IL-18 binding molecules
Interleukin 18 (IL-18) participates in both innate and acquired immunity. The bioactivity of IL-18 is negatively regulated by the IL-18 binding protein (IL18BP), a naturally occurring and highly specific inhibitor. This soluble protein forms a complex with free IL-18 preventing its interaction with the IL-18 receptor, thus neutralizing and inhibiting its biological activity. The present invention discloses binding molecules, in particular antibodies or fragments thereof, which bind IL-18 and do not bind IL-18 bound to IL-18BP (IL-18/IL-18BP complex). Apart from its physiological role, IL-18 has been shown to mediate a variety of autoimmune and inflammatory diseases. The binding molecules of the inventions may be used as therapeutic molecules for treating IL-18-related autoimmune and inflammatory diseases or as diagnostic tools for characterizing, detecting and/or measuring IL-18 not bound to IL-18BP as component of the total IL-18 pool.
1. An isolated antibody or fragment thereof, wherein the isolated antibody or a fragment comprises:
i) a heavy chain variable region H-CDR1 comprising SEQ ID NO: 3 and
ii) a heavy chain variable region H-CDR2 comprising SEQ ID NO: 4 or SEQ ID NO: 9 or SEQ ID NO: 10 or SEQ ID NO: 11 or SEQ ID NO: 12 or SEQ ID NO: 13 and
iii) a heavy chain variable region H-CDR3 comprising SEQ ID NO: 5 and
iv) a light chain variable region L-CDR1 comprising SEQ ID NO: 6 and
v) a light chain variable region L-CDR2 comprising SEQ ID NO: 7 and
vi) a light chain variable region L-CDR3 comprising SEQ ID NO: 8.
2. The isolated antibody or fragment thereof claim 1 , wherein the binding molecule inhibits IL-18-dependent interferon gamma (INF-γ) production.
3. The isolated antibody or fragment thereof claim 1 , wherein the binding molecule binds IL-18 with a K D of 100 pM or less.
4. The isolated antibody or fragment thereof claim 1 , wherein the binding molecule is an isolated fully human, humanized or chimeric antibody or a fragment thereof.
5. The isolated antibody or fragment thereof according to claim 4 , wherein the isolated antibody or fragment comprises a light chain variable domain comprising SEQ ID NO: 16 or SEQ ID NO: 20.
6. The isolated antibody or fragment thereof according to claim 5 , wherein the isolated antibody or fragment thereof comprises:
i) a heavy chain variable domain comprising SEQ ID NO: 14 or SEQ ID NO: 22 or SEQ ID NO: 25 or SEQ ID NO: 28 or SEQ ID NO: 31 or SEQ ID NO: 34 and a light chain variable domain comprising SEQ ID NO: 16 or
ii) a heavy chain variable domain comprising SEQ ID NO: 18 or SEQ ID NO: 37 or SEQ ID NO: 40 and a light chain variable domain comprising SEQ ID NO: 20.
7. The isolated antibody or fragment thereof according to claim 6 , wherein the isolated antibody or fragment thereof comprises a heavy chain variable domain comprising SEQ ID NO: 14 and a light chain variable domain comprising SEQ ID NO: 16.
8. The isolated antibody or fragment thereof according to claim 7 , wherein amino acid lysine (Lys; K) in position 30 of SEQ ID NO:14 is replaced by an amino acid selected from asparagine (Asn; N) or serine (Ser; S) or threonine (Thr; T) or alanine (Ala; A) or glutamate (Glu; E) or histidine (His; H) or leucine (Leu; L) or glutamine (Gln; Q) or arginine (Arg; R) or valine (Val; V) or tyrosine (Tyr; Y) or isoleucine (Ile; I).
9. The isolated antibody or fragment thereof claim 1 , wherein the binding molecule is an isolated fully human antibody.
10. The isolated antibody or fragment thereof claim 1 , wherein the binding molecule is an antibody fragment.
11. The isolated antibody or fragment thereof claim 10 , wherein the binding molecule is a Fab, a Fab′, a F(ab′) 2 , or a scFv.
12. The isolated antibody or fragment thereof claim 1 , wherein the binding molecule is an isolated bispecific antibody or fragment thereof comprising a first specificity to IL-18 and a second specificity to another polypeptide.
13. The isolated antibody or fragment thereof claim 1 , wherein the binding molecule is an isolated antibody comprising a mutated or chemically modified amino acid Fc region, wherein the mutated or chemically modified amino acid Fc region prevents or decreases antibody dependent cellular cytotoxic (ADCC) activity and/or increases half-life when compared with a wild type Fc region.
14. The isolated antibody according to claim 13 , wherein the mutated or chemically modified amino acid Fc region is a silent IgG1 Fc region.
15. A pharmaceutical composition comprising the isolated antibody or fragment thereof according to claim 4 and a pharmaceutical carrier, wherein the pharmaceutical composition optionally comprises a second therapeutic compound.
16. The pharmaceutical composition of claim 15 in intravenously, inhalable or sub-cutaneously administrable form.
17. A diagnostic kit comprising the isolated antibody or fragment thereof according to claim 4 , wherein the kit optionally comprises a first control compound.
18. The diagnostic kit according to claim 17 wherein the first control compound is free IL-18 and wherein the kit optionally comprises a second control compound wherein the second control compound is murine antibody 125-2H.
19. An isolated antibody or antigen binding fragment thereof that binds to IL-18, comprising:
i) a heavy chain variable region H-CDR1 comprising SEQ ID NO: 3;
ii) a heavy chain variable region H-CDR2 comprising SEQ ID NO: 9;
iii) a heavy chain variable region H-CDR3 comprising SEQ ID NO: 5;
iv) a light chain variable region L-CDR1 comprising SEQ ID NO: 6;
v) a light chain variable region L-CDR2 comprising SEQ ID NO: 7; and
vi) a light chain variable region L-CDR3 comprising SEQ ID NO: 8.
20. The antibody or antigen binding fragment thereof of claim 19 , wherein the isolated antibody or fragment thereof comprises a heavy chain variable domain comprising SEQ ID NO: 14, and a light chain variable domain comprising SEQ ID NO: 16.
21. The antibody or antigen binding fragment thereof of claim 19 , wherein the isolated antibody or fragment thereof comprises a heavy chain comprising SEQ ID NO: 43, and a light chain variable domain comprising SEQ ID NO: 45.
22. A pharmaceutical composition comprising the isolated antibody or fragment thereof according to claim 19 and a pharmaceutical carrier, wherein the pharmaceutical composition optionally comprises a second therapeutic compound.
23. The pharmaceutical composition of claim 22 in intravenously, inhalable, or sub-cutaneously administrable form.
24. A diagnostic kit comprising the isolated antibody or fragment thereof according to claim 19 , wherein the kit optionally comprises a first control compound.
25. The diagnostic kit according to claim 24 wherein the first control compound is free IL-18 and wherein the kit optionally comprises a second control compound wherein the second control compound is murine antibody 125-2H.