Antibody inhibiting stem cell factor activity and use for treatment of asthma

Abstract

The present invention provides human antibodies specific for stem cell factor that contain at least one CDR derived from a combinatorial antibody library. The invention also provides pharmaceutical compositions comprising the antibodies and methods of treating asthma. The invention further provides methods of detecting stem cell factor using the antibodies.

1 . A purified human antibody which binds to stem cell factor protein, said antibody comprising 
 a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 19-24 or    a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS:13-18,    said antibody being optionally bound to a cytotoxic molecule or detectable label.    
     
     
         2 . The antibody of  claim 1  wherein said antibody comprises heavy and light chain variable regions comprising a pair of amino acid sequences selected from the group consisting of SEQ ID NOS: 13 and 19, SEQ ID NOS: 14 and 20, SEQ ID NOS: 15 and 24, SEQ ID NOS: 16 and 21, SEQ ID NOS: 17 and 22, and SEQ ID NOS: 18 and 23.  
     
     
         3 . The antibody of  claim 1  wherein said heavy chain variable region comprises human VH3 consensus framework residues.  
     
     
         4 . The antibody of  claim 1  wherein said light chain variable region comprises human Vκ1 consensus framework residues.  
     
     
         5 . The antibody of  claim 1  wherein said light chain variable region comprises human Vκ1 consensus framework residues.  
     
     
         6 . The antibody of  claim 2  wherein said antibody comprises heavy and light chain variable regions comprising the pair of amino acid sequences SEQ ID NOS: 14 and 20.  
     
     
         7 . The antibody of  claim 6  wherein said antibody comprises a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 57, 59, 61, 63 or 65 and a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 67, 69, 71, 73 and 75.  
     
     
         8 . The antibody of  claim 7  wherein said antibody comprises a heavy chain variable region comprising SEQ ID NO: 14, a light chain variable region comprising SEQ ID NO: 20, a light chain variable region comprising SEQ ID NO: 59, and a light chain variable region comprising SEQ ID NO: 69.  
     
     
         9 . The antibody of  claim 8  wherein said antibody comprises heavy chain variable and constant regions having the amino acid sequence of SEQ ID NO: 77, and light chain variable and constant regions having the amino acid sequence of SEQ ID NO: 79.  
     
     
         10 . The antibody of  claim 1  wherein said antibody is a full-length antibody.  
     
     
         11 . The antibody of  claim 1  wherein said antibody is an IgG.  
     
     
         12 . The antibody of  claim 1  wherein said antibody is an antibody fragment.  
     
     
         13 . A preparation comprising the antibody of  claim 1 .  
     
     
         14 . A pharmaceutical composition comprising the antibody of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         15 . An isolated polynucleotide or nucleotides encoding the antibody of  claim 1 .  
     
     
         16 . An expression vector comprising the polynucleotide or polynucleotides of  claim 15 .  
     
     
         17 . A host cell comprising the expression vector of  claim 16 .  
     
     
         18 . A method of producing a human antibody, comprising the steps of: culturing a host cell of  claim 17  under conditions whereby the antibody is expressed; and purifying the antibody from the host cell or host cell culture medium.  
     
     
         19 . A method of treating asthma comprising the steps of administering to a human in need of such treatment an effective amount of a Human Stem Cell Factor antibody of  claim 1 .  
     
     
         20 . A method of treating a human disorder in which stem cell factor protein is expressed in certain cells, comprising the steps of administering to a human in need of such treatment an effective amount of a human stem cell factor antibody of  claim 1  wherein said antiody is bound to a cytotoxic molecule, which cytotoxic molecule is capable of inducing apoptosis in said stem cell factor expressing cells.  
     
     
         21 . A method for identifying a disorder in which stem cell factor protein level is elevated, comprising the steps of: contacting a sample from a patient suspected of having the disorder with an antibody of  claim 1 , and detecting the presence of an antibody-stem cell factor protein complex, whereby the presence of an amount of the complex which is greater than the amount of the complex in a normal sample identifies the patient as likely to have the disorder.  
     
     
         22 . The method of  claim 21  wherein said antibody of  claim 1  is bound to a detectable label.  
     
     
         23 . A purified human antibody which binds to stem cell factor protein, said antibody comprising a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 86-92, said antibody being optionally bound to a cytotoxic molecule or detectable label.  
     
     
         24 . The antibody of  claim 23  wherein said light chain variable region further comprises SEQ ID NO: 59 and SEQ ID NO: 69.  
     
     
         25 . The antibody of  claim 2  wherein said antibody comprises a heavy chain variable region comprising SEQ ID NO: 14.  
     
     
         26 . The antibody of  claim 25  wherein said heavy chain variable region comprises human VH3 consensus framework residues.  
     
     
         27 . The antibody of  claim 23  wherein said light chain variable region comprises human Vκ1 consensus framework residues.  
     
     
         28 . The antibody of  claim 23  wherein said light chain variable region comprises human Vλ1 consensus framework residues.  
     
     
         29 . The antibody of  claim 23  wherein said antibody comprises a heavy chain variable region comprising SEQ ID NO: 14, a light chain variable region comprising SEQ ID NO: 59, a light chain variable region comprising SEQ ID NO: 69, and a light chain variable region selected from the group consisting of SEQ ID NO: 86-92.  
     
     
         30 . The antibody of  claim 29  wherein said antibody comprises heavy chain variable and constant regions having the amino acid sequence of SEQ ID NO: 79, and light chain variable and constant regions having the amino acid sequence of SEQ ID NO: 77 wherein the amino acid subsequence at residues 87-94 is replaced with a sequence selected from the group consisting of SEQ ID NO: 86-92.  
     
     
         31 . The antibody of  claim 23  wherein said antibody is a full-length antibody.  
     
     
         32 . The antibody of  claim 23  wherein said antibody is an IgG.  
     
     
         33 . The antibody of  claim 1  wherein said antibody is an antibody fragment.  
     
     
         34 . A preparation comprising the antibody of  claim 23 .  
     
     
         35 . A pharmaceutical composition comprising the antibody of  claim 23  and a pharmaceutically acceptable carrier.  
     
     
         36 . An isolated polynucleotide or nucleotides encoding the antibody of  claim 23 .  
     
     
         37 . An expression vector comprising the polynucleotide or polynucleotides of  claim 36 .  
     
     
         38 . A host cell comprising the expression vector of  claim 37 .  
     
     
         39 . A method of producing a human antibody, comprising the steps of: culturing a host cell of  claim 38  under conditions whereby the antibody is expressed; and purifying the antibody from the host cell or host cell culture medium.  
     
     
         40 . A method of treating asthma comprising the steps of administering to a human in need of such treatment an effective amount of a Human Stem Cell Factor antibody of  claim 23 .  
     
     
         41 . A method of treating a human disorder in which stem cell factor protein is expressed in certain cells, comprising the steps of administering to a human in need of such treatment an effective amount of a human stem cell factor antibody of  claim 23  wherein said antiody is bound to a cytotoxic molecule, which cytotoxic molecule is capable of inducing apoptosis in said stem cell factor expressing cells.  
     
     
         42 . A method for identifying a disorder in which stem cell factor protein level is elevated, comprising the steps of: contacting a sample from a patient suspected of having the disorder with an antibody of  claim 23 , and detecting the presence of an antibody-stem cell factor protein complex, whereby the presence of an amount of the complex which is greater than the amount of the complex in a normal sample identifies the patient as likely to have the disorder.  
     
     
         43 . The method of  claim 42  wherein said antibody is bound to a detectable label.