Antigen Binding Proteins Capable of Binding Thymic Stromal Lymphopoietin

Abstract

The present disclosure provides compositions and methods relating to antigen binding proteins which bind to human thymic stromal lymphopoietin (TSLP), including antibodies. In particular embodiments, the disclosure provides fully human, humanized and chimeric anti-TSLP antibodies and derivatives of such antibodies. The disclosure further provides nucleic acids encoding such antibodies and antibody fragments and derivatives, and methods of making and using such antibodies including methods of treating and preventing TSLP-related inflammatory and fibrotic disorders.

1 . An isolated antigen binding protein comprising an amino acid sequence selected from the group consisting of:
 a. a light chain CDR3 sequence selected from the group consisting of:
 i. a light chain CDR3 sequence that differs by no more than a total of two amino acid additions, substitutions, and/or deletions from a CDR3 sequence selected from the group consisting of the light chain CDR3 sequences of A1 to All; 
 ii. QQAX 8 SFPLT (SEQ ID NO: 251); 
   and   b. a heavy chain CDR3 sequence selected from the group consisting of:
 i. a heavy chain CDR3 sequence that differs by no more than a total of three amino acid additions, substitutions, and/or deletions from a CDR3 sequence selected from the group consisting of the heavy chain CDR3 sequences of A1 to A27; 
 ii. GGGIX 12 VADYYX 13 YGMDV (SEQ ID NO: 255); and 
 iii. DX 21 GX 22 SGWPLFX 23 Y (SEQ ID NO: 259); 
   wherein   X 8  is an N residue or a D residue;   Xi 2  is a P residue or an A residue;   Xi 3  is a Y residue or an F residue;   X 21  is a G residue or an R residue;   X 22  is an S residue or a T residue;   X 23  is an A residue or a D residue,   and wherein said antigen binding protein specifically binds to TSLP.   
     
     
         2 . The isolated antigen binding protein of  claim 1 , further comprising an amino acid sequence selected from the group consisting of:
 a. a light chain CDRI sequence selected from the group consisting of:
 i. a light chain CDRI sequence that differs by no more than three amino acids additions, substitutions, and/or deletions from a light chain CDRI sequence of A1 -A27; 
 ii. RSSQSLX 1 YSDGX 2 TYLN (SEQ ID NO: 246); 
 iii. RASQX 4 X 5 SSWLA (SEQ ID NO: 249); and 
   b. a light chain CDR2 sequence selected from the group consisting of:
 i. a light chain CDR2 sequence that differs by no more than two amino acid additions, substitutions, and/or deletions from a CDR2 sequence of A1 -A27; 
 ii. KVSX 3 WDS (SEQ ID NO: 247); 
 iii. X 6 X 7 SSLQS (SEQ ID NO: 250); and iv. QDX 9 KRPS (SEQ ID NO: 252); 
   c. a heavy chain CDRI sequence selected from the group consisting of:
 i. a heavy chain CDRI sequence that differs by no more than two amino acid additions, substitutions, and/or deletions from a CDRI sequence of A1 -A27; 
 ii. X 10 YGMH (SEQ ID NO: 253); and 
 iii. X 15 X 16 YMX 17  (SEQ ID NO: 257); 
   d. a heavy chain CDR2 sequence selected from the group consisting of:
 i. a heavy chain CDR2 sequence that differs by no more than three amino acid additions, substitutions, and/or deletions from a CDR2 sequence of A1 -A27; 
 ii. VIWX 11 DGSNKYYADSVKG (SEQ ID NO: 254); 
 iii. VISYDGSX 14 KYYADSVKG (SEQ ID NO: 256); and 
 iv. WrNPNSGGTNXi 8 X 19 X 20 KFQG (SEQ ID NO: 258); 
   wherein
 X 1  is a V residue or an I residue; 
 X 2  is an N residue or a D residue; 
 X 3  is a Y residue or an N residue; 
 X 4  is a G residue or a S residue; 
 X 5  is a L residue or an I residue; 
 X 6  is an N residue or a T residue; 
 X 7  is a T residue or an A residue; 
 X 9  is a K residue or an N residue; 
 X 10  is an S residue or an N residue; 
 X 11  is a Y residue or an F residue; 
 X 14  is a Y residue or a N residue; 
 X 15  is a D residue or G residue; 
 X 16  is a Y residue or a D residue; 
 X 17  is a Y residue or an H residue; 
 X 18  is a Y residue or an H residue; 
 X 19  is a V residue or an A residue; 
 X 20  is a Q residue or an R residue, 
   and wherein said antigen binding protein specifically binds to TSLP.   
     
     
         3 . The isolated antigen binding protein of  claim 1  comprising either:
 a. a light chain variable domain comprising:
 i. a light chain CDRI sequence selected from A1 -A27; 
 ii a light chain CDR2 sequence selected from A1 -A27; 
 iii. a light chain CDR3 sequence selected from A1 -A27, or b. a heavy chain variable domain comprising: 
 i. a heavy chain CDRI sequence selected from A1 -A27; 
 ii. a heavy chain CDR2 sequence selected from Al-All, and 
 iii. a heavy chain CDR3 sequence selected from A1 -A27; or 
 
 c. the light chain variable domain of (a) and the heavy chain variable domain of (b). 
 
     
     
         4 . The isolated antigen binding protein of  claim 1  comprising either:
 a. a light chain variable domain sequence selected from the group consisting of;
 i. amino acids having a sequence at least 80% identical to a light chain variable domain sequence selected from L1-L27; 
 ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to a polynucleotide sequence encoding the light chain variable domain sequence of L1-L27; 
 iii. a sequence of amino acids encoded by a polynucleotide sequence that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of a light chain variable domain sequence of L1-L27; 
 
 b. a heavy chain variable domain sequence selected from the group consisting of:
 i. a sequence of amino acids that is at least 80% identical to a heavy chain variable domain sequence of H1-H27; 
 ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to a polynucleotide sequence encoding the heavy chain variable domain sequence of H1-H27; 
 iii. a sequence of amino acids encoded by a polynucleotide sequence that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of a heavy chain variable domain sequence of H1-H27; or 
 
 c. the light chain variable domain of (a) and the heavy chain variable domain of (b), wherein said antigen binding protein specifically binds to TSLP. 
 
     
     
         5 . An isolated antigen binding protein, comprising either:
 a. a light chain variable domain sequence selected from the group consisting of: L1-L27 b. a heavy chain variable domain sequence selected from the group consisting of: H1-H27; or, c. the light chain variable domain of (a) and the heavy chain variable domain of (b), wherein the antigen binding protein specifically binds to TSLP.   
     
     
         6 . (canceled) 
     
     
         7 . The isolated antigen binding protein of  claim 1 , wherein the binding protein binds to TSLP with substantially the same Kd as a reference antibody selected from the group of antibodies consisting of A2, A3, A4 and A5. 
     
     
         8 . The isolated antigen binding protein of  claim 1 , wherein the binding protein inhibits TSLP activity according to the primary cell OPG assay with the same IC50 as a reference antibody selected from the group of antibodies consisting of A2, A3, A4, and A5. 
     
     
         9 . The isolated antigen binding protein of  claim 1 , wherein the antigen binding protein is selected from the group consisting of a human antibody, a humanized antibody, chimeric antibody, a monoclonal antibody, a polyclonal antibody, a recombinant antibody, an antigen-binding antibody fragment, a single chain antibody, a monomeric antibody, a diabody, a triabody, a tetrabody, a Fab fragment, an F(fa′)x fragment, a domain antibody, an IgD antibody, an IgE antibody, and IgM antibody, and IgG1 antibody, and IgG2 antibody, and IgG3 antibody, and IgG4 antibody, and IgG4 antibody having at least one mutation in the hinge region that alleviates a tendency to for intra H-chain disulfide bonds. 
     
     
         10 . (canceled) 
     
     
         11 . A pharmaceutical composition comprising the antibody of  claim 9 . 
     
     
         12 . An isolated nucleic acid comprising a polynucleotide sequence encoding the light chain variable domain, the heavy chain variable domain, or both, of the antigen binding agent of  claim 5 . 
     
     
         13 . (canceled) 
     
     
         14 . A recombinant expression vector comprising the nucleic acid of  claim 12 . 
     
     
         15 - 17 . (canceled) 
     
     
         18 . A method of treating a TSLP-related inflammatory condition or a TSLP-related fibrotic disorder in a subject in need of such treatment comprising administering a therapeutically effective amount of composition of  claim 11  to the subject. 
     
     
         19 . The method of  claim 18 , wherein the inflammatory condition is selected from the group consisting of allergic asthma, allergic rhinosinusitis, allergic conjunctivitis, and atopic dermatitis. 
     
     
         20 - 21 . (canceled) 
     
     
         22 . An isolated antigen binding protein that cross-competes for binding TSLP with an antibody selected from the group consisting of A1 -A27. 
     
     
         23 - 33 . (canceled) 
     
     
         34 . An isolated antigen binding protein that binds wild-type TSLP with a wild-type affinity, wherein the antigen binding protein binds to any of a group of mutated TSLP with an affinity lower than the wild-type affinity, wherein the group of mutated TSLP includes mutated TSLP comprising a mutation selected from the group consisting of KIOE, A14R, K21E, D22R, K73E, K75E, and A76R. 
     
     
         35 . The isolated antigen binding protein of  claim 34 , wherein antigen binding protein has a lower binding affinity for any two or more members of the group of mutated TSLP than the wild-type affinity. 
     
     
         36 . The isolated antigen binding protein of  claim 35 , wherein antigen binding protein has a lower binding affinity for all members of the group of mutated TSLP than the wild-type affinity. 
     
     
         37 - 63 . (canceled)