Human antibodies specific for interleukin 15 (IL-15)
Isolated human monoclonal antibodies which specifically bind to IL-15 (e.g., human IL-15), and related antibody-based compositions and molecules, are disclosed. The human antibodies can be produced in a transfectoma or in a non-human transgenic animal, e.g., a transgenic mouse, capable of producing multiple isotypes of human monoclonal antibodies by undergoing V-D-J recombination and isotype switching. Also disclosed are pharmaceutical compositions comprising the human antibodies, non-human transgenic animals, and hybridomas which produce the human antibodies, and therapeutic and diagnostic methods for using the human antibodies.
1. An isolated human monoclonal antibody, or an antigen binding portion thereof, which binds IL-15, said antibody comprising
(a) a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences as shown in SEQ ID NOs:5, 6, and 7, respectively; and
(b) a light chain variable region comprising CDR1, CDR2, and CDR3 sequences as shown in SEQ ID NOs:8, 9, and 10, respectively.
2. The antibody, or an antigen binding portion thereof, of claim 1 , which inhibits IL-15-induced proinflammatory effects.
3. The antibody, or an antigen binding portion thereof, of claim 2 , which inhibits IL-15-induced TNFα production or T cell proliferation.
4. The antibody, or an antigen binding portion thereof, of claim 1 , which binds to human IL-15 with a dissociation equilibrium constant (K D ) of below 10 −7 M as determined by surface plasmon resonance (SPR) technology using recombinant human IL-15 as the analyte and the antibody as the ligand.
5. The antibody, or an antigen binding portion thereof, of claim 1 , which binds to an epitope located on the β-chain or the γ-chain interacting domain of human IL-15.
6. The antibody, or an antigen binding portion thereof, of claim 1 , which binds to receptor-bound human IL-15.
7. The antibody, or an antigen binding portion thereof, of claim 1 , wherein the antibody is selected from the group consisting of an IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgAsec, IgD, and IgE antibody.
8. The antibody, or an antigen binding portion thereof, of claim 7 , wherein the antibody is an IgG1antibody.
9. The antibody, or an antigen binding portion thereof, of claim 6 , comprising a variable region from an IgG1 heavy chain and a variable region from a kappa light chain.
10. The antibody, or an antigen binding portion thereof, of claim 1 , which is a Fab fragment or a single chain antibody.
11. The antibody, or an antigen binding portion thereof, of claim 1 , produced by a hybridoma comprising a B cell obtained from a transgenic non-human animal having a genome comprising a human heavy chain transgene and a human light chain transgene fused to an immortalized cell.
12. A hybridoma comprising a B cell obtained from a transgenic non-human animal having a genome comprising a human heavy chain transgene and a light chain transgene, fused to an immortalized cell, wherein the hybridoma produces antibody, or an antigen binding portion thereof, of claim 1 .
13. The antibody, or an antigen binding portion thereof, of claim 1 , produced by a transfectoma comprising nucleic acids encoding a human heavy chain and a human light chain.
14. A pharmaceutical composition comprising the antibody, or an antigen binding portion thereof, of claim 1 and a pharmaceutically acceptable carrier.
15. The composition of claim 14 further comprising a therapeutic agent.
16. The composition of claim 15 , wherein the agent is an immunosuppressive agent.
17. The composition of claim 16 , wherein the immunosuppressive agent is cyclosporine.
18. The composition of claim 15 , wherein the agent is an anti-inflammatory agent selected from the group consisting of a steroidal anti-inflammatory agent and a nonsteroidal anti-inflammatory agent.
19. The composition of claim 15 , wherein the agent is a disease-modifying anti-rheumatic drug (DMARD) selected from the group consisting of methotrexate, etanercept, and infliximab.
20. The composition of claim 15 , wherein the agent is a chemotherapeutic agent selected from the group consisting of doxorubicin, cisplatin, bleomycin, carmustine, cyclophosphamide, and chlorambucil.
21. The composition of claim 15 , wherein the agent is an agent for treating psoriasis.
22. The composition of claim 15 , wherein the agent is an antibody or a tumor necrosis factor-α (TNF-α) inhibitor.
23. The composition of claim 22 , wherein the antibody is selected from the group consisting of a CD4 specific antibody and an IL-2 specific antibody.
24. An immunoconjugate comprising the antibody, or an antigen binding portion thereof, of claim 1 and a therapeutic agent.
25. The immunoconjugate of claim 24 , wherein the therapeutic agent is an immunosuppressive agent.
26. The immunoconjugate of claim 24 , wherein the therapeutic agent is an anti-inflammatory agent selected from the group consisting of a steroidal anti-inflammatory agent, a nonsteroidal anti-inflammatory agent and a DMARD.
27. The immunoconjugate of claim 24 , wherein the therapeutic agent is a cytotoxic agent.
28. A pharmaceutical composition comprising the immunoconjugate of claim 24 and a pharmaceutically acceptable carrier.
29. The composition of claim 15 , wherein the agent is an antibody.
30. An isolated human monoclonal antibody, or an antigen binding portion thereof, which binds IL-15, said antibody comprising human heavy chain and human light chain variable regions which comprise the amino acid sequences set forth in SEQ ID NO:2 and SEQ ID NO:4, respectively.
31. An isolated human monoclonal antibody, or an antigen binding portion thereof, which binds IL-15, said antibody encoded by nucleic acids comprising nucleotide sequences in their variable regions as set forth in SEQ ID NO:1 and SEQ ID NO:3, respectively.
32. An isolated human monoclonal antibody, or antigen binding portion thereof, comprising a heavy chain variable region encoded by a human germline V H 5–51 gene and a light chain variable region encoded by a human germline V K A27 gene, wherein the antibody binds to human IL-15.