Antibodies and pharmaceutical compositions containing same useful for inhibiting activity of metalloproteins

Abstract

A method of producing a metalloprotein inhibitor, the method comprising generating antibodies directed at a composition including a metal ion-bound chelator, wherein the composition is selected having structural and electronic properties similar to a functional domain of the metalloprotein, thereby producing the metalloprotein inhibitor.

What is claimed is: 
     
         1 . A method of treating a disease associated with abnormal activity of a matrix metalloprotease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an antibody comprising an antigen recognition region which binds a transition metal ion-bound chelator, wherein the antibody inhibits an enzymatic activity of the matrix metalloprotease and wherein said antigen recognition region binds a pro-enzyme form of said matrix metalloprotease with a lower affinity than an active form of said matrix metalloprotease, thereby treating the disease. 
     
     
         2 . The method of  claim 1 , wherein said transition metal ion is selected from the group consisting of Vanadium, Selenium, Molybdenum, Cobalt, Zinc, Copper, Iron, Gallium, Bismuth, Aluminum, Gold, Platinum, Manganese, Chronium, Silver, Antimony, Thalium, Cadmium, Nickel, Mercury and Lead. 
     
     
         3 . The method of  claim 1 , wherein said chelator is a polyamine. 
     
     
         4 . The method of  claim 3 , wherein said polyamine is at least two histidine molecules. 
     
     
         5 . The method of  claim 3 , wherein said polyamine is selected from the group consisting of ethylene diamine, cyclam, porphyrin, diethylenetriamine, triethylenetetramine, triethylenediamine, tetraethylenepentamine, aminoethylethanolamine, aminoethylpiperazine, pentaethylenehexamine, captopril, penicilamine, N,N′-bis(3-aminopropyl)-1,3-propanediamine, N,N′-Bis-(2-animoethyl)-1,3-propanediamine, 1,7-dioxa-4,10-diazacyclododecane, 1,4,8,11-tetraaza cyclotetradecane-5,7-dione, 1,4,7-triazacyclononane, 1-oxa-4,7,10-triazacyclododecane, 1,4,8,12-tetraazacyclopentadecane, and 1,4,7,10-tetraazacyclododecane. 
     
     
         6 . The method of  claim 5 , wherein said polyamine is porphyrin. 
     
     
         7 . The method of  claim 6 , wherein said transition metal ion-bound chelator is Cobalt(II)-tetra-carbozyl phenyl porphyrin (Co-TCPP) or Zinc (II)-tetra-carboxy phenyl porphyrin (Zn-TCPP). 
     
     
         8 . The method of  claim 1 , wherein said antigen recognition region binds to said chelator in an absence of said transition metal ion with a lower affinity than to said transition metal ion bound chelator. 
     
     
         9 . The method of  claim 1 , wherein the antibody has a dissociation constant for said Co-TCPP of no greater than 9×10 −8  M. 
     
     
         10 . The method of  claim 1 , wherein said matrix metalloprotease is selected from the group consisting of neutrophil collagenase, collagenase-3, gelatinase A, gelatinase B, stromelysins-2 and 3, matrilysin, macrophage elastase; membrane-type MMPs, agrrecanase, tumor necrosis factor converting enzyme, cytokine convertases, adhesion molecule shedding enzymes, endothelin converting enzyme, angiotensin converting enzyme, neutral endopeptidase, FTSH—bacterial metalloprotease, metallo-lactamase (carbapenases), bacterial toxins and ras farnesyl protein transferase and carbonic anhydrase. 
     
     
         11 . The method of  claim 10 , wherein said matrix metalloprotease is gelatinase A. 
     
     
         12 . The method of  claim 11 , wherein the antibody is capable of inhibiting 50% of an activity of said gelatinase A at a concentration less than 10 −7 M. 
     
     
         13 . The method of  claim 1 , wherein said disease is selected from the group consisting of cancer, osteoarthritis (OA), rheumatoid arthritis (RA), septic arthritis, soft tissue rheumatism, polychondritis, tendonitis, periodontal disease, corneal ulceration, proteinuria, dytrophobic epidermolysis bullosa, osteoporosis, Paget's disease, hyperparathyroidism, cholesteatoma; diabetic retinopathy, macular degeneration; coronary thrombosis associated with atherosclerotic plaque rupture; pulmonary emphysema, wound healing and HIV infection. 
     
     
         14 . The method of  claim 1 , wherein said cancer is a metastasized cancer.