Antibodies specific for sclerostin and methods for increasing bone mineralization

Abstract

Compositions and methods relating to antibodies that specifically bind to TGF-beta binding proteins are provided. These methods and compositions relate to altering bone mineral density by interfering with the interaction between a TGF-beta binding protein sclerostin and a TGF-beta superfamily member, particularly a bone morphogenic protein. Increasing bone mineral density has uses in diseases and conditions in which low bone mineral density typifies the condition, such as osteopenia, osteoporosis, and bone fractures.

1 .- 51 . (canceled) 
     
     
         52 . An IgG antibody that binds to a sclerostin polypeptide comprising an amino acid sequence set forth in SEQ ID NO: 1, wherein said antibody binds to the sequence of SEQ ID NO: 53 within SEQ ID NO: 1. 
     
     
         53 . The antibody of  claim 52 , wherein the antibody is a monoclonal antibody. 
     
     
         54 . The antibody of  claim 52 , wherein the antibody is a human antibody, a humanized antibody or a chimeric antibody. 
     
     
         55 . A hybridoma cell producing the antibody of  claim 52 . 
     
     
         56 . A composition comprising the antibody of  claim 52  and a pharmaceutically acceptable carrier. 
     
     
         57 . A method for increasing bone mineral content in a warm-blooded animal, the method comprising administering to the warm-blooded animal the antibody of  claim 52 . 
     
     
         58 . The method of  claim 57 , wherein the warm-blooded animal is a human. 
     
     
         59 . The method of  claim 58 , wherein the human has a condition selected from the group consisting of achondroplasia, cleidocranial dysostosis, enchondromatosis, fibrous dysplasia, Gaucher's hypophosphatemic rickets, Marfan's, multiple hereditary exotoses, neurofibromatosis, osteogenesis imperfecta, osteopetrosis, osteopoikilosis sclerotic lesions, fractures, periodontal disease, pseudoarthrosis and pyogenic osteomyelitis. 
     
     
         60 . A method of treating bone fracture in a human wherein the method comprises administering to the human the antibody of  claim 52 . 
     
     
         61 . A method of treating dysplasia associated with abnormal growth or development of bone in a human wherein the method comprises administering to the human the antibody of  claim 52 . 
     
     
         62 . A method of treating osteoporosis or osteopenia in a human wherein the method comprises administering to the human the antibody of  claim 52 . 
     
     
         63 . The method of  claim 62 , wherein the osteopenia is caused by an anemic state, steroids, heparin, a bone morrow disorder, scurvy, malnutrition, calcium deficiency, idiopathic osteoporosis, congenital osteopenia or osteoporosis, alcoholism, chronic liver disease, senility, post menstrual state, oligomenorrhea, amenorrhea, pregnancy, diabetes mellitus, hyperthyroidism, Cushing's disease, acromegaly, hypogonadism, immobilization or disuse, reflex sympathetic dystrophy syndrome, transient regional osteoporosis or osteomalacia. 
     
     
         64 . The method of  claim 62 , wherein the human has been administered a therapeutic that affects bone resorption. 
     
     
         65 . An IgG antibody that (a) binds to the amino acid sequence of SEQ ID NO: 53 within SEQ ID NO: 1 and (b) binds to sclerostin of SEQ ID NO: 1 with an affinity K D  of less than or equal to about 10 −6  M. 
     
     
         66 . The antibody of  claim 65  that binds to a second amino acid sequence of SEQ ID NO: 1, wherein said second amino acid sequence is SEQ ID NO: 22 or SEQ ID NO: 33. 
     
     
         67 . The antibody of  claim 65  that is capable of increasing bone mineral content in a mammal. 
     
     
         68 . The antibody of  claim 65 , wherein the antibody is a monoclonal antibody. 
     
     
         69 . The antibody of  claim 65 , wherein the antibody is a human antibody, a humanized antibody or a chimeric antibody. 
     
     
         70 . The antibody of  claim 65  that is a humanized antibody. 
     
     
         71 . A hybridoma cell producing the antibody of  claim 65 . 
     
     
         72 . A composition comprising the antibody of  claim 65  and a pharmaceutically acceptable carrier. 
     
     
         73 . A method for increasing bone mineral content in a warm-blooded animal, the method comprising administering to the warm-blooded animal the antibody of  claim 65 . 
     
     
         74 . The method of  claim 73 , wherein the warm-blooded animal is a human. 
     
     
         75 . The method of  claim 74 , wherein the human has a condition selected from the group consisting of achondroplasia, cleidocranial dysostosis, enchondromatosis, fibrous dysplasia, Gaucher's hypophosphatemic rickets, Marfan's, multiple hereditary exotoses, neurofibromatosis, osteogenesis imperfecta, osteopetrosis, osteopoikilosis sclerotic lesions, fractures, periodontal disease, pseudoarthrosis and pyogenic osteomyelitis. 
     
     
         76 . A method of treating bone fracture in a human wherein the method comprises administering to the human the antibody of  claim 65 . 
     
     
         77 . A method of treating dysplasia associated with abnormal growth or development of bone in a human wherein the method comprises administering to the human the antibody of  claim 68 . 
     
     
         78 . A method of treating osteoporosis or osteopenia in a human wherein the method comprises administering to the human the antibody of  claim 68 . 
     
     
         79 . The method of claim  7 /, wherein the osteopenia is caused by an anemic state, steroids, heparin, a bone morrow disorder, scurvy, malnutrition, calcium deficiency, idiopathic osteoporosis, congenital osteopenia or osteoporosis, alcoholism, chronic liver disease, senility, post menstrual state, oligomenorrhea, amenorrhea, pregnancy, diabetes mellitus, hyperthyroidism, Cushing's disease, acromegaly, hypogonadism, immobilization or disuse, reflex sympathetic dystrophy syndrome, transient regional osteoporosis or osteomalacia. 
     
     
         80 . The method of  claim 78 , wherein the human has been administered a therapeutic that affects bone resorption. 
     
     
         81 . An isolated nucleic acid comprising a nucleic acid sequence encoding a heavy chain variable region of the antibody of  claim 52 . 
     
     
         82 . An isolated nucleic acid comprising a nucleic acid sequence encoding a light chain variable region of the antibody of  claim 52 . 
     
     
         83 . An isolated host cell comprising (a) a nucleic acid sequence encoding a heavy chain variable region of the antibody of  claim 52 , (b) a nucleic acid sequence encoding a light chain variable region of the antibody of  claim 52 , or (c) a nucleic acid sequence encoding a heavy chain variable region of the antibody of  claim 52  and a nucleic acid sequence encoding a light chain variable region of the antibody of  claim 52 . 
     
     
         84 . A vector comprising (a) a nucleic acid sequence encoding a heavy chain variable region of the antibody of  claim 52 , (b) a nucleic acid sequence encoding a light chain variable region of the antibody of  claim 52 , or (c) a nucleic acid sequence encoding a heavy chain variable region of the antibody of  claim 52  and a nucleic acid sequence encoding a light chain variable region of the antibody of  claim 52 . 
     
     
         85 . An isolated host cell comprising the vector of  claim 84 . 
     
     
         86 . A method of producing an antibody comprising the step of culturing host cells of  claim 83  and isolating an antibody produced therefrom.