Garp-tgf-beta antibodies

Abstract

The present invention relates to antibodies and antigen binding fragments thereof, which bind to a complex of GARP and TGF-β1, particularly a complex of human GARP and human TGF-β1. These antibodies and antigen binding fragments exhibit a combination of advantageous properties including high affinity antigen binding and the ability to inhibit the release of active TGF-β from regulatory T cells. The antibodies and antigen binding fragments of the present invention are relatively resistant to deamidation, isomerization and oxidation, such that they display improved stability.

1 . A recombinant antibody or antigen binding fragment thereof, which binds to a complex of human glycoprotein A repetitions predominant (GARP) and TGF-β1, wherein the antibody or antigen binding fragment thereof comprises
 a heavy chain variable domain (VH), wherein: 
 the VH CDR3 comprises the amino acid sequence YEWETVVVGDLMYEYEY (SEQ ID NO: 13), 
 the VH CDR2 comprises the amino acid sequence RIDPEDAGTKYAQKFQG (SEQ ID NO: 12), and 
 the VH CDR1 comprises the amino acid sequence SYYID (SEQ ID NO: 4); and 
 a light chain variable domain (VL), wherein: 
 the VL CDR3 comprises the amino acid sequence QQYASVPVT (SEQ ID NO: 11), 
 the VL CDR2 comprises the amino acid sequence GASRLKT (SEQ ID NO: 10), and 
 the VL CDR1 comprises the amino acid sequence QASQSISSYLA (SEQ ID NO: 9). 
 
     
     
         2 . The antibody or antigen binding fragment of  claim 1 , wherein the heavy chain variable domain (VH) is a humanised, germlined or affinity variant of a camelid-derived VH domain. 
     
     
         3 . The antibody or antigen binding fragment of  claim 1 , wherein the light chain variable domain (VL) is a humanised, germlined or affinity variant of a camelid-derived VL domain. 
     
     
         4 . The antibody or antigen binding fragment of  claim 1 , wherein the heavy chain variable domain (VH) comprises the amino acid sequence of SEQ ID NO: 14 or an amino acid sequence at least 90%, 95%, 97%, 98% or 99% identical thereto. 
     
     
         5 . The antibody or antigen binding fragment of  claim 1 , wherein the light chain variable domain (VL) comprises the amino acid sequence of SEQ ID NO: 15 or an amino acid sequence at least 90%, 95%, 97%, 98% or 99% identical thereto. 
     
     
         6 . The antibody or antigen binding fragment of  claim 1 , wherein the heavy chain variable domain (VH) comprises the amino acid sequence of SEQ ID NO: 14, and the light chain variable domain (VL) comprises the amino acid sequence of SEQ ID NO: 15. 
     
     
         7 . The antibody or antigen binding fragment of  claim 1 , further comprising the CH1 domain, hinge region, CH2 domain and/or CH3 domain of a human IgG. 
     
     
         8 . The antibody or antigen binding fragment of  claim 7 , wherein the human IgG is IgG1. 
     
     
         9 . The antibody or antigen binding fragment of  claim 7 , wherein the human IgG is IgG4. 
     
     
         10 . The antibody or antigen binding fragment of  claim 9 , wherein the human IgG4 has the substitution S228P in the CH3 domain. 
     
     
         11 . The antibody or antigen binding fragment of  claim 1 , comprising at least one heavy chain comprising the amino acid sequence of SEQ ID NO: 16 or an amino acid sequence at least 90%, 95%, 97%, 98% or 99% identical thereto. 
     
     
         12 . The antibody or antigen binding fragment of  claim 1 , comprising at least one light chain comprising the amino acid sequence of SEQ ID NO: 17 or an amino acid sequence at least 90%, 95%, 97%, 98% or 99% identical thereto. 
     
     
         13 . The antibody or antigen binding fragment of  claim 1 , wherein said VH domain and VL domain when tested as a Fab fragment exhibit an off-rate (k off ) for the complex of GARP and TGF-β1 of less than 5×10 s −1 . 
     
     
         14 . The antibody or antigen binding fragment of  claim 1 , wherein said VH domain and VL domain when tested as a mAb exhibit a K D  of less than 1.7×10 −9  M. 
     
     
         15 . The antibody or antigen binding fragment of  claim 1 , which blocks release of active TGF-β from regulatory T cells. 
     
     
         16 . An isolated polynucleotide which encodes the heavy chain variable domain of the antibody or antigen binding fragment of  claim 1 . 
     
     
         17 . The isolated polynucleotide of  claim 16 , which comprises the sequence of SEQ ID NO:18. 
     
     
         18 . An isolated polynucleotide which encodes the light chain variable domain of the antibody or antigen binding fragment of  claim 1 . 
     
     
         19 . The isolated polynucleotide of  claim 18 , which comprises the sequence of SEQ ID NO:19. 
     
     
         20 . An isolated polynucleotide which encodes the antibody or antigen binding fragment of  claim 1 . 
     
     
         21 .- 30 . (canceled)