Antigen binding proteins capable of binding thymic stromal lymphopoietin
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:
a. a light chain variable domain comprising:
i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:13;
ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:60;
iii. a light chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:105 and
b. a heavy chain variable domain comprising:
i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:145;
ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:173, and
iii. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:212,
wherein the antigen binding protein specifically binds to a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2.
2. The isolated antigen binding protein of claim 1 comprising either:
a. a light chain variable domain selected from the group consisting of:
i. a sequence of amino acids at least 80% identical to SEQ ID NO:363;
ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO:362;
iii. a sequence of amino acids encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO:362;
b. a heavy chain variable domain selected from the group consisting of:
i. a sequence of amino acids that is at least 80% identical to SEQ ID NO:361;
ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO:360;
iii. a sequence of amino acids encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO:360; or
c. a light chain variable domain of (a) and a heavy chain variable domain of (b).
3. The isolated antigen binding protein of claim 2 , comprising either:
a. a light chain variable domain comprising the amino acid sequence as set for in SEQ ID NO:363;
b. a heavy chain variable domain comprising the amino acid sequence as set forth in SEQ ID NO:361; or
c. the light chain variable domain of (a) and the heavy chain variable domain of (b).
4. The isolated binding protein of claim 3 , comprising the light chain variable domain of (a) and the heavy chain variable domain of (b).
5. The isolated antigen binding protein of claim 1 , wherein the binding protein binds to TSLP with substantially the same Kd as an antibody comprising a) a light chain comprising a light chain variable domain comprising the amino acid sequence as set for in SEQ ID NO:363 and a lambda light chain constant domain comprising the amino acid sequence as set forth in SEQ ID NO:369; and b) a heavy chain comprising a heavy chain variable domain comprising the amino acid sequence as set forth in SEQ ID NO:361 and an IgG2 heavy constant domain comprising the amino acid sequence as set forth in SE0 ID NO:365.
6. The isolated antigen binding protein of claim 1 , wherein the antigen binding protein inhibits TSLP activity to block osteoprotegerin (OPG) production from primary human dendritic cells with the same IC50 as an antibody comprising a) a light chain comprising a light chain variable domain comprising the amino acid sequence as set for in SEQ ID NO:363 and a lambda light chain constant domain comprising the amino acid sequence as set forth in SEQ ID NO:369; and b) a heavy chain comprising a heavy chain variable domain comprising the amino acid sequence as set forth in SEQ ID NO:361 and an IgG2 heavy constant domain comprising the amino acid sequence as set forth in SE0 ID NO:365.
7. 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, a chimeric antibody, a monoclonal 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 IgD antibody, an IgE antibody, an IgM antibody, an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, and an IgG4 antibody.
8. The isolated antigen binding protein of claim 1 , wherein the antigen binding protein is a human antibody.
9. A composition comprising the antibody of claim 7 .
10. 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 protein of claim 3 .
11. A recombinant expression vector comprising the nucleic acid of claim 10 .
12. A host cell comprising the vector of claim 11 .
13. A hybridoma capable of producing the antibody of claim 8 .
14. A method of producing an antigen binding protein that specifically binds to a TSLP polypeptide comprising amino acids 29-159 of SEQ ID NO:2, comprising incubating the host cell of claim 12 under conditions that allow it to express the antigen binding protein, wherein said host cell comprises (i) a recombinant expression vector encoding the light chain variable domain of the antigen binding protein of claim 3 and a recombinant expression vector encoding the heavy chain variable domain of the antigen binding protein of claim 3 , or (ii) a recombinant expression vector encoding both the light chain variable domain and the heavy chain variable domain of the antigen binding protein of claim 3 .
15. The isolated antigen binding protein of claim 4 , wherein the isolated antigen binding protein is a monoclonal antibody comprising one or more light chains and one or more heavy chains.
16. The isolated antigen binding protein of claim 15 , wherein the monoclonal antibody comprises a) a light chain comprising a light chain variable domain comprising the amino acid sequence as set for in SEQ ID NO:363 and a lambda light chain constant domain comprising the amino acid sequence as set forth in SEQ ID NO:369; and b) a heavy chain comprising a heavy chain variable domain comprising the amino acid sequence as set forth in SEQ ID NO:361 and an IgG2 heavy constant domain comprising the amino acid sequence as set forth in SEQ ID NO:365.