Organic compounds

Abstract

The present invention relates to human thymic stromal lymphopoietin (hTSLP) antibodies and especially those which neutralize hTSLP activity. It further relates to methods for using anti-hTSLP antibody molecules in diagnosis or treatment of hTSLP related disorders, such as asthma, atopic dermatitis, allergic rhinitis, fibrosis, inflammatory bowel disease and Hodgkin's lymphoma.

1 . An isolated human or humanized antibody or functional fragment thereof comprising an antigen-binding region that is specific for human TSLP, wherein the antibody or functional fragment thereof binds human TSLP with a KD of 39×10 −12  M or less. 
     
     
         2 . The antibody or functional fragment thereof according to  claim 1 , wherein the antibody or functional fragment thereof binds human TSLP with a KD of 14×10 −12  M or less. 
     
     
         3 . The antibody or functional fragment thereof according to  claim 1  which comprises an H-CDR1 region depicted in the amino acid sequence of SEQ ID NO: 3, an H-CDR2 region depicted in an amino acid sequence selected from the group of SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20, an H-CDR3 region depicted in the amino acid sequence SEQ ID NO: 28, an L-CDR1 region depicted in the amino acid sequence of SEQ ID NO: 38, an L-CDR2 region depicted in the amino acid sequence SEQ ID NO: 47, and an L-CDR3 region depicted in the amino acid sequence SEQ ID NO: 60, and conservative variants thereof. 
     
     
         4 . The antibody or functional fragment thereof according to  claim 3  which comprises an H-CDR1 region depicted in the amino acid sequence of SEQ ID NO: 3, an H-CDR2 region depicted in an amino acid sequence selected from the group of SEQ ID NO: 20, and an H-CDR3 region depicted in the amino acid sequence SEQ ID NO: 28, an L-CDR1 region depicted in the amino acid sequence of SEQ ID NO: 38, an L-CDR2 region depicted in the amino acid sequence SEQ ID NO: 47, and an L-CDR3 region depicted in the amino acid sequence SEQ ID NO: 60 and conservative variants thereof. 
     
     
         5 . The antibody or functional fragment thereof according to  claim 3  which comprises a sequence having at least 60, 70, 80, 90 or 95 percent sequence identity in the CDR regions. 
     
     
         6 . The isolated antibody according to  claim 1 , which is an IgG1, IgG2 or an IgG4. 
     
     
         7 . The isolated antibody according to  claim 6  comprising a heavy chain variable region selected from SEQ ID NO: 84, SEQ ID NO: 85 and SEQ ID NO: 86, and conservative variants thereof. 
     
     
         8 . The isolated antibody according to  claim 7  comprising the light chain variable region SEQ ID NO: 88. 
     
     
         9 . The isolated antibody according to  claim 7  where the heavy chain variable region is SEQ ID NO: 84, and conservative variants thereof. 
     
     
         10 . The isolated antibody according to  claim 7  where the heavy chain variable region is SEQ ID NO: 85, and conservative variants thereof. 
     
     
         11 . The isolated antibody according to  claim 7  where the heavy chain variable region is SEQ ID NO: 86, and conservative variants thereof. 
     
     
         12 . The isolated antibody according to  claim 7  which is an IgG1 having a light chain lamda sequence selected from SEQ ID NO: 99 or SEQ ID NO: 101, and a heavy chain sequence selected from SEQ ID NO: 103, SEQ ID No: 105, SEQ ID NO: 107, SEQ ID NO: 109, SEQ ID NO: 111 and SEQ ID NO: 113, and conservative variants thereof. 
     
     
         13 . An isolated or recombinant polynucleotide which encodes a polypeptide comprising an antigen-binding region of an antibody or functional fragment thereof according to  claim 1 . 
     
     
         14 . The polynucleotide of  claim 13 , wherein the antibody is a human antibody. 
     
     
         15 . The polynucleotide of  claim 13 , wherein the polynucleotide encodes am antibody comprising H-CDR1, H-CDR2, and H-CDR3 sequences, and L-CDR1, L-CDR2, and L-CDR3 sequences, selected from:
 (a) H-CDR SEQ ID NO: 3, SEQ ID NO: 15, SEQ ID NO: 28;
 L-CDR SEQ ID NO: 38, SEQ ID NO: 47, SEQ ID NO: 60. 
   (b) H-CDR SEQ ID NO: 3, SEQ ID NO: 17, SEQ ID NO: 28;
 L-CDR SEQ ID NO: 38, SEQ ID NO: 47, SEQ ID NO: 60. 
   (c) H-CDR SEQ ID NO: 3, SEQ ID NO: 18, SEQ ID NO: 28;
 L-CDR SEQ ID NO: 38, SEQ ID NO: 47, SEQ ID NO: 60. 
   (d) H-CDR SEQ ID NO: 3, SEQ ID NO: 19, SEQ ID NO: 28;
 L-CDR SEQ ID NO: 38, SEQ ID NO: 47, SEQ ID NO: 60. 
   (e) H-CDRSEQ ID NO: 3, SEQ ID NO: 20, SEQ ID NO: 28; and
 L-CDR SEQ ID NO: 38, SEQ ID NO: 47, SEQ ID NO: 60. 
   
     
     
         16 . The polynucleotide of  claim 13  which is a DNA. 
     
     
         17 . An isolated host cell comprising (1) a recombinant DNA segment encoding a heavy chain of the antibody of  claim 7 , and (2) a second recombinant DNA segment encoding a light chain of the antibody; wherein said DNA segments are respectively operably linked to a first and a second promoter, and are capable of being expressed in said host cell. 
     
     
         18 . The host cell of  claim 17 , wherein the monoclonal antibody is a human antibody. 
     
     
         19 . The host cell of  claim 17 , wherein the monoclonal antibody comprises a heavy and light chain sequence selected from:
 (a) H-CDR SEQ ID NO: 3, SEQ ID NO: 15, SEQ ID NO: 28;
 L-CDR SEQ ID NO: 38, SEQ ID NO: 47, SEQ ID NO: 60. 
   (b) H-CDR SEQ ID NO: 3, SEQ ID NO: 17, SEQ ID NO: 28;
 L-CDR SEQ ID NO: 38, SEQ ID NO: 47, SEQ ID NO: 60. 
   (c) H-CDR SEQ ID NO: 3, SEQ ID NO: 18, SEQ ID NO: 28;
 L-CDR SEQ ID NO: 38, SEQ ID NO: 47, SEQ ID NO: 60. 
   (d) H-CDR SEQ ID NO: 3, SEQ ID NO: 19, SEQ ID NO: 28;
 L-CDR SEQ ID NO: 38, SEQ ID NO: 47, SEQ ID NO: 60. 
   (e) H-CDRSEQ ID NO: 3, SEQ ID NO: 20, SEQ ID NO: 28; and
 L-CDR SEQ ID NO: 38, SEQ ID NO: 47, SEQ ID NO: 60. 
   
     
     
         20 . The host cell of  claim 17  that is a non-human mammalian cell line. 
     
     
         21 . A pharmaceutical composition comprising an antibody or functional fragment thereof according to  claim 1  and a pharmaceutically acceptable carrier or excipient therefor. 
     
     
         22 . The pharmaceutical composition according to  claim 21  for use in treating a disorder or condition associated with the presence of cell receptor target hTSLP, wherein the composition is administered to a subject in need thereof in an effective amount. 
     
     
         23 . The pharmaceutical composition according to  claim 22 , wherein the disorder or condition is asthma. 
     
     
         24 . The pharmaceutical composition according to  claim 22 , wherein the disorder or condition is atopic dermatitis.