Variants of tissue inhibitor of metalloproteinase type three (timp-3), compositions and methods

Abstract

There are disclosed TIMP-3 muteins, variants and derivatives, nucleic acids encoding them, and methods of making and using them.

1 .- 12 . (canceled) 
     
     
         13 . A method of treating a condition in which matrix metalloproteases (MMPs) and/or other proteinases that are inhibited or inhibitable by Tissue Inhibitor of Metalloproteinase Type Three (TIMP-3) play a causative or exacerbating role, comprising administering to an individual afflicted with such a condition an amount of a composition comprising a TIMP-3 mutein sufficient to treat the condition, wherein the TIMP-3 mutein comprises a mature region that is at least 90% identical in amino acid sequence to the mature region of TIMP-3 set forth in SEQ ID NO:2 and:
 (a) two or more pairs of mutations selected from K45N/V47T; K50N/V52T; P56N/G58T; H78N/Q80T; K94N/E96T; or D110N/K112T;   (b) one or more pairs of mutations selected from K45N/V47T; K50N/V52T; P56N/G58T; H78N/Q80T; K94N/E96T; or D110N/K112T; and an additional mutation selected from R138T; G173T, or both R138T and G173T; or   (c) the mutations of (a) or (b) further comprising the mutation F57N.   
     
     
         14 . The method of  13 , wherein the condition is an inflammatory conditions, osteoarthritis, myocardial ischemia, reperfusion injury, or progression to congestive heart failure. 
     
     
         15 . The method of  claim 13 , wherein the condition is asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), inflammatory bowel disease, psoriasis, myocarditis, inflammation related to atherosclerosis, or an arthritic conditions. 
     
     
         16 . The method of  claim 13 , wherein the condition is rheumatoid arthritis, psoriatic arthritis, viral myocarditis, dystrophic epidermolysis bullosa, osteoarthritis, pseudogout, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, periodontal disease, ulceration, wound healing after surgery, restenosis, emphysema, Paget's disease of bone, osteoporosis, scleroderma, pressure atrophy of bone or tissues as in bedsores, cholesteatoma, abnormal wound healing, pauciarticular rheumatoid arthritis, polyarticular rheumatoid arthritis, systemic onset rheumatoid arthritis, enteropathic arthritis, reactive arthritis, SEA Syndrome (Seronegativity, Enthesopathy, Arthropathy Syndrome), dermatomyositis, psoriatic arthritis, vasculitis, myolitis, polymyolitis, dermatomyolitis, osteoarthritis, polyarteritis nodossa, Wegener's granulomatosis, arteritis, polymyalgia rheumatica, sarcoidosis, sclerosis, primary biliary sclerosis, sclerosing cholangitis, Sjogren's syndrome, psoriasis, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, dermatitis, atopic dermatitis, atherosclerosis, lupus, Still's disease, Systemic Lupus Erythematosus (SLE), myasthenia gravis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, Celiac disease (nontropical Sprue), enteropathy associated with seronegative arthropathies, microscopic or collagenous colitis, eosinophilic gastroenteritis, pouchitis resulting after proctocolectomy and ileoanal anastomosis, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, multiple sclerosis (MS), asthma, extrinsic asthma, intrinsic asthma, hyperresponsiveness of the airways, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, Acute Respiratory Disorder Syndrome (ARDS), respiratory distress syndrome, cystic fibrosis, pulmonary hypertension, pulmonary vasoconstriction, acute lung injury, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonia, eosinophilic pneumonia, bronchitis, allergic bronchitis bronchiectasis, tuberculosis, hypersensitivity pneumonitis, occupational asthma, asthma-like disorders, sarcoid, reactive airway disease (or dysfunction) syndrome, byssinosis, interstitial lung disease, hyper-eosinophilic syndrome, rhinitis, sinusitis, parasitic lung disease, airway hyperresponsiveness associated with viral-induced conditions, Guillain-Barre disease, Graves' disease, Addison's disease, Raynaud's phenomenon, autoimmune hepatitis, graft versus host disease (GVHD), cerebral ischemia, traumatic brain injury, neuropathy, myopathy, spinal cord injury, or amyotrophic lateral sclerosis (ALS). 
     
     
         17 . The method of  claim 13 , wherein the condition is vascular plaque stabilization, vasculopathy, neointima formation, acute lung injury, or acute respiratory distress syndrome. 
     
     
         18 .- 20 . (canceled) 
     
     
         21 . The method of  claim 13 , wherein the TIMP-3 mutein comprises a group of mutations selected from:
 (i) K45N/V47T, P56N/G58T, Q126N, and R138T;   (ii) K45N/V47T, P56N/G58T, K94N/E96T, and R138T;   (iii) K45N/V47T, P56N/G58T, R138T and G173T;   (iv) K45N/V47T, K94N/E96T, D110N/K112T, and F57N;   (v) K45N/V47T, K94N/E96T, F57N and R138T;   (vi) K45N/V47T, H78N/Q80T, K94N/E96T, R138T, and G173T;   (vii) K45N/V47T, K94N/E96T, D110N/K112T, and R138T;   (viii) K45N/V47T, K94N/E96T, D110N/K112T, and G173T;   (ix) K45N/V47T, K94N/E96T, R138T and G173T;   (x) K94N/E96T, D110N/K112T, K45S, F57N, and R138T;   (xi) H78N/Q80T, K94N/E96T, K45S, F57N and R138T;   (xii) K50N/V52T, P56N/G58T, K94N/E96T, D110N/K112T, R138T;   (xiii) K50N/V52T, H78N/Q80T, K94N/E96T, R138T and G173T;   (xiv) K50N/V52T, K94N/E96T, D110N/K112T, and R138T;   (xv) K50N/V52T, K94N/E96T, D110N/K112T, R138T and G173T;   (xvi) K50N/V52T, K94N/E96T, R138T and G173T;   (xvii) K50N/V52T, Q126N, R138T, and G173T;   (xviii) P56N/G58T, H78N/Q80T, K94N/E96T, and R138T;   (xix) P56N/G58T, K94N/E96T, Q126N and R138T;   (xx) P56N/G58T, K94N/E96T, D110N/K112T, and R138T;   (xxi) P56N/G58T, H78N/Q80T, K94N/E96T, and G173T;   (xxii) P56N/G58T, Q126N, R138T, and G173T;   (xxiii) H78N/Q80T, K94N/E96T, R138T and G173T;   (xxiv) H78N/Q80T, K94N/E96T, D110N/K112T, and R138T;   (xxv) K50N/V52T, D110N/K112T, R138T and G173T;   (xxvi) K45N/V47T, D110N/K112T, R138T and G173T;   (xxvii) H78N/Q80T, D110N/K112T, R138T and G173T;   (xxviii) K45N/V47T, K50N/V52T, H78N/Q80T, R138T;   (xxix) K45N/V47T, H78N/Q80T, D110N/K112T, and G173T;   (xxxx) K45N/V47, H78N/Q80T, R138T and G173T;   (xxxi) K50N/V52T, H78N/Q80T, K94N/E96T, and G173T;   (xxxii) K50N/V52T, H78N/Q80T, D110N/K112T, and R138T;   (xxxiii) K45N/V47T, K50N/V52T, H78N/Q80T, and D110N/K112T;   (xxxiv) K50N/V52T, H78N/Q80T, R138T and G173T;   (xxxv) K45N/V47T, H78N/Q80T, R138T and G173T;   (xxxvi) K45N/V47T, H78N/Q80T, and D110N/K112T, and R138T;   (xxxvii) K45N/V47T, K50N/V52T, H78N/Q80T, D110N/K112T, and G173T;   (xxxviii) K45N/V47T, K50N/V52T, H78N/Q80T, and R138T and G173T;   (xxxix) K45N/V47T, K50N/V52T, H78N/Q80T, K94N/E96T, and G173T;   (xl) K45N/V47T, H78N/Q80T, K94N/E96T, R138T and G173T;   (xli) K50N/V52T, H78N/Q80T, K94N/E96T, R138T and G173T;   (xlii) K45N/V47T, H78N/Q80T, and D110N/K112T, R138T and G173T;   (xliii) K50N/V52T, H78N/Q80T, D110N/K112T, R138T and G173T; or   (xliv) K45N/V52T, K50N/V52T, H78N/Q80T, D110N/K112T, and R138T.   
     
     
         22 . The method of  claim 21 , wherein the TIMP-3 mutein comprises an amino acid sequence of any one of SEQ ID NOs: 3-26. 
     
     
         23 . The method of  claim 13 , wherein the TIMP-3 mutein is fused or conjugated to a moiety that extends half-life of a polypeptide. 
     
     
         24 . The method of  claim 23 , wherein the TIMP-3 mutein is fused to an antibody, an Fc portion of an antibody, the heavy chain or light chain of an antibody, or human serum albumin. 
     
     
         25 . The method of  claim 23 , wherein the TIMP-3 mutein is conjugated to polyethylene glycol.