Anti-IL-23 heterodimer specific antibodies
The present disclosure provides an isolated or recombinant IL-23-binding protein comprising an antigen binding domain of an antibody, wherein the antigen binding domain specifically binds to IL-23 but does not significantly bind to an IL-12p40 subunit and does not significantly bind to an IL-23p19 subunit when they are not components of IL-23. The present disclosure also provides uses of the IL-23-binding protein.
1. An isolated or recombinant antibody or antigen-binding fragment thereof that specifically binds to IL-23, comprising a heavy chain CDR1comprising the amino acid sequence of SEQ ID NO: 8, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 9 or 22, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 10, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 13, a light chain CDR2comprising the amino acid sequence of SEQ ID NO: 14, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15.
2. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof specifically binds to an IL-23heterodimeric complex, but does not specifically bind to an IL-12p40 subunit or an IL-23p19subunit individually.
3. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof specifically binds to:
(a) the heterodimeric interface of IL-23;
(b) the IL-23p19 subunit of IL-23 when said subunit is a component of an IL-23 heterodimeric complex; or
(c) the IL-23p19 subunit of IL-23 in a region comprising amino acids 112-144 of SEQ ID NO:2 when said subunit is a component of an IL-23 heterodimeric complex.
4. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof reduces binding of IL-23 to the IL-23receptor (IL-23R) with an IC 50 of 1nM or less or an EC 50 of 1nM or less.
5. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof is chimeric, deimmunized, CDR-grafted, humanized, primatized or synhumanized.
6. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof is a single chain Fv (scFv) or a dimeric scFv (di-scFv) that is optionally linked to an Fc, a heavy chain constant domain 2(C H 2), or heavy chain constant domain 3(C H 3).
7. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof is an Fab, F(ab') 2 , Fv, or a diabody, triabody, or tetrabody that is optionally linked to an Fc, a heavy chain constant domain 2 (C H 2), or heavy chain constant domain 3(C H 3).
8. The antibody or antigen-binding fragment thereof of claim 7 , wherein the antibody or antigen-binding fragment thereof is chimeric, de-immunized, humanized, primatized, or synhumanized.
9. The antibody or antigen-binding fragment thereof of claim 8 , wherein the antibody or antigen-binding fragment thereof is a humanized antibody comprising:
(a) a V H comprising amino acids 1-120 of SEQ ID NO: 30 and a V L comprising amino acids 1-113 of SEQ ID NO: 45;
(b) a V H comprising amino acids 1-120 of SEQ ID NO: 31 and a V L comprising amino acids 1-113 of SEQ ID NO: 45;
(c) a V H comprising amino acids 1-120 of SEQ ID NO: 32 and a V L comprising amino acids 1-113 of SEQ ID NO: 46; or
(d) a V H comprising amino acids 1-120 of SEQ ID NO: 33 and a V L comprising amino acids 1-113 of SEQ ID NO: 46.
10. The antibody or antigen-binding fragment thereof of claim 8 , wherein the antibody or antigen-binding fragment thereof is a chimeric antibody comprising a V H comprising the amino acid sequence of SEQ ID NO: 7 linked to a human heavy chain constant region and a V L comprising the amino acid sequence of SEQ ID NO: 12 linked to a human light chain constant region.
11. The antibody or antigen-binding fragment thereof of claim 8 , wherein the antibody or antigen-binding fragment thereof is a monoclonal antibody comprising a V H comprising the amino acid sequence of SEQ ID NO: 7 and a V L comprising the amino acid sequence of SEQ ID NO: 12, or a chimeric, deimmunized, CDR-grafted, humanized or synhumanized form thereof.
12. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof is conjugated to a compound.
13. A composition comprising the antibody or antigen-binding fragment thereof of claim 1 and a suitable carrier or diluent.
14. A recombinant nucleic acid encoding an antibody or antigen-binding fragment thereof that specifically binds to IL-23, and comprises a heavy chain CDR1comprising the amino acid sequence of SEQ ID NO: 8, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 9 or 22, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 10, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 13, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a light chain CDR3comprising the amino acid sequence of SEQ ID NO: 15.
15. A recombinant cell comprising the nucleic acid of claim 14 .
16. A method for treating an IL-23-mediated inflammatory condition in a subject, comprising administering to the subject an effective amount of an isolated or recombinant antibody or antigen-binding fragment thereof, that specifically binds to IL-23and comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a heavy chain CDR 2 comprising the amino acid sequence of SEQ ID NO: 9 or 22, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 10, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 13, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a light chain CDR3comprising the amino acid sequence of SEQ ID NO: 15, thereby treating the IL-23-mediated inflammatory condition.