Human Anti-NGF Neutralizing Antibodies as Selective NGF Pathway Inhibitors

Abstract

This invention provides antibodies that interact with or bind to human nerve growth factor (NGF) and neutralize the function of NGF thereby. The invention also provides pharmaceutical compositions of said antibodies and methods for neutralizing NGF function, and particularly for treating NGF-related disorders (e.g., chronic pain) by administering a pharmaceutically effective amount of anti-NGF antibodies. Methods of detecting the amount of NGF in a sample using anti-NGF antibodies are also provided.

1 - 25 . (canceled) 
     
     
         26 . A method of treating a condition caused by increased expression of nerve growth factor (NGF) or increased sensitivity to NGF in a patient, comprising administering to a patient a pharmaceutically effective amount of an isolated human antibody that binds specifically to NGF, wherein the antibody comprises a heavy chain variable region, said heavy chain variable region comprising CDR2 (SEQ ID NO: 18), and CDR3 (SEQ ID NO: 14) of SEQ ID NO: 10, and a light chain variable region, said light chain variable region comprising (SEQ ID NO: 20), and CDR3 (SEQ ID NO: 16) of SEQ ID 12, and wherein the antibody inhibits NGF signaling. 
     
     
         27 . The method of  claim 26 , wherein the condition is osteoarthritis. 
     
     
         28 . (canceled) 
     
     
         29 . A method of treating a condition caused by increased expression of NGF or increased sensitivity to NGF in a patient, comprising administering to a patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of an isolated human antibody that binds specifically to NGF, wherein the antibody comprises a heavy chain variable region, said heavy chain variable region comprising CDR1 (SEQ ID NO: 22), CDR2 ID NO: 18), and CDR3 (SEQ ID NO: 14) of SEQ ID NO: 10, and a light chain variable region, said light chain variable region comprising CDR1 (SEQ ID NO: 24), CDR2 (SEQ ID NO: 20), and CDR3 (SEQ ID NO: 16) of SEQ ID 12. 
     
     
         30 . A method for detecting NGF in a biological sample comprising:
 (a) contacting the sample with an isolated human antibody that binds specifically to NGF, wherein the antibody comprises a heavy chain variable region, said heavy chain variable region comprising CDR1 (SEQ ID NO: 22), CDR2 (SEQ ID NO: 18), and CDR3 (SEQ ID NO: 14) of SEQ ID NO: 10, and a light chain variable region, said light chain variable region comprising CDR1 (SEQ ID NO: 24), CDR2 (SEQ ID NO: 20), and CDR3 (SEQ ID NO: 16) of SEQ ID 12 under conditions that allow for binding of the antibody to NGF; and   (b) measuring the level of bound antibody in the sample.   
     
     
         31 - 49 . (canceled) 
     
     
         50 . The method of  claim 29 , wherein the antibody inhibits NGF signaling. 
     
     
         51 . The method of  claim 50 , wherein the condition is acute osteoarthritis. 
     
     
         52 . (canceled) 
     
     
         53 . A method of treating a condition caused by increased expression of NGF or increased sensitivity to NGF in a patient, comprising administering to a patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of an isolated human antibody that binds specifically to NGF, wherein the antibody comprises a heavy chain variable region, said heavy chain variable region comprising CDR1 (SEQ ID NO: 22), CDR2 (SEQ ID NO: 18), and CDR3 (SEQ ID NO: 14) of SEQ ID NO: 10, and a light chain variable region, said light chain variable region comprising CDR1 (SEQ ID NO: 24), CDR2 (SEQ ID NO: 20), and CDR3 (SEQ ID NO: 16) of SEQ ID 12, wherein the antibody inhibits NGF signaling. 
     
     
         54 . A method for detecting NGF in a biological sample comprising:
 (a) contacting the sample with
 (i) an isolated human antibody that specifically binds nerve growth factor, comprising a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence as set forth in any of SEQ ID NO: 10, SEQ ID NO: 79, SEQ ID NO: 81, SEQ ID NO: 83, SEQ ID NO: 85, or SEQ ID NO: 87, or an antigen-binding fragment thereof; 
 (ii) an isolated human antibody that specifically binds NGF, comprising a heavy chain and a light chain, wherein the light chain comprises a light chain variable region comprising an amino acid sequence that is at least 85% identical to the amino acid sequence as set forth in any of SEQ ID NO: 12, SEQ ID NO: 80, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, or SEQ ID NO: 131, or an antigen-binding fragment thereof; 
 (iii) an isolated human antibody that specifically binds NGF, comprising a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence that is at least 80% identical to the amino acid sequence as set forth in any of SEQ ID NO: 14, SEQ ID NO: 18, SEQ ID NO: 22, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 110, SEQ ID NO: 111, SEQ ID NO: 112, SEQ ID SEQ ID NO: 118, or an antigen-binding fragment thereof; 
 (iv) an isolated human antibody that specifically binds NGF, comprising heavy chain and a light chain, wherein the light chain comprises an amino acid sequence that is at least 85% identical to the amino acid sequence as set forth in any of SEQ ID NO: 16, SEQ ID NO: 20, SEQ ID NO: 24, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 107, SEQ any of SEQ ID NO: 119-134, or an antigen-binding fragment thereof; 
 (v) an isolated human antibody that specifically binds NGF comprising a CDR3 comprising an amino acid sequence selected from the group of sequences consisting of SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 94, SEQ ID NO: 97, SEQ ID NO: 100, SEQ ID NO: 103, SEQ ID NO: 106, SEQ ID NO: 109, SEQ ID NO: 112, SEQ ID NO: 115, SEQ ID NO: 118, SEQ ID NO: 121, SEQ ID NO: 124, SEQ ID NO: 127 SEQ ID NO: 130 SEQ ID NO: 134 and a variant thereof wherein the variant comprises no more than one amino acid substitution, insertion, or deletion; or 
 (vi) an isolated human antibody that specifically binds NGF comprising amino acid sequence at least 90% identical to a sequence selected from the group of sequences consisting of SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16 SEQ ID NO: 18 SEQ ID NO: 20 and SEQ ID NO: 22 and a variant thereof wherein the variant comprises no more than one amino acid substitution, insertion, or deletion; 
   under conditions that allow for binding of the antibody to NGF; and   (b) measuring the level of bound antibody in the sample.   
     
     
         55 - 59 . (canceled) 
     
     
         60 . A method of treating a condition caused by increased expression of NGF or increased sensitivity to NGF in a patient, comprising administering to a patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a NGF specific binding agent comprising least one amino acid sequence selected from SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 22, and any of SEQ ID NO: 79-130. 
     
     
         61 - 64 . (canceled) 
     
     
         65 . A method of treating a condition caused by increased expression of NGF or increased sensitivity to NGF in a patient, comprising administering to a patient a pharmaceutically effective amount of a NGF specific binding agent comprising at least one amino acid sequence selected from SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 22, and any of SEQ ID NO: 79-130. 
     
     
         66 . The method of  claim 65 , wherein the condition is osteoarthritis. 
     
     
         67 . A method for detecting NGF in a biological sample comprising:
 (a) contacting the sample with a NGF specific binding agent comprising at least one amino acid sequence selected from SEQ 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 22, and any of SEQ ID NO: 79-130, under conditions that allow for binding of the binding agent to NGF; and   (b) measuring the level of bound antibody in the sample.   
     
     
         68 . (canceled) 
     
     
         69 . An isolated human antibody or an antigen-binding or an immunologically functional immunoglobulin fragment thereof that binds specifically to NGF, wherein the antibody or fragment comprises a heavy chain variable region comprising:
 (a) a CDR1 region comprising an amino acid sequence of the formula:
   a 1 a 2 a 3 a 4 a 5    
 wherein:
 a 1  is a polar hydrophilic amino acid residue; 
 a 2  is an aromatic amino acid residue; 
 a 3  is a aliphatic, polar hydrophobic, aromatic amino acid residue; 
 a 4  is a neutral hydrophobic or aliphatic amino acid residue; and 
 a 5  is a aliphatic or polar hydrophilic amino acid residue; 
 
   (b) a CDR2 region comprising an amino acid sequence of the formula:
   b 1 b 2 b 3 b 4 b 5 b 6 b 7 b 8 b 9 b 10 b 11 b 12 b 13 b 14 b 15 b 16 b 17    
 wherein:
 b 1  is a aliphatic, polar hydrophobic, or aromatic amino acid residue; 
 b 2  is an aliphatic hydrophobic amino acid residue; 
 b 3  is a polar hydrophilic or aromatic amino acid residue; 
 b 4  is a polar hydrophilic, hydrophobic, or aromatic amino acid residue; 
 b 5 -b 9  are independently polar hydrophilic or aliphatic amino acid residues; 
 b 10  is a polar hydrophilic, aromatic, or aliphatic amino acid residue; 
 b 11  is an aromatic or hydrophobic amino acid residue; 
 b 12  is an aliphatic hydrophobic or polar hydrophilic amino acid residue; 
 b 13  is an aliphatic, hydrophobic or polar hydrophilic amino acid residue; 
 b 14  and b 16  are independently polar hydrophilic amino acid residues; 
 b 15  is an aliphatic or aromatic hydrophobic amino acid residue; and 
 b 17  is an aliphatic acidic amino acid residue; and 
 
   (c) a CDR3 region comprising an amino acid sequence of the formula:
   c 1 c 2 c 3 c 4 c 5 c 6 c 7 c 8 c 9 c 10 c 11 c 12 c 13 c 14 c 15 c 16 c 17    
 wherein:
 c 1  is absent or an aliphatic amino acid residue; 
 c 2  is absent or a polar hydrophilic or an aromatic hydrophobic amino acid residue; 
 c 3  and c 4  are independently absent or a polar hydrophilic, aromatic hydrophobic, or aliphatic amino acid residues; 
 c 5  is absent or a polar hydrophilic, aliphatic or an aromatic amino acid residue; 
 c 6  is absent or a polar hydrophilic or aliphatic amino acid residue; 
 c 7  is a polar hydrophilic or an aliphatic amino acid residue; 
 c 8  is a polar hydrophilic, hydrophobic or an aromatic amino acid residue; 
 c 9  is a polar hydrophilic, aliphatic or an aromatic hydrophobic amino acid residue; 
 c 10  a polar hydrophilic, aromatic hydrophobic, or an aliphatic hydrophobic amino acid residue; 
 c 11 -c 13  are independently polar hydrophilic or aromatic hydrophobic amino acid residues; 
 c 14  is an aliphatic or aromatic hydrophobic amino acid residue; 
 c 15  is a polar hydrophilic or neutral hydrophobic amino acid residue; 
 c 16  is absent or a polar hydrophilic amino acid residue; and 
 c 17  is an aromatic hydrophobic or aliphatic hydrophobic amino acid residue, and 
 
 wherein said antibody or fragment dissociates from a human NGF polypeptide with a K D  of about 1×10 −9  or less and neutralizes human NGF bioactivity in a standard in vitro assay with an IC 50  of about 1×10 −8  M or less. 
   
     
     
         70 . The antibody or fragment according to  claim 69  wherein:
 a 1  is a polar hydrophilic amino acid residue; 
 a 2  is an aromatic hydrophobic amino acid residue; 
 a 3  is an aliphatic hydrophobic amino acid residue; 
 a 4  is a neutral hydrophobic; 
 a 5  is a polar hydrophilic amino acid residue; 
 b 1  is a aliphatic or aromatic amino acid residue; 
 b 2  is Ile; 
 b 3  is a polar hydrophilic amino acid residue; 
 b 4  is a polar hydrophilic or aromatic amino acid residue; 
 b 5 -b 9  are independently polar hydrophilic or aliphatic amino acid residues; 
 b 10  is an aliphatic amino acid residue; 
 b 11  is Tyr; 
 b 12  is an aliphatic hydrophobic amino acid residue; 
 b 13  is an aliphatic or polar hydrophilic amino acid residue; 
 b 14  and b 16  are independently polar hydrophilic amino acid residues; and 
 b 15  is an aliphatic hydrophobic amino acid residue; 
 b 17  is an aliphatic acidic amino acid residue; 
 c 1  is absent or an aliphatic amino acid residue; 
 c 2  is absent or a polar hydrophilic or an aromatic hydrophobic amino acid residue; 
 c 3  and c 4  are independently absent or a polar hydrophilic, aromatic hydrophobic, or aliphatic amino acid residues; 
 c 5  is absent or a polar hydrophilic amino acid residue; 
 c 6  is absent or a polar hydrophilic or aliphatic amino acid residue; 
 c 7  is a polar hydrophilic or an aliphatic amino acid residue; 
 c 8  is a polar hydrophilic, hydrophobic or an aromatic amino acid residue; 
 c 9  is a polar hydrophilic, aliphatic or an aromatic hydrophobic amino acid residue; 
 c 10  is a polar hydrophilic, aromatic hydrophobic, or an aliphatic hydrophobic amino acid residue; 
 c 11 -c 13  are independently polar hydrophilic or aromatic hydrophobic amino acid residues; 
 c 14  is an aliphatic or aromatic hydrophobic amino acid residue; 
 c 15  is a polar hydrophilic or neutral hydrophobic amino acid residue; 
 c 16  is absent or a polar hydrophilic amino acid residue; and 
 c 17  is an aromatic hydrophobic or aliphatic hydrophobic amino acid residue. 
 
     
     
         71 . The antibody or fragment according to  claim 69  wherein:
 a 1  is Ser, Asp, or Thr; a 2  is Tyr; a 3  is Ala, Ser, Trp, or Gly; a 4  is Met or Ile; a 5  is His, Gly, or Asn; b′ is Tyr, Gly, Ile, or Asp; b 2  is Ile; b 3  is Ser, Thr, Tyr, or Asn; b 4  is Trp, Arg, or Pro; b 5  is Ser, Asn, or Gly; b 6  is Ser, Arg, Asp, or Gly; b 7  is Ser, His, or Gly; b 8  is Ser, Ile, Asp, or Thr; b 9  is Leu, Ile, or Thr; b 10  is Gly, Lys, or Phe; b 11  is Tyr; b 12  is Ala or Ser; b 13  is Asp, Gly, or Pro; b 14  is Ser; b 15  is Val or Phe; b 16  is Lys or Gln; b 17  is Gly; c′ is absent or an aliphatic amino acid residue; c 2  is absent or Tyr; c 3  and c 4  are independently absent, Tyr, Asn, Val, or Glu; c 5  is absent, Ser, Gly, or Trp; c 6  is absent, Ser, Gly, Glu, or Leu; c 7  is Gly, Arg, or Asp; c 8  is Trp, Pro, Ser, or Thr; c 9  is His, Gly, or Tyr; c 10  is Val, Tyr, or Arg; c 11 -c 13  are independently Ser, Phe, Tyr, Asp, or Asn; c 14  is Phe, Val, or Gly; c 15  is Met or Asp; c 16  is absent, Asp, or Asn; and c 17  is Tyr or Val. 
 
     
     
         72 . The antibody or fragment according to  claim 69  wherein:
 a 1  is Ser or Asp; a 2  is Tyr; a 3  is Ala or Ser; a 4  is Met or Ile; a 5  is His or Asn; b′ is Tyr or Gly; b 2  is Ile; b 3  is Ser, Thr, Tyr, or Asn; b 4  is Trp, Arg, or Pro; b 5  is Ser or Asn; b 6  is Ser or Arg; b 7  is His or Gly; b 8  is Ile or Thr; b 9  is Leu, Ile, or Thr; b 10  is Gly or Phe; b 11  is Tyr; b 12  is Ala or Ser; b 13  is As or Gly; b 14  is Ser; b 15  is Val or Phe; b 16  is Lys or Gln; b 17  is Gly; c 1  is absent or Gly; c 2  is absent or Tyr; c 3  and c 4  are independently absent, Tyr, Gly, or Val; c 5  is absent or Ser; c 6  is Ser or Gly; c 7  is Gly or Arg; c 8  is Trp or Pro; c 9  is His, Gly, or Tyr; c 10  is Val or Tyr; c 11 -c 13  are independently Ser, Tyr, Phe, or Asp; c 14  is Phe or Val; c 15  is Met or Asp; c 16  is absent or Asp; and c 17  is Tyr or Val. 
 
     
     
         73 . The antibody of  claim 69 , wherein:
 (a) the heavy chain CDR1 has an amino acid sequence as set forth in SEQ ID NO: 22, the heavy chain CDR2 has an amino acid sequence as set forth in SEQ ID NO: 18, and the heavy chain CDR 3 has an amino acid sequence as set forth in SEQ ID NO: 14;   (b) the heavy chain CDR1 has an amino acid sequence as set forth in SEQ ID NO: 92, the heavy chain CDR2 has an amino acid sequence as set forth in SEQ ID NO: 93, and the heavy chain CDR 3 has an amino acid sequence as set forth in SEQ ID NO: 94;   (c) the heavy chain CDR1 has an amino acid sequence as set forth in SEQ ID NO: 98, the heavy chain CDR2 has an amino acid sequence as set forth in SEQ ID NO: 99, and the heavy chain CDR 3 has an amino acid sequence as set forth in SEQ ID NO: 100;   (d) the heavy chain CDR1 has an amino acid sequence as set forth in SEQ ID NO: 104, the heavy chain CDR2 has an amino acid sequence as set forth in SEQ ID NO: 105, and the heavy chain CDR 3 has an amino acid sequence as set forth in SEQ ID NO: 106;   (e) the heavy chain CDR1 has an amino acid sequence as set forth in SEQ ID NO: 110, the heavy chain CDR2 has an amino acid sequence as set forth in SEQ ID NO: 111, and the heavy chain CDR 3 has an amino acid sequence as set forth in SEQ ID NO: 112; or   (f) the heavy chain CDR1 has an amino acid sequence as set forth in SEQ ID NO: 116, the heavy chain CDR2 has an amino acid sequence as set forth in SEQ ID NO: 117, and the heavy chain CDR 3 has an amino acid sequence as set forth in SEQ ID NO: 118.   
     
     
         74 . An isolated human antibody or an antigen-binding or an immunologically functional immunoglobulin fragment thereof that binds specifically to NGF, wherein the antibody or fragment comprises a light chain variable region comprising:
 (a) a CDR1 region comprising an amino acid sequence of the formula:
   a 1 a 2 a 3 a 4 a 5 a 6 a 7 a 8 a 9 a 10 a 11 a 12    
 wherein:
 a 1  is a polar hydrophilic amino acid residue; 
 a 2 , a 11  and a 12  are independently aliphatic or hydrophobic amino acid residues; 
 a 3 , a 5 , a 7  and a 8  are independently aliphatic, polar hydrophilic, or hydrophobic amino acid residues; 
 a 4  is a polar hydrophilic amino acid residue; 
 a 6  is an aliphatic or hydrophobic amino acid residue; 
 a 9  is absent, or an aliphatic or polar hydrophilic amino acid residue; and 
 a 10  is an aliphatic, aromatic, or hydrophobic amino acid residue; 
 
   (b) a CDR2 region comprising an amino acid sequence of the formula:
   b 1 b 2 b 3 b 4 b 5 b 6 b 7    
 wherein:
 b 1  is a aliphatic, polar hydrophobic, or hydrophobic amino acid residue; 
 b 2  is an aliphatic or hydrophobic amino acid residue; 
 b 3  and b 4  are independently polar hydrophilic, aliphatic or hydrophobic amino acid residues; 
 b 5  is a polar hydrophilic or aliphatic hydrophobic amino acid residues; 
 b 6  is a polar hydrophilic or aliphatic hydrophobic amino acid residue; and 
 b 7  is a polar hydrophilic amino acid residue; and 
 
   (c) a CDR3 region comprising an amino acid sequence of the formula:
   c 1 c 2 c 3 c 4 c 5 c 6 c 7 c 8 c 9 c 10 c 11 c 12 c 13 c 14 c 15 c 16 c 17    
 wherein:
 c 1  and c 2  are independently polar hydrophilic amino acid residues; 
 c 3  is a polar hydrophilic, aliphatic or hydrophobic amino acid residue; 
 c 4 , c 5  and c 6  are independently aliphatic, polar hydrophilic, or hydrophobic amino acid residues; 
 c 7  is absent or a polar hydrophilic or an aliphatic hydrophobic amino acid residue; 
 c 8  is a polar hydrophilic or hydrophobic amino acid residue; and 
 
   c 9  is a polar hydrophilic amino acid residue, and
 wherein said antibody or fragment dissociates from a human NGF polypeptide with a K D  of about 1×10 −9  or less and neutralizes human NGF bioactivity in a standard in vitro assay with an IC 50  of about 1×10 −8  M or less. 
   
     
     
         75 . The antibody or fragment according to  claim 74  wherein:
 a 1 , a 3 , a 4 , a 7  and a 8  are independently polar hydrophilic amino acid residues; 
 a 2 , a 6 , a 11  and a 12  are independently aliphatic hydrophobic amino acid residues; 
 a 5  is a polar hydrophilic or aliphatic amino acid residue; 
 a 9  is absent, or an aliphatic or polar hydrophilic amino acid residue; 
 a 10  is an aliphatic or aromatic amino acid residue; 
 b 1  is a aliphatic, polar hydrophobic, or hydrophobic amino acid residue; 
 b 2  is an aliphatic hydrophobic amino acid residue; 
 b 3 , b 4  and b 7  are independently polar hydrophilic amino acid residues; 
 b 5  and b 6  are independently polar hydrophilic or aliphatic hydrophobic amino acid residues; 
 c 1  and c 2  are independently polar hydrophilic amino acid residues; 
 c 3  is a polar hydrophilic, aliphatic or hydrophobic amino acid residue; 
 c 4 , c 5 , and c 6  are independently aliphatic, polar hydrophilic, or hydrophobic amino acid residues; 
 c 7  is absent or an aliphatic hydrophobic amino acid residue; 
 c 8  is a hydrophobic amino acid residue; and 
 c 9  is a polar hydrophilic amino acid residue. 
 
     
     
         76 . The antibody or fragment according to  claim 75  wherein:
 a 1 , a 3 , a 4 , and a 7  are Arg, Ser, Gln, and Ser, respectively; 
 a 2  is Ala; 
 a 5  is Gly or Ser; 
 a 8  is Ser or Ile; 
 a 9  is absent, Ser, or Gly; 
 a 10  is Ala, Tyr, Trp or Phe; 
 b 1  is Asp, Gly, Ala, or Val; 
 b 2  and b 3  are Ala and Ser, respectively; 
 b 4  is Ser or Asn; 
 b 5  is Leu or Arg; 
 b 6  is Glu, Ala, or Gln; 
 b 7  is Ser or Thr; 
 c 1  and c 2  are Gln; 
 c 3  is Phe, Tyr, Arg, or Ala; 
 c 4  is Asn, Gly, or Ser; 
 c 5  is Ser or Asn; 
 c 6  is Tyr, Ser, Trp, or Phe; 
 c 7  is absent, Pro, or His; 
 c 8  is Leu, Trp, Tyr, or Arg; and 
 c 9  is Thr. 
 
     
     
         77 . The antibody or fragment according to  claim 75  wherein:
 a 1 , a 2 , a 3 , a 4 , and a 7  are Arg, Ala, Ser, Gln, and Ser, respectively; 
 a 5  is Gly or Ser; 
 a 8  is Ser or Ile; 
 a 9  is absent, Ser, or Gly; 
 a 10  is Ala or Tyr; 
 b 1  is Asp or Gly; 
 b 2  and b 3  are Ala and Ser, respectively; 
 b 4  is Ser or Asn; 
 b 5  is Leu or Arg; 
 b 6  is Glu, Ala, or Gln; 
 b 7  is Ser or Thr; 
 c 1  and c 2  are Gln; 
 c 3  is Phe, Tyr, Arg, or Ala; 
 c 4  is Asn, Gly, or Ser; 
 c 5  is Ser or Asn; 
 c 6  is Tyr, Ser, Trp, or Phe; 
 c 7  is absent, Pro, or His; 
 c 8  is Leu, Trp, Tyr, or Arg; and 
 c 9  is Thr. 
 
     
     
         78 . The antibody of  claim 74 , wherein:
 (a) the light chain CDR1 has an amino acid sequence as set forth in SEQ ID NO: 24, the light chain CDR2 has an amino acid sequence as set forth in SEQ ID NO: 20, and the light chain CDR 3 has an amino acid sequence as set forth in SEQ ID NO: 16;   (b) the light chain CDR1 has an amino acid sequence as set forth in SEQ ID NO: 95, the light chain CDR2 has an amino acid sequence as set forth in SEQ ID NO: 96, and the light chain CDR 3 has an amino acid sequence as set forth in SEQ ID NO: 97;   (c) the light chain CDR1 has an amino acid sequence as set forth in SEQ ID NO: 101, the light chain CDR2 has an amino acid sequence as set forth in SEQ ID NO: 102, and the light chain CDR 3 has an amino acid sequence as set forth in SEQ ID NO: 103;   (d) the light chain CDR1 has an amino acid sequence as set forth in SEQ ID NO: 107, the light chain CDR2 has an amino acid sequence as set forth in SEQ ID NO: 108, and the light chain CDR 3 has an amino acid sequence as set forth in SEQ ID NO: 109;   (e) the light chain CDR1 has an amino acid sequence as set forth in SEQ ID NO: 113, the light chain CDR2 has an amino acid sequence as set forth in SEQ ID NO: 114, and the light chain CDR 3 has an amino acid sequence as set forth in SEQ ID NO: 115;   (f) the light chain CDR1 has an amino acid sequence as set forth in SEQ ID NO: 119, the light chain CDR2 has an amino acid sequence as set forth in SEQ ID NO: 120, and the light chain CDR 3 has an amino acid sequence as set forth in SEQ ID NO: 121;   (g) the light chain CDR1 has an amino acid sequence as set forth in SEQ ID NO: 122, the light chain CDR2 has an amino acid sequence as set forth in SEQ ID NO: 123, and the light chain CDR 3 has an amino acid sequence as set forth in SEQ ID NO: 124;   (h) the light chain CDR1 has an amino acid sequence as set forth in SEQ ID NO: 125, the light chain CDR2 has an amino acid sequence as set forth in SEQ ID NO: 126, and the light chain CDR 3 has an amino acid sequence as set forth in SEQ ID NO: 127;   (i) the light chain CDR1 has an amino acid sequence as set forth in SEQ ID NO: 128, the light chain CDR2 has an amino acid sequence as set forth in SEQ ID NO: 129, and the light chain CDR 3 has an amino acid sequence as set forth in SEQ ID NO: 130; or   (j) the light chain CDR1 has an amino acid sequence as set forth in SEQ ID NO: 132, the light chain CDR2 has an amino acid sequence as set forth in SEQ ID NO: 133, and the light chain CDR 3 has an amino acid sequence as set forth in SEQ ID NO: 134.   
     
     
         79 . A polynucleotide encoding the antibody or fragment according to any of  claims 69 - 78 . 
     
     
         80 . An expression vector comprising the polynucleotide of  claim 79 . 
     
     
         81 . A host cell comprising the expression vector of  claim 80 . 
     
     
         82 . The host cell according to  claim 81  wherein the cell is a eukaryotic cell. 
     
     
         83 . The host cell according to  claim 82  wherein the cell is a CHO cell.