High Affinity Human Antibodies to Human IL-4 Receptor

Abstract

The present invention provides nucleic acid molecules that encode antibodies or antigen-binding fragments thereof, which specifically bind human interleukin-4 receptor (IL-4R). Also provided are expression vectors comprising nucleic acid molecule that encode anti-IL-4R antibodies, host cells comprising the expression vectors, and methods of producing anti-IL-4R antibodies or antigen-binding fragments thereof comprising growing the host cells under conditions permitting production of the antibody or fragment, and recovering the antibody or fragment so produced

1 - 29 . (canceled) 
     
     
         30 . An antibody or antigen-binding fragment of an antibody which specifically binds human IL-4R, comprising heavy chain complementarity determining region 1 (HCDR1), 2 (HCDR2), 3 (HCDR3) and light chain complementarity determining region 1 (LCDR1), 2 (LCDR2), 3 (LCDR3), wherein
 HCDR1 comprises an amino acid sequence of the formula X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8  (SEQ ID NO:265), wherein X 1 =Gly; X 2 =Phe; X 3 =Thr; X 4 =Phe; X 5 =Asp or Arg; X 6 =Asp or Ser; X 7 =Tyr; and X 8 =Ala or Gly;   HCDR2 comprises an amino acid sequence of the formula X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8  (SEQ ID NO:266), wherein X 1 =Ile or Leu, X 2 =Ser, X 3 =Gly, Tyr or Arg, X 4 =Ser, Asp or Thr, X 5 =Gly or Ser, X 6 =Gly, Ser or Val, X 7 =Ser or Asn, and X 8 =Thr, Lys or Ile;   HCDR3 comprises an amino acid sequence of the formula X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 -X 18  (SEQ ID NO:267) wherein X 1 =Ala, X 2 =Lys, X 3 =Asp, Glu or Trp, X 4 =Gly or Arg, X 5 =Leu, Thr or Arg, X 6 =Gly, Arg or Ser, X 7 =Ile or Gly, X 8 =Thr, Phe or Tyr, X 9 =Ile, Asp or Phe, X 10 =Arg, Tyr or Asp, X 11 =Pro, Tyr or absent, X 12 =Arg or absent, X 13 =Tyr or absent, X 14 =Tyr or absent, X 15 =Gly or absent, X 16 =Leu or absent, X 17 =Asp or absent, and X 18 =Val or absent;   LCDR1 comprises an amino acid sequence of the formula X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11  (SEQ ID NO:268) wherein X=Gln, X 2 =Asp, Ser or Val, X 3 =Ile or Leu, X 4 =Ser, Leu or Asn, X 5 =Asn, Tyr or Ile, X 6 =Trp, Ser or Tyr; X 7 =ile or absent; X 8 =Gly or absent; X 9 =Tyr or absent; X 10 =Asn or absent; and X 11 =Tyr or absent;   LCDR2 comprises an amino acid sequence of the formula X 1 -X 2 -X 3  (SEQ ID NO:269) wherein X 1 =Leu, Ala or Val, X 2 =Ala or Gly, and X 3 =Ser; and   LCDR3 comprises an amino acid sequence of the formula X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9  (SEQ ID NO. 270) wherein X 1 =Gln or Met, X 2 =Gln, X 3 =Ala or Tyr, X 4 =Leu or Asn, X 5 =Gn or Ser, X 6 =Thr, Phe or His, X 7 =Pro, X 8 =Tyr, Ile or Trp, and X 9 =Thr.   
     
     
         31 . The antibody or antigen-binding fragment of  claim 30 , wherein the heavy and light chain CDR amino acid sequences (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) have the amino acid sequences of SEQ ID NO: 148, 150, 152, 156, 158, and 160, respectively. 
     
     
         32 . The antibody or antigen-binding fragment of  claim 30 , wherein the heavy and light chain CDR amino acid sequences (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) are encoded by nucleotide sequences of SEQ ID NO:147, 149, 151, 155, 157, and 159, respectively. 
     
     
         33 . The antibody or antigen-binding fragment according to  claim 30 , wherein the antibody or antigen binding fragment comprises a heavy chain variable region (HCVR) having an amino acid sequence of SEQ ID NO: 162 and a light chain variable region (LCVR) having an amino acid sequence of SEQ ID NO: 164. 
     
     
         34 . The antibody or antigen-binding fragment according to  claim 30 , characterized by an affinity for hIL-4R (K D ) of ≦300 pM. 
     
     
         35 . The antibody or antigen-binding fragment according to  claim 30 , characterized by an affinity for hIL-4R (K D ) of ≦100 pM. 
     
     
         36 . The antibody or antigen-binding fragment according to  claim 30 , characterized by an affinity for hIL-4R (K D ) of ≦50 pM. 
     
     
         37 . The antibody or antigen-binding fragment according to  claim 30 , wherein the antibody or fragment thereof cross-reacts with monkey IL-4R. 
     
     
         38 . The antibody or antigen binding fragment according to  claim 30  for use in the treatment of asthma or atopic dermatitis. 
     
     
         39 . A nucleic acid sequence encoding the antibody or antigen binding fragment of  claim 30 . 
     
     
         40 . A vector comprising the nucleic acid sequence of  claim 39 . 
     
     
         41 . An isolated host cell comprising the vector of  claim 40 . 
     
     
         42 . A therapeutic composition comprising the antibody or antigen-binding fragment according to  claim 30  and an acceptable carrier. 
     
     
         43 . The therapeutic composition of  claim 42 , further comprising a second therapeutic agent selected from montelukast, pranlukast, zafirlust, and rilonacept. 
     
     
         44 . The antibody or antigen binding fragment according to  claim 30  for use in the treatment of asthma. 
     
     
         45 . The antibody or antigen binding fragment according to  claim 30  for use in the treatment of atopic dermatitis. 
     
     
         46 . The antibody or antigen binding fragment of  claim 30 , wherein the antibody or antigen-binding fragment thereof is a human antibody, and wherein the antibody or antigen-binding fragment thereof is made in a transgenic mouse. 
     
     
         47 . The antibody or antigen binding fragment of  claim 30 , wherein the antibody or antigen-binding fragment is a human antibody, and wherein the antibody or antigen-binding fragment thereof is isolated from a hybridoma that is derived from a B cell that is isolated from a transgenic mouse. 
     
     
         48 . A therapeutic composition comprising an antibody or antigen-binding fragment, and a pharmaceutically acceptable carrier, wherein the antibody or antigen binding fragment comprises a heavy chain variable region (HCVR) having an amino acid sequence of SEQ ID NO: 162 and a light chain variable region (LCVR) having an amino acid sequence of SEQ ID NO:164. 
     
     
         49 . A therapeutic composition comprising an antibody or antigen-binding fragment, and a pharmaceutically acceptable carrier, wherein the antibody or antigen binding fragment comprises heavy and light chain CDR amino acid sequences (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) having the amino acid sequences of SEQ ID NO:148, 150, 152, 156, 158, and 160, respectively.