Compounds and methods for the modulation of beta-1 integrin function to mediate tissue repair

Abstract

The present invention provides methods and compositions that modulate beta 1 integrin activity by functioning as allosteric antagonists. In particular, the present invention provides methods for mediating tissue repair where insult or injury has occurred by antagonising the allosteric function of beta 1 integrin.

What is claimed is: 
     
         1 . A method for modulating one or more of the biological activities of beta 1 integrin in a beta 1 integrin-expressing cell or tissue in order to increase the lifespan of a cell to increase the viability of a tissue comprising:
 contacting the cell or tissue with an allosteric antagonist of beta 1 integrin in an amount sufficient to modulate one or more biological activities of beta 1 integrin in the cell or tissue to prevent the integrin assuming an active, extended form and to maintain extracellular matrix (ECM) anchoring and promote cell survival.   
     
     
         2 . The method of  claim 1 , wherein the beta 1 integrin expressing cell or tissue is a cell or tissue of the synovium, a neuronal cell or tissue, or a cell or tissue of the lung. 
     
     
         3 . The method of  claim 2 , wherein the subject is a human patient at risk of having tissue damage following tissue insult or injury to any of the cells of the lung, synovium, or central nervous system. 
     
     
         4 . The method of  claim 1 , wherein the beta 1 integrin is human beta 1 integrin or murine beta 1 integrin. 
     
     
         5 . The method of  claim 1 , wherein the beta 1 integrin allosteric antagonist binds to human beta 1 integrin. 
     
     
         6 . The method of  claim 1 , wherein the beta 1 integrin allosteric antagonist is selected from the group consisting of a protein, a peptide, a peptidomimetic, a nucleic acid, a polynucleotide, a polysaccharide, an oligopeptide, a carbohydrate, a lipid, a small molecule compound, an aptamer, and a naturally occurring compound. 
     
     
         7 . The method of  claim 1 , wherein the beta 1 integrin allosteric antagonist is an antibody molecule or a fragment thereof that binds specifically to beta 1 integrin. 
     
     
         8 . The method of  claim 7 , wherein the antibody molecule is a human, humanised, chimeric, or camelid antibody. 
     
     
         9 . The method of  claim 1 , wherein the beta 1 integrin allosteric antagonist is an antibody molecule or a fragment thereof that binds specifically to an epitope of beta 1 integrin that comprises or is present within amino acid residues 82 and 87 of mature human beta 1 integrin as defined in SEQ ID NO:1. 
     
     
         10 . The method of  claim 1 , wherein the beta 1 integrin allosteric antagonist is an antibody molecule or a fragment thereof that binds specifically to an epitope of beta 1 integrin that comprises or is present within amino acid residues 179 to 184 of mature human beta 1 integrin as defined in SEQ ID NO:1. 
     
     
         11 . The method of  claim 1 , wherein the beta 1 integrin allosteric antagonist is an antibody molecule or a fragment thereof that binds specifically to an epitope of beta 1 integrin that is present within amino acid residues 207 to 218 of mature human beta 1 integrin as defined in SEQ ID NO:1. 
     
     
         12 . The method of  claim 1 , wherein the beta 1 integrin allosteric antagonist is an antibody molecule or a fragment thereof that binds specifically to an epitope that is present within a hybrid domain comprising residues 60 to 139 of mature human beta 1 integrin as defined in SEQ ID NO:1. 
     
     
         13 . The method of  claim 1 , wherein the beta 1 integrin allosteric antagonist is an antibody molecule or a fragment thereof that binds specifically to an epitope that is present within amino acid residues 360 to 461 of mature human beta 1 integrin as defined in SEQ ID NO:1. 
     
     
         14 . A method for increasing the lifespan of a cell to increase the viability of a tissue and mediate tissue repair, the method comprising:
 providing a therapeutically effective amount of an allosteric antagonist of beta1 integrin, wherein binding of the allosteric antagonist to beta1 integrin induces the conformation of the beta1 integrin to assume an intermediate affinity state, thereby preventing the integrin assuming an active, extended form, and   prophylactically administering the same to a subject in need of such treatment to promote cell survival and prevent cell death following insult or injury to the tissue.   
     
     
         15 . The method of  claim 14 , wherein the tissue is a tissue of the lung or synovium or that is a neuronal tissue. 
     
     
         16 . The method of  claim 14 , wherein the agent is selected from the group consisting of a protein, a peptide, a peptidomimetic, a nucleic acid, a polynucleotide, a polysaccharide, an oligopeptide, a carbohydrate, a lipid, a small molecule compound, a naturally occurring compound, and an antibody molecule or a fragment thereof that binds specifically to a beta 1 integrin polypeptide. 
     
     
         17 . The method of  claim 16 , wherein the beta 1 integrin allosteric antagonist binds to an epitope on beta 1 integrin comprising or present within:
 amino acid residues 82 and 87 of a mature human beta 1 integrin polypeptide as defined in SEQ ID NO:1,   amino acid residues 179 to 184 of a mature human beta 1 integrin polypeptide as defined in SEQ ID NO:1,   amino acid residues 207 to 218 of a mature human beta 1 integrin polypeptide as defined in SEQ ID NO:1,   amino acid residues 60 to 139 of a mature human beta 1 integrin polypeptide as defined in SEQ ID NO:1,   amino acid residues 360 to 461 of a mature human beta 1 integrin polypeptide as defined in SEQ ID NO:1.   
     
     
         18 . The method of  claim 14 , wherein the therapeutically effective amount of the allosteric antagonist is an amount sufficient for prophylactic treatment of at least one condition selected from the group consisting of autoimmune arthritis, chronic obstructive pulmonary disease (COPD), a neurodegenerative disease, and cardiovascular disease. 
     
     
         19 . The method of  claim 18 , wherein:
 the autoimmune arthritis is selected from the group consisting of rheumatoid arthritis, inflammatory arthritis, juvenile rheumatoid arthritis, osteoarthritis, psoriatic arthritis, and collagen-induced arthritis; or   the chronic obstructive pulmonary disease (COPD) indication is emphysema or chronic bronchitis; or   the neurodegenerative disease is selected from the group consisting of Alzheimer's disease (AD), mild cognitive impairment (MCI), multiple sclerosis (MS), Parkinson's disease, Amyotrophic lateral sclerosis (ALS), Huntington's disease, a prion disease, Creutzfeldt-Jakob disease (CJD), AIDS-related dementia, encephalitis, stroke, and head trauma.   
     
     
         20 . A method for modulating one or more of the biological activities of a beta 1 integrin gene product in a beta 1 integrin-expressing cell or tissue in order to mediate growth of new cells and cellular structures, comprising contacting the cell or tissue with an allosteric antagonist of beta 1 integrin, in an amount sufficient to modulate one or more biological activities of beta 1 integrin in the cell or tissue to prevent the integrin assuming an active, extended form and to promote cell survival and proliferation and physically or mechanically restore damaged or diseased tissues by growth of new cells and cellular structures.