JP2008503465A - Targeting damaged lung tissue - Google Patents

Abstract

The present invention relates to methods and compositions for targeting damaged lung tissue. Provided compositions feature a targeting moiety coupled to one or more other moieties, including, for example, a crosslinkable moiety, an imaging moiety, and / or one or more other targeting moieties. The methods and compositions of the present invention find use in detecting and treating lung conditions such as emphysema.

Description

Related applications:
This application is incorporated by reference herein in its entirety, provisional application US60 / 580,444, entitled “Targeting Damaged Lung Tissue”, filed June 16, 2004; US60 / 586,932, entitled “Targeting Damaged Lung Tissue Using Various Formulations ", filed July 8, 2004; and US 60 / 586,950, entitled" Lung Volume Reduction Using Glue Composition ", filed July 8, 2004, claiming priority benefits. This application is a non-provisional application US11 / 008,577, entitled “Targeting Damaged Lung Tissue Using Compositions”, filed Dec. 8, 2004, each of which is hereby incorporated by reference in its entirety; US11 / 008,092, title “Targeting Damaged Lung Tissue ", filed December 8, 2004; US11 / 008,094, titled" Targeting Sites of Damaged Lung Tissue Using Composition ", filed December 8, 2004; US11 / 008,578, title" Targeting Sites of Damaged Lung Tissue ", 2004 Filed December 8, 2004; US11 / 008,649, titled “Imaging Damaged Lung Tissue Using Compositions”, filed December 8, 2004; US11 / 008,777, titled “Imaging Damaged Lung Tissue”, filed December 8, 2004; US11 / 008,087, title “Glue Compositions for Lung Volume Reduction”, filed December 8, 2004; US11 / 008,093, title “Lung Volume Reduction Using Glue Compositions”, filed December 8, 2004; US11 / 008,580, title “Glue “Composition for Lung Volume Reduction”, filed December 8, 2004; and US 11 / 008,782, title Claims priority benefit from “Lung Volume Reduction Using Glue Composition”, filed 8 December 2004.

Background of the invention:
Lung conditions affect millions of Americans and many additional individuals around the world. For example, chronic obstructive pulmonary disease (COPD), including emphysema, asthma, bronchiectais and chronic bronchitis, is one of the most common chronic conditions in the United States and is the leading cause of death 4th place. Various environmental and genetic factors can contribute to COPD, but smoking is the main cause. Tobacco smoke can induce an inflammatory response in the lung and activate elastase, cathepsin G, and matrix metalloproteinase (MMP). These enzymes are proteases that cause progressive destruction of lung elastic tissue and reduce lung recoil required for stretch and exhalation. The damaged alveolar wall eventually ruptures to form a “bleb” that is not stretchable. Emphysema is characterized, for example, by abnormal dilation of the alveolar airspace distal to the terminal bronchioles and destruction of the airspace parenchyma that produces these “small bubbles”.

  Current diagnosis involves estimation by a combination of factors, including history, lung function, and radiology images (eg, CT images), but the correlation between lung function data and the degree of emphysema is poor. For example, radiographs are less sensitive to mild emphysema, and only about 40% of moderately severe emphysema and about 66% of severe emphysema are affected by disease on chest x-ray. Show signs. Thus, there remains a need for improved methods for detecting and diagnosing lung conditions such as emphysema.

  Current treatments also have drawbacks. Treatment of pulmonary conditions often involves control and management rather than cure of the disease. In emphysema, for example, treatment may involve smoking cessation, exercise programs, medications that help open contracted airways, anti-inflammatory medications, oxygen therapy, placement of one-way valves, and lung volume reduction (LVRS). LVRS involves the surgical removal of damaged and over-inflated lung tissue to make room for the remaining undamaged tissue to expand. However, this technique requires invasive procedures and tends to diminish benefits over time. Furthermore, treatment with a one-way valve has not proved satisfactory. Thus, there remains a need for improved methods for treating lung conditions such as emphysema, as well as a need for better detection methods.

  The present invention provides methods and compositions directed thereto. Other methods and compositions directed thereto are each incorporated herein by reference in its entirety, non-provisional application US11 / 008,577, entitled “Targeting Damaged Lung Tissue Using Compositions”, filed December 8, 2004; US11 / 008,092, title “Targeting Damaged Lung Tissue”, filed December 8, 2004; US11 / 008,094, title “Targeting Sites of Damaged Lung Tissue Using Composition”, filed December 8, 2004; US11 / 008,578 , Title “Targeting Sites of Damaged Lung Tissue”, filed December 8, 2004; US 11 / 008,649, title “Imaging Damaged Lung Tissue Using Compositions”, filed December 8, 2004; title “Imaging” Damaged Lung Tissue ”, filed December 8, 2004; US11 / 008,087, title“ Glue Compositions for Lung Volume Reduction ”, filed December 8, 2004; US11 / 008,093, title“ Lung Volume Reduction Using Glue Compositions ” , Filed December 8, 2004; US11 / 008,580, title “Glue” "Composition for Lung Volume Reduction", filed December 8, 2004; and U.S.11 / 008,782, entitled "Lung Volume Reduction Using Glue Composition", filed December 8, 2004.

Brief summary of the invention:
One aspect of the present invention is a composition comprising a crosslinkable moiety and a targeting moiety, wherein the moiety is coupled and the targeting moiety targets damaged lung tissue About. In some embodiments, the pulmonary tissue comprises an epithelial lining fluid. In some embodiments, the composition does not include a polysaccharide or carbohydrate moiety. In some embodiments, the composition does not comprise a mutant type 1 plasminogen activator inhibitor.

  In some embodiments, the targeting moiety targets a damage correlation moiety. In some embodiments, the damage correlation moiety comprises a cell surface marker. In some embodiments, the damage correlation portion includes an ECM component. In some embodiments, the targeting moiety targets elastase. In some embodiments, the targeting moiety targets neutrophil elastase. In some embodiments, the targeting moiety comprises a protease inhibitor moiety. For example, in some embodiments, the targeting moiety comprises an alpha-1 antitrypsin moiety, such as a recombinant alpha-1 antitrypsin moiety. In some embodiments, the targeting moiety comprises an elafin moiety, such as a recombinant elafin moiety. In some embodiments, the targeting moiety comprises a serpin moiety, such as a recombinant serpin moiety, a secretory leucoprotease inhibitor (SLP1) moiety, and / or a recombinant secretory leucoprotease inhibitor (SLP1) moiety. In some embodiments, the targeting moiety is selected from MMP-1, MMP-2, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, and MMP-9. Targeting at least one matrix metalloproteinase. In some embodiments, the composition does not include hyaluronic acid or a salt thereof. In some embodiments, the targeting moiety targets desmosine and / or isodesmosine. In some embodiments, the targeting moiety targets CD8 and / or CD4. In some embodiments, the targeting moiety targets a tobacco-related moiety.

  In some embodiments, the crosslinkable moiety comprises a hydroxyl group. In some embodiments, the crosslinkable moiety comprises a carboxyl group. In some embodiments, the crosslinkable moiety comprises an ester group. In some embodiments, the crosslinkable moiety comprises a cyano group. In some embodiments, the crosslinkable moiety comprises a thiol group. In some embodiments, the crosslinkable moiety comprises a cysteine group. In some embodiments, the crosslinkable moiety comprises a carbonyl group. In some embodiments, the crosslinkable moiety comprises an aldehyde group. In some embodiments, the crosslinkable moiety comprises a ketone group. In some embodiments, the crosslinkable moiety comprises a primary amine group and / or a secondary amine group. In some embodiments, the crosslinkable moiety comprises a lysine group. In some embodiments, the crosslinkable moiety comprises fibrinogen and / or fibrin.

  In some embodiments, the composition is less than 10 microns. In some embodiments, the composition is less than 5 microns. In some embodiments, the composition is less than 1 micron. In another aspect of the invention, the composition further comprises an imaging moiety coupled to the targeting moiety and / or the crosslinkable moiety.

  Another aspect of the invention administers to a subject a composition comprising a crosslinkable moiety and a targeting moiety, wherein the moiety is coupled and the targeting moiety targets damaged lung tissue And relates to a method of reducing lung volume by bridging damaged lung tissue and thereby reducing lung volume. In some embodiments, the lung tissue comprises alveolar epithelial mucus. In some embodiments, the method is performed without previously identifying damaged lung tissue. In some embodiments, the method does not damage epithelial cells in lung tissue. In some embodiments, the method damages epithelial cells in lung tissue through the use of sclerosants. In some embodiments, the sclerosing agent is at least one compound selected from doxycycline, bleomycin, minocycline, doxorubicin, cisplatin + cytarabine, mitoxantrone, Corynebacterium Parvum, streptokinase, and urokinase. It is. In some embodiments, the composition does not include a polysaccharide or carbohydrate moiety. In some embodiments, the composition does not comprise a mutant type 1 plasminogen activator inhibitor.

In some embodiments, administration is via inhalation, for example, inhalation is via the mouth. In some embodiments, administration is via transthoracic administration.
In some embodiments, the method further comprises administering a second moiety that includes a cross-linking activating moiety. In some embodiments, the cross-linking activating moiety comprises at least one group selected from diols, polyols, dicarboxylic acids, polycarboxylic acids, diesters, polyesters, diamines, and polyamines. In some embodiments, the cross-linking activating moiety comprises at least one group selected from alkyl bis (2-cyanoacrylate), triallyl isocyanurate, alkylene diacrylate, alkylene dimethacrylate, and trimethylolpropane triacrylate. . In some embodiments, the cross-linking activating moiety comprises at least one group selected from disulfide, carbodiimide, and hydrazine. In some embodiments, the cross-linking activating moiety comprises a fibrin activator and / or a fibrinogen activator.

  In some embodiments, the method further comprises administering a growth factor. In some embodiments, the method further comprises administering an anti-surfactant. In some embodiments, the method further comprises administering an antibiotic.

  In some embodiments, the method further comprises the step of collapsing the first portion or all of the subject's lungs. In some embodiments, collapse includes the use of negative pressure from within the subject's lungs. In some embodiments, collapse includes the use of positive pressure from outside the subject's lungs. In some embodiments, the method further comprises reinflating a second portion of the subject's lung, wherein the second portion does not include the damaged lung tissue.

  In some embodiments, the composition further comprises an imaging moiety coupled to the targeting moiety and / or the crosslinkable moiety. In some embodiments, the method further comprises imaging damaged lung tissue. In some embodiments, the method further comprises administering a wash moiety.

  Another aspect of the invention administers to a subject a composition comprising a crosslinkable moiety and a targeting moiety, wherein the moiety is coupled and the targeting moiety targets damaged lung tissue And a method of treating a pulmonary condition by bridging damaged lung tissue and thereby treating the pulmonary condition. In some embodiments, the lung tissue comprises alveolar epithelial mucus. In some embodiments, the lung condition is emphysema. In some embodiments, the pulmonary condition is COPD.

  Another aspect of the present invention is a composition comprising a first targeting moiety and a second targeting moiety, wherein the targeting moiety is coupled, and the targeting moiety comprises damaged lung tissue The composition relates to targeting different sites. In some embodiments, the lung tissue comprises alveolar epithelial mucus. In some embodiments, the different sites include different sites within the expanded air space. In some embodiments, the first targeting moiety targets the first damage correlation moiety, and the second targeting moiety targets the second damage correlation moiety, and the first and second damage correlation moieties are different. Present in the site. In some embodiments, the first and second damage correlation portions are the same. In some embodiments, the first and second damage correlation portions are different.

  In some embodiments, the targeting moiety is 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 targeting moiety is coupled as a fusion polypeptide. In some embodiments, the targeting moiety is coupled via a protein. In some embodiments, the targeting moiety is coupled via an antibody. In some embodiments, the composition does not include a polysaccharide or carbohydrate moiety. In some embodiments, the composition does not comprise a mutant type 1 plasminogen activator inhibitor.

  In some embodiments, the first and / or second targeting moiety targets a damage correlation moiety. In some embodiments, the damage correlation moiety comprises a cell surface marker. In some embodiments, the damage correlation portion includes an ECM component. In some embodiments, the first and / or second targeting moiety targets elastase. In some embodiments, the first and / or second targeting moiety targets neutrophil elastase. In some embodiments, the first and / or second targeting moiety comprises a protease inhibitor moiety. For example, in some embodiments, the first and / or second targeting moiety comprises an alpha-1 antitrypsin moiety, such as a recombinant alpha-1 antitrypsin moiety. In some embodiments, the first and / or second targeting moiety comprises an elafin moiety, such as a recombinant elafin moiety. In some embodiments, the first and / or second targeting moiety is a serpin moiety, such as a recombinant serpin moiety, a secretory leucoprotease inhibitor (SLP1) moiety, and / or a recombinant secretory leucoprotease inhibitor (SLP1). ) Part. In some embodiments, the first and / or second targeting moiety is MMP-1, MMP-2, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, And at least one matrix metalloproteinase selected from MMP-9. In some embodiments, the composition does not include hyaluronic acid or a salt thereof. In some embodiments, the first and / or second targeting moiety targets desmosine and / or isodesmosine. In some embodiments, the first and / or second targeting moiety targets CD8 and / or CD4. In some embodiments, the first and / or second targeting moiety targets a tobacco-related moiety.

  In some embodiments, the composition is less than 10 microns. In some embodiments, the composition is less than 5 microns. In some embodiments, the composition is less than 1 micron.

  In another aspect of the invention, the composition further comprises a crosslinkable moiety coupled to the first and / or second targeting moiety. In yet another aspect of the invention, the composition further comprises an imaging moiety coupled to the first and / or second targeting moiety.

  Another aspect of the invention administers to a subject a composition comprising a first targeting moiety and a second targeting moiety, wherein the targeting moiety is coupled and the targeting moiety is damaged. A method for reducing lung volume by allowing a targeting moiety to target different sites of damaged lung tissue, thereby reducing lung volume. In some embodiments, the lung tissue comprises alveolar epithelial mucus. In some embodiments, the different sites include different sites within the expanded air space. In some embodiments, the first targeting moiety targets the first damage correlation moiety, and the second targeting moiety targets the second damage correlation moiety, and the first and second damage correlation moieties are different. Present in the site. In some embodiments, the first and second damage correlation portions are the same. In some embodiments, the first and second damage correlation portions are different.

  In some embodiments, the method is performed without previously identifying damaged lung tissue. In some embodiments, the method does not damage epithelial cells in lung tissue. In some embodiments, the method damages epithelial cells in lung tissue through the use of sclerosants. In some embodiments, the sclerosing agent is at least one compound selected from doxycycline, bleomycin, minocycline, doxorubicin, cisplatin + cytarabine, mitoxantrone, corynebacterium parvum, streptokinase, and urokinase. In some embodiments, the composition does not include a polysaccharide or carbohydrate moiety. In some embodiments, the composition does not comprise a mutant type 1 plasminogen activator inhibitor.

In some embodiments, administration is via inhalation, for example, inhalation is via the mouth. In some embodiments, administration is via transthoracic administration.
In some embodiments, the method further comprises administering a growth factor. In some embodiments, the method further comprises administering an anti-surfactant. In some embodiments, the method further comprises administering an antibiotic.

  In some embodiments, the method further comprises the step of collapsing the first portion or all of the subject's lungs. In some embodiments, collapse includes the use of negative pressure from within the subject's lungs. In some embodiments, collapse includes the use of positive pressure from outside the subject's lungs. In some embodiments, the method further comprises reinflating a second portion of the subject's lung, wherein the second portion does not include the damaged lung tissue.

  In some embodiments, the composition further comprises a crosslinkable moiety coupled to the first and / or second targeting moiety. In some embodiments, the method further comprises bridging the damaged lung tissue.

  In some embodiments, the composition further comprises an imaging moiety coupled to the first and / or second targeting moiety. In some embodiments, the method further comprises imaging damaged lung tissue. In some embodiments, the method further comprises administering a wash portion.

  Another aspect of the invention administers to a subject a composition comprising a first targeting moiety and a second targeting moiety, wherein the targeting moiety is coupled and the targeting moiety is damaged. A method for treating a lung condition by allowing a targeting moiety to target different sites of damaged lung tissue, thereby treating the lung condition. In some embodiments, the lung tissue comprises alveolar epithelial mucus. In some embodiments, the lung condition is emphysema. In some embodiments, the pulmonary condition is COPD.

  Another aspect of the invention is a composition comprising an imaging moiety and a targeting moiety, wherein the moiety is coupled and the targeting moiety targets damaged lung tissue About. In some embodiments, the lung tissue comprises alveolar epithelial mucus. In some embodiments, the composition does not include a polysaccharide or carbohydrate moiety. In some embodiments, the composition does not comprise an antibody. In some embodiments, the composition does not comprise a mutant type 1 plasminogen activator inhibitor. In some embodiments, the composition does not include a lung membrane dipeptidase binding molecule. In some embodiments, the targeting moiety does not target lung membrane dipeptidase.

  In some embodiments, the targeting moiety targets a damage correlation moiety. In some embodiments, the damage correlation moiety comprises a cell surface marker. In some embodiments, the damage correlation portion includes an ECM component. In some embodiments, the targeting moiety targets elastase. In some embodiments, the targeting moiety targets neutrophil elastase. In some embodiments, the targeting moiety comprises a protease inhibitor moiety. For example, in some embodiments, the targeting moiety comprises an alpha-1 antitrypsin moiety, such as a recombinant alpha-1 antitrypsin moiety. In some embodiments, the targeting moiety comprises an elafin moiety, such as a recombinant elafin moiety. In some embodiments, the targeting moiety comprises a serpin moiety, such as a recombinant serpin moiety, a secretory leucoprotease inhibitor (SLP1) moiety, and / or a recombinant secretory leucoprotease inhibitor (SLP1) moiety. In some embodiments, the targeting moiety is selected from MMP-1, MMP-2, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, and MMP-9. Targeting at least one matrix metalloproteinase. In some embodiments, the composition does not include hyaluronic acid or a salt thereof. In some embodiments, the targeting moiety targets desmosine and / or isodesmosine. In some embodiments, the targeting moiety targets CD8 and / or CD4. In some embodiments, the targeting moiety targets a tobacco-related moiety.

  In some embodiments, the imaging moiety includes a contrast agent. In some embodiments, the contrast agent is nonionic. In some embodiments, the contrast agent is ionic. In some embodiments, the imaging moiety comprises at least one metal compound selected from tantalum compounds and barium compounds. In some embodiments, the imaging moiety includes iodine. In some embodiments, the imaging moiety comprises at least one organic iodoacid selected from iodocarboxylic acid, triiodophenol, iodoform, and tetraiodoethylene. In some embodiments, the imaging portion includes a non-radioactive portion. In some embodiments, the imaging moiety includes a proton releasing moiety. In some embodiments, the imaging portion includes a radiopaque portion and / or a radioactive portion. In some embodiments, the imaging portion includes a magnetic portion. In some embodiments, the imaging moiety includes a radiopharmaceutical. In some embodiments, the imaging moiety includes an In-111 moiety. In some embodiments, the imaging moiety comprises a Tc-99m moiety. In some embodiments, the imaging moiety comprises a Xe-133 moiety.

  In some embodiments, the composition is less than 10 microns. In some embodiments, the composition is less than 5 microns. In some embodiments, the composition is less than 1 micron. In another aspect of the invention, the composition further comprises a coupled crosslinkable moiety and / or another coupled targeting moiety.

  Another aspect of the invention administers to a subject a composition comprising an imaging moiety and a targeting moiety, wherein the moiety is coupled and the targeting moiety targets damaged lung tissue And a method of imaging damaged lung tissue by imaging damaged lung tissue. In some embodiments, the lung tissue comprises alveolar epithelial mucus. In some embodiments, the composition does not include a polysaccharide or carbohydrate moiety. In some embodiments, the composition does not comprise an antibody. In some embodiments, the composition does not comprise a mutant type 1 plasminogen activator inhibitor. In some embodiments, the composition does not include a lung membrane dipeptidase binding molecule. In some embodiments, the targeting moiety does not target lung membrane dipeptidase.

  In some embodiments, administration is via inhalation, for example, inhalation is via the mouth. In some embodiments, administration is via transthoracic administration. In some embodiments, administration is via intravenous administration.

  In some embodiments, imaging of damaged lung tissue is performed via radiological techniques. In some embodiments, the radiological technique is at least one selected from x-ray, CT scan, PET scan, nuclear scan, SPECT, and scintigraphy.

  In some embodiments, the composition further comprises a coupled crosslinkable moiety and / or another coupled targeting moiety. In some embodiments, the method further comprises cross-linking and / or sealing damaged lung tissue. In some embodiments, the method further comprises administering a wash portion.

  Another aspect of the invention administers to a subject a composition comprising an imaging moiety and a targeting moiety, wherein the moiety is coupled and the targeting moiety targets damaged lung tissue And relates to a method of diagnosing lung conditions by imaging damaged lung tissue. In some embodiments, the lung tissue comprises alveolar epithelial mucus. In some embodiments, the lung condition is emphysema. In some embodiments, the pulmonary condition is COPD.

  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:

Detailed description of the invention:
One aspect of the invention provides a composition comprising a targeting moiety that targets damaged lung tissue, including lung fluid, eg, alveolar epithelial mucus. The targeting moiety can be affected, affected, or potentially affected by damaged lung tissue, eg, the condition of the lung, and / or Non-normal lung tissue sites are preferentially or selectively targeted. In a preferred embodiment, the targeting moiety is greater in the affected lung region compared to the lung region that is not affected or affected to a lesser extent by the lung condition. Recognize and / or bind to a damage-correlated moiety that may be present. Targeting damaged lung tissue, and its various grammatical applications, are any of these damage-correlated parts, such as those disclosed herein and / or incorporated herein. And targeting everything. The affected area of damaged lung tissue can also include lung fluid, such as alveolar epithelial mucus. Such damage-correlated moieties are present in the lungs of the subject, eg, due to disease progression, and need not be administered to the subject prior to administration of the composition comprising, eg, the targeting moiety.

Targeting, including preferential and / or selective targeting, does not mean that the targeting moiety does not bind to either normal and / or undamaged areas of the lung, or to any other non-pulmonary tissue. In some embodiments, targeting, for example, than other lung tissue components, in terms of relative K _i, to damage the correlation corresponding parts, at least about 20-fold, at least about 30 fold, at least about 50 It means to be selective at least about 75 times, at least about 100 times, at least about 150 times, or at least about 200 times. In some embodiments, the targeting moiety has at least about 50-fold selectivity, at least about 100-fold selectivity, at least about 200-fold selectivity, at least about 300-fold selectivity for the corresponding damage correlation portion. At least about 400 times selectivity, at least about 500 times selectivity, at least about 600 times selectivity, at least about 700 times selectivity, at least about 800 times selectivity, at least about 1000 times selectivity, or It has a selectivity of at least about 1500 times. For example, in some preferred embodiments, the targeting moiety has less than about 200 nM, less than about 150 nM, less than about 100 nM, or less than about 75 nM, K _i values for the damaged correlation portion. In some preferred embodiments, the targeting moiety is greater than about 50 nM, greater than about 25 nM, greater than about 20 nM, greater than about 15 nM, greater than about 10 nM, greater than about 5 nM, greater than about 3 nM, or greater than about 1 nM. K _i values for damage-correlated parts that exceed. In some preferred embodiments, the targeting moiety is less than about 10 ⁻⁸ M, less than about 10 ⁻⁹ M, less than about 10 ⁻¹⁰ M, less than about 10 ⁻¹¹ M, less than about 10 ⁻¹² M, about 10 ^−13. less than M, or about 10 ^-14 M of less than K _D, binding to damaged correlation portion is a target.

  Binding associated with a targeting moiety that recognizes and / or binds to a target damage-correlated moiety can also refer to both covalent and non-covalent bonds, eg, a targeting moiety can be covalently bonded and / or Alternatively, it can be bound to, attached to, or otherwise coupled to the target damaged correlation moiety by non-covalent bonding. Binding can be either high affinity or low affinity, preferably high affinity. 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. Power is included.

  “Injury-correlated parts” include, for example, higher concentrations in affected lung tissue than in areas of the lung that are not affected by a lung condition or affected to a lesser extent. Contains substances found in As used herein, the terms “region”, “section” and “site” are used interchangeably when referring to an area, site and / or area of damaged lung tissue. For example, the injury-correlated part is not affected by the lung condition or adheres to the affected lung tissue at a higher concentration than in areas of the lung that are affected to a lesser extent. , Bound, coupled, complexed, and / or otherwise associated. Bonding, attachment, coupling, complexation, and / or association may include, for example, dipolar interactions, electrostatic forces, hydrogen bonds, hydrophobic interactions, ionic bonds, and / or van der Waals forces, and Or it can involve non-covalent interactions.

  In some embodiments, the injury-correlated portion is not affected by the lung condition or is more affected on the cell surface of the affected lung tissue than in a region of the lung that is affected to a lesser extent. Bind, attach, couple, complex, and / or otherwise associate at higher concentrations. In some embodiments, the injury-correlated moiety can be attached to the cell wall. In some embodiments, the injury-correlated moiety can be complexed with a moiety that is itself bound to the cell wall. In some embodiments, the damage-correlated moiety can also include a cell surface marker, eg, in this case, the cell surface marker is associated with lung tissue affected by the lung condition, eg, in this case, Cell surface markers are not affected by lung conditions or are found at higher concentrations in affected areas of lung tissue than in affected areas of lung .

  Further, in some embodiments, the injury correlation portion is affected by an area of lung tissue that is affected by a condition of the lung that is not affected or affected to a lesser extent by the lung condition. At higher concentrations, can be seen associated with the extracellular matrix (ECM). For example, the injury-correlated part may have a higher concentration of affected lung tissue EMC components than in areas of the lung that are unaffected or affected to a lesser extent by the lung condition. Or can be associated with these EMC components.

  In some embodiments, the damage correlation moiety is at least 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. These include, for example, cell surface markers that include glycoprotein moieties and / or ECM components that include protein moieties.

  In some embodiments, the damage correlation portion is more affected in the affected lung region than in the lung region that is not affected or affected to a lesser extent by the lung condition. Contains proteases found in high concentrations. For example, in some preferred embodiments, the targeting moiety targets elastase. Elastase binds at higher concentrations to the cell walls of affected lung tissue than in areas of the lung that are unaffected or affected to a lesser extent by lung conditions, and And / or associated with its extracellular matrix. For example, elastase causes progressive destruction of stretchable fibers of lung tissue in some lung conditions, such as emphysema, resulting in dilatation and rupture of the expanded alveoli, characteristic “small bubbles” Form. Suki et al., “On the Progressive Nature of Emphysema, Pulmonary Perspective”, American Journal of Respiratory and Critical Care Medicine, Vol. 168, 516-520 (2003); Janoff et al., Am. Rev. Respir. Dis., Vol. 417-433 (1985); Senior and Kuhn, Fishman (supervised), Pulmonary Diseases and Disorders, 2nd edition, New York, McGraw-Hill, p. 1209-1218 (1988). In some preferred embodiments, the targeting moiety targets neutrophil elastase and / or neutrophils. In some preferred embodiments, the targeting moiety targets pancreatic elastase and / or macrophage elastase. In some preferred embodiments, the targeting moiety targets neutrophil proteinase 3 (Pr3). Pr3 is described in, for example, 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 pages 57-61 (2003). be written.

  For example, the targeting moiety may be alpha-1 antitrypsin, elafin, thypin (see eg WO 02/072769), and / or other serpins such as PAI-1, PAI-2, SCCA-1, SCCA-2, secretory leucoprotease inhibitor SLP-1, HMCIS41 (see, eg, US Pat. No. 6,753,164), and / or other serpin-related proteins (see, eg, US Publication No. 2004/0126777) As disclosed); may include (or exclude) any of these recombinant forms and / or any portion thereof that retains the ability to recognize and / or bind to the target May be) In some embodiments, the targeting moiety may (or may not include) a mucus proteinase inhibitor (MPI) that exhibits high affinity for binding to elastase. Belorgey et al., “Effect of polynuclotides on the inhibition of neutrophil elastase by mucus proteinase inhibitor and alpha-1 proteinase inhibitor”, Biochemistry, Vol. 37, pages 16416-22 (1998). Other targeting moieties capable of targeting elastase can also be used, such as inhibitors of elastase known in the art. For example, Janoff et al., Am. Rev. Respir. Dis. Vol. 132, pages 417-433 (1985); Zimmerman and Powers (1989), Hornebeck (supervised), Elastin and Elastases, Vol II, Boca Raton, CRC Press, 109-123; and Laurell and Eriksson Scand. J. Clin. Lab. Invest., Vol. 15 pages 132-140 (1963). Other targeting moieties may or may not include an inter-alpha trypsin inhibitor (ITI) family of protease inhibitors. The ITI protein family is described 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, pages 437-46 (2000 ) Can be constructed from different combinations of the polypeptides HC1, HC2, HC3 and bikunin.

  Alpha-1 antitrypsin useful for preparing the targeting moieties of the invention can be obtained by any technique known in the art and / or disclosed herein. For example, alpha-1 antitrypsin can be obtained by recombinant methods as known in the art (eg, Novartis recombinant alpha-1 antitrypsin). Techniques for purifying alpha-1 antitrypsin from, for example, biologically natural sources and / or recombinant sources are also known in the art. See, eg, International Publication No. WO 00/17227 and US Pat. No. 4,656,254, which describe the separation of alpha-1 antitrypsin from plasma.

  In some preferred embodiments, the targeting moiety targets desmosine and / or isodesmosine. Desmosine and / or isodesmosine are amino acids produced as a result of damage to lung tissue, particularly damage that involves destruction of elastin. For example, fragmented elastin is metabolized to free desmosine or a small peptide, which can be recovered in the urine of the subject. See, for example, Starcher B. C., “Lung Elastin and Matrix”, Chest, Vol. 117 pages 229S-234S (2000). In animal models of emphysema, for example, desmosine urine recovery can serve as a measure of lung injury. There are several micromethods for measuring desmosine, such as enzyme-linked immunosorbent assays (eg 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 pp. 293-296 (1995)); isotope dilution (eg Stone PJ et al. “Measurement of urinary desmosine by isotope dilution and high performance liquid chromatography”, Am Rev Respir Dis Vol. 144 pages 284-290) (See 1991)); high performance liquid chromatography (see eg Covault HP et al. “Liquid-chromatographic measurement of elastin”, Clin Chem Vol. 28 pages 1465-1468 (1982)); and / or radio Immunoassays (eg Starcher B. “A role for neutrophil elastase in the progression of solar elastosis”, Connect Tissue Res Vol.31 133-14 0 (see 1995)). For example, desmosine and / or isodesmosine are more abundant in affected lung regions compared to lung regions that are not affected or affected to a lesser extent by lung conditions. As can be seen, targeting desmosine and / or isodesmosine in the lung can also direct the targeting moiety to the site of lung injury.

  In some preferred embodiments, the targeting moiety targets a cathepsin, such as cathepsin G, that can be produced by inflammatory cells in the pathogenesis of COPD. In some embodiments, the targeting moiety targets other cysteine proteinases. In some embodiments, the targeting moiety targets cathepsins L, S, and K. In some embodiments, the targeting moiety targets RGS2, which accumulates at the site of macrophage activation, for example in activated macrophage related disorders including emphysema. See for example EP 1378518. In some embodiments, the targeting moiety targets alveolar macrophages. In some embodiments, the targeting moiety targets eosinophils. In some embodiments, the targeting moiety targets tumor necrosis factor-α. In some embodiments, the targeting moiety targets kallikrein.

  In some preferred embodiments, the targeting moiety targets collagenase. The presence of collagenase activity can be detected, for example, by released components such as amino acids known to be present in collagen, such as hydroxyproline and / or hydroxylysine. These components may be present in higher amounts in affected lung areas compared to lung areas that are not affected or affected to a lesser extent by lung condition And can serve as a damage-correlated part of the composition of the present invention.

  Examples of collagenase include, for example, one or more metalloproteinases. Metalloproteinases include, for example, MMP-1 (stromal collagenase or collagenase-1), MMP-2 (gelatinase-A or 72 kD gelatinase), MMP-3 (transine, human fibroblast stromelysin, or stromelysin -1), 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 also metalloproteinase ADAM22 (e.g. U.S. Publication No. 2003/0194797). Metalloproteinases (also referred to in the art as metalloproteases) are, for example, US Publication No. 2003/0199440; US Publication No. 2004/0048302; US Publication No. 2004/0043407; US Publication No. 2004/019479. And International Publication No. WO 02/072751. For example, a targeting moiety that includes an ilomastat moiety can be used. For example, see International Publication No. WO 2004/052236.

  In some embodiments, the composition does not include a polysaccharide or carbohydrate moiety, eg, in some embodiments, the composition does not include hyaluronic acid or a salt thereof; and in some embodiments, the composition includes dextran or glycosami. Contains noglycans. In some embodiments, the composition does not include a polysaccharide or carbohydrate moiety that binds to stretchable fibers. In some embodiments, the composition does not comprise an antibody. In some embodiments, the composition does not include a lung membrane dipeptidase binding molecule, for example, in some embodiments, the composition may not target lung membrane dipeptidase, and in some embodiments, The composition may be free of GFE-1 peptide. See, eg, Ruoslahti 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 pages 11593-8 (1999) and US Pat. No. 6,784,153. I want.

  Also, in some preferred embodiments, the targeting moiety targets CD8 and / or CD4, CD8 lymphocytes and / or CD4 lymphocytes, and / or interleukin 8 (see, eg, US Publication No. 2003/0232048). Wanna) In some embodiments, the targeting moiety targets a mitogen activated protein kinase (see, eg, International Publication No. WO 03/064639). In some embodiments, the targeting moiety may (or may not) target CIRL-2 homologues (see, eg, International Publication No. WO 2004/031235). Further, in some embodiments, the targeting moiety may (or may not include) an antibody and / or binding fragment thereof that targets the damage-correlated moiety. For example, the targeting moiety is unaffected or affected to a lesser extent by pulmonary conditions, as discussed, for example, in International Publication No. WO 02/072788 and / or US Publication No. 2003/0017150 Contains a COPD-related human Ig-derived protein that recognizes and / or can bind to a COPD-related protein that is found in greater amounts in the affected lung region compared to the lung region It is also possible. In yet another example, the targeting moiety can include an antibody against the secreted protein HCEJQ69 (see, eg, US Pat. No. 6,774,216).

  Preferred targeting moieties of the invention include a biological moiety, such as a protein or polypeptide, that recognizes and / or binds to a damage-related moiety in the lung, and a naturally occurring inhibitor of the damage-related moiety, such as alpha −1 antitrypsin and / or mutants and / or fragments thereof, and other protease inhibitor moieties may also be included. As with alpha-1 antitrypsin, other naturally occurring inhibitors of elastase can also be used as preferred targeting moieties of the present invention, such as monocyte elastase inhibitors and variants thereof (eg, International Publication No. WO 96/10418). US Pat. No. 5,827,672; see US Pat. No. 5,663,299); and tissue inhibitors of metalloproteinases (TIMP), such as TIMP-1, TIMP-2, TIMP-3, and TIMP-4. In a more preferred embodiment, the targeting moiety binds to its target damage-correlated moiety irreversibly, substantially irreversibly, or at least with a high binding constant, such as to resist dissociation for a desired period of time. Qualified. The targeting moiety may be selected and / or developed such that the binding affinity for the targeted damage-correlated moiety is increased. For example, alpha-1 antitrypsin can be mutated by random and / or designated synthesis to design mutants with higher binding constants for their target elastase.

  Other non-naturally occurring inhibitors of damage-related moieties that may (or may not) be used as targeting moieties of the invention include inhibitors of neutrophil elastase (eg, methyl ketone derivatives); macrophage metallo Inhibitors of proteinases (eg, inhibitors discussed in RSl13456 and US Publication No. 2003/0199440); cathepsin G inhibitors (eg, LEX-032 (Sparta)); various elastase inhibitors (eg, ABT-491 (Abbot)) An inhibitory composition (eg, as disclosed in US Publication No. 2003/0199440 and International Publication No. WO 03/090682, including lipase inhibitors and phospholipase inhibitors); a protease inhibitor composition (eg, International Publications WO 2004/045634); Erdosteine (Edmond Pharma); FK-706 (Fujisawa Pharmaceutical), GW-311616 (Glaxo-Wellcome) , Midsteine (Medea); a mutant type 1 plasminogen activator inhibitor capable of inhibiting neutrophil elastase (eg US Publication No. 2003/0216321); N-substituted azetidinones (eg EP 0529719) Peptidyl carbamate (eg, US Pat. No. 5,008,245 and / or EP 0367415), SR-268794 (Sanoti), and / or SYN-1134 (Syn. Pharm.); Other proteinase inhibitors (eg, CMP-777 (Dupont )); And benzamide and sulfonamide substituted aminoguanidines and alkoxyguanidines (see for example US 2004/0106633 and EP 1070049); and ON-elastase inhibitors (for example NX-21909 (Gilead)); and several HNE Inhibitors (eg CE-1037 (Cortech / United Ther), CE-2000 series (Cortech / Ono), EPI-HNE-4 (Dyax), EPI-HNE-1 (Protein Engineer), MD L-101146 (HMR), Ono-5046 (Ono Pharmaceutical), SPAAT (UAB Res. Found.), WIN-63759 (Sterling Winthrop), ZD-8321 (AstraZeneca), and / or ZD-0892 (AstraZeneca)) included. The targeting moiety is also an inhibitor and / or antibody of any of the damage-correlated moieties described herein, and a protein inhibitor and / or antibody described in International Publication No. WO 03/010327; and US Publication 2003/0224430. And / or other serine protease inhibitors and / or antibodies described in, for example, International Publication No. WO 2004/053117; and transmembrane as discussed, for example, in US Pat. No. 6,734,006 Serine protease inhibitors and / or antibodies; and inhibitors and / or antibodies of esterases described in International Publication No. WO 04/020620 may (or may not be included). In the present specification, the “antibody” includes binding fragments thereof.

  In some preferred embodiments, the targeting moiety comprises a compound that targets the damage-correlated moiety, eg, a small molecule compound. Such compounds can be obtained, for example, via ligand screening methods as known in the art, using the damage-correlated moiety as a target. For example, a biological sample or a defined candidate moiety may be isolated from and / or purified damage-correlated moieties such as purified and / or recombinant elastase, or fragments thereof, and alveolar epithelial mucus. May be contacted. Candidate moieties may be labeled with a detectable label, such as a fluorescent, radioactive, and / or enzymatic tag, and immobilized, eg, under conditions that allow binding, such as selective binding and / or preferential binding. It is also possible to allow contact with a good damage correlation part. After removing the unbound portion, the bound portion may be detected using any suitable method known in the art.

  For use in the present invention, candidate moieties that can be assayed to target a damage-correlated moiety are not limited. For example, such candidate moieties can be obtained from a wide variety of sources, including libraries of synthetic, semi-synthetic and / or natural materials. Random and / or specified synthesis can be used to generate a wide variety of organic compounds and biomolecules including, for example, randomized oligonucleotides and oligopeptides. For natural compounds, libraries from bacterial, fungal, plant and animal extracts are available and / or can be readily produced. In addition, natural, semi-synthetic, and / or synthetically produced libraries can be modified through conventional chemical, physical, recombinant, and / or biochemical techniques to produce combinatorial libraries. May be. Alternatively, a known or pharmacological agent may be modified by a specified or random chemical modification, including, for example, acylation, amidification, alkylation, and / or esterification to produce a structural analog ( analog) may be produced.

  Candidate moieties 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 may be included, eg, molecules generated through combinatorial chemistry approaches. Furthermore, if the candidate portion comprises a peptide or polypeptide, the candidate portion may be expressed by a phage clone belonging to a random peptide library based on phage (see, eg, Parmley and Smith, Gene Vol. 73 305-318). Pages (1988); Oldenburg et al., Proc. Natl. Acad. Sci. USA Vol. 89 5393-5397 (1992); Valadon et al., J. Mol. Biol., Vol. 261 pages 11-22 (1996); , Proc. Natl. Acad. Sci USA., Vol. 92, 4021-4025 (1995); and Felici et al., J. Mol. Biol., Vol. 222, pages 301-310 (1991)); The candidate portion may be expressed from cDNA cloned into a vector for performing a two-hybrid screening assay (US Pat. Nos. 5,667,973 and 5,283,173; Harper et al., Cell, Vol. 75 pages 805-816). (1993); Cho et al., Proc. Natl. Acad. Sci. USA, Vol. 95 (7) 3752. 3757 pages (1998); and Fromont-Racine et al., Nature Genetics, Vol.16 (3) 277-282 pages (1997)).

  Further, the targeting moiety includes one or more types of damage correlations, including any combination of the damage correlation moieties disclosed herein, eg, one or more proteases and / or one or more tobacco-related moieties as described below. It will be understood that it is also possible to target a portion.

  A “damage-correlated portion” can also include a tobacco-related portion. For example, targeting moieties are found in greater amounts in affected lung regions compared to lung regions that are not affected by a lung condition or affected to a lesser extent. It is also possible to recognize and / or bind to tobacco smoke particles, tar, tobacco, and / or other tobacco-related residues such as cadmium.

  Still other damage-correlated parts are also more affected in affected lung regions compared to lung regions that are not affected or affected to a lesser extent by lung condition. It is also possible to include modified polypeptides in which there are modifications. For example, a G protein-coupled receptor (GPCR) family member, eg, RAI-3, is modified, eg, phosphorylated and / or tyrosine phosphorylated after exposure to tobacco smoke. Meet with. See, for example, International Publication No. WO 04/001060 and / or US Publication No. 2004/0121362. In some embodiments of the invention, targeting moieties that target such modified proteins and / or protein complexes may be used. Such targeting moieties may (or may not include) modulators of RAI-3, as described in US Publication No. 2004/0121362. Further, in some embodiments, targeting moieties may be used (or not used) that target polypeptides related to the NFκB pathway found in lung tissue, eg, as described in US Publication No. 2004/0086896. May be).

  Other damage-correlated moieties may include moieties that inhibit the production of stretchable tissue and / or connective tissue proteins. Such moieties include, for example, moieties that inhibit fibroblast proliferation and / or moieties that inhibit procollagen production and / or moieties that inhibit proteoglycan synthesis, preferably major matrix-associated proteoglycans such as versican, decorin, and / or It may contain a moiety that inhibits the synthesis of giant heparan sulfate proteoglycans. “Inhibit” and its various grammatical applications reduce biological processes by an amount compared to the occurrence of the process in the absence (or in the presence of lower levels) of damage-correlated moieties, eg It can also mean reducing the synthesis of connective tissue components. In some embodiments, the amount can 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 can be reduced by less than about 60%, less than about 70%, less than about 80%, less than about 90%, or less than about 99%. “Inhibit” and its various grammatical applications need not mean to completely inhibit biological processes, eg, synthesis of connective tissue components to negligible and / or undetectable levels. There is no need to mean to inhibit. Damage-correlated moieties that can inhibit proteoglycan synthesis include, for example, cadmium. See, for example, Chambers et al., Cadmium inhibits proteoglycan and procollagen production by cultures human lung fibroblasts, ”Am. J. Respir. Cell Mol. Biol., Vol. 19 No. 3 pages 498-506 (1998). Damage correlates 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. 3 197 -Page 204 (2004). Still other damage-correlated parts may include parts that impair the repair of lung stretch and / or connective tissue.

  In some aspects of the invention, a composition comprising a targeting moiety also includes a crosslinkable moiety coupled to the moiety. A crosslinkable moiety is any moiety that facilitates linking between crosslinkable moieties coupled to a targeting moiety bound to a damage-correlated moiety between more than one crosslinkable moiety, preferably at different sites of damaged lung tissue. It may be. Crosslinkable moieties include, for example, hydroxyl groups, carboxyl groups, ester groups, cyano groups, thiol groups (eg, including cysteine groups), carbonyl groups, aldehyde groups, ketone groups, primary amine groups, and / or secondary amine groups, As well as a lysine group.

  In some embodiments, the crosslinkable moiety is any other amine group, sulfide group, carbonyl group (eg, α-halocarbonyl group and / or α, β-unsaturated carbonyl group), cyanate group (eg, isothiocyanate). Group), a carboxylate group (for example, an acetate group such as an α-haloacetate group), a hydrazine group, and / or a biotin group. See for example US Publication No. 2002/0071843.

  In some embodiments, the crosslinkable moiety can include fibrinogen and / or fibrin. Fibrinogen can be converted to fibrin, which is polymerized in a crosslinking reaction. In some embodiments, the crosslinkable moiety is a proteinaceous material comprising other proteins and / or proteinaceous materials such as albumin (bovine or human), collagen, PEI, oleic acid, chitin and / or chitosan, and US patents. US Pat. No. 5,385,606, US Pat. No. 5,583,114, US Pat. No. 6,310,036, US Pat. No. 6,329,337 and / or US Pat. No. 6,372,229. In some embodiments, more than one type of crosslinkable moiety may be coupled to a given targeting moiety, or used in combination, for example, in a single dose or in several consecutive doses May be coupled to the targeting moiety. Those skilled in the art will recognize other suitable crosslinkable moieties that can be used in the practice of the present invention, including any biocompatible crosslinkable moiety capable of forming, for example, a biocompatible crosslinkable product. It is.

  The targeting moiety may be coupled to the crosslinkable moiety by any technique and / or approach known in the art and described herein and / or developed by one of ordinary skill in the art. For example, coupling methods include, but are not limited to, use of bifunctional linkers, amide formation, imine formation, carbodiimide condensation, disulfide bond formation, and / or specific using eg biotin-avidin interaction Includes the use of bond pairs. These methods and other methods known in the art are described in, for example, Hermanson, “Bioconjugate Techniques,” Academic Press New York, 1996, and SS Wong, “Chemistry of Protein Conjugation and Cross-linking,” CRC Press, 1993. It is also possible to find it.

  In preferred embodiments, the crosslinkable moiety is coupled to the targeting moiety such that the targeting moiety does not interfere with the ability to target damaged lung tissue. For example, the region of the alpha-1 antitrypsin that does not modify the conformation or folding of alpha-1 antitrypsin or is necessary for and / or involved in recognition and / or binding to damage-related moieties such as elastase A crosslinkable moiety may be attached to the alpha-1 antitrypsin moiety at one or more sites that do not modify conformation or folding. For example, without being limited to a given hypothesis or mode of action, an alpha-1 antitrypsin activity inhibitory site is found around Ser358 of the polypeptide, e.g., a pseudo-irreversible equimolar complex with neutrophil elastase. Form the body. See, for example, Sifers et al., “Genetic Control of Human Alpha-1 Antitrypsin”, Mol. Biol. Med., Vol. 6 pages 127-135 (1989). In some preferred embodiments, the crosslinkable moiety may be attached to the alpha-1 antitrypsin moiety at a site other than around the Ser358 inhibitory site. Similarly, in some embodiments, without being limited to a given hypothesis or mode of action, the crosslinkable moiety is selected to be a specific region known to be involved in attachment to the target protease, such as the serpin hinge, You may make it adhere to a serpin part in parts other than the area | region containing a tear (breach), a shutter, and a gate area | region. Irving et al., Genome Res Vol.10 1845-64 (2000). Some serpins contain, for example, a reactive central loop (RCL) involved in inhibition, where a stable complex can form between the protease and the truncated form of serpin. Attachment to a site other than the RCL region of the serpin moiety is preferred in some embodiments. Similarly, in some embodiments, cysteine, a monocyte elastase inhibitor involved in interaction with target elastase and / or proteinase 3 and / or cathepsin G, without being limited to a given hypothesis or mode of action. A crosslinkable moiety may be attached to the inhibitor moiety at a site other than the residue. See, for example, International Publication No. WO96 / 10418; and US Pat. No. 5,827,672.

  In some embodiments, the crosslinkable moiety may be chemically conjugated to the targeting moiety, eg, a carboxyl group may be covalently attached to one or more sites of alpha-1 antitrypsin. In some embodiments, the crosslinkable moiety and the targeting moiety may be indirectly coupled by chemically coupling the crosslinkable moiety to a moiety that is itself chemically bonded to the targeting moiety.

  In a preferred embodiment, the size of the composition comprising a targeting moiety coupled to a crosslinkable moiety allows the composition to access an injury correlation moiety, e.g., an injury correlation moiety within an expanded alveoli distal to the terminal bronchiole. Not big enough to prevent. For example, the size of the composition comprising a targeting moiety coupled to a crosslinkable 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 about 1 Less than a micron. “Dilated alveoli” as used herein refers to alveoli that are larger than the average alveoli that are unaffected or affected to a lesser extent by the condition of the lungs. For example, dilated alveoli 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% of the average alveolar size. Good.

  Further, a composition that includes a targeting moiety coupled to a crosslinkable moiety may further include an imaging moiety that is coupled or not coupled, eg, depending on the intended use of the composition.

  Another aspect of the present invention is a composition comprising a first targeting moiety and a second targeting moiety, wherein the targeting moiety is coupled, and the targeting moiety is of damaged lung tissue. It relates to said composition capable of targeting different sites. In preferred embodiments, the different sites represent different sites within the alveolar wall of the hyperinflated alveoli distal to the distal bronchiole, characteristic of some pulmonary conditions including dilatation, eg, emphysema. Including. For example, a first targeting moiety can target a first damage correlation moiety, while a second targeting moiety can target a second damage correlation moiety, where The first and second damage correlation portions are present at different sites. The first and second targeting moieties can be the same or different, and the first and second damage correlation moieties can be the same or different.

  Furthermore, it is understood that any plurality of targeting moieties may be used, i.e., the invention may also be the same or different, respectively, or some may be the same, Also contemplated are compositions comprising any of a plurality of coupled targeting moieties, which may differ from each other. For example, in a composition comprising three coupled targeting moieties, the first targeting moiety is coupled to the second targeting moiety, which may be coupled to the third targeting moiety. The first and third portions may or may not be directly coupled to each other. In some embodiments, the three targeting moieties may be coupled to one moiety without being directly coupled to each other. All three parts may be the same or different, or the two may be the same and the third part may be different. Each targeting moiety may target the same type of damage correlation part, each may target a different type of damage correlation part, or two may target the same type of damage correlation part, while a third You may target the kind of damage correlation part from which a targeting part differs. The injury-correlated part targeted by the targeting part may be two or more different sites of damaged lung tissue, preferably in the expanded airspace, for example in the alveolar wall of the hyperinflated alveoli distal to the terminal bronchiole It is also possible to exist at different sites.

  The targeting moiety may be coupled by any technique and / or approach known in the art and described herein and / or can be developed by one skilled in the art. In some embodiments, the coupling is a covalent bond, dipole interaction, electrostatic force, hydrogen bond, hydrophobic interaction, ionic bond, van der Waals force, and / or other bond capable of coupling the targeting moiety. May be accompanied. For example, in some embodiments, the targeting moiety is coupled via a coupling moiety, such as a chemical linker. For example, any chemical linker containing an aliphatic group that covalently links the targeting moieties may be used. For example, a chemical linker useful in the present invention may include two (or more) functional groups, wherein each of the functional groups is chemically coupled to the targeting moiety to couple the targeting moiety. It is possible to work on. Examples of functional groups include, for example, hydroxyl groups, carboxyl groups, ester groups, cyano groups, thiol groups, cysteine groups, carbonyl groups, aldehyde groups, ketone groups, and / or amine groups, and lysine groups. Other functional groups include cyanate groups (eg, isothiocyanate) and / or carboxylate groups (eg, acetate groups such as α-haloacetate groups).

  Other coupling techniques can also be used. For example, the targeting moiety can be pre-cross-linked, using, for example, dimers of the targeting moiety and / or cross-linking techniques such that one or more cross-links are formed between cysteine residues of the peptide and / or polypeptide targeting moiety. Alternatively, multimers may be prepared. Linker length optimization techniques may also be used for use in the present invention (see, eg, US Pat. No. 5,478,925).

  In some embodiments, the targeting moiety is coupled as a fusion polypeptide. For example, when the targeting moiety is a peptide and / or polypeptide, two or more targeting moieties may be linked by a polypeptide linker as a coupling moiety to form a fusion polypeptide or fusion protein. Fusion proteins may be generated by a variety of methods including, for example, chemical coupling and cotranslation. In some preferred embodiments, a targeting moiety is recombinantly expressed as a fusion product from a recombinant nucleic acid molecule, wherein the targeting moiety is, for example, one or more intervening amino acids according to techniques known in the art. It is connected by. See, for example, Francis, “Focus on Growth Factors”, Vol. 3 pages 4-10 (Mediscript, London) (1992). Other techniques known in the art, such as those used to generate adzymes containing an address binding site conjugated to a catalytic domain (eg, US Publication No. 2004/0081648 and US And / or techniques by covalent linkage (eg, via a disulfide bond) between at least one amino acid of each coupled targeting moiety (eg, as described in Publication No. 2004/0081648). It is also possible to make fusion proteins using those described in US 2004/0087778.

  In some embodiments, the targeting moiety is coupled via a protein, eg, via an antibody and / or binding fragment thereof. In some embodiments, it is possible to prepare liposomes that include multiple targeting moieties.

  In some preferred embodiments, the targeting moiety is coupled in a manner that does not interfere with the ability of the targeting moiety to target damaged lung tissue. For example, two (or more) alpha-1 antitrypsin moieties do not modify the conformation or folding of alpha-1 antitrypsin, or are required for recognition and / or binding to damage-correlated moieties such as elastase, and They may also be coupled to each other at sites that do not modify the conformation or folding of the region of the alpha-1 antitrypsin moiety involved. For example, without being limited to a given hypothesis or mode of action, an alpha-1 antitrypsin activity inhibitory site is found around Ser358 of the polypeptide, e.g., a pseudo-irreversible equimolar complex with neutrophil elastase. Form the body. See, for example, Sifers et al., “Genetic Control of Human Alpha-1 Antitrypsin”, Mol. Biol. Med., Vol. 6 pages 127-135 (1989). In some preferred embodiments, alpha-1 antitrypsin moieties may be coupled to each other or to other targeting moieties at sites other than around the Ser358 inhibitory site. Similarly, in some embodiments, without being limited to a given hypothesis or mode of action, the serpin moiety is a specific region known to be involved in attachment to the target protease, such as the serpin hinge, cleft. In addition to the region including the shutter and gate regions, they may be coupled to each other or to other targeting moieties. Irving et al., Genome Res Vol.10 1845-64 (2000). Some serpins contain, for example, a reactive central loop (RCL) involved in inhibition, where a stable complex can form between the protease and the truncated form of serpin. Attachment through a site other than the RCL region of the serpin portion is preferred in some embodiments. Similarly, in some embodiments, cysteine, a monocyte elastase inhibitor involved in interaction with target elastase and / or proteinase 3 and / or cathepsin G, without being limited to a given hypothesis or mode of action. At sites other than the residues, the inhibitor moieties may be coupled to each other or to other targeting moieties. See, for example, International Publication No. WO96 / 10418 and US Pat. No. 5,827,672.

  In a preferred embodiment, the size of the composition comprising two (or more) coupled targeting moieties is such that the composition is in an injury-correlated part, eg, an injury-correlated part in an expanded airspace distal to the terminal bronchioles. Not big enough to prevent access. For example, the size of the composition comprising two (or more) targeting 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 about 1 micron Is less than.

  The coupling of the targeting moiety can also keep the targeting moiety in close or relatively close physical proximity. For example, in some preferred embodiments, chemical linkers containing aliphatic groups 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 may be used. In some preferred embodiments, chemical linkers containing aliphatic groups of less than about 30 carbon atoms, less than about 20 carbon atoms, or less than about 15 carbon atoms may be used. In some preferred embodiments, a polypeptide linker comprising at least about 1 amino acid, at least about 3 amino acids, or at least about 5 amino acids may be used. In some preferred embodiments, a polypeptide linker comprising less than about 12 amino acids, less than about 10 amino acids, or less than about 5 amino acids may be used.

  Further, a composition comprising two (or more) coupled targeting moieties may be coupled and / or uncoupled cross-linkable moieties and / or coupled, eg, depending on the intended use of the composition Or an imaging portion that is not coupled.

  In other aspects of the invention, the composition comprising a targeting moiety also includes an imaging moiety coupled thereto. The imaging moiety can be any moiety that facilitates detection, either directly or indirectly, preferably by non-invasive and / or in vivo visualization techniques. For example, the imaging moiety may be detectable by any known imaging technique including, for example, radiological techniques. The imaging moiety may include, for example, a contrast agent, for example, where the contrast agent is ionic or non-ionic. In some embodiments, for example, the imaging moiety comprises a tantalum compound and / or a barium compound, such as barium sulfate. In some embodiments, the imaging moiety includes iodine, such as radioactive iodine. In some embodiments, for example, the imaging moiety comprises an organic iodoacid, such as iodocarboxylic acid, triiodophenol, iodoform, and / or tetraiodoethylene. In some embodiments, the imaging moiety includes a non-radioactive imaging moiety, such as a non-radioactive isotope. For example, in certain embodiments, Gd may be used as a non-radioactive imaging moiety.

  Other examples of imaging moieties include parts that emit or can be made to emit detectable radiation (eg, fluorescence excitation, radioactive decoy, spin resonance excitation, etc.), parts that affect the local electromagnetic field (Eg, magnetic, ferromagnetic, ferromagnetic, paramagnetic, and / or superparamagnetic species), moieties that absorb or scatter radiant energy (eg, chromophores and / or fluorophores), quantum dots, heavy elements and / or The compound is included. See, for example, the imaging portion described in US Publication No. 2004/0009122. Other examples of imaging moieties include proton-emitting moieties, radiopaque moieties, and / or radioactive moieties such as radioactive nucleic acids such as Tc-99m and / or Xe-13. Such a part may be used as a radiopharmaceutical. In yet other embodiments, the compositions of the present invention may include one or more different types of imaging moieties, including any combination of imaging moieties disclosed herein.

  Further examples of radioimaging moieties include gamma releasing factors such as gamma releasing factors, In-111, I-125 and I-131, rhenium-186 and 188, and Br-77 (eg Thakur, ML et al., Throm Res Vol. 9 page 345 (1976); see Powers et al., Neurology Vol. 32 page 938 (1982); and US Pat. No. 5,011,686); positron releasing factors such as Cu-64, C-11, and O -15, and Co-57, Cu-67, Ga-67, Ga-68, Ru-97, Tc-99m, In-113m, Hg-197, Au-198, and Pb-203. Other radioimaging moieties include, for example, tritium, C-14 and / or thallium, and Rh-105, I-123, Nd-147, Pm-151, Sm-153, Gd-159, Tb-161, Er -171 and / or Tl-201 are included.

  Technitium-99m (Tc-99m) is preferred and has been described in other applications, see for example US Pat. No. 4,418,052 and US Pat. No. 5,024,829. Tc-99m is a gamma-emitting factor with a single photon energy of 140 keV and a half-life of about 6 hours and can be easily obtained from a Mo-99 / Tc-99 generator.

  In some embodiments, a composition comprising a radioimaging moiety can be prepared by coupling a radioisotope suitable for detection and a targeting moiety. Coupling is via a chelating agent such as diethylenetriaminepentaacetic acid (DTPA), 4,7,10-tetraazacyclododecane-N, N ′, N ″, N ′ ″-tetraacetic acid (DOTA) and / or metallothionein. It can also occur, any of which can be covalently attached to the targeting moiety. In some embodiments, an aqueous mixture of technetium-99m, a reducing agent, and a water soluble ligand may be prepared and then allowed to react with the targeting moiety of the present invention. Such methods are known in the art, see eg International Publication No. WO 99/64446. In some embodiments, an exchange reaction may be used to prepare a composition comprising radioactive iodine. For example, the exchange of radioactive iodine for non-radioactive iodine is well known in the art. Alternatively, a radioiodine labeled compound may be prepared from the corresponding bromo compound via a tributylstannyl intermediate.

  Magnetic imaging moieties include paramagnetic contrast agents such as gadolinium diethylenetriaminepentaacetic acid used in magnetic resonance imaging (MRI) (eg, De Roos, A. et al., Int. J. Card. Imaging Vol. 7 See page 133 (1991)). Some preferred embodiments have an atomic number of 21, 22, 23, 24, 25, 26, 27, 28, 29, 42, 44, 58, 59, 60, 61, 62, 63, 64, as the imaging moiety. Paramagnetic atoms that are divalent or trivalent ions of 65, 66, 67, 68, 69, or 70 elements are used. Suitable ions include, but are not limited to, chromium (III), manganese (II), iron (II), iron (III), cobalt (II), nickel (II), copper (II), praseodymium Includes (III), neodymium (III), samarium (III) and ytterbium (III), and gadolinium (III), terbium (III), dysoprosium (III), holmium (III), and erbium (III) It is. Some preferred embodiments use atoms with a strong magnetic moment, such as gadolinium (III).

  In some embodiments, it is also possible to prepare a composition comprising a magnetic imaging moiety by coupling a targeting moiety having a paramagnetic atom. For example, a suitable metal oxide or metal salt of a paramagnetic atom, such as nitrate, chloride or sulfate, may be dissolved or suspended in a water / alcohol medium such as methyl, ethyl, and / or isopropyl alcohol. . The mixture may be added to an equimolar amount of the targeting moiety solution in a similar water / alcohol medium and stirred. The mixture may be gently heated until the reaction is complete or nearly complete. The insoluble composition formed can be obtained by filtration, while the soluble composition can be obtained by evaporating the solvent. If acid groups on the chelating moiety remain in the composition of the present invention, inorganic bases (eg sodium, potassium and / or lithium hydroxides, carbonates and / or bicarbonates), organic bases, and / or Alternatively, basic amino acids may be used to neutralize acidic groups, for example to facilitate isolation or purification of the composition.

  In a preferred embodiment, the imaging moiety is coupled to the targeting moiety so as not to interfere with the ability of the targeting moiety to target damaged lung tissue. For example, regions of the alpha-1 antitrypsin moiety that do not modify the conformation or folding of alpha-1 antitrypsin or that are necessary for and / or involved in recognition and / or binding to damage-related moieties such as elastase The imaging moiety may be attached to the alpha-1 antitrypsin moiety at one or more sites that do not modify the conformation or folding of 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 and is a pseudo-irreversible equimolar complex with neutrophil elastase It is also possible to form a body. See, for example, Sifers et al., “Genetic Control of Human Alpha-1 Antitrypsin”, Mol. Biol. Med., Vol. 6 pages 127-135 (1989). In some preferred embodiments, the imaging moiety may be attached to the alpha-1 antitrypsin moiety at a site other than around the Ser358 inhibitory site. Similarly, in some embodiments, not limited to a given hypothesis or mode of action, the imaging moiety can be a specific region known to be involved in attachment to the target protease, such as the serpin hinge, cleft, You may make it adhere to a serpin part in parts other than the area | region containing a shutter and a gate area | region. Irving et al., Genome Res Vol.10 1845-64 (2000). Some serpins contain, for example, a reactive central loop (RCL) involved in inhibition, where a stable complex can form between the protease and the truncated form of serpin. Attachment to a site other than the RCL region of the serpin moiety is preferred in some embodiments. Similarly, in some embodiments, cysteine, a monocyte elastase inhibitor involved in interaction with target elastase and / or proteinase 3 and / or cathepsin G, without being limited to a given hypothesis or mode of action. An imaging moiety may be attached to the inhibitor moiety at a site other than the residue. See, for example, International Publication No. WO96 / 10418; US Pat. No. 5,827,672.

  In some embodiments, the imaging moiety may be chemically conjugated to the targeting moiety, eg, an iodine moiety may be covalently attached to one or more sites of alpha-1 antitrypsin. In some embodiments, the imaging moiety and the targeting moiety may be indirectly coupled by chemically coupling the imaging moiety to a moiety that is itself chemically bonded to the targeting moiety.

  In a preferred embodiment, the size of the composition comprising the targeting moiety coupled to the imaging moiety is such that the composition is accessible to an injury correlation moiety, e.g., an injury correlation moiety within an expanded airspace distal to the terminal bronchiole. Not big enough to prevent. For example, the size of the composition comprising the targeting moiety and the imaging 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. is there.

  In yet another aspect of the invention, the composition comprising a targeting moiety and an imaging moiety coupled to the moiety also includes a coupled crosslinkable moiety and / or another targeting moiety coupled, The size of the composition 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, and at least distal to the terminal bronchiole Is not so large as to prevent access of the composition to a lesion-correlated portion, such as a lesion-correlated portion in the expanded air cavity. In preferred embodiments, the crosslinkable moiety, other targeting moiety and / or imaging moiety, either directly or indirectly, in a manner that does not interfere with the ability of the targeting moiety to target damaged lung tissue, Each is coupled to a targeting moiety. In some embodiments, the crosslinkable moiety and the imaging moiety may each be chemically linked to the targeting moiety. In some embodiments, the crosslinkable moiety and the imaging moiety are each chemically bonded to the targeting moiety and chemically linked to the crosslinkable moiety, imaging moiety and targeting moiety, respectively. It may be bonded to. In still other embodiments, the crosslinkable moiety may be chemically attached to the targeting moiety, while the imaging moiety may be chemically attached to the moiety that is itself chemically attached to the targeting moiety. Or vice versa. In preferred embodiments comprising more than one coupled targeting moiety, it is also possible to couple one or more imaging moieties directly or indirectly to one or more targeting moieties.

Methods for detecting and / or treating lung conditions:
The present invention provides a method of detecting and / or treating a lung condition using a composition that targets damaged lung tissue. The term “pulmonary condition” as used herein refers to an abnormal condition of the lung and / or lung tissue, eg, damaged lung tissue. The term includes a greater amount of one or more in the affected lung region compared to a lung region that is not affected by a lung condition or affected to a lesser extent. The conditions characterized by the damage correlation part are included. Examples of such pulmonary conditions include emphysema (including both heterogeneous and homogeneous emphysema, preferably heterogeneous emphysema), asthma, bronchiectasis, and chronic bronchitis. Contains, includes COPD. Pulmonary conditions may also include other chronic lung disorders, sarcoidosis, pulmonary fibrosis, pneumothorax, sputum, bronchopleural fistula, cystic fibrosis, inflammatory conditions, and / or other respiratory disorders. Lung conditions also include tobacco-related and / or age-related changes to the lung, as well as traumatic events, infectious pathogens (eg, bacteria, viruses, fungi, tuberculin and / or viral pathogens), toxins (eg, chemotherapeutic agents) Exposure to environmental pollutants, exhaust gases, and / or pesticides), and / or genetic factors (eg alpha-1 antitrypsin deficiency, and degradation and / or stretch of lung stretch and / or connective tissue) Lung damage caused by impaired synthesis of sex tissue and / or connective tissue and / or other types of genetic disorders with impaired repair of stretch tissue and / or connective tissue may also be included.

  One aspect of the present invention is to administer to a subject in need a composition comprising a crosslinkable moiety coupled to a targeting moiety that targets damaged lung tissue and to crosslink damaged lung tissue. The process provides a method for reducing lung volume. In some preferred embodiments, the method can be performed without prior identification of damaged lung tissue. For example, to image a subject's lungs, it may not be necessary to identify an area or site of damaged tissue prior to administering the composition of the invention to the subject. Preferably, the targeting moiety is located in the affected lung area compared to an area of the lung that is not affected or affected to a lesser extent, for example by a lung condition. Will act to guide the administered composition to the site of damaged lung tissue. For example, when the alpha-1 antitrypsin moiety is used as a targeting moiety, the alpha-1 antitrypsin moiety is an elastase found in higher concentrations in certain lung conditions, such as emphysema, at sites of damaged lung tissue. It is recognizable and can be coupled to this.

  The cross-linking of damaged lung tissue can then cause a decrease in lung volume, for example by sealing and / or keeping the collapsed area of over-expanded lung tissue, preferably remaining Ensure space for the expansion of tissue that is not damaged or healthier. For example, in emphysema, a section of the lung that has lost the stretch necessary for expiration can be collapsed and / or sealed by the methods described herein. Because cross-linked tissue occupies a smaller volume than, for example, dilated alveoli at the site of damaged tissue, the method of the present invention can reduce lung volume as a whole. Thus, the present invention can also provide a non-surgical, less invasive and / or safer approach to achieve some of the benefits of lung volume reduction. Furthermore, targeting sites of damaged lung tissue can localize volume loss, which in turn can lead to worsening V / Q imbalance, altered arterial oxidation, or acute hypoxia It is also possible to minimize the troublesome side effects of lung volume reduction, such as the induction of symptoms. Ingenito et al. (2002) Bronchoscopic Lung Volume Reduction Using tissue engineering principles, American Journal of Respiratory and Critical Care Medicine, Vol. 167 771-778. The method of the present invention can be applied to surgical procedures such as using LVRS and a stapler without a scalpel (eg, Swanson et al., “No-cut thoracoscopic lung plication: A new technique for lung volume reduction surgery”, J Am Coll Surg Vol. 185 25-32 (1997)), and in combination with other approaches for treating pulmonary conditions, including the use of coupled targeting moieties and / or imaging methods described herein It should also be understood that it may be used.

  Crosslinking of the crosslinkable moiety may be accomplished by any method known in the art and / or described herein. For example, a second composition that includes a cross-linking activating moiety may be administered. A “cross-linking activating moiety” as used herein is capable of causing cross-linking between more than one cross-linkable moiety and / or more than one with damaged lung tissue components (eg, proteins) It refers to any part that can form a bond. Preferably, the cross-linking activating moiety comprises a difunctional or polyfunctional group. For example, the crosslinkable moiety is a hydroxyl group, carboxyl group, ester group, cyano group, thiol group (eg cysteine group), carbonyl group, aldehyde group, ketone group, primary amine group, secondary amine group, and / or lysine group. The cross-linking activating moiety comprises a diol, polyol, dicarboxylic acid (eg fumaric acid, maleic acid, phthalic acid or terephthalic acid), polycarboxylic acid, diester, polyester, diamine and / or polyamine. It is also possible. A bifunctional or polyfunctional group is a targeting moiety that binds to a damage-correlated moiety at more than one crosslinkable moiety and preferably at different sites of damaged lung tissue, such as different sites within the expanded alveoli. A covalent bond can be formed between the crosslinkable parts coupled to the. Linking includes, for example, amide formation (eg, through condensation of an amino group and an activated ester such as NHS or sulfo-NHS ester), imine formation, carbodiimide condensation, disulfide bond formation, and / or the use of specific binding pairs, such as Use of the biotin-avidin interaction may be included. Thus, cross-linking seals the collapsed airspace at the site of damaged lung tissue, for example in the region of over-inflated alveoli, which is characteristic for certain lung conditions including emphysema, And / or it can work to keep.

  Diamines and / or polyamines that can be used in the practice of the present invention include aliphatic and / or aromatic diamines and / or polyamines, and two or more aliphatic and / or aromatic monoamines suitably linked together. It is. For example, monomeric diamines and / or polyamines that can be used in the practice of the present invention include aminopyrimidine, aniline, benzidine, diaminodiphenylamine, diphenylamine, hydrazine, hydrazide, toluene-diamine, and / or triethylenediamine. It is also possible. Diamines and / or polyamines that can also be used can include, for example, acetamide, acrylamide, benzamide, cyanamide, and / or urea. Dialcohols and / or polyalcohols that can be used include aromatic alcohols and / or aliphatic alcohols, such as 1,4-butanediol, phenol, polyvinyl alcohol, and / or d-sorbitol. Examples of dicarbonyls that can be used in the practice of the present invention include dicarbonyls including acetate, such as α-haloacetate derivatives, acetylacetone, diethylmalonate, ethylacetone, malonamide, malonic acid and / or malonic acid esters or salts thereof. Is included. Other carbonyl groups that can be used include α, β-unsaturated carbonyl groups (eg, maleimide) and / or α-halocarbonyl groups (eg, iodoacetamide derivatives). Bifunctional and / or polyfunctional ketones can also be used, including for example 2,5-hexanedione, and / or two or more linked monofunctional ketones such as cyclohexane and / or cyclopentanone Bifunctional ketones and / or polyfunctional ketones are included. Bifunctional aldehydes and / or multifunctional aldehydes can also be used, see for example US Pat. No. 6,329,337 and / or US Pat. No. 6,372,229. For example, at least one aldehyde selected from gelatin-resorcin-aldehyde, glyoxal, succinaldehyde, glutaraldehyde, malealdehyde, dextran dialdehyde, and saccharide oxidized by m-periodate can be used.

  As will be appreciated by those skilled in the art, the aldehydes and / or ketones described herein can also exist as hydrates in aqueous solutions, such as hemiacetal and / or in aqueous solutions. Present as hemiketal. In preferred embodiments, such hydrates can be converted back to the corresponding aldehydes and / or ketones for crosslinking. In some embodiments, hydrates of aldehydes and / or ketones and / or hydrates of other cross-linking activating moieties themselves cause cross-linking between more than one cross-linkable moiety and / or damage It is also possible to form more than one bond with a component (eg protein) of the lung tissue that has been subjected to.

  Other cross-linking activating moieties that may (or may not) be used in the practice of the invention include proteins or mixtures of proteins (including synthetic peptides and / or recombinant proteins), such as other minor amounts Collagen and / or albumin and / or lipoprotein with additives, and optionally hydrogel, polyglycolic acid, polylactic acid, polydioxanone, polytrimethylene carbonate, polycarprolactone, and / or glutaraldehyde, polyethylene glycol, Polyethylene glycol disuccinimidyl succinate, and polymerizable monomers such as 1,1-disubstituted ethylene monomers or acetates such as α-haloacetates, acrylates, acrylate glues, polyol cross-linked anhydrides, Cyano Groups such as cyanoacrylate, epoxy, gelatin / resorcinol / formaldehyde, gelatin / resorcinol / glutaraldehyde, hyaluronic acid crosslinked with hydrazine, photopolymerizable monomer, silicone, silicone rubber, starch, urethane, vinyl-terminated monomer , And / or any combination thereof. Other cross-linking activating moieties that can be used in the practice of the present invention include alkyl bis (2-cyanoacrylate), triallyl isocyanurate, alkylene diacrylate, alkylene dimethacrylate, and / or trimethylolpropane triacrylate. . Other cross-linking activating moieties that can be used in the practice of the present invention include disulfides, carbodiimides and hydrazines. Other suitable cross-linking activating moieties are known in the art, for example, US Pat. No. 3,940,362; US Pat. No. 5,328,687; US Pat. No. 3,527,841; US Pat. No. 3,722,599, each incorporated herein by reference. US Pat. No. 3,995,641; and / or US Pat. No. 5,583,114. Still other cross-linking activating moieties that can be used include products formed by reacting glutaraldehyde with amino acids and / or peptides, as described in US Pat. No. 6,310,036. Crosslinkable and / or crosslinkable activating moieties also include suitable monomers such as those disclosed in US Publication No. 2002/0147462, such as monomeric n-butyl-2-cyanoacrylate (Eng et al., “ Successful closure of bronchopleural fistula with adhesive tissue ”, Scand J Thor Cardiovasc Surg, Vol. 24, pages 157-59 (1990) and Inaspettato et al.,“ Endoscopic treatment of bronchopleural fistulas using n-butyl-2-cyanoacrylate ”, Surgical Laparoscopy & Endoscopy Vol.4 No.1 pages 62-64 (1994)) may also be included.

  The choice of the cross-linking activating moiety may depend at least in part on the cross-linkable moiety used. Where the crosslinkable moiety is fibrin and / or fibrinogen, the cross-linking activating moiety may include a fibrin activator and / or a fibrinogen activator. For example, thrombin, thrombin receptor agonists, batroxobin, and / or calcium can be used to initiate cross-linking of fibrinogen. It should also be understood that any combination of cross-linking activating moieties may be used, for example depending on the combination of cross-linkable moieties administered. In addition, some embodiments provide a composition comprising a targeting moiety coupled to a cross-linking activating moiety to facilitate migration and / or distribution of the cross-linking activating moiety to a site of, for example, damaged lung tissue. To do. Those skilled in the art will recognize other suitable cross-linking activating moieties that can be used in the practice of the present invention, including any biocompatible cross-linking activating moiety capable of forming a biocompatible cross-linked product with, for example, the cross-linkable moiety used. Will recognize. In an even more preferred embodiment, the crosslinkable moiety and the crosslinkable activating moiety used are medically acceptable and form a medically acceptable crosslink.

  In some embodiments, one or more of the crosslinkable moiety, targeting moiety and / or crosslink activating moiety is thermally stable. That is, the moiety can be modified, adapted, and / or otherwise manipulated to withstand heat, eg, heat generated by a cross-linking reaction in the lung tissue of the subject. For example, thermostable glutaraldehyde can be used in an aqueous carrier, and in some embodiments, amino acid modifications of the protein targeting moiety can provide increased thermostability.

  It is also possible to add crosslinkable moieties and crosslinking activation moieties in appropriate ratios to promote crosslinking. The ratio used may depend on the crosslinkable and / or crosslink activating moiety used, the desired crosslinking rate, and / or other reaction conditions recognized by those skilled in the art. For example, ratios 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.

  It will be appreciated by those skilled in the art that certain of these cross-linking activating moieties may be suitable for use alone, ie without the corresponding cross-linkable moiety. For example, biotin group, amine group, carboxylic acid group, cyanate group (eg isothiocyanate group), thiol group, disulfide group, cyano group (eg α-halocarbonyl group, α, β-unsaturated carbonyl group), acetate group ( For example, α-haloacetate groups), hydrazine groups, cyanoacrylates, acrylic glues, and / or silicone moieties, and bifunctional linkers were used and damaged without the use of separate crosslinkable moieties It can also cause cross-linking of lung tissue. In addition, various combinations of cross-linking activating moieties may be used, co-administered simultaneously, or administered separately at different administration times. For example, dipolyaldehyde and / or polyaldehyde may be combined with a protein mixture, such as albumin and / or collagen, and optionally other minor additives. Also, as described above, the cross-linking activating moiety may in some embodiments be a targeting moiety, such as an alpha-1 antitrypsin molecule, fragment, and / or derivative thereof; or, for example, of the type provided herein A cross-linking activating moiety may be coupled to a combination of targeting moieties, including any combination of targeting moieties.

  It should also be understood that some embodiments do not require a cross-linking activating moiety for initiation of cross-linking. For example, if fibrin is used as the crosslinkable moiety, for example a fibrin monomer, such as fibrin I monomer, fibrin II monomer and / or des BB fibrin monomer, the monomer can spontaneously crosslink. . For example, fibrin I monomer is crosslinkable when in contact with the blood of a subject containing thrombin and factor XII.

  Various types of cross-linking reactions can be used in the practice of the present invention, including, for example, free radical reactions, cross-linking with zwitterions and / or ion pairs, anions and / or cations. See, for example, US Patent Nos. 6,010,714; 5,582,834; 5,575,997; 5,514,372; 5,514,371; 5,328,687; and 5,981,621. The cross-linking reactions of the present invention can also involve amide formation, imine formation, carbodiimide degeneracy, disulfide bond formation, and the use of specific binding pairs, such as the use of biotin-avidin interactions.

  In some preferred embodiments, the method of reducing lung volume does not damage epithelial cells in lung tissue, for example, it may not cause scar tissue formation and / or does not cause fibroblast proliferation. It is also possible and / or may not cause collagen synthesis. In some preferred embodiments, the method crosslinks and / or seals sites of damaged lung tissue within the alveoli, more preferably within the dilated alveoli distal to the terminal bronchioles. . In some preferred embodiments, the methods of the invention do not cause obstruction of the bronchial lumen of the subject's lungs. Without being limited to a particular mechanism, the method of the present invention is not intended to attempt to (mechanically) block airflow to damaged lung tissue, but to expand the airway and / or Alternatively, lung volume can be reduced by maintaining sealing. That is, in a preferred embodiment, the cross-linking is distal to the cross-linking site and serves to maintain the collapse and / or sealing of the end sac without an exit, rather than having some or some substantial amount of lung tissue.

  In some preferred embodiments, the method for reducing lung volume can involve damage to lung tissue. For example, in some embodiments, a curing agent may be used as part of the composition to be administered, eg, the curing agent may be coupled to the targeting moiety of the present invention. In some embodiments, the sclerosing agent may be administered alone; or at the same time, prior to, or after administration of the targeting moiety, crosslinkable moiety, and / or crosslinking activating moiety of the present invention. May be administered separately. The sclerosing agent can act to cause scar tissue formation and / or fibroblast proliferation, and / or collagen synthesis, and can promote sealing of areas of damaged lung tissue. Curing agents that can 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 can also be used in the practice of the present invention, optionally together with extracellular matrix components such as hyaluronic acid. See, for example, US Publication No. 2004/0047855.

  In a further preferred embodiment, without the use of a catheter and / or without the use of an endotracheal applicator and / or without the use of bronchoscopy (eg without the use of a bronchoscope) and / or abdominal cavity The cross-linking method of the present invention can be performed without the use of a laproscopy and / or without the use of open therapy, such as thractomy.

  In some embodiments, the cross-linking activating moiety is administered after allowing sufficient time to target the administered cross-linkable moiety to a site of damaged lung tissue. In preferred embodiments, the targeting moiety recognizes and binds to the damage-correlated moiety 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 targeting moiety is less than about 3 hours, less than about 2 hours, less than about 1 hour, less than about 45 minutes, less than about 30 minutes, less than about 20 minutes, or less than about 10 minutes and Recognize and bind to the part. Also, in some embodiments, unbound targeting moieties are removed from the lung prior to administration of the cross-linking activating moiety, eg, by lavage fluid and / or lavage (eg, with saline) and / or by collapse. Is also possible.

  Cross-linking can also be facilitated by causing the first portion or all of the subject's lungs to contract and / or collapse. Such contraction and / or collapse may be accomplished by any technique known in the art or disclosed herein. For example, collapse may involve the use of negative pressure from inside the lung and / or positive pressure from outside the lung. In some embodiments, a preparation that induces and / or promotes collapse may also be used, such as a physiology containing an anti-surfactant, such as an agent that can increase the surface tension of alveolar coating fluid. There is an acceptable solution. For example, the anti-surfactant may be administered before, during and / or after administration of a composition comprising a crosslinkable moiety and / or a cross-linking activating moiety. For example, fibrin and / or fibrinogen that can act as both an anti-surfactant and a crosslinking aid may be used.

  Other suitable surfactants that can be used to promote crosslinking include Triton x-100, veracant, corfoseryl, and / or palmitate; anionic surfactants such as sodium tetradecyl sulfate; tetrabutylammonium bromide and A cationic surfactant such as butyrylcholine chloride; a nonionic surfactant such as polysorbate 20 (eg Tween 20), polysorbate 80 (eg Tween 80), and / or poloxamer; dodecyldimethyl (3-sulfopropyl) ammonium hydroxy Amphoteric and / or zwitterionic surfactants such as amines, inert salts; amines, imines and / or amides such as arginine, imidazole, povidin, tryptamine and / or urea; ascorbic acid, ethylene glycol, gallic acid Methyl, tannin and / or ta Alcohols such as ninnic 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 thioureas; polymeric cyclic ethers such as calixarene, crown ether, monensin, nonactin, and / or polymeric epoxides; cyclic and acyclic carbonates; organometallics such as naphthenates and acetylacetonic acid Manganese); phase transfer catalysts (eg Aliquat 336); and radical initiators and radicals (eg di-tert-butyl peroxide and / or azobisisobutyronitrile).

  Cross-linking can also be facilitated by filling the lungs or portions thereof with an absorbable gas such as oxygen to promote, for example, pulmonary diastolic failure. 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, pages 295-301 (2001).

  In some embodiments, saline lavage can be used to reduce the amount of surfactant naturally present in the lung. Cross-linking can also be facilitated, for example, by the use of a wash solution that can prevent, reduce, and / or remove any other moiety that can otherwise interfere with targeting. For example, in some embodiments, cross-linking can be facilitated by the use of antisecretory agents that interfere with and / or prevent mucus secretion in the lung or portions thereof. For example, the antisecretory agent may be administered before, during and / or after administration of a composition comprising a crosslinkable moiety, a cross-linking activating moiety, and / or other moieties and / or agents. Examples of antisecretory agents that can be used include, for example, an anticholinergic moiety, an atronie, and / or an atropine-like moiety. Removal of mucus or excess mucus from the lung, preferably from the dilated alveoli distal to the distal bronchioles, for example by lavage, can also promote cross-linking and / or binding of the targeting moiety to the damage-correlated moiety It is. The present invention to mucous-coated walls in the bronchi, bronchioles, or alveoli in order that the targeting moiety of the present invention binds to each damage-correlated moiety and reduces, for example, and / or avoids slipping Adhesion of the composition can be promoted.

  In some embodiments, mechanical force may be used externally to push one region of the lung closer to another region, for example, to assist collapse and / or contraction of an expanded air space. For example, a portion of the lung lobe may be externally pressed using a device such as a balloon, air pressure, hand pressure, and / or paddle, net, synched up strap, or magnet. In some embodiments, such pressure is applied simultaneously to more than one side of the lung lobe. For example, local pressure (applenate) may be applied to more than one side using an endoscope and / or magnetic probe.

  In some embodiments, it is also possible to pull the first portion or all of the lungs together from inside, for example towards the user, for example using cables and hooks to grab and pull tissue. Other devices that can be used include a grasper, for example an expanding capture device assembly that can be heathed; and / or from a cable or wire after, for example, lung tissue is pulled together An anchor that can be left behind by being released is included. In some embodiments, it is also possible to place magnetic probes at different locations inside the lungs, where the probes attract each other, thereby causing one area of the lungs to move to the other area, eg, one bronchus Can be attracted to another bronchus. It is also possible to change the shape of such devices after insertion by using mechanical forces, for example by using a core wire or by activating NiTi devices after placement. In yet another embodiment, the lung or a first portion thereof is contracted transthoracically. Other methods and / or devices known in the art to promote lung contraction and / or collapse can also be used, see, eg, US Publication No. 2003/0070682.

  Preferably, such contraction and / or collapse occurs after the administered cross-linking activated moiety has given sufficient time to be distributed in the area of damaged lung tissue. In some embodiments, for example, contraction and / or collapse occurs approximately 2 to approximately 3 minutes after administration of the cross-linking activating moiety. Also, the lung or the first portion thereof is preferably allowed to remain collapsed and / or contracted for a time sufficient to allow crosslinking to occur. Depending on the composition used, for example, depending on the targeting moiety used, the lung or first portion thereof may be 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 Contraction for 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 And / or can be kept collapsed. In some embodiments, the lung or first portion thereof can be kept contracted 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. is there.

  In some embodiments, a catalytic amount of a rate modifier may be added to modify the crosslinking reaction rate. For example, various set times or recovery times can be used, where the crosslinking reaction is 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 It occurs for 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, at least about 15 minutes. The cross-linking reaction can occur for less than about 20 minutes, less than about 25 minutes, less than about 30 minutes, less than about 1 hour, less than about 2 hours, or less than about 3 hours. The recovery time may be optimized by using various techniques known in the art, for example by using buffers having different pH values.

  The second part of the lung may then be reinflated, in which case the second part comprises the first part or all of the lungs that have contracted and / or collapsed, but preferably all Not included. In preferred embodiments, this second portion does not include at least some of the damaged lung tissue, which remains collapsed and / or sealed for crosslinking. The cross-linking preferably forms a stable mesh that keeps the collapsed area from re-expanding. In a more preferred embodiment, the majority of the damaged lung tissue remains cross-linked and / or collapsed, while the majority of the intact lung tissue remains functional. . For example, at least about 60%, at least about 80%, and most preferably at least about 90% of damaged lung tissue is cross-linked; whereas, less than about 40%, less than about 20% of intact lung tissue And most preferably less than about 10% remain uncrosslinked. Reduction in overall lung volume improves mechanical function, such as that of healthier and / or more stretchable tissue.

  In preferred embodiments, the cross-linking is at least about 0.5% total lung volume reduction, at least about 1% total lung volume reduction, at least about 1.5% total lung volume reduction, at least about 2% total lung volume. Lung volume reduction, at least about 3% total lung volume reduction, at least about 4% total lung volume reduction, at least about 5% total lung volume reduction, or at least about 10% total lung volume Causes volume reduction. In preferred embodiments, the crosslinking results in a decrease in overall lung volume of less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, or less than about 15%. Such a reduction can be achieved upon single or multiple administrations of the composition of the present invention. A reduction in total lung volume of about 2% to about 3% can be expected to produce a beneficial effect in subjects receiving such treatment, for example, at least to the same extent as occurs with LVRS.

  In still preferred embodiments, the cross-linking is permanent or at least semi-permanent and is biodegradable (e.g., during a period between successive treatments described herein, e.g., between administrations of the composition of the invention). Resistant to hydrolysis). In certain embodiments, at least about 70%, at least about 80%, at least about 90%, or at least about 98% of the crosslinks remain intact over a period of time. In some preferred embodiments, the period is at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 1 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 the most preferred embodiment, the cross-linking keeps some damaged lung tissue collapsed and / or sealed for the rest of the life of the subject, eg resisting biodegradation indefinitely.

  One skilled in the art will appreciate that the persistence and / or biodegradability of the cross-linking may depend on the cross-linkable moiety, the cross-linking activated moiety, and / or the state of the cross-linking and / or other agents and / or moieties used. And, thus, for example, will be recognized as controllable by techniques known in the art and / or disclosed herein.

  In preferred embodiments, some or all of the crosslinks are very strong and resist the mechanical pressure experienced in the lungs. For example, the strain range corresponding to functional residual capacity during normal breathing is at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about at least about crosslinking in some preferred embodiments. Does not cause about 70%, at least about 80%, at least about 90%, or at least about 95% destruction.

  In some preferred embodiments, the crosslink exhibits a tear strength of at least about 50 g / cm 2, at least about 100 g / cm 2, at least about 200 g / cm 2, or at least about 300 g / cm 2. In some preferred embodiments, the crosslinking is 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, about 1000 g / sq. It exhibits a tear strength of less than square cm, less than about 800 g / square cm, less than about 600 g / square cm, or less than about 400 g / square cm.

  Similarly, in a preferred embodiment, the binding interaction between the targeting moiety and its corresponding damage correlation moiety is permanent, or at least semi-permanent, and is a period between successive treatments described herein, eg, irreversibly It binds substantially irreversibly or at least with a high binding constant and resists dissociation, for example during the period between administrations of the composition of the invention. For example, the alpha-1 antitrypsin moiety can form a pseudo-irreversible equimolar complex with neutrophil elastase in some embodiments. See, for example, Sifers et al., “Genetic Control of Human Alpha-1 Antitrypsin”, Mol. Biol. Med., Vol. 6 pages 127-135 (1989). Without being limited to a particular theory or mode of action, the alpha-1 antitrypsin moiety can form an acyl-enzyme complex with its target. In some embodiments, binding can be further enhanced by genetic modification or by shuffling known binding domains. As another example, a serpin moiety can react with a target 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 the serpin and the target protease can also involve a covalent ester bond, where the active site serine residue of the protease is the serpin To form an acyl-enzyme complex. See, for example, US Publication No. 2003/0216321. As yet another example, the monocyte elastase inhibitor moiety can form a covalent complex and / or an essentially irreversible complex with elastase. See, for example, International Publication No. WO 96/10418 and US Pat. No. 5,827,672.

  In certain embodiments, at least about 70%, at least about 80%, at least about 90%, or at least about 98% of the targeting moiety remains bound to the corresponding damage correlation moiety over a period of time. In some preferred embodiments, the period is at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 1 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 the most preferred embodiment, the binding maintains some collapse and / or sealing of the damaged lung tissue for the rest of the life of the subject, eg resists biodegradation indefinitely.

  FIG. 1a illustrates one embodiment of a method of reducing lung volume using a composition comprising a crosslinkable moiety coupled to a targeting moiety that targets damaged lung tissue. This figure provides only an overview and is not intended to be limiting with respect to the present invention in any way. For example, those skilled in the art will readily recognize variations and modifications of the illustrated figures. The figure illustrates the terminal bronchiole 101 ending in the airspace of the alveoli 102. As mentioned above, the air space may over-expand and / or dilate in certain pulmonary conditions such as emphysema. A large amount of damage-correlated portion 103 is found inside the airway wall, for example at the site of damaged lung tissue and / or in alveolar epithelial mucus.

  A targeting moiety 104 is administered wherein a composition of the invention is administered, wherein the composition targets damaged lung tissue, for example by recognizing and binding to the target injury-correlated moiety 103. including. In the illustrated embodiment, the composition also includes a crosslinkable moiety (X) 105 coupled to the targeting moiety 104. FIG. 1a illustrates how different targeting moieties recognize and bind to a damage-correlated moiety at various sites in the airspace.

  After cross-linking, the cross-linkable portion 105 is cross-linked, for example, via a cross-linking activation portion Cross-linking activating moiety 106 is shown in the figure as -Y-R-Y- (wherein Y can be coupled to cross-linkable moiety (X) 105 to form a covalent bond between, for example, two cross-linkable moieties. And R may include a bifunctional group denoted as a linking moiety between Y groups, such as, but not limited to, an aliphatic chain. The cross-linking activating moiety 106 is coupled to a cross-linkable moiety 105, which is itself coupled to a targeting moiety 104 that is bound to a damage correlating moiety 103 found at various sites within the airspace. FIG. 1a illustrates how, after collapse, bridging can keep airway walls closer together and thereby reduce lung volume.

  The methods described herein for reducing lung volume find use in the treatment of several lung conditions in animal subjects. The term “animal subject” as used herein includes humans as well as other animals. 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 emphysema patients, therapeutic benefits include eradication or improvement of the underlying emphysema, including lung function, exercise capacity, improved quality of life, and reduced hospitalization. Also, eradication of one or more physiological symptoms associated with the underlying lung condition so that improvement is observed in the subject despite the fact that the subject may still suffer from the lung condition Or, with improvement, a therapeutic benefit is achieved. For example, for emphysema, administration of the composition of the present invention may improve in subjects not only when the area lacking elasticity collapses, but also with other disorders associated with emphysema, such as chronic lung infection. If observed, it can also provide a therapeutic benefit. For example, the addition of a targeting moiety that includes a protease inhibitor can improve emphysema, for example, by reducing protease activity, as described in the art. With respect to prophylactic benefits, to subjects who are at risk of developing pulmonary conditions, such as emphysema, or to subjects who have reported one or more physiological symptoms of these conditions, even if not diagnosed. It is also possible to administer the composition of the present invention.

  Another aspect of the invention is a method of reducing lung volume, comprising administering a composition comprising a first targeting moiety and a second targeting moiety to a subject in need, wherein the targeting moiety is a cup. The targeting moiety targets damaged lung tissue; and allows the targeting moiety to target different sites of damaged lung tissue, thereby reducing lung volume The method is provided comprising a step. In a preferred embodiment, the different sites include different sites in the alveolar wall of the hyperinflated alveoli distal to the distal bronchioles characteristic of some pulmonary conditions including dilated air spaces, eg emphysema . For example, the first targeting moiety can target the first damage correlation moiety, while the second targeting moiety can target the second damage correlation moiety, where the first and second The damage-correlated parts of are present at different sites. As the coupled targeting moiety binds to different sites within the air cavity after contraction and / or collapse, the coupled targeting moiety can act to keep the different sites closer together, thereby The cavity remains collapsed and / or sealed. Also, the targeting moiety is found in greater amounts in affected lung areas compared to lung areas that are not affected by the lung condition or affected to a lesser extent As the damage-correlated part is recognized and / or bound to the part, the damaged lung tissue area is selectively and / or preferentially collapsed and / or sealed, preferably with the remaining damage. Ensure space for the expansion of tissues that have not received or are healthier.

  In a preferred embodiment, it is possible to perform a method that utilizes the coupled targeting moiety without previously identifying damaged lung tissue. For example, prior to administering a composition of the present invention to a subject, it may not be necessary to image the lungs of the subject to identify areas of damaged tissue. For example, there is a greater amount of damage correlation in the affected lung region compared to the lung region that is not affected by the lung condition or affected to a lesser extent The targeting moiety acts to direct the administered composition to the site of damaged lung tissue. For example, when the alpha-1 antitrypsin moiety is used as a targeting moiety, the alpha-1 antitrypsin moiety is an elastase found in higher concentrations in certain lung conditions, such as emphysema, at sites of damaged lung tissue. It is recognizable and can be coupled to this.

  Since collapsed tissue occupies a smaller volume than the expanded alveoli at the site of damaged tissue, the method of the invention can reduce lung volume as a whole. Thus, the present invention can also provide a non-surgical, less invasive and / or safer approach to achieve at least some of the benefits of lung volume reduction. Furthermore, targeting sites of damaged lung tissue can localize volume loss, which in turn can lead to worsening V / Q imbalance, altered arterial oxidation, or acute hypoxia Troublesome side effects such as induction of symptoms can be minimized. Ingenito et al., “Bronchoscopic Lung Volume Reduction Using tissue engineering principles”, American Journal of Respiratory and Critical Care Medicine, Vol. 167 771-778 (2002). The methods of the invention can also be used in combination with surgical procedures such as LVRS, and other approaches for treating pulmonary conditions, including the crosslinking methods and / or groups described herein. Non-provisional application US 11 / 008,577, entitled “Targeting Damaged Lung Tissue Using Compositions”, filed Dec. 8, 2004; title, US 11 / 008,092, each incorporated herein by reference in its entirety. Targeting Damaged Lung Tissue “, filed December 8, 2004; US 11 / 008,094, title“ Targeting Sites of Damaged Lung Tissue Using Composition ”, filed December 8, 2004; US 11 / 008,578, title“ Targeting Sites of Damaged Lung Tissue “, filed December 8, 2004; US11 / 008,649, title“ Imaging Damaged Lung Tissue Using Compositions ”, filed December 8, 2004; US11 / 008,777, title“ Imaging Damaged Lung Tissue ”, 2004 Filed December 8; US11 / 008,087, title “Glu” e Compositions for Lung Volume Reduction “, filed December 8, 2004; US11 / 008,093, title“ Lung Volume Reduction Using Glue Compositions ”, filed December 8, 2004; US11 / 008,580, title“ Glue Composition for Lung Other methods described in any of the Volume Reduction “, filed December 8, 2004; and US 11 / 008,782, entitled“ Lung Volume Reduction Using Glue Composition ”, filed December 8, 2004 are also included.

  Further, in some preferred embodiments, the method for reducing lung volume does not damage epithelial cells within the lung tissue and may not cause, for example, scar tissue formation and / or fibrosis. It may not cause blast proliferation and / or may not cause collagen synthesis. In some preferred embodiments, the method seals and / or maintains a collapsed site of damaged lung tissue within the alveoli, more preferably within the dilated alveoli distal to the terminal bronchioles. In some preferred embodiments, the methods of the invention do not cause obstruction of the bronchial lumen of the subject's lungs. Without being limited to a particular mechanism, the method of the present invention seals the dilated air space rather than by attempting to (mechanically) block airflow to damaged lung tissue. Can reduce lung volume. That is, in a preferred embodiment, targeting of the different parts of damaged lung tissue by the coupled targeting moiety is distal to the collapsed area and not in any amount or any substantial amount of lung tissue, It serves to seal and / or keep the collapsed distal capsule without an exit. In a further preferred embodiment, without the use of a catheter and / or without the use of an endotracheal applicator and / or without the use of bronchoscopy (eg without the use of a bronchoscope) and / or abdominal cavity The lung volume reduction method of the present invention can be performed without the use of a mirror and / or without the use of open therapy, such as thoracotomy.

  In some preferred embodiments, the method for reducing lung volume can involve damage to lung tissue. For example, in some embodiments, a curing agent may be used as part of the composition of the invention to be administered, eg, the curing agent may be coupled to the targeting moiety of the invention. In some embodiments, the sclerosing agent may be administered alone; or it may be administered separately, simultaneously with, prior to, or after administration of the targeting moiety of the invention. The sclerosing agent can act to cause scar tissue formation and / or fibroblast proliferation, and / or collagen synthesis, and can promote sealing of areas of damaged lung tissue. Curing agents that can 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 can also be used in the practice of the present invention, optionally together with extracellular matrix components such as hyaluronic acid. See, for example, US Publication No. 2004/0047855.

  Collapse of the lung tissue, for example, collapse of the expanded air cavity with the composition of the invention bound therein, can also involve contraction and / or collapse of the first part or all of the subject's lungs. Such collapse can be achieved by any technique known in the art or disclosed herein. For example, contraction and / or collapse may involve the use of negative pressure from inside the lung and / or positive pressure from outside the lung. Also, in some embodiments, a preparation that induces and / or promotes contraction and / or collapse may be used, eg, an anti-surfactant, such as an agent that can increase the surface tension of alveolar coating fluid There is a physiologically acceptable solution containing For example, the anti-surfactant may be administered before, during and / or after administration of a composition comprising a coupled targeting moiety. For example, fibrin and / or fibrinogen may be used. In some embodiments, a saline lavage may be used to reduce the amount of surfactant naturally present in the lung. Other suitable surfactants that can be used to promote collapse and / or contraction include Triton x-100, veracant, corfoseryl, and / or palmitate; anionic surfactants such as sodium tetradecyl sulfate; bromide Cationic surfactants such as tetrabutylammonium and / or butyrylcholine chloride; nonionic surfactants such as polysorbate 20 (eg Tween 20), polysorbate 80 (eg Tween 80) and / or poloxamer; dodecyldimethyl (3-sulfopropyl) ) Amphoteric and / or zwitterionic surfactants such as ammonium hydroxide, inert salts; amines, imines and / or amides such as arginine, imidazole, povidin, tryptamine and / or urea; ascorbic acid, ethylene glycol , Methyl gallate, tannin And / or alcohols such as 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 thioureas; polymeric cyclic ethers such as calixarene, crown ethers, monensin, nonactin, and / or polymeric epoxides; cyclic and acyclic carbonates; organometallics such as naphthenates And manganese acetylacetonate); phase transfer catalysts (eg Aliquat 336); and radical initiators and radicals (eg di-tert-butyl peroxide and / or azobisisobutyronitrile) .

  Shrinkage and collapse can also be facilitated by the use of a washing solution that can interfere with, reduce, and / or remove any other part that could otherwise interfere with targeting. For example, in some embodiments, cross-linking can be facilitated by the use of antisecretory agents that interfere with and / or prevent mucus secretion in the lung or portions thereof. For example, the antisecretory agent may be administered before, during and / or after administration of a composition comprising a coupled targeting moiety. Examples of antisecretory agents that can be used include, for example, an anticholinergic agent moiety, atrony, and / or an atropine-like moiety. Removal of mucus or excess mucus from the lung, preferably from the dilated alveoli distal to the distal bronchioles, for example by lavage, also promotes binding of the coupled targeting moiety to the respective damage-correlated moiety Is possible. The present invention to mucous-coated walls in the bronchi, bronchioles, or alveoli in order that the targeting moiety of the present invention binds to each damage-correlated moiety and reduces, for example, and / or avoids slipping Adhesion of the composition can be promoted.

  In some embodiments, mechanical force may be used externally to push one region of the lung closer to another region, for example, to assist collapse of an expanded air space. For example, a portion of the lung lobe may be pressed externally using a device such as a balloon, air pressure, hand pressure, and / or paddle, net, tunable strap, or magnet. In some embodiments, such pressure is applied simultaneously to more than one side of the lung lobe. For example, local pressure (applenate) may be applied to more than one side using an endoscope and / or magnetic probe.

  In some embodiments, it is also possible to pull the first portion or all of the lungs together from inside, for example towards the user, for example using cables and hooks to grab and pull tissue. Other devices that can be used include capture devices, such as an expandable capture device assembly that can be layered; and / or later by being separated from the cable or wire after the lung tissue is pulled together, for example. An anchor that can remain is included. In some embodiments, it is also possible to place magnetic probes at different locations inside the lungs, where the probes attract each other, thereby causing one area of the lungs to move to the other area, eg, one bronchus Can be attracted to another bronchus. It is also possible to change the shape of such devices after insertion by using mechanical forces, for example by using a core wire or by activating NiTi devices after placement. In yet another embodiment, the lung or a first portion thereof is contracted transthoracically. Other methods and / or devices known in the art to promote lung collapse can also be used, see, eg, US Publication No. 2003/0070682.

  Preferably, such contraction and / or collapse occurs after the administered, coupled targeting moiety has given sufficient time to be distributed to the site of damaged lung tissue. In some embodiments, for example, contraction and / or collapse occurs about 2 to about 3 minutes after administration of the composition of the invention. Also, the lung or first portion thereof preferably allows recognition and / or binding of more than one coupled targeting moiety to the corresponding damage-correlated moiety at different sites of damaged lung tissue. It is allowed to remain in a contracted and / or collapsed state for a sufficient time to do. Depending on the type or types of targeting moiety used, the lung or first part thereof is 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. Or it can be kept collapsed. In some embodiments, the lung or first portion thereof can be kept contracted 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. is there.

  The second part of the lung may then be reinflated, in which case the second part comprises the first part or all of the lungs that have contracted and / or collapsed, but preferably all Not included. In a preferred embodiment, this second portion does not include at least some of the damaged lung tissue, which is due to the coupled targeting moiety bound to different sites of the damaged lung tissue. And / or remain sealed. The bond preferably keeps the collapsed area from re-expanding. In a more preferred embodiment, the majority of damaged lung tissue remains collapsed and / or sealed, while the majority of intact lung tissue remains functional. For example, at least about 60%, at least about 80%, and most preferably at least about 90% of damaged lung tissue collapses; whereas, less than about 40%, less than about 20% of intact lung tissue And most preferably less than about 10% does not collapse and / or re-inflate. Reduction in overall lung volume improves mechanical function, such as that of healthier and / or more stretchable tissue.

  In preferred embodiments, coupling of the coupled targeting moiety comprises at least about 0.5% overall lung volume reduction, at least about 1% overall lung volume reduction, at least about 1.5% overall lung volume reduction, at least About 2% overall lung volume reduction, at least about 3% overall lung volume reduction, at least about 4% overall lung volume reduction, at least about 5% overall lung volume reduction, at least about 10 % Overall lung volume reduction. In preferred embodiments, coupling of the coupled targeting moiety is less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20% lung volume reduction, or less than about 15% overall. Causes a decrease in lung volume. Such a reduction can be achieved upon single or multiple administrations of the composition of the present invention. A reduction in total lung volume of about 2% to about 3% can be expected to produce a beneficial effect in subjects receiving such treatment, for example, at least as much as occurs with LVRS. .

  In still preferred embodiments, the coupling between targeting moieties is permanent, or at least semi-permanent, and is a period between consecutive treatments described herein, eg, a period between administrations of the compositions of the invention. Resistant to biodegradation (eg hydrolysis). In certain embodiments, at least about 70%, at least about 80%, at least about 90%, or at least about 98% of the coupling between targeting moieties remains intact over a period of time. In some preferred embodiments, the period is at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 1 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 the most preferred embodiment, the coupled targeting moiety retains some collapsed lung tissue collapse and / or sealing for the rest of the life of the subject, eg resists biodegradation indefinitely. One skilled in the art will recognize that the persistence and / or biodegradability of the coupling between the targeting moieties may depend on the coupling technique selected and / or the coupling moiety used.

  In preferred embodiments, some or all of the coupling moieties are very strong and resist the mechanical pressure experienced in the lungs. For example, the range of tension corresponding to functional residual capacity during normal breathing is at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about at least about the coupling portion in some preferred embodiments. Does not cause 70%, at least about 80%, at least about 90%, or at least about 95% destruction.

  In some preferred embodiments, the coupling portion exhibits a tear strength of at least about 50 g / square cm, at least about 100 g / square cm, at least about 200 g / square cm, or at least about 300 g / square cm. In some preferred embodiments, the coupling moiety is less than about 5,000 g / square cm, less than about 3,000 g / square cm, less than about 1500 g / square cm, less than about 1300 g / square cm, less than about 1200 g / square cm, about It exhibits a tear strength of less than 1000 g / square cm, less than about 800 g / square cm, less than about 600 g / square cm, or less than about 400 g / square cm.

  Similarly, in a preferred embodiment, the binding interaction between the targeting moiety and its corresponding damage correlation moiety is permanent, or at least semi-permanent, and is a period between successive treatments described herein, eg, irreversibly Binds substantially irreversibly or at least with a high binding constant and resists dissociation during the period between administrations of the compositions of the invention. For example, the alpha-1 antitrypsin moiety can form a pseudo-irreversible equimolar complex with neutrophil elastase in some embodiments. See, for example, Sifers et al., “Genetic Control of Human Alpha-1 Antitrypsin”, Mol. Biol. Med., Vol. 6 pages 127-135 (1989). Without being limited to a particular theory or mode of action, the alpha-1 antitrypsin moiety can form an acyl-enzyme complex with its target. In some embodiments, binding can be further enhanced by genetic modification or by shuffling known binding domains. As another example, a serpin moiety can react with a target 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 the serpin and the target protease can also involve a covalent ester bond, where the active site serine residue of the protease is the serpin To form an acyl-enzyme complex. See, for example, US Publication No. 2003/0216321. As yet another example, the monocyte elastase inhibitor moiety can form a covalent complex and / or an essentially irreversible complex with elastase. See, for example, International Publication No. WO 96/10418 and US Pat. No. 5,827,672.

  In certain embodiments, at least about 70%, at least about 80%, at least about 90%, or at least about 98% of the targeting moiety remains bound to the corresponding damage correlation moiety over a period of time. In some preferred embodiments, the period is at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 1 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 the most preferred embodiment, the binding maintains some collapse and / or sealing of the damaged lung tissue for the rest of the life of the subject, eg resists biodegradation indefinitely.

  FIG. 1b illustrates one embodiment of a method for reducing lung volume using a composition comprising a first targeting moiety 104a and a second targeting moiety 104b, wherein the targeting moiety is coupled. This figure provides only an overview and is not intended to be limiting with respect to the present invention in any way. For example, those skilled in the art will readily recognize variations and modifications of the illustrated figures. The figure illustrates the terminal bronchiole 101 ending in the airspace of the alveoli 102. As mentioned above, the air space may over-expand and / or dilate in certain pulmonary conditions such as emphysema. A large amount of damage-correlated parts 103, 107 are found within the airway wall, for example at different sites of damaged lung tissue and / or within alveolar epithelial mucus.

  A composition of the invention is administered, where the composition comprises a first targeting moiety 104a and a second targeting moiety 104b, wherein the targeting moiety is coupled via, for example, coupling moiety 108. Yes. FIG. 1b illustrates how, after administration, one targeting moiety 104a recognizes and binds to the damage-correlated moiety 107.

  FIG. 1b also illustrates how the two targeting moieties recognize and bind to corresponding damage-correlated moieties at two different sites in the airspace. After contraction, the alveolar wall 102 is brought closer, and the second targeting portion 104b recognizes and binds to the damage-correlated portion 103 at different sites of damaged lung tissue. It becomes possible. The coupling of the coupled targeting moiety to the previously far-off damage-correlated moiety serves to keep the airway walls closer together. Alveoli that were previously dilated and / or dilated can thus remain collapsed and / or sealed after reinflation, thereby reducing lung volume.

  Another aspect of the present invention is to administer to a subject in need a composition comprising an imaging moiety coupled to a targeting moiety that targets damaged lung tissue and image the damaged lung tissue. Providing a method of imaging damaged lung tissue. The targeting portion has a greater damage correlation portion in the affected lung region compared to, for example, the lung region that is not affected by the lung condition or affected to a lesser extent As such, it acts to direct the administered composition to the site of damaged lung tissue. For example, when the alpha-1 antitrypsin moiety is used as a targeting moiety, the alpha-1 antitrypsin moiety is an elastase found in higher concentrations in certain lung conditions, such as emphysema, at sites of damaged lung tissue. It is recognizable and can be coupled to this. The imaging portion may then allow detection of damaged areas, preferably non-invasive and / or in vivo detection. For example, in emphysema, the method described herein can also be used to detect lung areas with dilated air spaces that have high amounts of elastase.

  Targeting the imaging portion to a site of damaged lung tissue, for example, by an unbound imaging portion of a region of the lung that is unaffected by a lung condition or affected to a lesser extent, It is also possible to help reduce “background”. In some preferred embodiments, the unbound targeting moiety may be removed from the lung, for example, by contraction and / or collapse, for example, prior to detecting the imaging moiety.

  In some embodiments, the imaging moiety is detected after allowing sufficient time to target the administered composition to an area of damaged lung tissue. In preferred embodiments, the targeting moiety recognizes and binds to the damage-correlated moiety in at least about 30 minutes, at least about 20 minutes, at least about 10 minutes, or at least about 5 minutes. In preferred embodiments, the targeting moiety is less than about 3 hours, less than about 2 hours, less than about 1 hour, less than about 45 minutes, less than about 30 minutes, less than about 15 minutes, or less than about 10 minutes and Recognize and bind to this.

  The imaging moiety may be imaged by any of the methods known in the art and / or described herein. For example, via traditional radiological techniques, including the use of X-rays, computed tomography (CT) and / or positron emission tomography (PET) scans, nuclear scans and / or scintigraphy, and magnetic Imaging through the use of more advanced techniques such as resonance imaging (MRI), functional magnetic resonance imaging (FMRI), magnetoencephalography (MEG), and single photon emission computed tomography (SPECT) It is feasible. Such imaging techniques may be used to detect bound imaging moieties in vitro or in vivo, preferably in vivo. A high resolution scan, such as a high resolution CT scan, is preferred. In a more preferred embodiment, such an imaging method yields a detailed map of the lung, for example, the site of damaged tissue and / or the degree of damage, depending on the relative amount of imaging moiety bound to various sites within the lung. Indicates.

  The detection method used may depend on the imaging moiety to be administered. For example, ultrasound imaging can be used to detect echogenic imaging portions and / or imaging portions and / or other ultrasound imaging portions that are capable of generating echogenic signals. X-rays can also be used to detect heavy atom imaging moieties (eg, having an atomic weight of about 38 or greater). Optical imaging can also be used to detect imaging moieties that can scatter and / or absorb and / or emit light. MR imaging can also be used to detect imaging moieties that contain non-zero nuclear spin isotopes (eg, F-19) and / or imaging moieties that have unpaired electron spins. It is also possible to detect radionuclide imaging moieties using PET, scintigraphy, and / or SPECT.

  For example, in some embodiments, an imaging moiety that includes a radioactive gamma releasing factor may be used and detected via a gamma camera, a scintillation counter, and / or other devices capable of detecting gamma radiation. It is also possible. Radiation imaging cameras can also use a conversion medium that absorbs high energy gamma rays and moves electrons, which emit photons as they return to a lower orbital state. Some cameras also help to produce an image by analyzing photons detected in the chamber, as well as a photoelectron detector placed in the spatial detection chamber, eg, determining the position of the emitted photons A circuit is also used.

  In embodiments using an imaging moiety that includes a magnetic species, such as a paramagnetic atom, the imaging moiety can be detected by MR imaging, for example, a magnetic resonance imaging system can be used. In such a system, it is also possible to parallel nuclear spin vectors of atoms such as paramagnetic atoms using a strong magnetic field at a damaged lung tissue site. The field can then be distributed by paramagnetic atoms at these sites. As the nuclei return to equilibrium parallel, images of damaged lung tissue sites can be obtained.

  FIG. 2 illustrates one embodiment of a method of imaging damaged lung tissue using a composition comprising an imaging moiety coupled to a targeting moiety that targets damaged lung tissue. This figure provides only an overview and is not intended to be limiting with respect to the present invention in any way. For example, those skilled in the art will readily recognize variations and modifications of the illustrated figures. The figure schematically illustrates the terminal bronchiole 101 ending in the airspace of the alveoli 102. As mentioned above, the air space may over-expand and / or dilate in certain pulmonary conditions such as emphysema. A large amount of damage-correlated portion 103 is found inside the airway wall, for example at the site of damaged lung tissue and / or in alveolar epithelial mucus.

  A targeting moiety 104 is administered wherein a composition of the invention is administered, wherein the composition targets damaged lung tissue, for example by recognizing and binding to the target injury-correlated moiety 103. including. In the illustrated embodiment, the composition also includes an imaging moiety (I) 201. FIG. 2 illustrates how the targeting moiety recognizes and binds to an injury-correlated moiety at various sites of damaged lung tissue. Detection of imaging portion 201 with an appropriate detection technique can provide an image of such damage, and preferably facilitates diagnosis of pulmonary conditions.

  The imaging methods described herein provide for the detection of damaged lung tissue and preferably diagnose and / or monitor the presence, degree, improvement and / or exacerbation of lung conditions such as emphysema. make it easier. The imaging methods described herein can also be used in combination with the therapeutic methods described herein, other methods currently known, and other methods that can be developed. For example, lung volume reduction may be performed after detection of an area of damaged lung tissue. Alternatively, area refers to a location suitable for placement of a one-way valve and / or the need to seal an area of damaged lung tissue using, for example, the compositions and / or methods described herein. Is also possible.

  Some embodiments of the present invention use both the imaging and volume reduction aspects of the present invention described herein. For example, damaged lung tissue can be imaged using a composition comprising an imaging moiety coupled to a targeting moiety. The degree of damage can also indicate whether further treatment is needed and / or desirable. Such further treatment can also include lung volume reduction by a cross-linking composition comprising a targeting moiety coupled to a cross-linkable moiety and / or by using a composition comprising a coupled targeting moiety. In some embodiments, the imaging moiety can be coupled to a targeting moiety, which itself is coupled to a crosslinkable moiety and / or one or more other targeting moieties. In some embodiments, a second composition comprising a targeting moiety coupled to a crosslinkable moiety and / or to one or more other targeting moieties may be used. Further, in some embodiments, lung volume reduction using, for example, the compositions and / or methods described herein, for example, precedes and / or can precede imaging. To determine the extent to which collapse and / or sealing has been achieved, for example in the area of damaged lung tissue, preferably the presence, location, degree and / or degradation of cross-linking and / or coupling moieties, And / or facilitates monitoring of the dissociation of the targeting moiety.

Washing is followed by administration of the composition comprising an imaging moiety, a crosslinkable moiety, a crosslinking activation moiety, other targeting moieties, and / or a targeting moiety coupled to any or all of the other moieties and / or agents. It is also possible. The term “washing” as used herein removes the targeting moiety from each damage-correlated moiety so that the damage-correlated moiety is available for further binding to, for example, subsequently added targeting moieties. Refers to the administration of a wash portion capable of facilitating For example, the cleaning step can be freed of the target site following administration and imaging of a composition comprising a targeting moiety coupled to the imaging moiety. After lavage, a composition comprising a targeting moiety coupled to a crosslinkable moiety and / or coupled to another targeting moiety is administered to a subject to achieve lung volume reduction, for example, by the methods described herein. It is also possible to do. Washing moieties suitable for use in the present invention include soluble damage-correlated moieties that are capable of competing with damage-correlated moieties at sites of damaged lung tissue, eg, for binding to targeting moieties. Preferably, the soluble damage correlative moiety is modified to reduce and / or eliminate undesirable properties prior to administration to a subject. For example, using a mutant elastase polypeptide that is still capable of binding to alpha-1 antitrypsin but is unable to degrade lung tissue or degrades lung tissue to a lesser extent than non-mutant elastase May be.
Formulations, routes of administration, and effective doses Several routes of administration or modes of administration are used to deliver targeting moieties, crosslinkable moieties, crosslinking activated moieties, and / or imaging moieties useful in the practice of the present invention to a subject. It is also possible. The moiety may be delivered per se or as a pharmaceutically acceptable salt. The term “pharmaceutically acceptable salt” retains the biological effectiveness, selected conformation and other desirable properties of the portions and / or agents of the present invention and is biologically or otherwise It means a salt that is not desirable in terms. These salts include 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, apple Salts with acids, citric acid, tartaric acid or maleic acid are included. Furthermore, if the moiety contains a carboxyl group or other acidic group, it may be converted to a pharmaceutically acceptable addition salt using an inorganic or organic base. Examples of suitable bases include sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

  For administering a targeting moiety, a crosslinkable moiety, a crosslinking activating moiety, an imaging moiety, and / or other moieties and / or agents, or pharmaceutically acceptable salts thereof, to a subject in need thereof, It can also be blended with an acceptable carrier. “Pharmaceutically acceptable carriers” are well known in the pharmaceutical industry and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (supervised by A. R. Gennaro 1985). Suitable carriers include carriers such as alcohol, DMSO, saline solution, and / or water. In a conventional manner, with one or more physiologically acceptable carriers, including excipients and / or adjuvants, that facilitate the processing of the active moiety into a pharmaceutically usable preparation. It is also possible to formulate a pharmaceutical composition for use according to the invention. Proper formulation is dependent upon the route of administration chosen.

  In some embodiments, the 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. It is also possible to perform the drying in such a way that the desired properties of the composition, for example the targeting moiety, retain the ability to recognize and / or bind to the targeted damage-correlated moiety. For example, vacuum concentration, spray drying, open drying, freeze drying and the like can be used. The resulting residue can then be ground and / or further pulverized.

  In some preferred embodiments, the targeting moiety, the crosslinkable moiety, the crosslinking activating moiety, and / or the imaging moiety, or a pharmaceutically acceptable salt thereof, and other moieties and / or agents, and / or the pharmacy thereof The physiologically acceptable salt is formulated as a dry powder that can be delivered to the lungs of a subject or as a physiologically acceptable aerosolized solution. Powder and / or liquid formulations may be prepared to facilitate administration, for example, from the delivery device, preferably down to the alveoli distal to the distal bronchioles to facilitate transport into the respiratory tract. Is possible.

  It is also possible to prepare the powder formulation in various ways using conventional techniques. It is also possible to process the powder formulation to improve its ability to be delivered to a subject, for example via inhalation and / or transthoracically. It is also possible to improve the manner in which the formulation flows and / or flows out through an inhalation device or other device, for example by forming agglomerates by dry granulation processing. Spherical aggregates can also provide excellent handling characteristics to the compositions of the present invention. However, it should be understood that the present invention contemplates the use of aggregates and / or other particles of all shapes, including both spherical and non-spherical types. The powder and / or liquid formulation also preferably has physical properties that help avoid clogging of the aerosol device and agglomeration of the aerosolized material. For example, additives such as alcohol, soaps, surfactants, and / or vitamin E can be used to help reduce aggregation and promote the formation of small particles and / or droplets. .

  It is also possible to produce a liquid formulation by adding a volume of sterile delivery solvent to an amount of powdered or liquid form of the sterile composition of the present invention. In some embodiments, compounding temperatures of at least about 0 ° C., at least about 4 ° C., at least about 5 ° C., at least about 10 ° C., or at least about 15 ° C. may be used. In some embodiments, compounding temperatures of less than about 100 ° C, less than about 80 ° C, less than about 60 ° C, less than about 37 ° C, or less than about 30 ° C may be used.

  It is also possible to prepare the formulations of the present invention to provide other suitable physiological parameters for use in the lung, including, for example, a suitable pH. For example, 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.

  In a preferred embodiment, the formulation comprises a targeting moiety, a crosslinkable moiety, a crosslinking activating moiety and / or an imaging moiety, and other moieties and / or agents, and / or pharmaceutically acceptable salt concentrations, sizes and The formulation results in a range of particle and / or droplet sizes that can be delivered to the lung when selected, such as viscosity, aerosolized and / or nebulized. For example, providing a rheological profile. With a suitable milling device, such as a jet milling device, in a size range that facilitates or preferably maximizes access to sites of damaged lung tissue, including sites distal to the distal bronchiole Particles can be produced. In some embodiments, nozzles that include tapered holes can be used, for example, to increase the uniformity of the aerosol produced. See, for example, US Publication No. 2004/0124185.

  In a more preferred embodiment, a formulation is prepared that allows for respiratory zone or deep lung delivery. In such embodiments, the formulation can produce a range of particle and / or droplet sizes adapted for delivery to the deep lung. In an even more preferred embodiment, the formulation comprises a targeting moiety, a crosslinkable moiety, a crosslinking activating moiety and / or an imaging moiety, and other moieties and / or agents, and / or pharmaceutically acceptable salt concentrations thereof, Be able to be delivered to the alveoli, preferably to the alveoli distal to the terminal bronchioles when selected, such as size and / or viscosity, is aerosolized and / or nebulized It involves causing a range of particle and / or droplet sizes to be generated by the formulation.

  By selecting appropriate delivery devices, molecular weights, concentrations, and / or additives as known in the art and / or as described herein, droplets and / or particles in an appropriate size range It is also possible to obtain See, for example, US Publication No. 2002/0086842. For example, various formulations can be screened to determine those that produce a desired range of droplets and / or particle sizes.

  In a preferred embodiment, the composition of the invention is administered via the respiratory tract, for example via inhalation. The term “inhalation” includes inhalation through the mouth, nose, trachea, or a combination thereof. Pharmaceutical formulations for administration via inhalation can be made according to techniques known in the pharmaceutical industry and administered via aerosol inhalation, dry powder inhalation, liquid inhalation, and / or instillation. For example, a diagnostically and / or therapeutically effective amount of a composition of the invention can be delivered by inhalation of a breathable mist by an animal subject.

  The preparation of inhalable formulations is known in the art, see for example US Publication No. 2003/0232019 and International Publication No. WO 2004/054556. For example, the composition of the present invention can be formulated with a respirable fluorocarbon propellant. Inhalable preparations preferably provide droplets and / or particles with a 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 have a median mass distribution size of less than 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 Of droplets and / or particles. The particle and / or droplet size is preferably between about 2 microns and about 5 microns.

  The size may be selected to allow the composition of the present invention to access sites of damaged tissue within various lung areas. The respiratory system can be divided into three areas: (i) tracheal / pharyngeal area, (ii) bronchial area, and (iii) alveolar area. Droplets and / or particles from about 10 microns to about 50 microns typically migrate to the trachea / pharynx and / or lung bronchial area; while from about 0.5 microns to about 5 microns droplets and / or Particles, such as droplets and / or particles of about 2 microns, typically migrate to the alveolar area. Larger sizes cannot reach the alveoli less effectively through the distal bronchioles. Smaller droplets and / or particles can be exhaled by the subject before the targeting moiety contacts its damage-correlated moiety. It is also possible to measure the droplet and / or particle size of the compositions of the present invention by techniques known in the art, including, for example, those described herein.

  A variety of physical parameters can be used to facilitate access of the composition of the present invention to various sites of damaged tissue in the lung. For example, aerodynamic median particle size (MMAD), usually expressed in microns, can be used to predict where droplets and / or particles are distributed in the lung. It is also possible to measure the aerodynamic median particle size using a cascade impactor for the composition size of the present invention. A humidified cascade impactor is preferably used to better reflect the status of pulmonary delivery. It is also possible to measure the particle size distribution, for example using a Malvern laser. Geometric standard deviation (GSD) is another parameter that can be used. A GSD of about 1 correlates with a normal distribution. A GSD of less than about 1 can exhibit a narrow size variance, while a GSD greater than about 1 can exhibit a wide size variance. These parameters are further influenced by the ability of the targeting moiety of the composition of the invention to recognize and / or bind to its target damage-correlated moiety.

  It is also possible to use the charge to promote aerosol formation. For example, in some embodiments, droplets and / or particles can be created to carry a negative charge. Similar charges repel each other, helping the particles and / or droplets to disperse in the aerosol cloud, for example by electrostatic forces. Similar positive charges on particles and / or droplets can also be used in a similar manner.

  Animal models can also be used to determine the appropriate range of droplets and / or particle size for delivery of the composition of the invention to damaged lung tissue, for example Raabe et al., See Ann. Occup. Hyg., Vol. 32, pages 53-63 (1998), investigating particle size access to various regions of the lung in experimental animals.

  It is also possible to aerosolize a solution or liquid formulation to form a respirable mist via devices such as inhalers, nebulizers, and / or atomizers. In some embodiments, the formulation is a dry powder, which can be configured, for example, in a saline or water solution prior to aerosolization. In some further embodiments, by devices such as intra-alveolar devices (IADs), air gun powered aerosol chambers, and / or other dry powder delivery devices such as Dura Delivery Systems and / or Glaxo Wellcome, It is also possible to deliver the dry powder itself.

  It is possible to aerosolize the compositions of the present invention by any technique known in the art and described herein and / or developed by one skilled in the art. For example, the composition can be pressurized through the micropores and then blown through an in-line blower such as a high pressure fan system. The fan or pump is preferably timed consistently with the time of inspiration or just before inspiration. In some embodiments, it is possible to meter the delivery of the composition, for example, as a function of inflow volume.

  The aerosolized composition can be delivered by any method known in the art and / or described herein. For example, the composition can be insufflated directly under pressure, into the bronchi and / or into an expanded air space. In some embodiments, the catheter can be used to draw air from a less distal lumen of the lung through another route. In some embodiments, the first catheter is used to inflate the composition into the dilated air space, while the second catheter draws air through another route, eg, from another bronchial branch. Thus, it is possible to obtain a circulation flow path. In yet another approach, the flow around a catheter or other infusion device is blocked using balloons, coated blazed structures, expandable foam, flaps that create a one-way valve, and / or expandable corrugation. It is also possible to do.

  It is also possible to administer the compositions of the invention via inhalation using a portable (eg handheld) inhalation device, such as a device used to deliver an anti-asthma or anti-inflammatory agent. For example, a fine dry powder may be delivered as an aerosol by compressing air into the powder inside the inhaler. It is also possible to disperse the powder as a cloud of particles, preferably in a size range that allows access to the alveoli distal to the distal bronchioles.

  In some embodiments, the inhalation device is designed to deliver single or multiple doses to minimize the risk of accidental large doses, and from light, excessive humidity, and / or other contaminants It is also possible to protect the formulation. It is also possible to administer the composition of the present invention to the lung air passage of a subject in need using a dry powder and a metered dose inhaler. The metered dose inhaler can deliver the drug in a dispersed and / or solubilized form. These inhalation devices can also contain relatively high vapor pressure propellants that push the aerosolized material into the respiratory tract upon activation of the device.

  Some embodiments involve delivery by nebulization to the lung, where, for example, the delivery device can be a nebulizer. For example, it is possible to use an atomizer that produces an aerosol containing the composition of the invention, preferably an aerosol of droplets and / or particles smaller than about 10 microns. Nebulizers are known in the art and can be, for example, air or liquid jet nebulizers; ultrasonic nebulizers; compressed air nebulizers (eg AeroEclipse, Pari LC, Parijet; and / or Whisper Jet) and / or It can also be a pressure mesh sprayer. Compressed air atomizers can generate droplets by crushing a liquid stream with rapidly moving air. Ultrasonic nebulizers can atomize solutions using ultrasound, for example using a piezoelectric transducer, by converting the current into mechanical vibrations; while pressure mesh nebulizers are under pressure to liquid Pass through a mesh-like surface. The nebulizer can 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 can use pressures of less than about 60 psi, less than about 50 psi, or less than about 40 psi. For administration using a nebulizer, the subject can inhale the aerosolized composition of the invention via continuous nebulization, for example, in a manner similar to that used to administer an aerosolized bronchodilator. . For example, aerosols may be delivered via tubing or mask to the mouth and / or nose and by using Ambu bags, blow-by masks, endotracheal tubes, nasal cannulas, nasal covers, and / or non-rebreathers. .

  A volume flow rate (l / min) suitable for the nebulizer can be selected. It is preferred that the volumetric flow does not exceed twice the subject's ventilation since the average inspiration is about twice the volume of breath with exhalation and inspiration, each corresponding to about half of the respiratory 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 can be used. It is also possible to select the nebulizer to produce the desired range of particle sizes and / or droplet sizes. As will be appreciated by those skilled in the art, a variety of factors can be considered along with the volume flow rate. These factors include aerosol mass output (mg / l) and / or retention volume (ml). For example, for a compressed air atomizer, factors such as air flow, hole diameter, and / or air pressure can affect the size distribution. For ultrasonic nebulizers, factors include air flow velocity, hole diameter, and / or ultrasonic frequency.

  Administration can also involve delivery of the aerosolized droplets and / or powders of the invention under positive pressure ventilation. For example, a device such as a continuous positive airway pressure device can be used to provide ventilatory assistance. This aid may facilitate the access of the composition of the present invention to damaged tissue sites in the alveoli of the deep airways. In addition, positive end-breath pressure can be used to provide further assistance in this regard. In some embodiments, a device that delivers a composition of the present invention when a subject produces a level of negative inspiratory pressure, eg, at an inspiratory flow rate, may be used.

  Other devices that can be used include, for example, small containers adapted to contain a preparation comprising the composition of the invention under pressure. The small container, for example, features a valve for controlling the delivery of the preparation; a nozzle connected to the valve for converting the pressurized preparation inside the small container into an inhalable aerosol mist upon valve actuation. Is also possible. See for example US Publication No. 2002/0086852. Other devices for delivering the composition of the invention to the lungs of a subject in need include a spray atomizer.

It is also possible to deliver the compositions of the invention in a non-aerosolized form. Furthermore, a combination of aerosol type and / or non-aerosol type can also be used.
For example, solutions, suspensions, viscous liquids, liquid films, slurries, foams, and / or thicksotropiec type (s) can be used. Any of these types can be delivered to the lung by any of the techniques known and developed in the art and / or described herein. For example, solutions, suspensions, viscous liquids, liquid films, slurries, foams, and / or thixotropic forms may be administered by liquid lavage, liquid ventilation, bolus drops, and / or lung lavage. In some embodiments, a fluorochemical medium may be used.

  Administration solutions include, for example, physiologically acceptable solutions of the targeting moieties, crosslinkable moieties, crosslink activating moieties and / or imaging moieties (and / or other moieties and / or agents) of the present invention. May be. After delivery to the lung or first portion thereof, the solvent is evaporated so that the targeting moiety, the crosslinkable moiety, the crosslinking activating moiety and / or the imaging moiety (and / or other moieties and / or agents) remain behind And / or dissipate.

  Further, in some embodiments, the composition may be delivered as a solid, semi-solid, solid film, hydrogel, agar, and / or sol-gel. For example, the compositions of the present invention may be administered as an absorbable sponge, such as an absorbable gelatin sponge (eg, GelfoaMTM) and / or as an absorbable wax. Non-absorbable waxes can also be used. Further, in some embodiments, petroleum based compounds (eg, petroleum jelly), latex, natural or synthetic rubber, starch, and / or alginic acid compounds may be used in formulating the compositions of the present invention.

  In some embodiments, the compositions of the invention are delivered to the lungs via instillation, for example through the airway, eg, direct instillation through the front of the airway. The compositions of the present invention may be administered as a solution, including for example water or an aqueous solution containing buffered physiological solutions such as saline. Instillation may be administered over a period of at least about 2 minutes, at least about 5 minutes, or at least about 10 minutes. The drip period can be less than about 30 minutes, less than about 20 minutes, or less than about 15 minutes. The length of the drip time can be selected based on several factors, including the composition used, the degree of damage, and the like. Instillation can also involve delivery via bronchoscopy and / or endoscopy.

  For example, impregnated applicator tips such as US Pat. No. 5,928,611; and / or applicators for delivering liquid and / or semi-liquid compositions via laparoscopic and / or endoscopic methods, such as US Pat. No. 6,494,896. Other techniques for delivering the compositions of the present invention to damaged lung tissue can also be used. Fibers, microfibers, latticework stents, gold wire designs, and / or porous structures, for example, whose structures are coated with the composition of the present invention, can also be used.

  It is also possible to deliver the compositions of the invention via transthoracic administration. For example, in some embodiments, the airspace may be targeted directly through the ribs, for example through a scope, for more controlled localization. Transthoracic delivery may involve percutaneous delivery to the pleural cavity using a needle and / or using a catheter and / or thoracic tube. In some embodiments, the composition may be delivered via bronchoscopy and / or the use of an endotracheal tube. However, such aspects are less preferred as discussed above. It is also possible to deliver the composition of the present invention to the lungs during liquid ventilation or lung lavage using a fluorochemical vehicle.

  It is also possible to administer the composition of the invention intravenously. For example, the pharmaceutical composition and / or diagnostic composition of the present invention can be formulated with a pharmaceutically acceptable carrier to provide a sterile solution or suspension for administration via injection. . The injectable material is prepared in a conventional manner, for example as a solid form suitable for making a solution or suspension in a liquid before suspension, and / or injection and / or as an emulsion. It is also possible. Suitable excipients that can be used include, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride and the like. In some embodiments, injectable pharmaceutical compositions may contain auxiliary substances such as wetting agents, pH buffering agents, and the like. For example, a carbonate / bicarbonate buffer system may be used.

  In some embodiments, a delivery vehicle is used to administer the composition of the invention. “Delivery vehicle” as used herein refers to any particle that can be used to carry a composition of the invention. Examples of delivery vehicles include, but are not limited to, liposomes, viruses, bacteriophages, cosmids, plasmids, and fungal vectors, and other recombinant vehicles typically used in the art.

  The delivery vehicle may carry the composition of the invention encoded by the polynucleotide sequence. Expression of the sequence can produce a composition, eg, a fusion polypeptide of two or more coupled targeting moieties.

  Vectors that contain both a promoter and a cloning site into which a polynucleotide can be operably linked are well known in the art. Such vectors can transcribe RNA in vitro or in vivo and are commercially available from sources such as Stratagene (La Jolla, Calif.) And Promega Biotech (Madison, Wis.). To enhance in vitro transcription and / or expression, the 5 ′ and / or 3 ′ untranslated portion is removed, added, and / or modified to an excess, potentially inappropriate alternative translation initiation codon, or It may be necessary to remove other sequences that can interfere with or reduce expression at either the transcriptional or translational level. In some embodiments, a consensus ribosome binding site can be inserted immediately 5 'of the start codon to enhance expression.

  In some embodiments, viral vectors may be used. Viral vectors can include naturally occurring or recombinantly produced viruses or viral particles containing the polynucleotide to be delivered, either in vivo, ex vivo or in vitro. Examples of viral vectors include baculovirus vectors, retrovirus vectors, adenovirus vectors, adeno-associated virus vectors and the like. Viral vectors can enter host cells via their normal infection mechanisms, or bind to different host cells, for example by binding to different surface receptors or ligands and entering different host cells. It is also possible to be modified.

  The delivery vehicle may also include non-viral vectors, including liposome complexes. Liposomes can also include an aqueous concentric layer attached to a hydrophobic or lipidic layer. The hydrophobic layer can also contain, for example, phospholipids such as lecithin and sphingomyelin, steroids such as cholesterol, and ionic surfactants such as dicetiphosphate, phosphatidic acid, stearylamine and the like. A variety of liposome complexes known in the art can be used to assist in delivering the compositions of the invention to the lung in aerosol and / or non-aerosol formulations. For example, a microparticle formulation may be used in which a compound having a biocompatible hydrophobic domain is combined with a conjugate having both a hydrophobic region and a hydrophilic region. See, for example, US Pat. No. 6,500,461. In some embodiments, lipid vesicles comprising a bilayer with a salt form of an organic acid derivative of a sterol, for example as described in US Pat. No. 6,352,716 may be used. In some embodiments, the use of liposomal complexes, for example, can be used to ensure that the composition is intact and / or necessary for recognition and / or binding to damage-correlated moieties and / or suitable contributors involved in these. By keeping it home, delivery of the composition of the invention can be facilitated.

  In some further embodiments, the liposomes containing the composition of the invention are coated with a hydrophilic polymer chain, such as a hydrophilic agent, eg, polyethylene glycol (PEG). Examples of PEG-liposomes are known in the art, see for example US Publication No. 2003/0138481 and US Publication No. 2003/0113369. In some embodiments, the targeting moiety can be coupled to the exposed PEG chain to facilitate targeting of the damage-correlated moiety. In some embodiments, the hydrophilic chain can also temporarily shield the targeting moiety from interacting with its target damage correlation moiety. Such liposomes are described, for example, in US Publication No. 2004/0009217.

  In some embodiments, the liposomal complex can facilitate targeted delivery to areas of damaged lung tissue. For example, by incorporating the peptide-lipid conjugate into a liposome, for example, in the vicinity of a lesion-correlated moiety, e.g., unaffected by a lung condition, or compared to a region of the lung that is affected to a lesser extent, It is also possible to selectively destabilize the liposomes in the affected lung region near higher concentrations of elastase or other damage-correlated parts. See, for example, peptide-lipid conjugates described in US Pat. No. 6,087,325.

  Delivery vehicles can also include other delivery systems associated with membranes (eg, biocompatible or biodegradable membranes), including dendrimer based methods and compositions for targeted delivery, for example. Things are included. See, for example, US Publication No. 2004/0120979. See also, eg, US Publication No. US2003 / 0064050, which describes dendritic polymer conjugates useful as drug delivery systems. For example, dendritic polymer conjugates useful as delivery systems in the practice of the invention can include dendritic polymers coupled to targeting moieties described herein.

  In some embodiments, the solubility and / or pharmacological compatibility of targeting moieties, crosslinkable moieties, cross-linking activating moieties and / or imaging moieties, and other moieties and / or agents, for example, by increasing hydrophobicity A composition of the present invention may be used with a portion that increases the properties. For example, in some embodiments, absorption enhancing preparations (eg, the liposomes described above) may be utilized. The parts that can be co-administered to achieve these effects include, for example, amphotericin B, betamethasone valerate, beclomethasone, cortisone, dexamethasone, DPPC / DPPG phospholipid, doxorubicin, estradiol, isosorbide dinitrate, nitroglycerin, prostaglandin , Progesterone, testosterone, and / or vitamin E, and / or any ester thereof.

  A composition for use in treating and / or detecting a pulmonary condition preferably has a low level of toxicity during the period of use and is preferably sterile. Sterilization can be accomplished by techniques known in the art, and these techniques include, for example, chemical methods, physical methods, and / or radiation methods. Physical methods include aseptic filling, filtration, use of heat (dry or wet) and / or retort canning. Sterilization irradiation methods can also include gamma irradiation, electron beam irradiation, and / or microwave irradiation. Preferred methods are dry and wet heat sterilization and electron beam irradiation. Different parts of the invention can be sterilized separately, for example to form a final sterile composition, as described, for example, in EP 1433486.

  Preferably, the 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 can also be used, including but not limited to hydroquinoline, pyrocatechol, resorcinol, 4-n-hexylresorcinol, captan (ie 3α, 4,7,7α-tetrahydro- 2-((trichloromethyl) thio) -1H-isoindole-1,3 (2H) -dione), benzalkonium chloride, benzalkonium chloride solution, benzethonium chloride, benzoic acid, benzyl alcohol, cetylpyridinium chloride, chloro Butanol, dehydroacetic acid, o-phenylphenol, phenol, phenylethyl alcohol, potassium benzoate, potassium sorbate, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, thimerosal, thymol, phenylmercury compounds such as boric acid Phenylmercury, nitric acid Formaldehyde generators such as phenylmercury and phenylmercuric acetate, formaldehyde, and preservatives Germall II.RTM. And Germall 115.TM. (available from imidazolidinyl urea, Sutton Laboratories, Chartan, NJ), and the like. Furthermore, preferred preparations contain non-toxic concentrations of toxins, such as heavy metals, for example using established standards for UPS water for inhalation.

  The present invention also includes diagnostic and / or pharmaceutical compositions for storage prior to administration. Such compositions preferably contain preservatives and / or stabilizers. For example, sorbic acid and / or esters of hydroxybenzoid acid may be added. In addition, antioxidants and suspending agents may be used.

  The pharmaceutical and / or diagnostic compositions useful in the present invention can also include stabilizers, for example to reduce immature crosslinking. Stabilizers can include, for example, gas phase stabilizers such as anionic gas phase stabilizers, and / or liquid phase stabilizers such as an anionic liquid phase stabilizer. Such stabilizers may also include radical stabilizers and / or mixtures of various stabilizers, preferably in which case the mixture does not interfere with the desired reaction and delays it. And / or do not disturb. See, for example, US application Ser. No. 09 / 099,457.

  If necessary or desired, the compositions of the invention may be administered in combination with one or more other therapeutic agents. The choice of therapeutic agent that can be co-administered with the composition of the invention will depend, in part, on the condition being treated and the desired effect to be achieved. Coupling of such agents to the targeting moiety of the present invention may improve efficacy, for example, by targeting the agent to a site of damaged lung tissue.

For example, the composition can be administered with other therapeutic agents, including growth factors, anti-surfactants and / or antibiotics, or small molecule or polypeptide agents. Examples of usable growth factor, fibroblast growth factor, transforming growth factor-beta _1, and / or platelet-derived growth factor (PDGF), as well as their functional analogs. Determination of the dosage range is well within the knowledge and / or skill of one of ordinary skill in the art, eg, from about 1 to about 100 nM polypeptide growth factor can be used.

  Examples of antibiotics that can be used include ampicillin, sisomycin, cefotaxime, gentamicin, penicillin, nebasetine and the like. Further, in some embodiments, an antimicrobial agent, antiviral agent, antiseptic, bacteriocin, bactericidal agent, anesthetic agent, antifungal agent, anti-inflammatory agent, or other active agent, or a mixture thereof, It may be administered with the composition. These compounds include acetic acid, aluminum acetate, bacitracin, zinc bacitracin, benzalkonium chloride, benzethonium chloride, betadine, captan (ie 3α, 4,7,7α-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, sertrimid, chloride Cetylpyridinium, chlorobutanol, chloramine T, chlorhexidine phosphanylate, chlorhexidine, chlorhexidine sulfate, chloropenidine, chloroplatinic acid, ciprofloxacin, clindamycin, clioquinol, cresol, chlorocresol, Sisostafin, dehydroacetic acid, doxorubicin, formaldehyde, gentamicin, hydroquinone, hydrogen peroxide, iodinated polyvinylidone, iodine, iodophor, imidazolidinyl urea, minocycline, mupirocin, neomycin, neomycin sulfate, nitrofurazone, non-oninol 9, o-phenylphenol, phenylmercury 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 (eg alkylparabens and salts thereof such as butylparaben) Ethylparaben, methylparaben, methylparaben sodium, propylparaben, propylparaben sodium and / or pyrocatechol), quinoline / thiourea, rifampin, rifamycin, resorcinol, 4-n-hexylresorcinol, 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, sphingolipid, sulfone Amides, tetracyclines, sulfadiazine salts (eg, silver, sodium, and zinc), thimerosal, thymol, tiotropium bromide, zinc oxide, and the like, and combinations thereof can also be included.

  Other drug parts that can be co-administered include, for example, antioxidants, atropine methyl nitrate, albuterol sulfate (salbutamol), acetylcysteine, anticholinergics, atrial natriuretic peptide, vitorterol mesylate, beta agonist, other bronchi Extending agents such as isoethalin, methylxanthine, captopril, calcitonin, cromolyn sodium, cyclosporine, ephedrine sulfate, ephedrine ditartrate, epidermal growth factor, etoposide, fluroisolide, heparin, ibuprofen, insulin, interferon, isoetaline hydrochloride, insulin, Interleukin-2, isoetarine mesylate, isoproteranol hydrochloride, isoproteranol sulfate, leukotriene inhibitor, lipase inhibitor, lipocortin, lung boundary Surfactant protein, mast cell stabilizer, metaproteranol sulfate, narcotic, n-acetylcysteine, pentamidine, non-steroidal anti-inflammatory drug (NSAID), peptide, phosphodiesterase inhibitor, phospholipase inhibitor, plasma factor 8, Procaterol, propranolol (propranalol), plumozyme (Genentech), P2Y2 receptor agonist, steroid, superoxide dismutase, terbutaline, terbutaline sulfate, theophylline, tissue plasminogen activator (TPA), tobermycin, tumor necrosis Factors, vasopressin, and / or verapamil are included.

  Furthermore, the compositions can also be administered with nucleic acids, eg, nucleic acids encoding polypeptides, antisense oligonucleotides, or interfering RNA (eg, siRNA). The composition of the present invention may also serve as a “depot” for slow release of a therapeutic moiety or other active agent at a site of damaged lung tissue.

  All formulations for aerosol, transthoracic, instillation, intravenous and / or other administration can be formulated in dosage forms suitable for administration. Diagnostic and / or pharmaceutical compositions suitable for use in the present invention include compositions in which a moiety is present in an effective amount, ie, a diagnostic and / or pharmaceutically effective amount. A diagnostically effective amount includes an imaging moiety that allows detection of the presence of the imaging moiety, preferably in damaged lung tissue, and more preferably by non-invasive and / or in vivo imaging techniques. A sufficient amount of the composition is included. A pharmaceutically effective amount includes a therapeutic moiety in the at least one pulmonary condition being treated with a composition comprising a targeting moiety, a crosslinkable moiety, a crosslinking activating moiety (and / or other moieties and / or agents). An amount sufficient to produce a prophylactic benefit is included. It is also possible to administer the effective amount in a single dose or in a series of doses separated by appropriate time intervals, eg minutes, hours or days. The actual amount effective for a particular application is the lung condition to be detected and / or treated, the route of administration used, the targeting moiety to be used, the crosslinkable moiety, the crosslink activating moiety, the imaging moiety, and It will depend on the identity of other parts and / or agents and other considerations as would be recognized by one skilled in the art. Determination of an effective amount is well within the capability of those skilled in the art, especially in light of the disclosure herein.

  When referring to a composition comprising a targeting moiety, a crosslinkable moiety, a crosslinking activating moiety, an imaging moiety, and / or other moieties and / or agents, an effective amount is generally a variety of medical or pharmaceutical industries. It may mean a dosage range, mode of administration, formulation, etc., recommended or approved by a supervisory or advisory organization (eg FDA, AMA) or by the manufacturer or supplier. When referring to producing benefits in treating a pulmonary condition such as emphysema, effective amounts are generally determined by various supervisory or advisory organizations (eg, FDA, AMA) in the medical or surgical industry, or It will mean an amount that achieves clinical lung volume reduction as recommended or approved by the manufacturer or supplier.

  A person of ordinary skill in the art will use techniques known in the art to target, crosslinkable, cross-linking activating, imaging, and / or other portions and / or agents of the composition to be administered. The effective amount of can be determined. The effective amount may depend on the moiety and / or agent to be used, and the known data such as the binding constant for the targeting moiety, the concentration at which the crosslinkable moiety and the crosslinking activating moiety achieve crosslinking, and detection. It can be inferred from data on the imaging part sufficient to make it possible.

  In some embodiments, the dosage is at least about 0.001 μg / kg / body weight, at least about 0.005 μg / kg / body weight, at least about 0.01 μg / kg / body weight, at least about 0.05 μg / kg / body weight, or at least about 0.1 It can also be μg / kg / body weight. In some embodiments, the dosage is 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 of the composition of the invention. , 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. In some embodiments, the dosage is 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, about 100 mg of the composition of the invention. It can be less than / kg / body weight, less than about 150 mg / kg / body weight, or less than about 200 mg / kg / body weight.

The dosage can vary depending on the part used and the known biological properties. For example, fibrinogen is known to constitute about 2 to about 4 g / l plasma protein, and fibrinogen is cleaved to fibrin when exposed to thrombin at the start of the clotting cascade. Prepare a formulation containing useful concentrations of fibrinogen and / or fibrin as a crosslinkable moiety and thrombin, batroxobin, thrombin receptor agonist, and / or calcium as a crosslinkable activating moiety in connection with lung volume reduction It is also possible. For example, 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 Formulations can be used (eg, in saline, eg, about 0.8%, about 0.9%, about 1%, or about 1.2% saline), and at least about 0.5, at least about 1, per ng fibrinogen At least about 5, at least about 10, or at least about 12 units of thrombin, 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 (eg, CaCl ₂ Can be used to activate this formulation. Some embodiments may use preparations of less than about 40 mM, less than about 30 mM, or less than about 20 mM calcium (eg, in a CaCl ₂ solution). Furthermore, it is also possible to promote cross-linking with 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 transglutaminase. Formulations of fibrin-based compositions to achieve crosslinking are also known in the art, for example, and greater than about 10 mg / ml, greater than about 20 mg / ml, greater than about 25 mg / ml, or about 50 mg. It is possible to contain more than / ml. Fibrin-based compositions useful in the practice of the present invention 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. Is also possible. See other fibrin sealant compositions, for example as provided in US Pat. No. 5,739,288.

  In addition, an effective amount for use in humans may be determined from animal models such as mice, rabbits, dogs, sheep, or pigs. For example, emphysema is described, for example, in a paper in Ingenito et al., Tissue heterogeneity in the mouse lung: effects of elastase treatment, Press. J Appl Physiol (March 12, 2004). 10.1152 / japplphysiol.01246.2003, It can be induced in C57BL / 6 mice by administering nebulized porcine pancreatic elastase (about 30 IU / day, about 6 days). Similarly, an emphysematous condition can be induced in sheep exposed to papain (7,000 units / week of inhalation for 4 consecutive weeks). Emphysema can also be induced in animal models by exposure to cadmium chloride, high concentrations of oxygen, and / or tobacco smoke. Ingenito et al., “Bronchoscopic lung volume reduction using tissue engineering principles”, American Journal of Respiratory and Critical Care Medicine, Vol. 167 771-778 (2003). In animal models, based on doses found to be effective in reducing lung volume and ensuring space for expansion of remaining intact or healthier tissue In humans, it is also possible to formulate a dose suitable for sealing damaged lung tissue. Other techniques will be apparent to those skilled in the art. Further, administration comprising a crosslinkable moiety and / or a coupled targeting moiety so as to avoid local hydrostatic pressure above capillary perfusion pressure, which may lead to abscess formation, so that it is not so high as to produce high local hydrostatic pressure It is also possible to select the amount of the composition.

  Similarly, it is possible to formulate doses for imaging damaged tissue in humans based on the amount used for imaging in the lungs of appropriate animal models. It is also possible to prepare a diagnostic composition comprising a targeting moiety and an imaging moiety using a pharmaceutically acceptable carrier and a diagnostically effective amount of the composition. The diagnostically effective amount required as a dose that allows imaging is the route of administration, the condition being treated, the targeting moiety being used, the imaging moiety being used, and the diagnostic details to be obtained, as well as medicine Other factors as will be recognized by those skilled in the diagnostics industry will depend. One of ordinary skill in the medical diagnostic arts can readily determine an appropriate dosage, particularly in light of the disclosure provided herein.

  In preferred embodiments, the dosage for imaging is sufficient to detect the presence of the imaging moiety at the site of damaged lung tissue. For example, in some embodiments, radiological imaging may require providing an imaging moiety with a dose of at least about 3 μC, at least about 5 μC, or at least about 10 μC. In some embodiments, radiological imaging may require providing an imaging moiety having a dose of less than about 30 μC, less than about 20 μC, or less than about 15 μC. Some embodiments using magnetic resonance imaging are 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 relative to the body weight of the subject. A dose of imaging moiety of mmol / kg, at least about 0.1 mmol / kg, at least about 0.5 mmol / kg, or at least about 1 mmol / kg may be required. In some embodiments, the magnetic imaging is 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 the subject's body weight. May require a dose of fluorinated moiety. As a further example, iodine may be used as the imaging moiety at 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 composition. The iodine imaging moiety can be a dose of less than about 20 mol percent, less than about 15 mol percent, less than about 12 mol percent, or less than about 10 mol percent of the administered composition.

The exact dosage will be determined by the practitioner, in light of factors related to the subject that requires diagnosis and / or treatment. Factors that can be taken into account include the severity or degree of lung condition, the subject's general health, the subject's age, weight, and diet, and the timing and frequency of administration, available to the subject Reaction sensitivity, allergy, tolerance and / or response to other diagnostic and / or therapeutic techniques, and composition (s) of the invention, and / or desirable and / or used in a subject. included.
EXAMPLE In accordance with the present invention, in an experimental model for imaging damaged lung tissue and / or reducing lung volume, a targeting moiety coupled to a crosslinkable moiety and coupled to an imaging moiety It is also possible to administer the composition comprising the rabbit. In this example, the targeting moiety includes an alpha-1 antitrypsin moiety that is covalently coupled to the fibrinogen moiety and covalently coupled to the Tc-99m moiety. Fibrinogen and Tc-99m moieties each couple to a region of the alpha-1 antitrypsin moiety other than around the Ser358 inhibitory site of alpha-1 antitrypsin, and crosslinking occurs using the thrombin moiety.

  An emphysema-like condition can be induced in rabbits as follows. Under light anesthesia, pig elastase can be administered to rabbits through an endotracheal tube and via a nebulizer. This treatment is repeated once a week for 4 weeks. A detailed lung function test is performed under anesthesia before and after 4 weeks of treatment to determine a baseline. Rabbits can be divided into two groups, a test group and a control group.

  An intra-alveolar device (IAD) may be used to administer a composition comprising a cross-linkable moiety and a targeting moiety coupled to an imaging moiety to a test group of animals. The composition is nebulized and administered to the animal via an endotracheal tube to the lung without prior identification of the area of damaged lung tissue. Allow the composition to distribute for about 5 to about 7 minutes and allow elastase to be targeted. After this time, the lungs are washed with saline and aspirated to remove unbound composition. The alpha-1 antitrypsin moiety is not affected by the state induced by porcine elastase, or is affected in the affected lung region as compared to the affected lung region. Because of the higher amount of elastase, it targets damaged lung tissue. It is also possible to monitor the animal's heart rate and arterial oxygen saturation using an oximeter and tongue probe during the procedure.

  A CT scan of the lung is then taken to image the Tc-99m moiety coupled to the alpha-1 antitrypsin moiety bound to elastase. A scan can also be used to indicate and / or confirm the extent of attachment and / or induced damage of the composition of the present invention to an area of damaged lung tissue.

  The cross-linking is then activated by administering thrombin. Thrombin is nebulized and administered to the lungs or areas of the lungs identified as damaged by CT scan via an endotracheal tube. The lungs are then aspirated again, for example, using about 120-140 mmHg for about 3 to about 5 minutes to promote collapse. Allow the bridge to heal for about 7 to about 10 minutes. It is also possible to take a second CT scan of the lung to image the degree of collapse and / or sealing achieved in the area of damaged lung tissue. The lungs are then reinflated and allow the animal to recover from anesthesia, after which it is closely monitored for about 1 hour.

  A control group of animals can undergo a similar treatment except that no composition of the invention is administered. Approximately one day after treatment, the lung function test is repeated for both the test group and the control group to determine the effectiveness of lung volume reduction in the test group animals.

  In lung function tests, Ingenito et al., (2002) Bronchoscopic Lung Volume Reduction Using tissue engineering principles, American Journal of Respiratory and Critical Care Medicine, Vol. 167 771-778 and / or Ingenito et al., “Bronchoscope volume reduction − A safe. and assessment of static and dynamic lung physiology, as described in American Journal of Respiratory and Critical Care Medicine, Vol. 164, pages 295-301 (2001).

  In control animals, little change in the QSPV profile is expected. However, the animals in the test group are expected to show a significant decrease in RV and TLC with a significant increase in the RV / TLC ratio. A significant decrease in vital capacity and airway resistance when compared to controls is also expected in the test group animals. Furthermore, it is expected that there will be few post-treatment complications due to minimal invasiveness of the procedure. For example, reduced incidence and severity of fever, dyspnea, wound infection, and / or death would also be expected.

  While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Here, many variations, changes, and substitutions will occur to those skilled in the art without departing from the invention, and various alternatives to the embodiments of the invention described herein are available. It should be understood that it can be used to practice the present invention. The claims define the scope of the invention and, as a result, the methods and compositions within the scope of these claims are intended to be included together with their equivalents.

  All publications, patents, and patent applications mentioned in this specification are indicated to be incorporated herein by reference, specifically and individually, for each individual publication, patent or patent application. To the same extent.

FIG. 1a illustrates one embodiment of a method of reducing lung volume using a composition comprising a crosslinkable moiety coupled to a targeting moiety that targets damaged lung tissue. FIG. 1b illustrates one embodiment of a method for reducing lung volume using a composition comprising a coupled targeting moiety that targets different sites of damaged lung tissue. FIG. 2 illustrates one embodiment of a method of imaging damaged lung tissue using a composition comprising an imaging moiety coupled to a targeting moiety that targets damaged lung tissue.

Claims (302)

  A composition comprising a crosslinkable moiety and a targeting moiety, wherein the moiety is coupled and the targeting moiety targets damaged lung tissue.   2. The composition of claim 1, wherein the lung tissue comprises alveolar epithelial mucus.   2. The composition of claim 1, wherein the composition does not comprise a polysaccharide or carbohydrate moiety.   2. The composition of claim 1, wherein the composition does not comprise a mutant type 1 plasminogen activator inhibitor.   2. The composition of claim 1, wherein the targeting moiety targets a damage-correlated moiety.   6. The method of claim 5, wherein the damage correlation moiety comprises a cell surface marker.   6. The method of claim 5, wherein the damage correlation portion comprises an ECM component.   2. The composition of claim 1, wherein the targeting moiety targets elastase.   2. The composition of claim 1, wherein the targeting moiety targets neutrophil elastase.   2. The composition of claim 1, wherein the targeting moiety comprises a protease inhibitor moiety.   2. The composition of claim 1, wherein the targeting moiety comprises an alpha-1 antitrypsin moiety.   12. The composition of claim 11, wherein the alpha-1 antitrypsin moiety is a recombinant alpha-1 antitrypsin moiety.   2. The composition of claim 1, wherein the targeting moiety comprises an elafin moiety.   14. The composition of claim 13, wherein the elafin moiety is a recombinant elafin moiety.   2. The composition of claim 1, wherein the targeting moiety comprises a serpin moiety.   16. The composition of claim 15, wherein the serpin moiety is a recombinant serpin moiety.   16. The composition of claim 15, wherein the serpin moiety is a secretory leucoprotease inhibitor (SLP1) moiety.   18. The composition of claim 17, wherein the secretory leucoprotease inhibitor (SLP1) moiety is a recombinant secretory leucoprotease inhibitor (SLP1) moiety.   At least one matrix wherein the targeting moiety is selected from MMP-1, MMP-2, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, and MMP-9 The composition of claim 1, which targets a metalloproteinase.   20. The composition of claim 19, wherein the composition does not comprise hyaluronic acid or a salt thereof.   2. The composition of claim 1, wherein the targeting moiety targets desmosine and / or isodesmosine.   2. The composition of claim 1, wherein the targeting moiety targets CD8 and / or CD4.   2. The composition of claim 1, wherein the targeting moiety targets a tobacco-related moiety.   2. The composition of claim 1, wherein the crosslinkable moiety comprises a hydroxyl group.   2. The composition of claim 1, wherein the crosslinkable moiety comprises a carboxyl group.   2. The composition of claim 1, wherein the crosslinkable moiety comprises an ester group.   The method of claim 1, wherein the crosslinkable moiety comprises a cyano group.   The method of claim 1, wherein the crosslinkable moiety comprises a thiol group.   2. The method of claim 1, wherein the crosslinkable moiety comprises a cysteine group.   2. The method of claim 1, wherein the crosslinkable moiety comprises a carbonyl group.   2. The method of claim 1, wherein the crosslinkable moiety comprises an aldehyde group.   2. The method of claim 1, wherein the crosslinkable moiety comprises a ketone group.   2. The composition of claim 1, wherein the crosslinkable moiety comprises a primary amine group and / or a secondary amine group.   2. The composition of claim 1, wherein the crosslinkable moiety comprises a lysine group.   The composition of claim 1, wherein the crosslinkable moiety comprises fibrinogen and / or fibrin.   2. The composition of claim 1, wherein the composition is less than 10 microns.   2. The composition of claim 1, wherein the composition is less than 5 microns.   2. The composition of claim 1, wherein the composition is less than 1 micron.   2. The composition of claim 1, further comprising an imaging moiety coupled to the targeting moiety and / or the crosslinkable moiety. A method for reducing lung volume, comprising:
A subject is administered a composition comprising a crosslinkable moiety and a targeting moiety, wherein the moiety is coupled and the targeting moiety targets damaged lung tissue; and the damaged Said method comprising the step of cross-linking lung tissue and thereby reducing lung volume.   41. The method of claim 40, wherein the lung tissue comprises alveolar epithelial mucus.   41. The method of claim 40, wherein the method is performed without prior identification of the damaged lung tissue.   41. The method of claim 40, wherein the method does not damage epithelial cells in lung tissue.   41. The method of claim 40, wherein the use of a sclerosing agent damages epithelial cells in lung tissue.   The sclerosing agent is at least one compound selected from doxycycline, bleomycin, minocycline, doxorubicin, cisplatin + cytarabine, mitoxantrone, Corynebacterium Parvum, streptokinase, and urokinase. 44. The method according to 44.   41. The method of claim 40, wherein the composition does not comprise a polysaccharide or carbohydrate moiety.   41. The method of claim 40, wherein the composition does not comprise a mutant type 1 plasminogen activator inhibitor.   41. The method of claim 40, wherein the targeting moiety targets a damage correlation moiety.   49. The method of claim 48, wherein the damage correlation moiety comprises a cell surface marker.   49. The method of claim 48, wherein the damage correlation portion comprises an ECM component.   41. The method of claim 40, wherein the targeting moiety targets elastase.   41. The method of claim 40, wherein the targeting moiety targets neutrophil elastase.   41. The method of claim 40, wherein the targeting moiety comprises a protease inhibitor moiety.   41. The method of claim 40, wherein the targeting moiety comprises an alpha-1 antitrypsin moiety.   55. The method of claim 54, wherein the alpha-1 antitrypsin moiety is a recombinant alpha-1 antitrypsin moiety.   41. The method of claim 40, wherein the targeting moiety comprises an elafin moiety.   57. The method of claim 56, wherein the elafin moiety is a recombinant elafin moiety.   41. The method of claim 40, wherein the targeting moiety comprises a serpin moiety.   59. The method of claim 58, wherein the serpin moiety is a recombinant serpin moiety.   59. The method of claim 58, wherein the serpin moiety is a secretory leucoprotease inhibitor (SLP1) moiety.   61. The method of claim 60, wherein the secretory leucoprotease inhibitor (SLP1) moiety is a recombinant secretory leucoprotease inhibitor (SLP1) moiety.   At least one matrix wherein the targeting moiety is selected from MMP-1, MMP-2, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, and MMP-9 41. The method of claim 40, wherein the method targets a metalloproteinase.   64. The method of claim 62, wherein the composition does not comprise hyaluronic acid or a salt thereof.   41. The method of claim 40, wherein the targeting moiety targets desmosine and / or isodesmosine.   41. The method of claim 40, wherein the targeting moiety targets CD8 and / or CD4.   41. The method of claim 40, wherein the targeting moiety targets a tobacco-related moiety.   41. The method of claim 40, wherein the crosslinkable moiety comprises a hydroxyl group.   41. The method of claim 40, wherein the crosslinkable moiety comprises a carboxyl group.   41. The method of claim 40, wherein the crosslinkable moiety comprises an ester group.   41. The method of claim 40, wherein the crosslinkable moiety comprises a cyano group.   41. The method of claim 40, wherein the crosslinkable moiety comprises a thiol group.   41. The method of claim 40, wherein the crosslinkable moiety comprises a cysteine group.   41. The method of claim 40, wherein the crosslinkable moiety comprises a carbonyl group.   41. The method of claim 40, wherein the crosslinkable moiety comprises an aldehyde group.   41. The method of claim 40, wherein the crosslinkable moiety comprises a ketone group.   41. The method of claim 40, wherein the crosslinkable moiety comprises a primary amine group and / or a secondary amine group.   41. The method of claim 40, wherein the crosslinkable moiety comprises a lysine group.   41. The method of claim 40, wherein the crosslinkable moiety comprises fibrinogen and / or fibrin.   41. The method of claim 40, wherein the composition is less than 10 microns.   41. The method of claim 40, wherein the composition is less than 5 microns.   41. The method of claim 40, wherein the composition is less than 1 micron.   41. The method of claim 40, wherein the administration is performed via inhalation.   83. The method of claim 82, wherein the inhalation is performed through the mouth.   41. The method of claim 40, wherein the administration is performed via transthoracic administration.   41. The method of claim 40, further comprising administering a second composition comprising a cross-linking activating moiety.   86. The method of claim 85, wherein the cross-linking activating moiety comprises at least one group selected from diols, polyols, dicarboxylic acids, polycarboxylic acids, diesters, polyesters, diamines, and polyamines.   86. The cross-linking activating moiety comprises at least one group selected from alkyl bis (2-cyanoacrylate), triallyl isocyanurate, alkylene diacrylate, alkylene dimethacrylate, and trimethylolpropane triacrylate. the method of.   86. The method of claim 85, wherein the cross-linking activating moiety comprises at least one group selected from disulfide, carbodiimide, and hydrazine.   86. The method of claim 85, wherein the cross-linking activating moiety comprises a fibrin activator and / or a fibrinogen activator.   41. The method of claim 40, further comprising administering a growth factor.   41. The method of claim 40, further comprising administering an anti-surfactant.   41. The method of claim 40, further comprising administering an antibiotic.   41. The method of claim 40, further comprising the step of causing a first portion or all of the subject's lungs to collapse.   94. The method of claim 93, wherein the collapse comprises the use of negative pressure from within the subject's lungs.   94. The method of claim 93, wherein the collapse comprises the use of positive pressure from outside the subject's lungs.   94. The method of claim 93, further comprising the step of reinflating a second portion of the subject's lung, wherein the second portion does not include the damaged lung tissue.   41. The method of claim 40, wherein the composition further comprises an imaging moiety coupled to the targeting moiety and / or the crosslinkable moiety.   98. The method of claim 97, further comprising imaging the damaged lung tissue.   41. The method of claim 40, further comprising administering a wash portion. A method of treating a lung condition comprising:
The subject is administered a composition comprising a crosslinkable moiety and a targeting moiety, wherein the moiety is coupled and the targeting moiety targets damaged lung tissue; and the damaged Said method comprising the step of cross-linking lung tissue and thereby treating a lung condition.   101. The method of claim 100, wherein the lung tissue comprises alveolar epithelial mucus.   101. The method of claim 100, wherein the lung condition is emphysema.   101. The method of claim 100, wherein the lung condition is COPD.   A composition comprising a first targeting moiety and a second targeting moiety, wherein the targeting moiety is coupled and the targeting moiety targets different sites of damaged lung tissue object.   105. The composition of claim 104, wherein the lung tissue comprises alveolar epithelial mucus.   105. The composition of claim 104, wherein the different sites comprise different sites within an expanded air space.   The first targeting moiety targets a first damage-correlated moiety, and the second targeting moiety targets a second damage-correlated moiety, and the first and second damage-correlated moieties are the 105. The composition of claim 104, wherein the composition is present at different sites.   108. The composition of claim 107, wherein the first and second damage correlation portions are the same.   108. The composition of claim 107, wherein the first and second damage correlation portions are different.   105. The composition of claim 104, wherein the targeting moiety is coupled via a chemical linker.   111. The composition of claim 110, wherein the chemical linker comprises two functional groups.   112. The composition of claim 111, wherein at least one of the functional groups is a hydroxyl group, a carboxyl group, an ester group, an amine group, or a lysine group.   112. The composition of claim 111, wherein 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.   105. The composition of claim 104, wherein the targeting moiety is coupled as a fusion polypeptide.   105. The composition of claim 104, wherein the targeting moiety is coupled via a protein.   105. The composition of claim 104, wherein the targeting moiety is coupled via an antibody.   105. The composition of claim 104, wherein the composition does not comprise a polysaccharide or carbohydrate moiety.   105. The composition of claim 104, wherein the composition does not comprise a mutant type 1 plasminogen activator inhibitor.   105. The composition of claim 104, wherein the first and / or second targeting moiety targets a damage correlation moiety.   120. The method of claim 119, wherein the damage-correlated moiety comprises a cell surface marker.   120. The method of claim 119, wherein the damage correlation portion comprises an ECM component.   105. The composition of claim 104, wherein the first and / or second targeting moiety targets elastase.   105. The composition of claim 104, wherein the first and / or second targeting moiety targets neutrophil elastase.   105. The composition of claim 104, wherein the first and / or second targeting moiety comprises a protease inhibitor moiety.   105. The composition of claim 104, wherein the first and / or second targeting moiety comprises an alpha-1 antitrypsin moiety.   126. The composition of claim 125, wherein said alpha-1 antitrypsin moiety is a recombinant alpha-1 antitrypsin moiety.   105. The composition of claim 104, wherein the first and / or second targeting moiety comprises an elafin moiety.   128. The composition of claim 127, wherein the elafin moiety is a recombinant elafin moiety.   105. The composition of claim 104, wherein the first and / or second targeting moiety comprises a serpin moiety.   129. The composition of claim 129, wherein said serpin moiety is a recombinant serpin moiety.   129. The composition of claim 129, wherein said serpin moiety is a secretory leucoprotease inhibitor (SLP1) moiety.   132. The composition of claim 131, wherein said secretory leucoprotease inhibitor (SLP1) moiety is a recombinant secretory leucoprotease inhibitor (SLP1) moiety.   The first and / or second targeting moiety is MMP-1, MMP-2, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, and MMP-9. 105. The composition of claim 104, wherein the composition targets at least one matrix metalloproteinase selected from.   134. The composition of claim 133, wherein the composition does not comprise hyaluronic acid or a salt thereof.   105. The composition of claim 104, wherein the first and / or second targeting moiety targets desmosine and / or isodesmosine.   105. The composition of claim 104, wherein the first and / or second targeting moiety targets CD8 and / or CD4.   105. The composition of claim 104, wherein the first and / or second targeting moiety targets a tobacco-related moiety.   105. The composition of claim 104, wherein the composition is less than 10 microns.   105. The composition of claim 104, wherein the composition is less than 5 microns.   105. The composition of claim 104, wherein the composition is less than 1 micron.   105. The composition of claim 104, further comprising a crosslinkable moiety coupled to the first and / or second targeting moiety.   105. The composition of claim 104, further comprising an imaging moiety coupled to the first and / or second targeting moiety. A method for reducing lung volume, comprising:
A subject is administered a composition comprising a first targeting moiety and a second targeting moiety, wherein the targeting moiety is coupled, and the targeting moiety targets damaged lung tissue; and The method comprising the step of allowing the targeting moiety to target different sites of damaged lung tissue, thereby reducing lung volume.   145. The method of claim 143, wherein the lung tissue comprises alveolar epithelial mucus.   145. The method of claim 143, wherein the different sites include different sites within the expanded air space.   The first targeting moiety targets a first damage-correlated moiety, and the second targeting moiety targets a second damage-correlated moiety, and the first and second damage-correlated moieties are the 145. The method of claim 143, wherein the method is present at different sites.   147. The method of claim 146, wherein the first and second damage correlation portions are the same.   147. The method of claim 146, wherein the first and second damage correlation portions are different.   145. The method of claim 143, wherein the targeting moiety is coupled via a chemical linker.   150. The method of claim 149, wherein the chemical linker comprises two functional groups.   161. The method of claim 150, wherein at least one of the functional groups is a hydroxyl group, a carboxyl group, an ester group, an amine group, or a lysine group.   161. The method of claim 150, wherein 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.   145. The method of claim 143, wherein the targeting moiety is coupled as a fusion polypeptide.   145. The method of claim 143, wherein the targeting moiety is coupled via a protein.   145. The method of claim 143, wherein the targeting moiety is coupled via an antibody.   145. The method of claim 143, wherein the method is performed without prior identification of the damaged lung tissue.   145. The method of claim 143, wherein the method does not damage epithelial cells in lung tissue.   145. The method of claim 143, wherein the use of a sclerosing agent damages epithelial cells in lung tissue.   159. The method of claim 158, wherein the sclerosing agent is at least one compound selected from doxycycline, bleomycin, minocycline, doxorubicin, cisplatin + cytarabine, mitoxantrone, corynebacterium parvum, streptokinase, and urokinase. .   145. The method of claim 143, wherein the composition does not comprise a polysaccharide or carbohydrate moiety.   145. The method of claim 143, wherein the composition does not comprise a mutant type 1 plasminogen activator inhibitor.   145. The method of claim 143, wherein the first and / or second targeting moiety targets a damage correlation moiety.   163. The method of claim 162, wherein the damage-correlated moiety comprises a cell surface marker.   163. The method of claim 162, wherein the damage correlation portion comprises an ECM component.   145. The method of claim 143, wherein the first and / or second targeting moiety targets elastase.   144. The method of claim 143, wherein said first and / or second targeting moiety targets neutrophil elastase.   145. The method of claim 143, wherein the first and / or second targeting moiety comprises a protease inhibitor moiety.   145. The method of claim 143, wherein the first and / or second targeting moiety comprises an alpha-1 antitrypsin moiety.   171. The method of claim 168, wherein said alpha-1 antitrypsin moiety is a recombinant alpha-1 antitrypsin moiety.   145. The method of claim 143, wherein the first and / or second targeting moiety comprises an elafin moiety.   171. The method of claim 170, wherein the elafin moiety is a recombinant elafin moiety.   145. The method of claim 143, wherein the first and / or second targeting moiety comprises a serpin moiety.   173. The method of claim 172, wherein said serpin moiety is a recombinant serpin moiety.   173. The method of claim 172, wherein said serpin moiety is a secretory leucoprotease inhibitor (SLP1) moiety.   175. The method of claim 174, wherein the secretory leucoprotease inhibitor (SLP1) moiety is a recombinant secretory leucoprotease inhibitor (SLP1) moiety.   The first and / or second targeting moiety is MMP-1, MMP-2, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, and MMP-9. 145. The method of claim 143, wherein the method targets at least one matrix metalloproteinase selected from.   177. The method of claim 176, wherein the composition does not comprise hyaluronic acid or a salt thereof.   145. The method of claim 143, wherein the first and / or second targeting moiety targets desmosine and / or isodesmosine.   144. The method of claim 143, wherein the first and / or second targeting moiety targets CD8 and / or CD4.   145. The method of claim 143, wherein the first and / or second targeting moiety targets a tobacco-related moiety.   145. The method of claim 143, wherein the composition is less than 10 microns.   144. The method of claim 143, wherein the composition is less than 5 microns.   145. The method of claim 143, wherein the composition is less than 1 micron.   145. The method of claim 143, wherein the administration is performed via inhalation.   185. The method of claim 184, wherein the inhalation is performed through the mouth.   145. The method of claim 143, wherein the administration is performed via transthoracic administration.   145. The method of claim 143, further comprising administering a growth factor.   145. The method of claim 143, further comprising administering an anti-surfactant.   145. The method of claim 143, further comprising administering an antibiotic.   145. The method of claim 143, further comprising the step of collapsing a first portion or all of the subject's lungs.   191. The method of claim 190, wherein the collapse comprises the use of negative pressure from within the subject's lungs.   191. The method of claim 190, wherein the collapse includes the use of positive pressure from outside the subject's lungs.   191. The method of claim 190, further comprising the step of reinflating a second portion of the subject's lung, wherein the second portion does not include the damaged lung tissue.   144. The method of claim 143, wherein the composition further comprises a crosslinkable moiety coupled to the first and / or second targeting moiety.   195. The method of claim 194, further comprising bridging the damaged lung tissue.   145. The method of claim 143, wherein the composition further comprises an imaging moiety coupled to the first and / or second targeting moiety.   196. The method of claim 196, further comprising imaging the damaged lung tissue.   144. The method of claim 143, further comprising administering a wash portion. A method of treating a lung condition comprising:
A subject is administered a composition comprising a first targeting moiety and a second targeting moiety, wherein the targeting moiety is coupled, and the targeting moiety targets damaged lung tissue; and The method comprising the step of allowing the targeting moiety to target different sites of damaged lung tissue, thereby treating the lung condition.   200. The method of claim 199, wherein the lung tissue comprises alveolar epithelial mucus.   199. The method of claim 199, wherein the lung condition is emphysema.   199. The method of claim 199, wherein the lung condition is COPD.   A composition comprising an imaging moiety and a targeting moiety, wherein the moiety is coupled and the targeting moiety targets damaged lung tissue.   204. The composition of claim 203, wherein the lung tissue comprises alveolar epithelial mucus.   204. The composition of claim 203, wherein the composition does not comprise a polysaccharide or carbohydrate moiety.   204. The composition of claim 203, comprising no antibody.   204. The composition of claim 203, wherein the composition does not comprise a mutant type 1 plasminogen activator inhibitor.   204. The composition of claim 203, wherein the composition does not comprise a lung membrane dipeptidase binding molecule.   204. The composition of claim 203, wherein the targeting moiety does not target lung membrane dipeptidase.   204. The composition of claim 203, wherein the targeting moiety targets a damage correlation moiety.   223. The composition of claim 210, wherein the damage-correlated moiety comprises a cell surface marker.   223. The composition of claim 210, wherein the damage-correlated moiety comprises an ECM component.   204. The composition of claim 203, wherein the targeting moiety targets elastase.   204. The composition of claim 203, wherein the targeting moiety targets neutrophil elastase.   204. The composition of claim 203, wherein the targeting moiety comprises a protease inhibitor moiety.   204. The composition of claim 203, wherein the targeting moiety comprises an alpha-1 antitrypsin moiety.   227. The composition of claim 216, wherein the alpha-1 antitrypsin moiety is a recombinant alpha-1 antitrypsin moiety.   204. The composition of claim 203, wherein the targeting moiety comprises an elafin moiety.   227. The composition of claim 218, wherein the elafin moiety is a recombinant elafin moiety.   204. The composition of claim 203, wherein the targeting moiety comprises a serpin moiety.   223. The composition of claim 220, wherein said serpin moiety is a recombinant serpin moiety.   223. The composition of claim 220, wherein said serpin moiety is a secretory leucoprotease inhibitor (SLP1) moiety.   223. The composition of claim 222, wherein the secretory leucoprotease inhibitor (SLP1) moiety is a recombinant secretory leucoprotease inhibitor (SLP1) moiety.   At least one matrix wherein the targeting moiety is selected from MMP-1, MMP-2, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, and MMP-9 204. The composition of claim 203, wherein said composition targets a metalloproteinase.   224. The composition of claim 224, free of hyaluronic acid or a salt thereof.   204. The composition of claim 203, wherein the targeting moiety targets desmosine and / or isodesmosine.   204. The composition of claim 203, wherein the targeting moiety targets CD8 and / or CD4.   204. The composition of claim 203, wherein the targeting moiety targets a tobacco-related moiety.   204. The composition of claim 203, wherein the imaging moiety comprises a contrast agent.   229. The composition of claim 229, wherein the contrast agent is nonionic.   229. The composition of claim 229, wherein the contrast agent is ionic.   204. The composition of claim 203, wherein the imaging moiety comprises at least one metal compound selected from tantalum compounds and barium compounds.   204. The composition of claim 203, wherein the imaging moiety comprises iodine.   204. The composition of claim 203, wherein the imaging moiety comprises at least one organic iodoacid selected from iodocarboxylic acid, triiodophenol, iodoform, and tetraiodoethylene.   204. The composition of claim 203, wherein the imaging moiety comprises a non-radioactive moiety.   204. The composition of claim 203, wherein the imaging moiety comprises a proton releasing moiety.   204. The composition of claim 203, wherein the imaging portion comprises a radiopaque portion and / or a radioactive portion.   204. The composition of claim 203, wherein the imaging moiety comprises a magnetic moiety.   204. The composition of claim 203, wherein the imaging moiety comprises a radiopharmaceutical.   204. The composition of claim 203, wherein the imaging moiety comprises an In-111 moiety.   204. The composition of claim 203, wherein the imaging moiety comprises a Tc-99m moiety.   204. The composition of claim 203, wherein the imaging moiety comprises a Xe-133 moiety.   204. The composition of claim 203, wherein the composition is less than 10 microns.   204. The composition of claim 203, wherein the composition is less than 5 microns.   204. The composition of claim 203, wherein the composition is less than 1 micron.   204. The composition of claim 203, further comprising a coupled crosslinkable moiety and / or another coupled targeting moiety. A method of imaging damaged lung tissue comprising:
A composition comprising an imaging moiety and a targeting moiety is administered to a subject in need, wherein said moiety is coupled and said targeting moiety targets damaged lung tissue; and said injury Imaging said lung tissue.   248. The method of claim 247, wherein the lung tissue comprises alveolar epithelial mucus.   248. The method of claim 247, wherein the composition does not comprise a polysaccharide or carbohydrate moiety.   248. The method of claim 247, wherein the composition does not comprise an antibody.   248. The method of claim 247, wherein the composition does not comprise a mutant type 1 plasminogen activator inhibitor.   248. The method of claim 247, wherein the composition does not comprise a lung membrane dipeptidase binding molecule.   248. The method of claim 247, wherein the targeting moiety does not target lung membrane dipeptidase.   248. The method of claim 247, wherein the targeting moiety targets a damage correlation moiety.   254. The method of claim 254, wherein the damage correlation moiety comprises a cell surface marker.   254. The method of claim 254, wherein the damage correlation portion comprises an ECM component.   248. The method of claim 247, wherein the targeting moiety targets elastase.   248. The method of claim 247, wherein the targeting moiety targets neutrophil elastase.   248. The method of claim 247, wherein the targeting moiety comprises a protease inhibitor moiety.   248. The method of claim 247, wherein the targeting moiety comprises an alpha-1 antitrypsin moiety.   262. The method of claim 260, wherein the alpha-1 antitrypsin moiety is a recombinant alpha-1 antitrypsin moiety.   248. The method of claim 247, wherein the targeting moiety comprises an elafin moiety.   262. The method of claim 262, wherein the elafin moiety is a recombinant elafin moiety.   248. The method of claim 247, wherein the targeting moiety comprises a serpin moiety.   264. The method of claim 264, wherein the serpin moiety is a recombinant serpin moiety.   264. The method of claim 264, wherein the serpin moiety is a secretory leucoprotease inhibitor (SLP1) moiety.   273. The method of claim 266, wherein the secretory leucoprotease inhibitor (SLP1) moiety is a recombinant secretory leucoprotease inhibitor (SLP1) moiety.   At least one matrix wherein the targeting moiety is selected from MMP-1, MMP-2, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, and MMP-9 248. The method of claim 247, wherein said method targets a metalloproteinase.   268. The method of claim 268, wherein the composition does not comprise hyaluronic acid or a salt thereof.   248. The method of claim 247, wherein the targeting moiety targets desmosine and / or isodesmosine.   248. The method of claim 247, wherein the targeting moiety targets CD8 and / or CD4.   248. The method of claim 247, wherein the targeting moiety targets a tobacco-related moiety.   248. The method of claim 247, wherein the imaging moiety comprises a contrast agent.   274. The method of claim 273, wherein the contrast agent is nonionic.   The method of claim 273, wherein the contrast agent is ionic.   248. The method of claim 247, wherein the imaging moiety comprises at least one metal compound selected from tantalum compounds and barium compounds.   248. The method of claim 247, wherein the imaging moiety comprises iodine.   247. The method of claim 247, wherein the imaging moiety comprises at least one organic iodo acid selected from iodocarboxylic acid, triiodophenol, iodoform, and tetraiodoethylene.   248. The method of claim 247, wherein the imaging portion comprises a non-radioactive portion.   248. The method of claim 247, wherein the imaging moiety comprises a proton releasing moiety.   248. The method of claim 247, wherein the imaging portion comprises a radiopaque portion and / or a radioactive portion.   248. The method of claim 247, wherein the imaging portion comprises a magnetic portion.   248. The method of claim 247, wherein the imaging moiety comprises a radiopharmaceutical.   248. The method of claim 247, wherein the imaging portion comprises an In-111 portion.   248. The method of claim 247, wherein the imaging portion comprises a Tc-99m portion.   248. The method of claim 247, wherein the imaging portion comprises a Xe-133 portion.   248. The method of claim 247, wherein the composition is less than 10 microns.   248. The method of claim 247, wherein the composition is less than 5 microns.   248. The method of claim 247, wherein the composition is less than 1 micron.   248. The method of claim 247, wherein the administration is performed via inhalation.   290. The method of claim 290, wherein the inhalation is performed through the mouth.   248. The method of claim 247, wherein the administration is performed via transthoracic administration.   248. The method of claim 247, wherein the administration is performed via intravenous administration.   248. The method of claim 247, wherein the imaging of the damaged lung tissue is performed via radiological techniques.   295. The method of claim 294, wherein the radiological technique is at least one selected from x-ray, CT scan, PET scan, nuclear scan, SPECT, and scintigraphy.   247. The method of claim 247, further comprising a coupled crosslinkable moiety and / or another coupled targeting moiety.   296. The method of claim 296, further comprising the step of cross-linking and / or sealing the damaged lung tissue.   248. The method of claim 247, further comprising administering a wash portion. A method for diagnosing lung conditions, comprising:
A subject is administered a composition comprising an imaging moiety and a targeting moiety, wherein the moiety is coupled and the targeting moiety targets damaged lung tissue; and the damaged The method comprising the step of imaging lung tissue.   302. The method of claim 299, wherein the lung tissue comprises alveolar epithelial mucus.   302. The method of claim 299, wherein the lung condition is emphysema.   302. The method of claim 299, wherein the lung condition is COPD.

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