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 isolated antibody, or antigen-binding fragment thereof, that binds to a sclerostin polypeptide comprising an amino acid sequence set forth in SEQ ID NO: 1, wherein said antibody or fragment binds to the sequence of SEQ ID NO: 53. 
     
     
         53 . The antibody or antigen-binding fragment of  claim 52  that is capable of increasing bone mineral content in a mammal. 
     
     
         54 . The antibody or antigen-binding fragment of  claim 52 , wherein the antibody is a monoclonal antibody. 
     
     
         55 . The antibody or antigen-binding fragment of  claim 52 , wherein the antibody is a human antibody, a humanized antibody or a chimeric antibody. 
     
     
         56 . The antibody or antigen-binding fragment of  claim 52  that comprises an antigen-binding fragment. 
     
     
         57 . The antibody or antigen-binding fragment of  claim 56 , wherein the antigen-binding fragment is selected from the group consisting of F(ab′)2, Fab, Fab′, Fd, and Fv. 
     
     
         58 . A hybridoma cell producing the antibody or antigen-binding fragment of  claim 52 . 
     
     
         59 . A nucleic acid comprising a nucleic acid sequence encoding the antibody or antigen-binding fragment of  claim 52 . 
     
     
         60 . An isolated host cell comprising the nucleic acid of  claim 59 . 
     
     
         61 . A vector comprising the nucleic acid of  claim 59 . 
     
     
         62 . An isolated host cell comprising the vector of  claim 61 . 
     
     
         63 . A method of producing an antibody or antigen-binding fragment thereof comprising the step of culturing the host cell of  claim 60  and isolating the antibody produced therefrom. 
     
     
         64 . A method of producing an antibody or antigen-binding fragment thereof comprising the step of culturing the host cell of  claim 62  and isolating the antibody produced therefrom. 
     
     
         65 . A composition comprising the antibody or antigen-binding fragment of  claim 52  and a pharmaceutically acceptable carrier. 
     
     
         66 . A method for increasing bone mineral content in a warm-blooded animal, the method comprising administering to the warm-blooded animal the antibody or antigen-binding fragment of  claim 52 . 
     
     
         67 . The method of  claim 66 , wherein the warm-blooded animal is a human. 
     
     
         68 . The method of  claim 67 , wherein the human has a condition selected from the group consisting of achondroplasia, cleidrocranial dysostosise, echondromatosis, fibrous dysplasia, Gaucher's hypophosphatemic rickets, Marfan's, multiple hereditary exotoses, neurofibromatosis, osteogenesis inperfecta, osteopetrosis, osteopoikilosis sclerotic lesions, fractures, periodontal disease, pseudoarthosis and pyogenic osteolmyelitis. 
     
     
         69 . A method of treating bone fracture, dysplasia associated with abnormal growth or development of bone, osteoporosis, or osteopenia in a human wherein the method comprises administering to the human the antibody or antigen-binding fragment of  claim 52 . 
     
     
         70 . The method of  claim 69 , wherein the osteopenia is caused by an anaemic 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. 
     
     
         71 . An isolated antibody, or antigen binding fragment thereof, that binds to the amino acid sequence of SEQ ID NO: 53 within SEQ ID NO: 1 with an affinity K D  of less than or equal to about 10 −6  M. 
     
     
         72 . The antibody or antigen-binding fragment of  claim 71  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. 
     
     
         73 . The antibody or antigen-binding fragment of  claim 71  that is capable of increasing bone mineral content in a mammal. 
     
     
         74 . The antibody or antigen-binding fragment of  claim 71 , herein the antibody is a monoclonal antibody. 
     
     
         75 . The antibody or antigen-binding fragment of  claim 71 , wherein the antibody is a human antibody, a humanized antibody or a chimeric antibody. 
     
     
         76 . The antibody or antigen-binding fragment of  claim 71  that comprises an antigen-binding fragment. 
     
     
         77 . The antibody or antigen-binding fragment of  claim 76 , wherein the antigen-binding fragment is selected from the group consisting of F(ab′) 2 , Fab, Fab′, Fd, and Fv. 
     
     
         78 . A hybridoma cell producing the antibody or antigen-binding fragment of  claim 71 . 
     
     
         79 . A nucleic acid comprising a nucleic acid sequence encoding the antibody or antigen-binding fragment of  claim 71 . 
     
     
         80 . An isolated host cell comprising the nucleic acid of  claim 79 . 
     
     
         81 . A vector comprising the nucleic acid of  claim 79 . 
     
     
         82 . An isolated host cell comprising the vector of  claim 81 . 
     
     
         83 . A method of producing an antibody comprising the step of culturing the host cell of  claim 80  and isolating the antibody produced therefrom. 
     
     
         84 . A method of producing an antibody comprising the step of culturing the host cell of  claim 82  and isolating the antibody produced therefrom. 
     
     
         85 . A composition comprising the antibody or antigen-binding fragment of  claim 71  and a pharmaceutically acceptable carrier. 
     
     
         86 . A method for increasing bone mineral content in a warm-blooded animal, the method comprising administering to the warm-blooded animal the antibody or antigen-binding fragment of  claim 71 . 
     
     
         87 . The method of  claim 86 , wherein the warm-blooded animal is a human. 
     
     
         88 . The method of  claim 87 , wherein the human has a condition selected from the group consisting of achondroplasia, cleidrocranial dysostosise, echondromatosis, fibrous dysplasia, Gaucher's hypophosphatemic rickets, Marfan's, multiple hereditary exotoses, neurofibromatosis, osteogenesis inperfecta, osteopetrosis, osteopoikilosis sclerotic lesions, fractures, periodontal disease, pseudoarthosis and pyogenic osteomyelitis. 
     
     
         89 . A method of treating bone fracture, dysplasia associated with abnormal growth or development of bone, osteoporosis, or osteopenia in a human wherein the method comprises administering to the human the antibody or antigen-binding fragment of  claim 71 . 
     
     
         90 . The method of  claim 89 , wherein the osteopenia is caused by an anaemic 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.