
as well as of other moieties and/or agents and/or pharmaceutically
acceptable salts thereof, such that when aerosolized and/or
nebulized, the formulation produces a range of particle and/or
droplet sizes capable of being delivered to the lung alveoli,
preferably to a lung alveolus distal to a terminal bronchiole, and
more preferably to the deepest terminal branches of selected lung
segments.
[0061] Droplets and/or particles of suitable size ranges can be
obtained by selecting appropriate delivery devices, molecular
weight, concentration, and/or additives as known in the art and/or
described herein. See, e.g., U.S. Publication No. 2002/0086842. For
example, various glue formulations can be screened to determine
ones that produce droplet and/or particle size in desired
ranges.
[0062] In preferred embodiments, the glue compositions of the
present invention are administered to a selected localized region
of damaged lung tissue via the respiratory tract, e.g., via
inhalation. The term "inhalation" includes inhalation via the
mouth, nose, tracheae, or any combination thereof. A pharmaceutical
formulation for administration via inhalation may be made up
according to techniques known in the pharmaceutical arts and
administered via aerosol inhalation, dry powder inhalation, liquid
inhalation, and/or instillation. For example, a diagnostically
and/or therapeutically effective amount of a glue composition of
the invention may be delivered by inhalation of a breathable mist
by the animal subject.
[0063] Preparation of inhalable formulations are known in the art,
e.g., see U.S. Publication No, 2003/0232019 and International
Publication No. WO 2004/054556. For example, a glue composition of
the present invention can be formulated with a breathable
fluorocarbon propellant. Inhalable preparations preferably provide
droplets and/or particles with median mass distribution size of at
least about 0.1 microns, at least about 0.3 microns, at least about
0.5 microns, at least about 1 micron, or at least about 2 microns.
Inhalable preparations preferably provide droplets and/or particles
with median mass distribution size of less man about 20 microns,
less than about 15 microns, less than about 10 microns, less than
about 6 microns, less than about 5 microns, less than about 3
microns, or less than about 2 microns. Particle and/or droplet
sizes are preferably between about 2 microns to about 5
microns.
[0064] Size may be selected to allow glue compositions of the
present invention access to sites of damaged tissue in selected
lung regions. The respiratory system can be divided into three
regions: (i) the tracheal/pharyngeal region, (ii) the bronchial
region, and (iii) the alveolar region. Droplets and/or particles of
about 10 microns to about 50 microns typically migrate to the
tracheal/pharyngeal and/or bronchial region of the lungs; while
droplets and/or particles of about 0.5 microns to about 5 microns,
e.g., droplets and/or particles of about 2 microns, typically
migrate to the alveolar region. Larger sizes may not as efficiently
reach alveoli through distal bronchioles. Smaller droplets and/or
particles may be exhaled by the subject before the adhering moiety
contacts and/or adheres to lung tissue. Droplet and/or particle
size of glue compositions of the present invention can be measured
by techniques known in the art, including, e.g., those described
herein.
[0065] Various physical parameters may be used to facilitate access
of glue compositions of the present invention to selected localized
sites of damaged tissue within the lungs. For example, the mass
median aerodynamic diameter (MMAD), usually expressed in microns,
can be used to predict where a droplet and/or particle distributes
in the lungs. Mass Median Aerodynamic Diameter can be measured
using a Cascade Impactor relating to size of compositions of the
present invention. A humidified Cascade Impactor is preferably used
to better reflect conditions of pulmonary delivery. Further,
particle size distribution can also be measured with a Malvern
Laser, for example. The geometric standard deviation (GSD) is
another parameter that can be used. A GSD of about 1 correlates to
a normal distribution. A GSD of less than about one can indicate a
narrow size dispersion while a GSD of more than about 1 can
indicate a broad size dispersion.
[0066] Charge may also be used to facilitate aerosol formation. For
example, in some embodiments, droplets and/or particles can be made
to carry a negative charge. The like charges can repel each other,
helping to disperse the particles and/or droplets into an aerosol
cloud by, e.g., by electrostatic forces. Like positive charges on
particles and/or droplets may also be used in a similar manner.
[0067] Animal models can also be used to determine suitable ranges
of droplet and/or particle size for delivery of glue compositions
of the present invention to damaged lung tissue, e.g., see Raabe et
al., "Studies of the Chronic Inhalation of Coal Fly Ash by Rats"
Ann. Occup. Hyg. (1982), 26(1 -4); 189-211 (surveying access of
particle size to various regions of the lungs in laboratory
animals).
[0068] Solution or liquid formulations may be aerosolized to form a
breathable mist via, e.g., a device such as an inhaler, a
nebulizer, and/or an atomizer. In some embodiments, the formulation
is a dry power, which can be made up into solution, e.g., with
saline or water before aerosolization. In still some embodiments, a
dry powder can be delivered per se by a device such as an intra
alveolar device (IAD), an air gun powered aerosol chamber, and/or
other dry powder delivery devices, e.g., from Dura Delivery Systems
and/or Glaxo Wellcome.
[0069] A glue composition of the present invention may be
aerosolized by any techniques known in the art, described herein
and/or that can be developed. For example, the glue composition may
be pressurized through micro pores and then blown through an inline
blower, such as a high-pressure fan system. The fan or pump is
preferably timed to coincide with the time of inspiration or a time
just before inspiration. In some embodiments, for example, the
delivery of the glue compositions can be metered as a function of
the in-flow volume.
[0070] The aerosolized composition can be delivered by any methods
known in the art and/or described herein. For example, the glue
composition can be infused under pressure directly into a bronchus
and/or into an enlarged air space. A catheter can be used to suck
air out of a less distal lumen of the lungs through another path.
In some embodiments, the glue composition can be infused into an
enlarged air space using a first catheter while sucking air out
with a second catheter through another path leading from the same
air space, e.g., from another bronchi branch, to get a circular
flow path. In yet another approach, the flow around a catheter or
other infusion device can be blocked using balloons, covered braid
structures, expanding foam, flaps that make one-way valves, and/or
expanding corrugations.
[0071] Glue compositions of the present invention may also be
administered via inhalation using a portable (e.g., hand held)
inhaler device, such as devices used to deliver anti-asthmatic
agents or anti-inflammatory agents. For example, a fine dry powder
can be delivered as an aerosol by compressing air into the powder
inside the inhaler. This can disperse the powder as a cloud of
particles, preferably of the size ranges that allow access to
alveoli distal to terminal bronchioles.
[0072] In some embodiments, the inhaler device may be designed to
deliver single or multiple doses, minimizing risks from accidental
large doses, and protecting the formulation from light, excessive
moisture, and/or other contaminants. Dry powder and metered dose
inhalers can be used to administer glue compositions of the
invention to the pulmonary air passages of a subject in need
thereof. Metered dose inhalers can deliver medicaments in a
dispersion and/or in solubilized form. These inhalers can include a
relatively high vapor pressure propellant, which forces aerosolized
material into the respiratory tract upon activation of the
device.
[0073] Some embodiments involve delivery by nebulization to the
lungs, where, e.g., the delivery device can be a nebulizer. For
example, a nebulizer can be used that generates an aerosol
containing the glue compositions of the present invention,
preferably an aerosol of droplets and/or particles of less than
about 10 microns. Nebulizers are known in the art, and include,
e.g., a jet nebulizer, which can be an air or liquid jet nebulizer;
an ultrasonic nebulizer; a compressed air nebulizer (e.g., an
AeroEclipse, Pari L.C., a Parijet; and/or a Whisper Jet) and/or a
pressure mesh nebulizer. Compressed air nebulizers can generate
droplets by using fast moving air to shatter a liquid stream.
Ultrasonic nebulizers can nebulize a liquid solution using
ultrasonic waves, e.g., by using a piezoelectric transducer to
transform electrical current into mechanical oscillations; while
pressure mesh nebulizers force fluid through a mesh-like surface
under pressure. The nebulizer may use a pressure of at least about
5 psi, at least about 10 psi, at least about 15 psi, at least about
20 psi, at least about 25 psi, or at least about 30 psi. The
nebulizer may use a pressure of less than about 60 psi, less than
about 50 psi, or less than about 40 psi. For administration using a
nebulizer, a subject can inhale aerosolized composition of the
present invention via continuous nebulization, e.g., in a manner
similar to that used to administer aerosolized bronchodilators. For
example, the aerosol may be delivered via tubing or a mask to the
mouth and/or nose, as well as by using an Ambu bag, blow-by mask,
endotracheal tube, nasal cannula, nasal covering, and/or
nonrebreather.
[0074] A suitable volumetric flow rate (L/min) for the nebulizer
may be selected. It is preferable that the volumetric flow rate not
exceed twice the subject's minute ventilation, as the average
inspiratory rate is about twice the minute ventilation with
exhalation and inhalation each representing about half of the
breathing cycle. For example, a nebulizer with a volumetric flow
rate of less than about 20 L/min, less than about 15 L/min or less
than about 10 L/min may be used. A nebulizer can also be selected
to generate desired ranges of particle and/or droplet size. Along
with volumetric flow rate, various factors may be considered as
will be appreciated by one of skill in the art. Such factors
include aerosol mass output (mg/L) and/or retained volume (mL). For
example, with respect to a compressed air nebulizers, factors such
as air flow, hole diameter, and/or air pressure can influence size
distribution. With respect to an ultrasonic nebulizer, factors
include rate of air flow, hole diameter, and/or ultrasound
frequency.
[0075] Administration can also involve delivery of aerosolized
droplets and/or powders of the present invention under positive
pressure ventilation. For example, a device such as a Continuous
Positive Airway Pressure device can be used to afford ventilatory
assistance. This assistance can facilitate access of the glue
compositions of the present invention to sites of damaged tissue in
alveoli of the deep airways. Additionally, positive end expiratory
pressure may be used to provide further assistance in this regard.
In some embodiments, a device can be used that delivers a glue
composition of the present invention when the subject produces a
level of negative inspiratory pressure, e.g., at inspiratory flow
rates.
[0076] Other devices that may be used include, for example, include
a canister adapted to contain a preparation comprising a glue
composition of the present invention under pressure. The canister
may feature a valve, e.g., for regulating delivery of the
preparation; a nozzle connected to the valve for converting the
pressurized preparation inside the canister into an inhalable
aerosol mist upon actuating the valve. See, e.g., U.S. Publication
No. 2002/0086852. Other devices for delivery of glue compositions
of the present invention to the lungs of a subject in need thereof
include a spray atomizer.
[0077] Glue compositions of the present invention can also be
delivered in a non-aerosolized form. Further, any combination of
aerosol and/or non-aerosol forms may be used.
[0078] For example, a liquid, solution, suspension, viscous liquid,
liquid film, slurry, foam, and/or thicksotropiec form(s) may be
used. Any of such forms can be delivered to selected localized
regions of the lungs by any techniques known in the art, to be
developed, and/or described herein. For example, a liquid,
solution, suspension, viscous liquid, liquid film, slurry, foam,
and/or thicksotropiec form can be administered by fluid washings,
liquid, ventilation, bolus liquid drip and/or pulmonary lavage,
e.g., to a selected region of damaged lung tissue. In some
embodiments, a fluorochemical medium may be used.
[0079] Administered solutions may include, for example,
physiologically acceptable solutions of adhering, cross-linkable,
cross-linking activating and/or imaging moieties (and/or other
moieties and/or agents) of the present invention. After delivery at
a selected region of damaged lung tissue, the solvent can evaporate
and/or dissipate such that the adhering moiety, cross-linkable
moiety, cross-linking activating and/or imaging moiety (and/or
other moiety and/or agent) is left behind.
[0080] In still some embodiments; the glue compositions may be
delivered as solids, semi-solids, solid films, hydrogels, agars,
and/or sol-gels. For example, glue compositions of the present
invention may be administered to a selected localized region of the
lungs as an absorbable sponge, e.g., as an absorbable gelatin
sponge (e.g., GelfoaMTM) and/or as an absorbable wax.
Non-absorbable waxes may also be used. Further, in some
embodiments, petroleum-based compounds (e.g., petrolatum), latex,
natural or synthetic rubber, starches, and/or alginate compounds
may be used in formulating glue compositions of the present
invention.
[0081] Aerosol and/or non-aerosol formulations can be delivered to
a localized region of damaged lung tissue, preferably a localized
region that has been selected for volume reduction. For example, a
localized region of lung tissue showing a large portion of damaged
alveoli, e.g., "blebs" or other damage due to a pulmonary
condition, such as emphysema, can be selected. The region
identified via radiology for diagnosis, e.g., can be located via
bronchoscopy for treatment.
[0082] In some preferred embodiments, a bronchoscope is placed down
the trachea of a subject (e.g., an anesthetized intubated patient)
and into a bronchus, most preferably, as distally as possible to
the selected region of damaged lung tissue. The anatomical site for
administration, e.g., administration by a bronchoscope, may depend
on the location and/or extent of lung tissue damage. Within the
respiratory tree, segmental bronchi branch and/or subdivide to
produce subsegmental bronchi, which in turn branch and/or subdivide
to produce bronchioles that terminate in alveoli. The bronchoscope
can be placed in the trachea and advanced towards the branching
bronchi. The bronchoscope that may be used is not limited, and may
include, e.g., a rigid or fiberoptic bronchoscope, e.g., a
bronchoscope that allows visualization of an illuminated field. Use
of an imaging moiety with a glue composition of the present
invention can facilitate such visualization (e.g. using
fluoroscopy), as discussed in more detail below. Bronchoscopes that
may be used in the practice of the present invention include, for
example, Fujinon, Olympus, and/or Pentax bronchoscopes.
[0083] A catheter can then be advanced through the bronchoscope,
e.g., through the working channel of the bronchoscope. The catheter
used is not limiting, but preferably comprises a small diameter
catheter, having a diameter at least less than that of the working
channel of the bronchoscope. The catheter can be a single or dual
lumen catheter. The catheter can be advanced beyond the trachea and
bronchi, e.g., to reach a segmental bronchus, a subsegmental
bronchus, a bronchiole and/or an alveolus of the selected localized
region of damaged lung tissue. The catheter can be allowed to
become wedged in one or more of these segmental bronchi,
subsegmental bronchi, bronchioles and/or alveoli, therein anchoring
the distal tip of the catheter.
[0084] In some embodiments, the catheter used further comprises an
expandable structure at and/or near its distal tip, e.g., a balloon
or balloon-like structure. The expandable structure may be
distended, e.g., with air, saline, any other suitable fluid and/or
other medium, to assist, for example, in anchoring the tip of the
catheter and/or positioning it for delivery of a glue composition
of the present invention (in aerosol and/or non-aerosol form) to
the selected localized region of damaged lung tissue. The balloon
(or balloon-like structure) may be spherical, cylindrical, or any
other shape. The distended balloon (or balloon-like structure) may
have a diameter of at least about 0.1 mm, at least about 0.5 mm, at
least about 1.0 mm, at least about 1.5 mm, at least about 3 m, at
least about 4 mm, at least about 5 mm, at least about 6 mm, at
least about 7 mm, at least about 8 mm, at least about 9 mm, or at
least about 10 mm. The balloon diameter may be less than about 30
mm, less than about 20 mm, less than about 15 mm, or less than
about 12 mm. The diameter selected can help position the balloon
(or balloon-like structure) in a segmental bronchi, subsegmental
bronchi, bronchiole and/of alveolus within a deep region of the
lung. This anchoring and/or positioning can facilitate delivery of
the glue composition of the present invention to the selected
localized region of damaged lung tissue. A glue composition may
then be administered in aerosol and/or non-aerosol forms,
preferably at a controlled flow, to the selected localized region
of damaged lung tissue. The inflated balloon (or balloon-like
structure) may additionally help contain the administered glue
composition to areas of the selected region of the lung that are
distal to the balloon (or balloon-like structure). That is, the
balloon (or balloon-like structure) can help prevent the
administered glue composition from spreading to other regions of
the lungs other than the selected localized regions of damaged lung
tissue.
[0085] A number of administrations may be carried out before
removal of the bronchoscope. For example, co positions containing
additional moieties, e.g., a cross-linking activating moiety, a
sclerosing agent, and/or any other moiety and/or agent, may also be
administered at the same time or at separate times before removal.
The balloon (or balloon-like structure) may then be deflated and
withdrawn through the bronchoscope. In some embodiments, additional
glue composition is administered after removal of the catheter,
e.g., to seal any gap due to the physical location of the balloon
(or balloon-like structure). See, e.g., Publication No. U.S.
2002/0147462. In some embodiments, glue composition is delivered by
the catheter distal to the balloon (or balloon-like structure) so
that no additional administration of glue composition is
required.
[0086] As well as or instead of a catheter, forceps and/or other
suitable instruments may be used to deliver glue compositions of
the present invention to a selected localized region of damaged
lung tissue. For example, an endotracheal tube and/or applicator
may be used and/or, in some embodiments, administration may
achieved by laproscopy. In less preferred embodiments,
administration can be achieved by open surgery, e.g., by a
thracotomy, hot less-invasive procedures are preferred, as
indicated above.
[0087] In some embodiments, glue compositions of the present
invention are delivered to the lungs via instillation, e.g., direct
instillation through the trachea, e.g., through the anterior aspect
of the trachea. The glue compositions of the present invention can
be administered as a liquid solution, including, e.g., an aqueous
solution comprising water or a buffered physiological solution,
such as saline. Instillation administration can be carried out over
a period of at least about 2 minutes, at least about 5 minutes, at
or least about 10 minutes. The instillation period may be less than
about 30 minutes, less than about 20 minutes, or less than about 15
minutes. The length of instillation time may be selected based on a
number of factors, including the glue composition used, the size of
the selected region of damaged lung tissue to be heated, the extent
of the damage, and the like. Instillation may involve delivery via
bronchoscopy and/or endoscopy.
[0088] Other techniques for delivering glue compositions of the
present invention to a selected localized region of damaged lung
tissue may also be used, including, e.g., use of an impregnated
applicator tip, e.g., U.S. Pat. No. 5,928,611; and/or an applicator
for delivering liquid and/or semi-liquid compositions via
laproscopy and/or endoscopy e.g., U.S. Pat. No. 6,494,896. Fibers,
micro fibers, lattice-work stents, filagree designs, and/or porous
structures may also be used, e.g., where the structure is coated
with a glue composition of the present invention and delivered to a
selected localized region of damaged lung tissue
[0089] The glue compositions of the present invention can also be
delivered via trans-thoracic administration. For example, in some
embodiments, air spaces of selected damaged regions of lung tissue
can be targeted directly through the ribs for more controlled
localization, e.g., being applied through a scope. Trans-thoracic
delivery may involve delivery into the pleural space using a needle
percutaneously and/or using a catheter and/or chest tube. Glue
compositions of the present invention can also be delivered to the
lungs during liquid ventilation or pulmonary lavage using a
fluorochemical medium.
[0090] The glue compositions of the present invention can also be
given intravenously. For example, the pharmaceutical glue
compositions of the present invention may be formulated with a
pharmaceutically acceptable carrier to provide sterile solutions or
suspensions for administration via injection, injectables can be
prepared in conventional forms, e.g., as liquid solutions,
suspensions and/or solid forms suitable for making a solution or
suspension in liquid prior to injection, and/or as emulsions.
Suitable excipients that may be used include, for example, water,
saline, dextrose, mannitol, lactose, lecithin, albumin, sodium
glutamate, cysteine hydrochloride, and the like. In some
embodiments, pharmaceutical compositions for injection may contain
auxiliary substances, such as wetting agents, pH buffering agents,
and the like. For example, a carbonate/bicarbonate buffer system
may be used.
[0091] In some embodiments, the glue compositions of the invention
are administered using a delivery vehicle. A "delivery vehicle" as
used herein refers to any particle that can be used to carry
compositions of the present invention. Examples of delivery
vehicles include, but are not limited to, liposomes, viral,
bacteriophage, cosmid, plasmid, and fungal vectors and other
recombinant vehicles typically used ill the art.
[0092] Delivery vehicles can carry a glue composition of the
present invention encoded by a polynucleotide sequence. Expression
of the sequence can produce the glue composition, e.g., a fusion
polypeptide of two or more coupled adhering moieties. Vectors that
contain both a promoter and a cloning site into which a
polynucleotide can be operatively linked are well known in the art.
Such vectors are capable of transcribing RNA in vitro or in vivo,
and are commercially available from sources such as Strategene (La
Jolla, Calif.) and Promega Biotech (Madison, Wis.). In order to
enhance in vitro transcription and/or expression, it may be
necessary to remove, add, and/or after 5' and/or 3' untranslated
portions to eliminate extra, potentially inappropriate alternative
translation initiation codons, or other sequences that may
interfere with or reduce expression, either at the level of
transcription or translation. In some embodiments, consensus
ribosome binding sites can be inserted immediately 5' of the-start
codon to enhance expression.
[0093] In some embodiments, a viral vector can be used. A viral
vector can include a natural or recombinantly produced virus or
viral particle that comprises a polynucleotide to be delivered,
either in vivo, ex vivo or in vitro. Examples of viral vectors
include baculovirus vectors, retroviral vectors, adenovirus
vectors, adeno-associated virus vectors and the like. A viral
vector can enter a host cell via its normal mechanism of infection
or can be modified such that it binds to a different host cell,
e.g., by binding to a different surface receptor or ligand to enter
the different host cell.
[0094] Delivery vehicles can also include non-viral vectors,
including liposome complexes. Liposomes may comprise an aqueous
concentric layer adherent to a hydrophopic or lipidic layer. The
hydrophobic layer may comprise, for example, phospholipids, such as
lecithin and sphingomyelin, steroids such as cholesterol, as well
as ionic surface active substances such as dicetyphosphate,
phosphatidic acid, stearylamine, and the like. Various liposome
complexes known in the art may be used to aid delivery of the glue
compositions of the invention to the lungs, in aerosol and/or
non-aerosol formulation. For example, particulate formulations
combining compounds having biocompatible hydrophobic domains with
conjugates having both hydrophobic and hydrophilic regions may be
used. See, e.g., U.S. Pat. No. 6,500,461. In some embodiments,
lipid vesicles may be used comprising bilayers with a salt form of
an organic acid derivative of a sterol, as described, e.g., in U.S.
Pat. No. 6,352,716. In some embodiments, the use of liposome
complexes can facilitate delivery of glue compositions of the
present invention, e.g., by keeping the glue composition intact
and/or in appropriate conformation necessary and/or involved in
adhering to lung tissue.
[0095] In still some embodiments, liposomes containing compositions
of the invention are coated with, e.g., a hydrophilic agent, such
as hydrophilic polymer chains like polyethylene glycol (PEG).
Examples of PEG-liposomes are known in the art, e.g., see U.S.
Publication No. 2003/0138481 and U.S. Publication No. 2003/0113369.
In some embodiments, the adhering moiety may be coupled to exposed
PEG chains to facilitate adhering to lung tissue. In some
embodiments, the hydrophilic chains may temporarily shield the
adhering moiety from interaction with lung tissue. Such liposomes
are described, e.g., in U.S. Publication No. 2004/0009217.
[0096] In some embodiments, liposome complexes may facilitate
selective delivery to localized regions of damaged lung tissue. For
instance, peptide-lipid conjugates may be incorporated into
liposomes, for example to selectively destabilize the liposomes in
the vicinity of high amounts of elastase or other peptidases, as
found in certain pulmonary conditions. See, e.g., peptide-lipid
conjugates described in U.S. Pat. No. 6,087,325.
[0097] Delivery vehicles can also include other delivery systems
associated with membranes (e.g., biocompatible or bioerodable
membranes), including, e.g., dendrimer-based methods. See, e.g., US
Publication No. 2004/0120979. See also, e.g., US Publication No.
US2003/0064050, describing dendritic polymer conjugates useful as
drug delivery systems. For example, a dentritic polymer conjugate
useful as a delivery system in the practice of the present
invention can comprise a dendritic polymer coupled to an adhering
moiety described herein.
[0098] In some embodiments, a glue composition of the present
invention may be used with a moiety that increases solubility
and/or pharmacologic compatibility of the adhering, cross-linkable,
cross-linking activating and/or imaging moiety, as well as other
moieties and/or agents, for example, by enhancing hydrophobicity.
For example, in some embodiments, absorption enhancing preparations
(e.g., liposomes described above) may be utilized. Moieties that
may be co-administered to achieve such effects include, for
example, amphotericin B, betamethasone valerete, beclomethasone,
cortisone, dexamethasone, DPPC/DPPG phospholipids, doxorubicin,
estradiol, isosorbide dinitrate, nitroglycerin, prostaglandins,
progesterone, testosterone, and/or vitamin E, and/or esters of any
of these.
[0099] Glue compositions for use in treating pulmonary conditions
preferably have low levels of toxicity during useable life and are
preferably sterilized. Sterilization may be accomplished by
techniques known to in the art, including, for example, chemical,
physical, and/or irradiation methods. Physical methods can include
sterile fill, filtration, use of heat (dry or moist) and/or retort
canning. Irradiation methods of sterilization can include gamma
irradiation, electron beam irradiation, and/or microwave
irradiation. Preferred methods are dry and moist heat sterilization
and electron beam irradiation. Different moieties of the invention
can be sterilized separately, e.g., as described in EP 1433486,
e.g., to form final sterile glue compositions.
[0100] Preferably, the glue compositions of the present invention
have a bacterial count of less than about 2 cfu/g, less than about
1 cfu/g, or less than about 0.1 cfu/g. Such precautions can reduce
abscess formation. Preservatives may also be used including, but
not limited to, hydroquinone, pyrocatechol, resorcinol, 4-n-hexyl
resoreinol, captan (i.e., 3
.alpha.,4,7,7.alpha.-tetrahydro-2-((trichloromethyl)thio)-1H-iso-
indole-1,3 (2H)-dione), benzalkonium chloride, benzalkonium
chloride solution, benzethonium chloride, benzoic acid, benzyl
alcohol, cetylpyridinium chloride, chlorobutanol, dehydroacetic
acid, o-phenylphenol, phenol, phenylethyl alcohol, potassium
benzoate, potassium sorbate, sodium benzoate, sodium
dehydroacetate, sodium propionate; sorbic acid, thimerosal, thymol,
phenylmercuric compounds such as phenylmercuric borate,
phenylmercuric nitrate and phenylmercuric acetate, formaldehyde,
and formaldehyde generators such as the preservatives Germall
II..RTM.. and Germall 115.TM. (imidazolidinyl urea; available from
Sutton laboratories, Charthan, N.J.), and the like. Further,
preferred preparations contain nontoxic concentrations of toxins,
such a heavy metals, for example, using established criteria for
USP water for inhalation.
[0101] The present invention also encompasses pharmaceutical glue
compositions prepared for storage before administration. Such
compositions preferably contain preservatives and/or stabilizers.
For example, sorbic acid and/or esters of phydroxybenzoic acid may
be added. In addition, antioxidants and suspending agents may be
used.
[0102] Pharmaceutical glue compositions useful in this invention
may also include stabilizing agents, e.g., to reduce premature
cross-linking. Stabilizing agents can include, e.g., vapor phase
stabilizers, such as an anionic vapor phase stabilizer, and/or
liquid phase stabilizers, e.g., an anionic liquid phase
stabilizers. Such stabilizing agents may also include radical
stabilizing agents, and/or a mixture of various stabilizing agents,
preferably where the mixture does not interfere with, retard,
and/or prevent the desired reaction. See, e.g., U.S. Pat. No.
6,512,023.
[0103] If necessary or desirable, the glue compositions of the
present invention may be administered in combination with one or
more other therapeutic agents. The choice of therapeutic agent that
can be co-administered with a glue composition of the present
invention will depend, in part, on the condition being treated and
the desired effect to be achieved.
[0104] For example, the glue composition may be administered with a
growth factor, an anti-surfactant and/or an antibiotic or other
therapeutic agent, including small molecule or polypeptide drugs.
Examples of growth factors that may be used include a fibroblast
growth factor, a transforming growth factor-.beta..sub.1, and/or a
platelet-derived growth factor (PDGF), as well as functional
analogs thereof. Determination of dosage ranges are well within the
knowledge and/or skill of those in the art, e.g., about 1 to about
100 nM of polypeptide growth factor can be used.
[0105] Examples of antibiotics that may be used include ampicillin,
sisomicin, cefotaxim, gentamycin, penicillin, nebacetin, and the
like. Additionally, in some embodiments, antimicrobial agents,
antiviral agents, antiseptics, bacteriocins, disinfectants,
anesthetics, fungicides, anti-inflammatory agents, or other active
agents or mixtures thereof may be administered with a glue
composition of the present invention. Such compounds can include
acetic acid, aluminum acetate, bacitracin, bacitracin zinc,
benzalkonium chloride, benzethonium chloride, betadine, captan
(i.e., 3
.alpha.,4,7,7.alpha.-tetrahydro-2-((trichloromethyl)thio)-1H-isoindole-1,-
3 (2H)-dione), benzalkonium chloride, benzalkonium chloride
solution, benzethonium chloride, benzoic acid, benzyl alcohol,
bleomycin, calcium chloroplatinate, cephalosporin, cetrimide,
cetylpyridinium chloride, chlorobutanol, cloramine T, chlorhexidine
phosphanilate, chlorhexidine, chlorhexidine sulfate,
chloropenidine, chloroplatinatic acid, ciprofloxacin, clindamycin,
clioquinol, cresol, chlorocresol, cysostaphin, dehydroacetic acid,
doxorubicin, formaldehyde, gentamycin, hydroquinone, hydrogen
peroxide, iodinated polyvinylidone, iodine, iodophor,
imidazolidinyl urea, minocycline, mupirocin, neomycin, neomycin
sulfate, nitrofurazone, non-onynol 9, .alpha.-phenylphenol,
phenylmercuric additives such as phenylmercuric borate,
phenylmercuric nitrate and/or phenylmercuric acetate phenol,
phenylethyl alcohol, potassium benzoate, potassium sorbate,
potassium permanganate, polymycin, polymycin B, polymyxin,
polymyxin B sulfate, polyvinylpyrrolidone iodine, povidone iodine,
8-hydroxyquinoline, preservatives (e.g., alkyl parabens and salts
thereof, such as butylparaben, ethylparaben, methylparaben,
methylparaben sodium, propylparaben, propylparaben, sodium, and/or
pyrocatechol), quinolone thioureas, rifampin, rifamycin,
resorcinol, 4-n-hexyl resoreinol, silver acetate, silver benzoate,
silver carbonate, silver chloride, silver citrate, silver iodide,
silver nitrate, silver oxide, silver sulfate, sodium benzoate,
sodium dehydroacetate, sodium propionate, sorbic acid, sodium
chloroplatinate, sodium hypochlorite, sphingolipids, sulfonamide,
tetracycline, sulfadiazine salts (such as silver, sodium, and
zinc), thimerosal, thymol, tiotropium bromide, zinc oxide, and the
like, and any combinations thereof.
[0106] Other drug moieties that may be co-administered, include,
for example anti-oxidants, atropine methyl nitrate, albuterol
(salbutamol) sulfate, alcetylcysteine, anticholinergics,
atriopeptin, bitolterol mesylate, beta agonists, other
bronchodilators, e.g., isoetharine, methylxanthines, captopril,
calcitonin, cromolyn sodium, cyclosporin, ephedrine sulfate,
ephedrine bitartrate, epidermal growth factor, etoposide,
fluroisolide, heparin, ibuprofin, insulin, interferon, isoetharine
hydrochloride, insulin, interleukin-2, isoetharine mesylate,
isoproteranol hydrochloride, isoproteranol sulfate, leukotriene
inhibitors, lipase inhibitors, lipocortin, lung surfactant protein,
mast cell stabilizers, metaproteranol sulfate, narcotics, n-acetyl
cysteine, pentamidin, non-steroidal anti-inflammatory drugs
(NSAIDs), peptides, phosphodiesterase inhibitors, phospholipase
inhibitors, plasma factor 8, procaterol, propranalol, pulmozyme
(Genentech), P2Y2 receptor agonists, steroids, superoxide
dismutase, terbutaline, terbutaline sulfate, theophylline, tissue
plasminogen activator (TPA), tobermycin, tumor necrosis factor,
vasopressin, and/or verapamil.
[0107] Further, the glue composition may also be administered with
a nucleic acid, e.g., a nucleic acid encoding a polypeptide,
antisense oligonucleotide, or interfering RNA (e.g., siRNA).
Compositions of the present invention may also serve as "depot" for
slow release of therapeutic moieties or other active agents at
selected localized regions of damaged lung tissue.
[0108] All formulations for aerosol, trans-thoracic, instillation,
intravenous and/or other administration pan be formulated in
dosages suitable for administration. Pharmaceutical compositions
suitable for use in the present invention include glue compositions
wherein the moieties and/or agents are present in an effective
amount, i.e., in a diagnostically and/or pharmaceutically effective
amount. A diagnostically effective amount includes a sufficient
amount of a glue composition comprising an imaging moiety to allow
detection of the presence of the imaging moiety, preferably at a
site of sealed lung tissue, and more preferably by a non-invasive
and/or in vivo imaging technique. A pharmaceutically effective
amount includes a sufficient amount of a glue composition
comprising an adhering moiety, cross-linkable moiety, cross-linking
activating moiety and/or other agent to produce a therapeutic
and/or a prophylactic benefit in at least one pulmonary condition
being treated. The effective amount can be administered in a single
dose or in a series of doses separated by appropriate time
intervals, such as minutes, hours or days. The actual amount
effective for a particular application will depend on the pulmonary
condition, being treated, the route of administration used, the
identity of the adhering, cross-linkable, cross-linking activating
and/or other moieties and/or agents to be used, and other
considerations that will be appreciated by those of skill in the
art. Determination of an effective amount is well within the
capabilities of those skilled in the art, especially in light of
the disclosures herein.
[0109] The effective amount when referring to a glue composition
comprising an adhering, cross-linkable, cross-linking activating,
imaging moiety and/or other moiety and/or agent will generally mean
the dose ranges, modes of administration, formulations, etc., that
have been recommended or approved by any of the various regulatory
or advisory organizations in the medical or pharmaceutical arts
(e.g., FDA, AMA) or by the manufacturer or supplier. The effective
amount when referring to producing a benefit in treating a
pulmonary condition, such as emphysema, will generally mean the
amount that achieves clinical lung volume reduction recommended or
approved by any of the various regulatory or advisory organizations
in the medical or surgical arts (e.g., FDA, AMA) or by the
manufacturer or supplier.
[0110] A person of ordinary skill using techniques known in the art
can determine the effective amount of the adhering moiety,
cross-linkable moiety, cross-linking activating moiety and/or other
moiety and/or agent of the glue composition to be administered. The
effective amount may depend on the moiety and/or agent to be used,
and can be deduced from known data, e.g., data regarding binding
constants for an adhering moiety, concentrations to achieve
cross-linking for cross-linkable and cross-linking activating
moieties, and sufficient imaging moiety to permit detection.
[0111] In some embodiments, dosages can be at least about 0.001
.mu.g/kg/body weight, at least about 0.005 .mu.g/kg/body weight, at
least about 0.01 .mu.g/kg/body weight, at least about 0.05
.mu.g/kg/body weight, or at least about 0.1 .mu.g/kg/body weight.
In some embodiment, dosages can be less than about 0.05 mg/kg/body
weight, less than about 0.1 mg/kg/body weight, less than about 0.5
mg/kg/body weight, less than about 1 mg/kg/body weight, less than
about 2 mg/kg/body weight, less than about 3 mg/kg/body weight, or
less than about 5 mg/kg/body weight of a composition of the
invention. In some embodiment, dosages can be less than about 10
mg/kg/body weight, less than about 25 mg/kg/body weight, less than
about 50 mg/kg/body weight, less than about 75 mg/kg/body weight,
less than about 100 mg/kg/body weight, less than about 150
mg/kg/body weight, or less than about 200 mg/kg/body weight of a
composition of the present invention.
[0112] The dosage may vary depending on the moieties used and their
known biological properties. For example, it is known that
fibrinogen comprises about 2 to about 4 g/L blood plasma protein
and is cleaved to fibrin upon exposure to thrombin at the
initiation the blood clotting cascade. In the context of reducing
lung volume, formulations can be prepared containing useful
concentrations of fribnogen and/or fibrin as a cross-linkable
moiety and thrombin, batroxobin, a thrombin receptor agonist,
and/or calcium as a cross-linking activating moiety. For example, a
formulation comprising at least about 1%, at least about 2%, at
least about 3%, at least about 4%, at least about 5%, at least
about 8%, at least about 10%, at least about 12%, or at least about
15% fibrinogen may be used (e.g., in saline solution, for instance
about 0.8%, about 0.9%, about 1%, or about 1.2% saline), and may be
activated using at least about 0.5, at least about 1, at least
about 5, at least about 10, or at least about 12 units of thrombin
per ng of fibrinogen, and/or more than about 1 mM, more than about
1.5 mM, more than about 3 mM, more than about 5 mM, or more than
about 8 mM calcium (e.g., in a CaCl.sub.2 solution). Some
embodiments may use a preparation of less than about 40 mM, less
than about 30 mM, or less than about 20 mM calcium (e.g., in a
CaCl.sub.2 solution). Additionally, at least about 0.5%, at least
about 1%, at least about 3%, at least about 5%, or at least about
6% of factor XIIa transglutaminanse may also be used to promote
cross-linking. Formulation of fibrin-based compositions for
achieving cross-linking are also known in the art, e.g., and may
contain about more than about 10 mg/ml, more than about 20 mg/ml,
more than about 25 mg/ml, or more than about 50 mg/ml. Fibrin-based
compositions useful in the practice of this invention may also
contain less than about 250 mg/ml, less than about 200 mg/ml, less
than about 150 mg/ml, less than about 100 mg/ml, or less than about
50 mg/ml. See, e.g., other fibrin sealant compositions as provided
in e.g., U.S. Pat. No. 5,739,288.
[0113] Further, the effective amount for use in humans can be
determined from animal models, e.g., mice, rabbits, dogs, sheep, or
pigs. For example, emphysema can be induced in C57BL/6 mice by
administering nebulized porcine pancreatic elastase (about 30
IU/day for about 6 days), as described, for instance, in Ito, S. et
al., "Tissue Heterogeneity in the Mouse Lung: Effects of Elastase
Treatment," J. Appl. Physiology 97(1):201-212 (July 2004).
Similarly, emphysema-like conditions may be induced in sheep
exposed to papain (inhalation of about 7,000 units/week for four
consecutive weeks). Emphysema can also be induced in animal models
by exposure to cadmium chloride, high concentrations of oxygen,
and/or cigarette smoke. Ingenito, et al., "Bronchoscopic lung
volume reduction using tissue engineering principles", American
Journal of Respiratory and Critical Care Medicine, Vol. 167 pgs.
771-778 (2003). A dose suitable for sealing damaged lung tissue in
humans can be formulated baaed on doses found to be effective in
animal models in reducing lung volume and freeing up space for
expansion of remaining non-damaged or healthier tissue. Other
techniques would be apparent to one of ordinary skill in the art.
Further, the amount of administered glue composition comprising a
cross-linkable moiety and/or coupled adhering moieties can be
selected to be not so large as to generate high local hydrostatic
pressures, preferably avoiding local hydrostatic pressures that
exceed capillary perfusion pressure that can lead to abscess
formation.
[0114] Similarly, a dose for imaging damaged lung tissue in humans
can be formulated based on that used to image the lungs of a
suitable animal model. Diagnostic compositions comprising an
adhering moiety and an imaging moiety can be prepared using a
pharmaceutically acceptable carrier and a diagnostically effective
amount of the glue composition. Diagnostically effective amount
required as a dose to allow imaging will depend upon the route of
administration, the condition being treated, the adhering moiety
being used, the imaging moiety being used, the imaging detail
sought to be obtained, e.g. the extent of sealing achieved, as well
as other factors that will be appreciated by those of skill in the
art of medical diagnostics. One of skill in the art of medical
diagnostics will readily be able to determine suitable dosages,
especially in light of the disclosures provided herein.
[0115] In preferred embodiments, the dose for imaging is sufficient
to detect the presence of an imaging moiety at a site of damaged
(preferably sealed) lung tissue. For example, in some embodiments,
radiological imaging can require that the dose provide at least
about 3 .mu.C, at least about 5 .mu.C, or at least about 10 .mu.C
of imaging moiety. In some embodiments, radiological imaging can
require that the dose provide less than about 30 .mu.C, less than
about 20 .mu.C, or less than about 15 .mu.C of imaging moiety. Some
embodiments using magnetic resonance imaging can require a dose of
at least about 0.0005 mmol/kg, at least about 0.001 mmol/kg, at
least about 0.005 mmol/kg, at least about 0.01 mmol/kg, at least
about 0.05 mmol/kg, at least about 0.1 mmol/kg, at least about 0.5
mmol/kg, or at least about 1 mmol/kg of imaging moiety to body
weight of the subject. In some embodiments, magnetic imaging can
require a dose of less than about 10 mmol/kg, less than about 8
mmol/kg, less than about 5 mmol/kg, less than about 3 mmol/kg, or
less than about 2 mmol/kg of an imaging moiety to the body weight
of the subject. As a further example, iodine may be used as an
imaging moiety in a dose of at least about 2 mol percent, at least
about 5 mol percent, at least about 7 mol percent, or at least
about 8 mol percent of the administered glue composition. The
iodine imaging moiety can be in a dose of less than about 20 mol
percent, less than about 15 mol percent, less than about 12, or
less than about 10 mole percent, of the administered glue
composition.
[0116] The exact dosage will be determined by the practitioner, in
light of factors related to the subject in need of diagnosis and/or
treatment Factors which may be taken into account include the
severity or extent of the pulmonary condition, the general health
of the subject, age, weight, and diet of the subject, as weir as
the timing and frequency of administration, other diagnostic and/or
therapeutic techniques available and/or desirable to the subject
and/or being used by the subject, as well as reaction
sensitivities, allergies, tolerance and/or response to the glue
composition(s) of the present invention.
[0117] Methods of Treating Pulmonary Conditions
[0118] The present invention provides methods of treating pulmonary
conditions using compositions that adhere lung tissue, including
damaged lung tissue. The term "pulmonary condition" as used herein
refers to a non-normal condition of the lungs and/or lung tissue,
for example, where there is damaged lung tissue. Examples of such
pulmonary conditions include COPD, which includes emphysema,
(including both heterogeneous emphysema and homogenous emphysema,
preferably heterogeneous emphysema), asthma, bronchiectais, and
chronic bronchitis. Pulmonary conditions can also include other
chronic pulmonary disorders, sarcoidosis, pulmonary fibrosis,
pneumothorax, fistulae, bronchopleural fistulae, cystic fibrosis,
inflammatory states, and/or other respiratory disorders. Pulmonary
conditions can also include smoking-related and/or age related
changes to the lung as well as lung damage caused by a traumatic
event, infectious agents (e.g., bacterial, viral fungal, tuberculin
and/or viral agents), exposure to toxins (e.g., chemotherapeutic
agents, environmental pollutants, exhaust fumes, and/or
insecticides), and/or genetic factors (e.g., alpha-1 antitrypsin
deficiency and other types of genetic disorders which involve
elastic and/or connective tissue degradation and/or impaired
synthesis of elastic and/or connective tissues and/or impaired
repair of elastic and/or connective tissues of the lungs).
[0119] One aspect of the present invention provides a method of
reducing lung volume by providing a glue composition comprising a
cross-linkable moiety and an adhering moiety wherein said moieties
are coupled and wherein said adhering moiety adheres lung tissue;
administering said glue composition to a localized region of
damaged lung tissue of a subject; collapsing a first portion or all
of the lung of said subject wherein said first portion comprises
said localized region of damaged lung tissue; cross-linking damaged
lung tissue; and re-inflating a second portion of the lung of said
subject wherein said second portion does not comprise said damaged
lung tissue, thereby reducing lung volume.
[0120] In some preferred embodiments, the method is performed with
prior identification of the damaged lung tissue. For example, the
lungs of the subject may be imaged to identify regions or sites of
damaged tissue before administering a glue composition of the
invention to the subject, e.g., to determine regions that may
benefit from volume reduction. As used herein, the terms "regions,"
"sites," and "areas" are used interchangeably when referring to
regions, sites and/or areas of damaged lung tissue, e.g., localize
regions, sites and/or areas of damaged lung tissue selected for
administration of a glue composition of the present invention. Such
identification may involve any techniques known, to be developed,
described herein, and/or described, in U.S. nonprovisional
applications entitled "Targeting Damaged Lung Tissue Using
Compositions," filed Dec. 8, 2004; "Targeting Damaged Lung Tissue,"
filed Dec. 8, 2004; "Targeting Sites of Damaged Lung Tissue Using
Composition," filed Dec. 8, 2004; "Targeting Sites of Damaged Lung
Tissue," filed Dec. 8, 2004; "Imaging Damaged Lung Tissue Using
Compositions," filed Dec. 8, 2004; "Imaging Damaged Lung Tissue,"
filed Dec. 8, 2004; "Glue Compositions for Lung Volume Reduction,"
filed Dec. 8, 2004; "Lung Volume Reduction Using Glue
Compositions," filed Dec. 8, 2004; and "Lung Volume Reduction Using
Glue Composition," filed Dec. 8, 2004, each of which is herein
incorporated in its entirely that facilitate identification of
regions of damaged lung tissue. Regions of damaged lung tissue
include areas of the lung affected by a pulmonary condition or that
are affected to a greater extent compared with other, healthier
areas of the lung. In emphysema, for example, such regions can
include regions featuring "blebs," that is, regions where
progressive destruction of elastic tissue has caused loss of lung
recoil and consequent hyper-extension.
[0121] Current techniques that may be used to identify damaged lung
tissue in the present invention include radiology (e.g., chest
X-rays) and CT scans. For example, review of CT scans of the chest,
preferably high-resolution CT scans, can indicate localized regions
of damaged lung tissue that may be selected for volume
reduction.
[0122] Cross-linking of the damaged lung tissue can then bring
about a reduction in lung volume, for example, by sealing and/or
keeping collapsed regions of over-inflated lung tissue, preferably
freeing up space for the expansion of remaining non-damaged or
healthier tissue. In emphysema, for instance, regions of the lung
that have lost elasticity required for exhalation can be collapsed
and/or sealed by the methods described herein. Because the
cross-linked tissue occupies a smaller volume than, e.g., the
enlarged alveoli at sites of damaged tissue, methods of this
invention can reduce lung volume overall. The present invention can
thus provide a non-surgical, less-invasive and/or safer approach
for achieving some of the benefits of lung volume reduction
surgery. Further, providing the glue composition to a localized
region of damaged lung tissue allows for localized volume
reduction, which in turn can minimize untoward side effects of lung
volume reduction, such as exacerbating V/Q imbalance, changing
arterial oxygenation, or triggering acute hypoxemia. Ingenito et
al., (2003) Bronchoscopic Lung Volume Reduction Using tissue
engineering principles, American Journal of Respiratory and
Critical Care Medicine, Vol. 167 pgs 771-778. It is to be
understood also that the methods of the present invention may be
used in conjunction with a surgical procedure, such as LVRS and the
use of knifeless staplers (see, e.g., Swanson et al., "No-cut
thoracoscopic lung plication: A new technique for lung volume
reduction surgery", J Am Coil Surg Vol. 185 pgs 25-32 (1997)), as
well as other approaches for treating pulmonary conditions,
including use of coupled adhering moieties described herein.
[0123] Cross-linking of the cross-linkable moieties can be achieved
by any methods known in the art and/or described herein. For
example, a second composition may be administered that comprises a
cross-linking activating moiety. "Cross-linking activating moiety"
as used herein refers to any moiety that can bring about
cross-linking between more than one cross-linkable moieties and/or
that can form more than one bond with components (e.g., proteins)
of lung tissue. Preferably, a cross-linking activating moiety
comprises a di- or polyfunctional group. For example, where the
cross-linkable moiety is at least one of a hydroxyl group, a
carboxyl group, an ester group, a cyano group, a thiol group (e.g.,
a cysteine group), a carbonyl group, an aldehyde group, a ketone
group, a primary amine group, a secondary amine group, and/or a
lysine group the cross-linking activating moiety may comprise a
diol, a polyol, a dicarboxylic acid (e.g., fumaric, maleic,
phthalic or terephthalic acid), a polycarboxylic acid, a diester, a
polyester, a diamine and/or a polyamine. The di- or polyfunctional
group can form covalent linkages with more than one cross-linkable
moieties, preferably between cross-linkable moieties coupled to
adhering moieties binding to different sites of damaged lung
tissue, e.g., at different sites within an enlarged alveolus.
Linkage may include, for example, amide formation (e.g., through
the condensation of an amino group with an activated ester, such
as, e.g., an NHS or sulfo-NHS ester), imine formation, carbodiimide
condensation, disulfide bond formation, and/or use of a specific
binding pair e.g., using a biotin-avidin interaction. The
cross-linking can therefore serve to seal and/or keep collapsed air
spaces at sites of damaged lung tissue, e.g., in areas of
over-inflated alveoli, as characteristic of certain pulmonary
conditions, including emphysema.
[0124] Di- and/or polyamines that may be used in the practice of
this invention include aliphatic and/or aromatic di- and/or
polyamines, as well as two or more aliphatic and/or aromatic
monoamines suitably linked together. For example, monomeric, di-
and/or polyamines that may be used in the practice of this
invention can comprise aminopyrimidine, aniline, benzidine,
diaminodiphenylamine, diphenylamine, hydrazine, hydrazide,
toluene-diamine, and/or triethylenediamine. Di- and/or polyamines
that may be used also can comprise, for example, acetamide,
acrylamide, benzamide, cyanamide, and/or urea. Di- and/or
polyalcohols that may be used include aromatic and/or aliphatic
alcohols, including, for example, 1,4-butanediol, phenols,
polyvinyl alcohols, and/or d-sorbitol. Examples of dicarbonyls that
may be used in the practice of the present invention include
dicarbonyls comprising acetate, e.g., .alpha.-haloacetate
derivatives, acetylacetone, diethylmalonate, ethylacetone,
malonamide, malonic acid and/or malonic esters or salts thereof.
Other carbonyl groups that may be used include .alpha.,
.beta.-unsaturated carbonyl groups (e.g., maleimide) and/or
.alpha.-halocarbonyl groups (e.g., iodoacetamide derivatives). Di-
and/or polyfunctional ketones may also be used, including, e.g.,
2,5-hexanedione, and/or di- and/or polyfunctional ketones
comprising two or more linked monofunctional ketones, such as
cyclohexanone and/or cyclopentanone. Di- and/or polyfunctional
aldehydes may also be used, see, e.g., U.S. Pat. No. 6,329,337
and/or U.S. Pat. No. 6,372,229. For example, at least one aldehyde
selected from gelatin-resorcin-aldehyde, glyoxal, succinaldehyde,
glutaraldehyde, malealdehyde, dextrandialdehyde, and saccharides
oxidized by m-periodate may be used.
[0125] As will be appreciated by one skilled in the art, aldehydes
and/or ketones described herein can exist as hydrates in aqueous
solution, e.g., existing as hemi-acetals and/or hemi-ketals in
aqueous solution. In preferred embodiments, such hydrates can
revert back to the corresponding aldehyde and/or ketone for
cross-linking. In some embodiments, hydrates of aldehydes and/or
ketones and/or hydrates of other cross-linking activating moieties
are themselves capable of bringing about cross-linking between more
than one cross-linkable moieties and/or of forming more than one
bond with components (e.g. proteins) of lung tissue.
[0126] Other cross-linking activating moieties that may (or may
not) be used in the practice of the present invention include a
protein or a mixture of proteins (including synthetic peptides
and/or recombinant proteins), such as collagen and/or albumin
and/or lipoprotein, along with other minor additives, optionally as
well as hydrogel, polyglycolic acid, polylactic acid,
polydioxanone, polytrimethylene carbonate, polycarprolactone,
and/or glutaraldehyde, polyethylene glycol polyethlyene glycol
disuccinimidoyl succinate, as well as polymerizable monomers, such
as 1,1-disubstituted ethylene monomers or acetates, e.g.,
.alpha.-haloacetate, acrylate, acrylate glue, anhydrides
cross-linked with polyols, cyano groups, e.g., cyanoacrylate,
epoxy, gelatin resorcinol formaldehyde, gelatin resorcinol
glutaraldehyde, hyaluronic acid cross-linked with hydrazines,
photopolymerizable monomers, silicone, silicone rubber, starches,
urethane, vinyl-terminated monomers, and/or any combination
thereof. Other cross-linking activating moieties that may be used
in the practice of the present invention include alkyl
bis(2-cyanoacrylate), triallyl isocyanurate, alkylene diacrylate,
alkylene dimethylacrylate, and/or trimethylol propane triacrylate.
Other cross-linking activating moieties that may be used in the
practice of the present invention include disulfide, carbodiimide
and hydrazine. Other suitable cross-linking activating moieties may
be found in the art, for example, U.S. Pat. No. 3,940,362; U.S.
Pat. No. 5,328,687; U.S. Pat. No. 3,527,841; U.S. Pat. No.
3,722,599; U.S. Pat. No. 3,995,641; and/or U.S. Pat. No. 5,583,114,
each incorporated herein by reference. Still another cross-linking
activating moiety that may be used includes a product formed by
reading glutaraldehyde with amino acids and/or peptides, as
described in U.S. Pat. No. 6,310,036. Cross-linkable and/or
cross-linking activating moieties may also include suitable
monomers disclosed in U.S. Publication No. 2002/0147462, such as,
for instance, monomeric n-butyl-2-cyanoacrylate (Eng et al.,
"Successful closure of bronchopleural fistula with adhesive
tissue", Scand J Thor Cardiovasc Surg, Vol. 24 pgs 157-59 (1990)
and Inaspettato et al., "Endoscopic treatment of bronchopleural
fistulas using n-butyl-2-cyanoacrylate", Surgical Laparoscopy &
Endoscopy, Vol. 4 No. 1 pgs 62-64 (1994)).
[0127] The choice of cross-linking activating moiety can depend, at
least in part, on the cross-linkable moieties used. Where the
cross-linkable moiety is fibrin and/or fibrinogen, the
cross-linking activating moiety may comprise a fibrin activator
and/or a fibrinogen activator. For example, thrombin, a thrombin
receptor agonist, batroxobin, and/or calcium can be used to
initiate cross-linking of fibrinogen. It is also to be understood
that any combination of cross-linking activating moieties may be
used, depending on, for example, the combination of cross-linkable
moieties administered. Further, some embodiments provide a glue
composition comprising an adhering moiety coupled to a
cross-linking activating moiety. Those of skill in the art will
recognize other suitable cross-linking activating moieties that may
be used in the practice of the instant invention, including, for
example, any biocompatible cross-linking activating moiety that can
form a biocompatible cross-linked product with a cross-linkable
moiety used. In still more preferred embodiments, the
cross-linkable and cross-linking activating moieties used are
medically acceptable and form medically acceptable cross-links.
[0128] In some embodiments, one or more of the cross-linkable,
adhering and/or cross-linking activating moieties are thermally
stabilized. That is, the moiety may be modified, adapted and/or
otherwise engineered to withstand heat, e.g., heat generated by a
cross-linking reaction within lung tissue of a subject. For
example, heat-stabilized glutaraldehyde in an aqueous carrier may
be used, and in some embodiments amino acid modifications in
protein adhering moieties may confer increased thermal
stability.
[0129] The cross-linkable and cross-linking activating moieties can
be added in appropriate ratios to facilitate cross-linking. The
ratio to be used may depend on the cross-linkable and/or
cross-linking activating moieties used, the rate of cross-linking
desired, and/or other reaction conditions appreciated by those of
skill in the art. For example, a ratio of at least about 1:1; at
least about 1:2, at least about 1:5, at least about 1:10; at least
about 1:15, or at least about 1:20 may be used.
[0130] It will be recognized by those of skill in the art that
certain of these cross-linking activating moieties may be suitable
for use alone, i.e., without a corresponding cross-linkable moiety.
For example, biotin groups, amine groups, carboxylic acid groups,
cyanate groups (e.g. isothiocyanate), thiol groups, disulfide
groups, cyano groups (e.g., .alpha.-halocarbonyl groups, .alpha.,
62 -unsaturated carbonyl groups), an acetate group (e.g.,
.alpha.-haloacetate group), hydrazine groups, cyanoacrylate,
acrylic glue, and/or silicone moieties, as well as bifunctional
linkers, may be used to bring about cross-linking of damaged lung
tissue without the use of a separate cross-linkable moiety.
Further, various combinations of cross-linking activating moieties
may be used, administered together at the same time or separately
at different times of administration. For instance, a
dipolyaldehyde and/or polyaldehyde may be combined with a mixture
of proteins, such as albumin and/or collagen, and optionally other
minor additives. Also, as mentioned above, the cross-linking
activating moiety may in some embodiments be coupled to an adhering
moiety, for example, to an alpha-1 antitrypsin molecule, fragment
thereof, and/or derivative thereof, or to a combination of adhering
moieties, including, for example, any combination of types of
adhering moieties provided herein.
[0131] It is also to be understood that some embodiments would not
require a cross-linking activating moiety for initiation of
cross-linking. For example, if fibrin is used as the cross-linkable
moiety, e.g., a fibrin monomer, such as fibrin I monomers, fibrin
II monomers and/or des BB fibrin monomers, the monomers may
spontaneously cross-link. For instance, fibrin I monomers may
cross-link upon contacting a subject's blood, which contains
thrombin and factor XII.
[0132] Various types of cross-linking reactions may be used in the
practice of the present invention including, for example, free
radical reactions, cross-linking by zwitterions and/or ion pairs,
anions and/or cations. See e.g., U.S. Pat. Nos. 6,010,714;
5,582,834; 5,575,997; 5,514,372; 5,514,371 and 5,328,687 to Leung
et al. and U.S. Pat. No. 5,981,621. Cross-linking reactions of the
present invention may also involve amide formation, imine
formation, carbodiimide condensation, disulfide bond formation, and
use of a specific binding pair, e.g., using a biotin-avidin
interaction.
[0133] In some preferred embodiments, the method for reducing lung
volume does not damage epithelial cells within lung tissues, e.g.,
it may not cause scar tissue formation, and/or may not cause
fibroblast proliferation, and/or may not cause collagen synthesis.
In some preferred embodiments, the methods cross-link and/or seal
sites of damaged lung tissue within an alveolus, more preferably
within an enlarged alveolus distal to a terminal bronchiole. In
some preferred embodiments, the methods of the present invention do
not cause occlusion of a lumen of a bronchial tube of a lung of the
subject. Without being limited to a particular mechanism, methods
of the present invention can reduce lung volume by keeping
cross-linked and/or sealed enlarged air spaces, rather than by
(mechanically) attempting to block air-flow to damaged lung tissue.
That is, in preferred embodiments, cross-linking serves to keep
collapsed and/or sealed blind ending sacs, rather than there being
any or any substantial amount of lung tissue distal to the
cross-linked sites. In yet still preferred embodiments, the lung
volume reducing methods of the present invention can be carried out
without the use of open surgery, e.g., thoracotomy.
[0134] In some preferred embodiments, the method for reducing lung
volume can involve damage to lung tissue. For example, in some
embodiments a sclerosing agent can be used as part of the
administered glue composition, for instance, a sclerosing agent may
be coupled to an adhering moiety of the present invention. In some
embodiments, the sclerosing agent may be administered alone; or it
may be administered separately at the same time as, before, or
after administration of adhering, cross-linkable, and/or
cross-linking activating moieties of the present invention. The
sclerosing agent can serve to bring about scar tissue formation,
and/or fibroblast proliferation, and/or collagen synthesis,
facilitating sealing of regions of damaged lung tissue. Sclerosing
agents that may be used in the present invention include
Doxycycline, Bleomycin, Minocycline, Doxorubicin,
Cisplatin+Cytarabine, Mitoxantrone, Corynebacterium Parvum,
Streptokinase, Urokinase, and the like. Other agents and/or methods
for damaging lung tissue may also be used in the practice of the
present invention, optionally along with components of the
extracellular matrix e.g., hyaluronic acid. See e.g., U.S.
Publication No. 2004/0047855.
[0135] In some embodiments, cross-linking activating moieties are
administered after allowing sufficient time for adhering of the
administered cross-linkable moieties to lung tissue. In preferred
embodiments, the adhering moiety adheres in at least about 30
seconds, at least about 1 minute, at least about 3 minutes, or at
least about 5 minutes. In preferred embodiments, the adhering
moiety adheres in less than about 3 hours, in less than about 2
hours, in less than about 1 hour, in less than about 45 minutes, in
less than about 30 minutes, in less than about 20 minutes, or in
less than about 10 minutes. Also, in some embodiments, unbound
adhering moiety may be removed from the lungs, e.g., by lavage
and/or washing (e.g., with saline) and/or by collapsing, before
administration of cross-linking activating moiety.
[0136] Cross-linking and/or gluing may be facilitated by deflating
and/or collapsing a first portion or all of the lung of the
subject, preferably where the first portion comprises a selected
localized region of damaged lung tissue. Such deflating and/or
collapsing can be achieved by any techniques known in the art or
herein disclosed. For example, the collapsing may involve the use
of negative pressure from within the lung and/or positive pressure
from without the lung. Also, in some embodiments, a preparation to
induce and/or facilitate collapse may be used, e.g., a
physiologically acceptable solution containing an anti-surfactant,
such as an agent that can Increase surface tension of fluids lining
alveoli. For example, an anti-surfactant may be administered prior
to, during and/or after administration of the composition
comprising a cross-linkable moiety and/or a cross-linking
activating moiety. For instance, fribrin and/or fibrinogen may be
used, which can act both as an anti-surfactant as well as aiding
cross-linking.
[0137] Other suitable surfactants that may be used to facilitate
cross-linking and/or gluing include Triton x-100, beractant,
colfosceril, and/or palmitate; anionic surfactants such as sodium
tetradecyl sulfate; cationic surfactants such as tetrabutylammonium
bromide and/or butyrylcholine chloride; nonionic surfactants such
as polysorbate 20 (e.g., Tween 20), polysorbate 80 (e.g. Tween 80),
and/or poloxamers; amphoteric and/or zwitterionic surfactants such
as dodecyldimethyl(3-sulfopropyl)ammonium hydroxide, inner salt;
amines, imines and/or amides, such as arginine, imidazole,
povidine, tryptamine, and/or urea; alcohols such as ascorbic acid,
ethylene glycol, methyl gallate, tannins and/or tannic acid;
phosphines, phosphites and phosphonium slats, such as
triphenylphosphine and/or triethyl phosphite; inorganic bases
and/or salts, such as calcium sulfate, magnesium hydroxide, sodium
silicate, and/or sodium bisulfite; sulfur compounds such as
polysulfides and/or thiourea; polymeric cyclic ethers such as
calixarenes, crown ethers, monensin, nonactin, and/or polymeric
epoxides; cyclic and acyclic carbonates; organometallics (e.g.,
naphthenate and manganese acetylacetonate); phase transfer
catalysts (e.g., Aliquat 336); and radical initiators and radicals
(e.g., di-t-butyl peroxide and/or azobisisobutyronitrile).
[0138] Cross-linking and/or gluing may also be facilitated by
filling the lung or a portion thereof with an absorbable gas, such
as oxygen, e.g., to promote atelectasis. Ingenito et al.,
"Bronchoscope volume reduction--A safe and effective alternative to
surgical therapy for emphysema," American Journal of Respiratory
and Critical Care Medicine, Vol 164 pgs 295-301 (2001).
[0139] In some embodiments, a lavage of saline may be used to
reduce the amount of surfactant naturally occurring in the lungs.
Cross-linking and/or gluing may also be facilitated by use of a
lavage capable of removing, e.g., any other moieties that may
impede, reduce and/or otherwise interfere with adhering. For
example, in some embodiments, cross-linking may be facilitated by
use of an anti-secretory agent that hinders and/or prevents mucous
secretion in the lung or a portion thereof. For example, the
anti-secretory agent may be administered prior to, during, and/or
after administration of the glue composition comprising the
cross-linkable moiety and/or the cross-linking activating moiety
and/or other moiety. Examples of anti-secretory agents that may be
used include, for example, anticholinergic moieties, atronie,
and/or atropinic moieties. Removal of mucous or excessive mucous
from the lung, preferably from enlarged alveoli distal to terminal
bronchioles, e.g., by washing, can also facilitate cross-linking
and/or gluing and/or the adhering of an adhering moiety to lung
tissue. Adhesion of a glue composition to a mucous-coated wall
within a bronchus, bronchiole, or alveolus can be facilitated by
virtue of adhering moieties of the present invention adhering to
lung tissue and, for example, reducing and/or avoiding
slippage.
[0140] In some embodiments, mechanical force may be used externally
to push one area of the lung closer to another, for example, to
help collapse and/or deflate an enlarged air space. A portion of a
lobe of the lung may be pressed externally using, for example, a
balloon, air pressure, manual pressure, and/or an instrument such
as a paddle, a net, a strap that can be synched up, or magnets. In
some embodiments, such pressure is applied to two or more sides of
a lung lobe simultaneously. For example, endoscopes and/or magnetic
probes can be used to apply local pressure (applenate) to more than
one side.
[0141] In some embodiments, a first portion or all of the lung may
be drawn together from the inside using, for example, a cable and
hook to grab and pull tissue, for instance, towards the user. Other
devices that can be used include graspers, such as an expanding
grasper assembly that can be sheathed; and/or anchors that can be
left behind, for example, by being uncoupled from a cable or wire
after lung tissue has been drawn together. In some embodiments,
magnetic probes can be placed at different locations within the
lung where the probes attract one another, thereby attracting one
region of the lung to the other, e.g., one bronchi to another.
Additionally, mechanical force may be used to change the shape of
such devices after insertion, such as by using a core wire or
activating a NiTi device after placement. In still other
embodiments, the lungs or a first portion thereof are deflated
trans-thoracically. Other methods and/or devices known in the art
to facilitate lung deflation and/or collapse may also be employed,
e.g. see U.S. Publication No. 2003/0070682.
[0142] Such deflating and/or collapsing is preferably carried out
after allowing sufficient time for distribution of the administered
glue composition to damaged lung tissue. In some embodiments, for
example, deflating and/or collapsing is carried out approximately 2
to approximately 3 minutes after administration. Also, the lung, or
a first portion thereof, is preferably allowed to remain in a
collapsed and/or deflated state for a time sufficient to permit
cross-linking and/or gluing to take place, sealing segments of the
lung to which the glue composition has been administered. Depending
on the glue composition used, e.g., the adhering moieties used, the
lung or a first portion thereof can be kept deflated and/or
collapsed for at least approximately 3 days, at least approximately
2 days (48 hours), at least approximately 24 hours, at least
approximately 12 hours, at least approximately 5 hours, at least
approximately 1 hour, at least approximately 45 minutes, at least
approximately 20 minutes, at least approximately 10 minutes, at
least approximately 5 minutes, at least approximately 2 minutes, at
least approximately 1 minute, at least approximately 30 seconds, or
at least approximately 15 seconds. In some embodiments, the lung or
a first portion thereof can be kept deflated and/or collapsed for
less than about 30 minutes, less than about 20 minutes, less than
about 10 minutes, or less than about 8 minutes.
[0143] In some embodiments, a catalytic amount of a rate modifier
may be added to modify the rate of the cross-linking and/or gluing
reaction. For example, various set or cure times may be used, where
the cross-linking reaction occurs in at least about 20 seconds, at
least about 30 seconds, at least about 1 minute, at least about 90
seconds, at least about 2 minutes, at least about 150 seconds, at
least about 3 minutes, at least about 4 minutes, at least about 5
minutes, at least about 6 minutes, at least about 10 minutes, or at
least about 15 minutes. The cross-linking reaction may occur in
less than about 20 minutes, in less than about 25 minutes, in less
than about 30 minutes, in less than about 1 hour, in less than
about 2 hours, or in less than about 3 hours. Cure times may be
tailored by use of various techniques known in the art, for
example, by using buffers having different pH values.
[0144] A second portion of the lung can then be re-inflated, where
the second portion comprises part, but preferably not all, of the
first portion or all of the lung that was deflated and/or
collapsed. In preferred embodiments, this second portion does not
comprise at least some damaged lung tissue, which remains collapsed
and/or sealed by virtue of the cross-linking and/or gluing. The
cross-linking and/or gluing preferably forms a stable mesh that
keeps the collapsed region from re-inflating. In more preferred
embodiments, the majority of damaged lung tissue remains
cross-linked and/or glued (and thereby collapsed), while the
majority of non-damaged lung tissue is left in a functional
condition. For example, at least about 60%, at least about 80%, and
most preferably at least about 90% of damaged lung tissue is
cross-linked and/or glued; while less than about 40%, less than
about 20%, and most preferably less than about 10% of non-damaged
lung tissue remains not cross-linked and/or not glued. Reduction in
overall lung volume improves mechanical inaction, e.g., mechanical
functioning of healthier and/or more elastic tissue.
[0145] In preferred embodiments, cross-linking and/or gluing
results in at least about a 0.5% overall lung volume reduction, at
least about a 1% overall lung volume reduction, at least about a
1.5% overall lung volume reduction, at least about a 2% overall
lung volume reduction, at least about a 3% overall lung volume
reduction, at least about a 4% overall lung volume reduction, at
least about a 5% overall lung volume reduction, or at least about a
10% overall lung volume reduction. In preferred embodiments,
cross-linking and/or gluing results in less than about a 40%, less
than about a 35%, less than about a 30%, less than about a 25%,
less than about a 20%, or less than, about a 15% overall lung
volume reduction. Such reduction may be achieved upon a single or
multiple administrations of compositions of the present invention.
A reduction of about 2% to about 3% overall lung volume reduction
can be expected to produce a beneficial effect in a subject
receiving such treatment, e.g., at least to a similar extent as
that produced in LVRS.
[0146] Also in preferred embodiments, the cross-linking and/or
gluing is permanent, or at least semi-permanent, for a period of
time between successive treatments as described herein, e.g.,
resisting biodegradation (e.g., hydrolysis) for the period of time
between administrations of a glue composition of the present
invention. In certain embodiments, at least about 70%, at least
about 80%, at least about 90%, or at least about 98% of the
cross-links and/or glue remain intact for a period of time. In some
preferred embodiments, the period is at least about one month, at
least about 2 months, at least about 3 months, at least about 6
months, at least about a year, at least about 2 years, at least
about 3 years, at least about 5 years, or at least about 10 years.
In some preferred embodiments, the period is less than about 50
years, less than about 30 years, less than about 20 years, or less
than about 15 years. In most preferred embodiments, the
cross-linking and/or gluing keeps some damaged lung tissue
collapsed and/or sealed for the remainder of the life of the
subject, for example, resisting biodegradation indefinitely.
[0147] One of skill in the art will recognize that the permanence
and/or biodegradability of the cross-links and/or glue can depend
on the cross-linkable moiety, the cross-linking activating moiety,
and/or the conditions of cross-linking and/or other agents and/or
moieties used, and can be controlled accordingly, e.g., by
techniques known the art and/or disclosed herein.
[0148] In preferred embodiments, some or all of the cross-links
and/or glue are strong enough to withstand mechanical pressures
experienced within the lung. For example, the strain range
corresponding to functional residual capacity during normal
breathing does not result in breakage of at least about 30%, at
least about 40%, at least about 50%, at least about 60%, at least
about 70%, at least about 80%; at least about 90%, or at least
about 95% of the cross-links and/or glue in some preferred
embodiments.
[0149] In some preferred embodiments, the cross-links and/or glue
exhibit a tear strength of at least about 50 g/sq. cm, at least
about 100 g/sq. cm, at least about 200 g/sq. cm, or at least about
300 g/sq. cm. In some preferred embodiments, the cross-links and/or
glue exhibit a tear strength of 5,000 g/sq. cm, less than about
3,000 g/sq. cm, less than about 1500 g/sq. cm, less than about 1300
g/sq. cm, less than about 1200/g/sq. cm, less than about 1000 g/sq.
cm, less than about 800 g/sq. cm, less than about 600 g/sq. cm, or
less than about 400 g/sq. cm.
[0150] Similarly, in preferred embodiments, the binding interaction
between an adhering moiety and lung tissue is permanent, or at
least semi-permanent, for a period of time between successive
treatments as described herein, e.g., binding irreversibly,
substantially irreversibly, or at least with a high binding
constant, e.g., to resist dissociation for the period of time
between administrations of a glue composition of the present
invention. For example, an alpha-1 antitrypsin moiety may form a
pseudo-irreversible equimolar complex with neutrophil elastase in
some embodiments. See, e.g., Sifers et al., "Genetic Control of
Human Alpha-1 Antitrypsin", Mol. Biol. Med., Vol. 6 pgs. 127-135
(1989). Without being limited to a particular theory or mode of
action, the alpha-1 antitrypsin moiety may form an acyl-enzyme
complex with an elastase component of lung tissue. In some
embodiments, binding can be further enhanced by genetic
modification or by shuffling of known binding domains. As another
example, a serpin moiety may react with its corresponding protease
to form a sodium dodecyl sulfate (SDS)-stable equimolar complex.
Without being limited to a particular theory or mode of action, the
complex between a serpin and its corresponding protease may involve
a covalent ester bond linkage, where an active site Serine residue
of the protease binds a C-terminal residue of a cleaved form of the
serpin to form an acyl-enzyme complex. See, e.g., U.S. Publication
No. 2003/0216321. As yet another example, a monocyte elastase
inhibitor moiety can form a covalent complex and/or an essentially
irreversible complex with elastase. See, e.g., International
Publication WO 96/10418 and U.S. Pat. No. 5,827,672.
[0151] In certain embodiments, at least about 70%, at least about
80%, at least about 90%, or at least about 98% of the adhering
moieties remain bound to lung tissue for a period of time. In some
preferred embodiments, the period is at least about one month, at
least about 2 months, at least about 3 months, at least about 6
months, at least about a year, at least about 2 years, at least
about 3 years, at least about 5 years, or at least bout 10 years.
In some preferred embodiments, the period is less than about 50
years, less than about 30 years, less than about 20 years, or less
than about 15 years. In most preferred embodiments, the binding
keeps some damaged lung tissue collapsed and/or sealed for the
remainder of the life of the subject, for example, resisting
dissociation indefinitely,
[0152] FIG. 1a illustrates one embodiment of a method to reduce
lung volume using a glue composition comprising a cross-linkable
moiety coupled to an adhering moiety that adheres to lung tissue.
This figure provides an overview only, and is in no way intended to
be limiting with respect to the present invention. For example,
those skilled in the art will readily appreciate variations and
modifications of the scheme illustrated. FIG. 1a schematically
illustrates a bronchoscope placed in a bronchus from which a
catheter extends to a segmental and subsegmental bronchus. The
catheter features a distended balloon-like structure near its
distal tip. The balloon-like structure anchors the catheter within
the subsegmental bronchus, positioning it for delivery of a glue
composition of the present invention in aerosol and/or non-aerosol
form to a selected localized region of damaged lung tissue.
[0153] FIG. 1b schematically illustrates a terminal bronchiole,
terminating in the airspace of an alveolus. The figure also
illustrates a component of lung tissue found within the walls of
the air space and/or within the epithelial lining fluid. As
mentioned above, the airspace may be over-inflated and/or enlarged
in certain pulmonary conditions, such as emphysema.
[0154] A glue composition of the invention is administered, where
the glue composition comprises a cross-linkable moiety (X) coupled
to an adhering moiety that can adhere to lung tissue, such as a
component of lung tissue. FIG. 1b illustrates how different
adhering moieties adhere to lung tissue components at various sites
within the air space.
[0155] Following collapse and cross-linking, the cross-linkable
moieties become cross-linked, for example, via a cross-linking
activating moiety. The cross-linking activating moiety may comprise
a di-functional group, depicted in the figure as Y--R--Y-- where Y
represents a group capable of coupling to the cross-linkable
moieties (X), e.g., to form covalent linkages between two
cross-linkable moieties, and R represents a linking moiety between
the Y groups, for example, but not limited to, an aliphatic chain.
The cross-linking activating moiety couples the cross-linkable
moieties that are themselves coupled to adhering moieties bound to
lung tissue components found at various sites within the air space.
FIG. 1b illustrates how cross-linking can keep the walls of the air
space closer together even after re-inflation of the lung, thereby
reducing overall lung volume.
[0156] The methods of reducing lung volume described herein find
use in the treatment of a number of pulmonary conditions in animal
subjects. The term "animal subject" as used herein includes humans
as well as other mammals. The term "treating" as used herein
includes achieving a therapeutic benefit and/or a prophylactic
benefit. By therapeutic benefit is meant eradication or
amelioration of the underlying pulmonary condition being treated.
For example, in an emphysematous patient, therapeutic benefit
includes eradication or amelioration of the underlying emphysema,
including improved lung function, exercise capacity, quality of
life, and reduced hospitalization. Also, a therapeutic benefit is
achieved with the eradication or amelioration of one or more of the
physiological symptoms associated with the underlying pulmonary
condition such that an improvement is observed in the subject,
notwithstanding the fact that the subject may still be afflicted
with the pulmonary condition. For example, with respect to
emphysema, administration of compositions of the invention can
provide therapeutic benefit not only when areas lacking elasticity
are collapsed, but also when an improvement is observed in the
subject with respect to other disorders that accompany emphysema
like chronic pulmonary infection. For example, addition of adhering
moieties comprising protease inhibitors may ameliorate emphysema by
reducing protease activity, e.g., as described in the art. For
prophylactic benefit, a glue composition of the present invention
may be administered to a subject at risk of developing a pulmonary
condition, for example, emphysema, or to a subject reporting one or
more of the physiological symptoms of such a condition, even though
a diagnosis may not have been made.
[0157] Another aspect of the present invention provides a method of
reducing lung volume by providing a glue composition comprising a
first adhering moiety and a second adhering moiety wherein said
adhering moieties are coupled and wherein said adhering moieties
adhere lung tissue; administering said glue composition to a
localized region of damaged lung tissue of a subject; collapsing a
first portion or all of the lung of said subject wherein said first
portion comprises said localized region of damaged lung tissue;
allowing said adhering moieties to adhere different sites of lung
tissue, and re-inflating a second portion of the lung of said
subject wherein said second portion does not comprise said damaged
lung tissue, thereby reducing lung volume.
[0158] In preferred embodiments, the different sites comprise
different sites within an enlarged air space, e.g., within alveolar
walls of an over-inflated alveolus distal to a terminal bronchiole,
as characteristic of some pulmonary conditions, including
emphysema. For example, the first adhering moiety can adhere to a
first component of lung tissue and the second adhering moiety can
adhere to a second component of lung tissue, where the first and
second components occur at different sites. As the coupled adhering
moieties bind to different sites within an air space, following
deflation and/or collapse, the coupled adhering moieties can act to
keep different sites closer together, thereby keeping the air space
in a collapsed and/or sealed state. Also regions of damaged lung
tissue can be selectively collapsed and/or sealed by administering
a glue composition of the present invention to a selected localized
region of damaged lung tissue, preferably freeing up space for the
expansion of remaining non-damaged or healthier tissue.
[0159] In some preferred embodiments, the method is performed with
prior identification of the damaged lung tissue. For example, the
lungs of the subject may be imaged to identify regions or sites of
damaged tissue before administering a glue composition of the
invention to the subject. Such identification may involve any
techniques known in the art, to be developed, described herein,
and/or described in U.S. nonprovisional applications entitled
"Targeting Damaged Lung Tissue Using Compositions," filed Dec. 8,
2004; "Targeting Damaged Lung Tissue," filed Dec. 8, 2004;
"Targeting Sites of Damaged Lung Tissue Using Composition," filed
Dec. 8, 2004; "Targeting Sites of Damaged Lung Tissue," filed Dec.
8, 2004; "Imaging Damaged Lung Tissue Using Compositions," filed
Dec. 8, 2004; "Imaging Damaged Lung Tissue," filed Dec. 8, 2004;
"Glue Compositions for Lung Volume Reduction," filed Dec. 8, 2004;
"Lung Volume Reduction Using Glue Compositions," filed Dec. 8,
2004; and "Lung Volume Redaction Using Glue Composition," filed
Dec. 8, 2004, each of which is herein incorporated in its entirety
that facilitate identification of regions of damaged lung tissue.
Regions of damaged lung tissue include areas of the lung affected
by a pulmonary condition or that are affected to a greater extent
compared with other, healthier areas of the lung. In emphysema, for
example, such regions can include regions featuring "blebs," that
is, regions where progressive destruction of elastic tissue has
caused loss of lung recoil and consequent hyper-extension.
[0160] Current techniques that may be used to identify damaged lung
tissue in the present invention include radiology (e.g., chest
X-rays) and CT scans. For example, review of CT scans of the chest,
preferably high-resolution CT scans, can indicate localized regions
of damaged lung tissue that may be selected for volume
reduction.
[0161] Because the collapsed tissue occupies a smaller volume than
the enlarged alveoli at sites of damaged tissue, methods of this
invention can reduce lung volume overall. The present invention can
thus provide a non-surgical, less-invasive and/or safer approach
for achieving at least some of the benefits of lung volume
reduction surgery. Further, providing the glue composition to a
localized region of aged lung tissue allows localized volume
reduction, which in turn minimizes untoward side effects, such as
exacerbating V/Q imbalance, changing arterial oxygenation, or
triggering acute hypoxemia. Ingenito et al., "Bronchoiscopic Lung
Volume Reduction Using tissue engineering principles", American
Journal of Respiratory and Critical Care Medicine, Vol. 167 pgs.
771-778 (2002). It is to be understood also that the methods of the
present invention may be used in conjunction with a surgical
procedure, such as LVRS, as well as other approaches for treating
pulmonary conditions, including cross-linking and/or gluing methods
described herein, and/or other methods described in any of the
applications entitled "Targeting Damaged Lung Tissue Using
Compositions," filed Dec. 8, 2004; "Targeting Damaged Lung Tissue,"
filed Dec. 8, 2004; "Targeting Sites of Damaged Lung Tissue Using
Composition," filed Dec. 8, 2004; "Targeting Sites of Damaged Lung
Tissue," filed Dec. 8, 2004; "Imaging Damaged Lung Tissue Using
Compositions," filed Dec. 8, 2004; "Imaging Damaged Lung Tissue,"
filed Dec. 8, 2004; "Glue Compositions for Lung Volume Reduction,"
filed Dec. 8, 2004; "Lung Volume Reduction Using Glue
Compositions," filed Dec. 8, 2004; and "Lung Volume Reduction Using
Glue Composition," filed Dec. 8, 2004, each of which is herein
incorporated in its entirely.
[0162] In some preferred embodiments, the method for reducing lung
volume does not damage epithelial cells within lung tissues, e.g.,
it may not cause scar tissue formation, and/or may not cause
fibroblast proliferation, and/or may not cause collagen synthesis.
In some preferred embodiments, the methods cross-link and/or seal
sites of damaged lung tissue within an alveolus, more preferably
within an enlarged alveolus distal to a terminal bronchiole, in
some preferred embodiments, the methods of the present invention do
not cause occlusion of a lumen of a bronchial tube of a lung of the
subject. Without being limited to a particular mechanism, methods
of the present invention can reduce lung volume by sealing enlarged
air spaces, rather than by (mechanically) attempting to block
air-flow to damaged lung tissue. That is, in preferred embodiments,
administering a glue composition to a localized region of damaged
lung tissue serves to seal and/or keep collapsed blind ending sacs,
rather than there being any or any substantial amount of lung
tissue distal to the collapsed region. In yet still preferred
embodiments, the lung volume reducing methods of the present
invention can be carried out without the use of open surgery, e.g.,
thoracotomy.
[0163] In some preferred embodiments, the method for reducing lung
volume can involve damage to lung tissue. For example, in some
embodiments a sclerosing agent can be used as part of the
administered glue composition, for instance, a sclerosing agent may
be coupled to an adhering moiety of the present invention. In some
embodiments, the sclerosing agent may be administered alone; or it
may be administered separately at the same time as, before, or
after administration of adhering moieties of the present invention.
The sclerosing agent can serve to bring about scar tissue
formation, and/or fibroblast proliferation, and/or collagen
synthesis, facilitating sealing of regions of damaged lung tissue.
Sclerosing agents that may be used in the present invention include
Doxycycline, Bleomycin, Minocycline, Doxorubicin,
Cisplatin+Cytarabine, Mitoxantrone, Corynebacterium Parvum,
Streptokinase, Urokinase, and the like. Other agents and/or methods
for damaging lung tissue may also be used in the practice of the
present invention, optionally along with components of the
extracellular matrix, e.g., hyaluronic acid. See e.g., U.S.
Publication No. 2004/0047855.
[0164] Collapse of lung tissue, e.g., collapse of an enlarged air
spaces within which a glue composition of the present invention
adheres, may involve deflating and/or collapsing a first portion or
all of the lung of the subject, preferably where the first portion
comprises the selected localized region of damaged lung tissue.
Such collapsing can be achieved by any techniques known in the art
or herein disclosed. For example, the deflating and/or collapsing
may involve the use of negative pressure from within the lung
and/or positive pressure from without the lung. Also, in some
embodiments, a preparation to induce and/or facilitate deflation
and/or collapse may be used, e.g., a physiologically acceptable
solution containing an anti-surfactant, such as an agent that can
increase surface tension of fluids lining alveoli. For example, an
anti-surfactant may be administered prior to, during and/or after
administration of the composition comprising coupled adhering
moieties. For instance, fribrin and/or fibrinogen may be used. In
some embodiments, a lavage of saline may be used to reduce the
amount of surfactant naturally occurring in the lungs. Other
suitable surfactants that may be used to facilitate collapse and/or
deflation include Triton x-100, beractant, colfosceril, and/or
palmitate; anionic surfactants such as sodium tetradecyl sulfate;
cationic surfactants such as tetrabutylammonium bromide and/or
butyrylcholine chloride; nonionic surfactants such as polysorbate
20 (e.g., Tween 20), polysorbate 80 (e.g. Tween 80), and/or
poloxamers; amphoteric and/or zwitterionic surfactants such as
dodecyldimethyl(3-sulfopropyl)ammonium hydroxide, inner salt;
amines, imines and/or amides, such as arginine, imidazole,
povidine, tryptamine, and/or urea; alcohols such as ascorbic acid,
ethylene glycol, methyl gallate, tannins and/or tannic acid;
phosphines, phosphites and phosphonium salts, such as
triphenylphosphine and/or triethyl phosphite; inorganic bases
and/or salts, such as calcium sulfate, magnesium hydroxide, sodium
silicate, and/or sodium bisulfite; sulfur compounds such as
polysulfides and/or thiourea; polymeric cyclic ethers such as
calixarenes, crown ethers, monensin, nonactin, and/or polymeric
epoxides; cyclic and acyclic carbonates; organometallics (e.g.,
naphthenate and manganese acetylacetonate); phase transfer
catalysts (e.g., Aliquat 336); and radical initiators and radicals
(e.g., di-t-butyl peroxide and/or azobisisobutyronitrile).
[0165] Deflation and/or collapse may also be facilitated by use of
a lavage capable of removing any other moieties that may impede,
reduce and/or otherwise interfere with adhering. For example, in
some embodiments, cross-linking may be facilitated by use of an
anti-secretory agent that hinders and/or prevents mucous secretion
in the lung or a portion thereof. For example, the anti-secretory
agent may be administered prior to, during, and/or after
administration of the glue composition comprising coupled adhering
moieties. Examples of anti-secretory agents that may be used
include, for example, anticholinergic moieties, atronie, and/or
atropinic moieties. Removal of mucous or excessive mucous from the
lung, preferably from enlarged alveoli distal to terminal
bronchioles, e.g., by washing, can also facilitate binding of the
coupled adhering moieties to lung tissue. Adhesion of a composition
of the present invention to a mucous-coated wall within a bronchus,
bronchiole, or alveolus can be facilitated by virtue of adhering
moieties of the present invention adhering components of lung
tissue and, e.g., reducing and/or avoiding slippage.
[0166] In some embodiments, mechanical force may be used externally
to push one area of the lung closer to another, for example, to
help collapse an enlarged air space. A portion of a lobe of the
lung may be pressed, externally using, for example, a balloon, air
pressure, manual pressure, and/or an instrument such as a paddle, a
net, a strap that can be synched up, or magnets. In some
embodiments, such pressure is applied to two or more sides of a
lung lobe simultaneously. For example, endoscopes and/or magnetic
probes can be used to apply local pressure (applenate) to more than
one side.
[0167] In some embodiments, a first portion or all of the lung may
be drawn together from the inside using, for example, a cable and
hook to grab and pull tissue, for instance, towards the user. Other
devices that can be used include graspers, such as an expanding
grasper assembly that can be sheathed; and/or anchors that can be
left behind, for example, by being uncoupled from a cable or wire
after lung tissue has been drawn together. In some embodiments,
magnetic probes can be placed at different locations within the
lung where the probes attract one another, thereby attracting one
region of the lung to the other, e.g., one bronchi to another.
Additionally, mechanical force may be used to change the shape of
devices after insertion, such as by using a core wire or activating
a NiTi device after placement. In still other embodiments, the
lungs or a first portion thereof are deflated, trans-thoracically.
Other methods and/or devices known in the art to facilitate lung
collapse may also be employed, e.g. see U.S. Publication No.
2003/0070682.
[0168] Such deflation and/or collapsing is preferably carried out
after allowing sufficient time for distribution of the administered
glue composition to a selected localized region of damaged lung
tissue. In some embodiments, for example, deflation and/or collapse
is carried out approximately 2 to approximately 3 minutes after
administration of a glue composition of the present invention.
Also, the lung, or a first portion thereof is preferably allowed to
remain in a deflated and/or collapsed state for a time sufficient
to permit adhering of more than one of the coupled adhering
moieties to lung tissue components at different sites of lung
tissue in localized regions to which the glue composition has been
administered. Depending on the glue composition used, e.g., the
adhering moieties used, the lung or a first portion thereof can be
kept deflated and/or collapsed for at least approximately 3 days,
at least approximately 2 days (48 hours), at least approximately 24
hours, at least approximately 12 hours, at least approximately 5
hours, at least approximately 1 hour, at least approximately 45
minutes, at least approximately 20 minutes, at least approximately
10 minutes, at least approximately 3 minutes, at least
approximately 2 minutes, at least approximately 1 minute, at least
approximately 30 seconds, or at least approximately 15 seconds. In
some embodiments, the lung or a first portion thereof can be kept
deflated and/or collapsed for less than about 30 minutes, less than
about 20 minutes, less than about 10 minutes, or less than about 8
minutes.
[0169] A second portion of the lung can then be re-inflated, where
the second portion comprises part, but preferably not all, of the
first portion or all of the lung that was deflated and/or
collapsed. In preferred embodiments, this second portion does not
comprise at least some damaged lung tissue, which remains collapsed
and/or sealed by virtue of coupled adhering moieties bound to
different sites of damaged lung tissue. The adhering preferably
keeps the collapsed region from re-inflating. In more preferred
embodiments, the majority of damaged lung tissue remains collapsed
and/or sealed, while the majority of non-damaged lung tissue is
left in a functional condition. For example, at least about 60%, at
least about 80%, and most preferably at least about 90% of damaged
lung tissues is collapsed; while less than about 40%, less than
about 20%, and most preferably less than about 10% of non-damaged
lung tissue is not and/or re-inflates. Reduction in overall lung
volume improves mechanical function, e.g., mechanical functioning
of healthier and/or more elastic tissue.
[0170] In preferred embodiments, binding of coupled adhering
moieties results in at least about a 0.5% overall lung volume
reduction, at least about a 1% overall lung volume reduction, at
least about a 1.5% overall lung volume reduction, at least about a
2% overall lung volume reduction, at least about a 3% overall lung
volume reduction, at least about a 4% overall lung volume
reduction, at least about a 5% overall lung volume reduction, at
least about a 10% overall lung volume reduction. In preferred
embodiments binding of coupled adhering moieties results in less
than about a 40%, less than about a 35%, less than about a 30%,
less than about a 25% less than about a 20%, or less than about a
15% overall lung volume reduction. Such reduction may be achieved
upon a single or multiple administrations of glue compositions of
the present invention. A reduction of about 2% to about 3% overall
lung volume reduction can be expected to produce a beneficial
effect in a subject receiving such treatment, e.g., at least to a
similar extent as that produced in LVRS.
[0171] Also in preferred embodiments, the coupling between adhering
moieties is permanent or at least semi-permanent for a period of
time between successive treatments as described herein, e.g.,
resisting biodegradation (e.g., hydrolysis) for the period of time
between administrations of a glue composition of the present
invention. In certain embodiments, at least about 70%, at least
about 80%, at least about 90%, or at least about 98% of the
coupling between adhering moieties remains intact for a period of
time. In some preferred embodiments, the period is at least about
one month, at least about 2 months, at least about 3 months, at
least about 6 months, at least about a year, at least about 2
years, at least about 3 years, at least about 5 years, or at least
about 10 years. In some preferred embodiments, the period is less
than about 50 years, less than about 30 years, less than about 20
years, or less than about 15 years. In most preferred embodiments,
the coupled adhering moieties keep some damaged lung tissue
collapsed and/or sealed for the remainder of the life of the
subject, for example, resisting biodegradation indefinitely. One of
skill in the art will recognize that the permanence and/or
biodegradability of the coupling between adhering moieties can
depend on the coupling technique chosen and/or the coupling moiety
used.
[0172] In preferred embodiments, some or all of the coupling
moieties are strong enough to withstand mechanical pressures
experienced within the lung. For example, the strain range
corresponding to functional residual capacity during normal
breathing does not result in breakage of at least about 30%, at
least about 40%, at least about 50%, at least about 60%, at least
about 70%, at least about 80%, at least about 90%, or at least
about 95% of the coupling moieties in some preferred
embodiments.
[0173] In some preferred embodiments, the coupling moieties exhibit
a tear strength of at least about 50 g/sq. cm, at least about 100
g/sq. cm, at least about 200 g/sq. cm, or at least about 300 g/sq.
cm. In some preferred embodiments, the coupling moieties exhibit a
tear strength of less than about 5,000 g/sq. cm, less than about
3,000 g/sq. cm, less than about 1500 g/sq. cm, less than about 1300
g/sq/ cm, less than about 1200 g/sq. cm, less than about 1000 g/sq.
cm, less than about 800 g/sq. cm, less than about 600 g/sq. cm, or
less than about 400 g/sq. cm.
[0174] Similarly, in preferred embodiments, the binding between
adhering moieties and lung tissue is permanent or at least
semi-permanent for a period of time between successive treatments
as described herein, e.g., binding irreversibly, substantially
irreversibly, or at least with a high binding constant to resist
dissociation for the period of time between administrations of a
glue composition of the present invention. For example, an alpha-1.
antitrypsin moiety may form a pseudo-irreversible equimolar complex
with neutrophil elastase in some embodiments. See, e.g., Sifers et
al., "Genetic Control of Human Alpha-1 Antitrypsin", Mol. Biol.
Med., Vol. 6 pgs. 127-135 (1989). Without being limited to a
particular theory or mode of action, the alpha-1 antitrypsin moiety
may form an acyl-enzyme complex with an elastase component of lung
tissue. In some embodiments, binding can be further enhanced by
genetic modification or by shuffling of known binding domains. As
another example, a serpin moiety may react with its corresponding
protease to form a sodium dodecyl sulfate (SDS)-stable equimolar
complex. Without being limited to a particular theory or mode of
action, the complex between a serpin and its corresponding protease
may involve covalent ester bond linkage, where an active site
Serine residue of the protease binds a C-terminal residue of a
cleaved form of the serpin to form an acyl-enzyme complex. See,
e.g., U.S. Publication No. 2003/0216321. As yet another example, a
monocyte elastase inhibitor moiety can form a covalent complex
and/or an essentially irreversible complex with elastase. See,
e.g., International Publication WO 96/10418 and U.S. Pat. No.
5,827,672.
[0175] In certain embodiments, at least about 70%, at least about
80%, at least about 90%, or at least about 98% of the adhering
moieties remain bound to lung tissue for a period of time. In some
preferred embodiments, the period is at least about one month, at
least about 2 months, at least about 3 months, least about 6
months, at least about a year, at least about 2 years, at least
about 3 years, at least about 5 years, or at least about 10 years.
In some preferred embodiments, the period is less than about 50
years, less than about 30 years, less than about 20 years, or less
than about 15 years. In most preferred embodiments, the adhering
keeps some damaged lung tissue collapsed and/or sealed for the
remainder of the life of the subject, for example, resisting
dissociation indefinitely.
[0176] FIG. 2 illustrates one embodiment of a method to reduce lung
volume using a glue composition composing coupled adhering
moieties. This figure provides an overview only, and is in no way
intended to be limiting with respect to the present invention. For
example, those skilled in the art will readily appreciate
variations and modifications of the scheme illustrated. FIG. 2a
schematically illustrates a bronchoscope placed in a bronchus from
which a catheter extends to a segmental and subsegmental bronchus.
The catheter features a distended balloon-like structure near its
distal tip. The balloon-like structure anchors the catheter within
the subsegmental bronchus, positioning it for delivery of a glue
composition of the present invention in aerosol and/or non-aerosol
form to a selected localized region of damaged lung tissue.
[0177] FIG. 2b schematically illustrates a terminal bronchiole,
terminating in the airspace of an alveolus. The figure also
illustrates lung tissue components found within the walls of the
airspace and/or within the epithelial lining fluid. As mentioned
above, the air space may be over-inflated and/or enlarged in
certain pulmonary conditions, such as emphysema.
[0178] A glue composition of the invention is administered, where
the glue composition comprises adhering moieties that are coupled,
for example, via a coupling moiety. FIG. 2b illustrates how,
following administration, one of the adhering moieties can adhere
to a lung tissue component within the air space.
[0179] FIG. 2b also illustrates how the two adhering moieties can
adhere to lung tissue components at two different sites within the
air space. Following deflation, the walls of the alveolus are
brought into closer proximity, allowing the second adhering moiety
to adhere to a lung tissue component at a different site within the
air space. The binding of coupled adhering moieties to hitherto
further-apart sites of lung tissue serves to help keep the walls of
the air space closer together. A previously enlarged and/or
distended alveolus may thus be kept in a collapsed and/or sealed
state after re-inflation, thereby reducing overall lung volume.
[0180] Glue compositions of the present invention may also comprise
an imaging moiety, for example, an imaging moiety coupled to an
adhering moiety, a cross-linkable moiety, a cross-linking moiety
and/or a sclerosing agent used. An imaging moiety may assist in
non-intrusive visualization and/or monitoring of the collapsed
and/or sealed lung tissue. For example, imaging moieties can afford
detection of sealed damaged lung tissue and preferably facilitate
monitoring of the presence, position, extent, and/or degradation of
the cross-links, coupling moieties and/or glue, and/or dissociation
of the adhering moiety.
[0181] The imaging moiety may be imaged by any methods known in the
art and/or described herein. For example, imaging may be carried
out via traditional radiological techniques, including, for example
the use of an X-ray, computer tomography (CT), scan, nuclear scans,
and/or scintigraphy, as well as magnetic resonance imaging (MRI),
functional magnetic resonance imaging (FMRI),
magnetoencephalography (MEG), and single photon emission
computerized tomography (SPECT). Such imaging techniques can be
used to detect localized imaging moieties in vitro or in vivo,
preferably in vivo. High resolution scans, e.g., a high resolution
CT scan, are preferable. In more preferred embodiments, such as
imaging produces a detailed map of the lungs, showing sites of
glued and/or sealed tissue and/or the extent of collapse, e.g., by
the concentration of imaging moieties at localized sites within the
lungs to which the glue composition was administered.
[0182] The method of detection used may depend on the imaging
moiety administered. For example, ultrasound imaging can be used to
detect an echogenic imaging moiety and/or an imaging moiety capable
of generating an echogenic signal and/or other ultrasound imaging
moieties. X-ray can be used to detect a heavy atom imaging moiety
(e.g., having atomic weight of about 38 or above). Light imaging
can be used to detect an imaging moiety capable of scattering
and/or absorbing and/or emitting light. MR imaging can be used to
detect an imaging moiety comprising a non-zero nuclear spin isotope
(such as F-19) and/or an imaging moiety having unpaired electron
spins. PET, scintigraphy, and/or SPECT can be used to detect a
radionuclide imaging moiety.
[0183] For example, in some embodiments, an imaging moiety
composing a radioactive gamma emitter can be used, and can be
detected via a gamma camera, scintillation counter, and/or other
device capable of detecting gamma radiation. Radiation imaging
cameras can use a conversion medium to absorb high-energy gamma
rays and displace an electron, which emits a photon on its return a
lower orbital state. Some cameras also use photoelectric detectors,
e.g., arranged in a spatial detection chamber to determine the
position of an emitted photon, as well as circuitry to analyze the
photons detected in the chamber to help produce an image.
[0184] In embodiments using an imaging moiety comprising a magnetic
species, e.g., a paramagnetic atom, the imaging moiety can be
detected by MR imaging, e.g., a magnetic resonance imaging system
can be used. In such systems, a strong magnetic field can be used
to align nuclear spin vectors of atoms, such as paramagnetic atoms
at localized sites of lung tissue. The field can then be
distributed by the paramagnetic atoms at such sites. As the nuclei
return to equilibrium alignments, an image of lung tissue, e.g.,
localized sites of collapsed and/or sealed lung tissue, can be
obtained.
[0185] Some embodiments of the present invention employ both
imaging and volume-reducing aspects of the invention described
herein. In some embodiments, the imaging moiety may be coupled to
an adhering moiety that itself is coupled to a cross-linkable
moiety and/or one or more other adhering moieties. In some
embodiments, a second composition comprising an adhering moiety
coupled to an imaging moiety can be used. In some embodiments, lung
volume reduction, e.g., using glue compositions and/or methods
described herein, may be preceded and/or followed by imaging, e.g.,
and the images compared, e.g., to determine the extent of collapse
and/or sealing achieved in regions of selected damaged lung
tissue.
[0186] Administration of a glue composition comprising an adhering
moiety coupled to all and any of an imaging moiety, a
cross-linkable moiety, a cross-linking activating moiety, other
adhering moiety, and/or other moiety and/or agent, may be followed
by washing. The term "washing" as used herein refers to
administration of a washing moiety that can facilitate removal of
an adhering moiety from lung tissue. For instance, a washing step
may follow administration and imaging of a glue composition
comprising an adhering moiety coupled to an imaging moiety to free
up sites. Following washing, a glue composition comprising an
adhering moiety coupled to a cross-linkable moiety and/or coupled
to another adhering moiety may be administered to the subject, for
example to achieve lung volume reduction by methods described
herein. Washing moieties suitable for use in the present invention
include, for example, soluble components of lung tissue to which
adhering moieties can bind. The soluble components can compete with
lung tissue components for binding with the adhering moieties.
Preferably, the soluble components are modified so as to reduce
and/or eliminate undesirable properties before administration to a
subject. For example, a mutant elastase polypeptide may be used
that can still bind to alpha-1 antitrypsin but that cannot degrade
lung tissue or degrades lung tissue to a lesser extent than
non-mutant elastase.
[0187] While preferred embodiments of the present invention have
been shown and described herein, it will be obvious to those
skilled in the art that such embodiments are provided by way of
example only. Numerous variations, changes, and substitutions will
now occur to those skilled in the art without departing from the
invention, and it should be understood that various alternatives to
the embodiments of the invention described herein may be employed
in practicing the invention. It is intended that the following
claims define the scope of the invention and that methods and
compositions within the scope of these claims, along with their
equivalents, are covered thereby.
[0188] All publications, patents, and patent applications mentioned
in this specification are herein incorporated by reference to the
same extent as if each individual publication, patent or patent
application was specifically and individually indicated as being
incorporated by reference.
* * * * *