Method for the treatment of rheumatoid arthritis using a TLR2 antagonistic antibody
Inventors
Heffernan, Mark • O'Neill, Luke • Mcguirk, Peter • Keogh, Brian • Locher, Christopher
Assignees
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Publication Number
US-8580255-B2
Publication Date
2013-11-12
Expiration Date
Abstract
The present invention provides compositions and methods for the treatment of autoimmune diseases, in particular rheumatoid arthritis. Compounds which function as antagonists of Toll-like Receptor 2 are shown to suppress the immune response which result in the onset and progression of autoimmune disease. In particular monoclonal antibodies which have a binding specificity to Toll-like receptor 2 are disclosed for use in methods for the treatment and/or prophylaxis of autoimmune disease.
Core Innovation
Treating and/or preventing rheumatoid arthritis is achieved by antagonizing Toll-like Receptor 2 (TLR2). The approach uses an antibody or binding fragment that antagonizes the function of Toll-like Receptor 2 to a subject in need of treatment. By antagonizing TLR2, pro-inflammatory signaling associated with TLR2 activity is reduced, as reflected in modulation of cytokine expression profiles in synovial tissue and related measures.
The disclosed concept centers on TLR2 activation by synovial fluid and downstream pro-inflammatory signaling, including IL-8 production. Synovial fluid stimulates IL-8 in HEK-293-hTLR2 cells but not in TLR4 cells, and blocking TLR2 activity with a TLR2 antagonist is described as reducing IL-8 and aberrant immune activation associated with rheumatoid arthritis.
Therapeutic agents include anti-TLR2 antibodies with defined epitope concepts and formats, including specified human and murine TLR2 contexts and antibody binding characteristics such as dissociation constant (Kd) ranges for an inhibitory epitope. Additional disclosed formats include soluble TLR2 or soluble ectodomains, and gene-silencing approaches using inhibitory nucleic acids, including RNA interference (RNAi), siRNA/shRNA, and antisense oligonucleotides directed to TLR2.
Claims Coverage
The partial content provides four independent claims. Across these claims, the inventive features are concentrated on administering an antibody or binding fragment that antagonizes TLR2 function for rheumatoid arthritis, optionally together with formulation components and/or a selected immunosuppressant compound or class.
Antagonizing Toll-like Receptor 2 with an antibody for rheumatoid arthritis treatment
A method for the treatment of rheumatoid arthritis comprising administering a therapeutically effective amount of a pharmaceutical composition consisting of an antibody or binding fragment thereof which antagonizes the function of Toll-like Receptor 2 to a subject in need of such treatment.
TLR2 antagonism with pharmaceutical composition formulation components
A method for the treatment of rheumatoid arthritis comprising administering a therapeutically effective amount of a pharmaceutical composition consisting of an antibody or binding fragment thereof which antagonizes the function of Toll-like Receptor 2 and one or more compounds selected from a pharmaceutically acceptable carrier, a diluent, a solubilizer, an emulsifier, a preservative and an adjuvant to a subject in need of such treatment.
Sequential TLR2 antagonism followed by an immunosuppressant selected from specified agents
A method for the treatment of rheumatoid arthritis comprising administering a therapeutically effective amount of an antibody or binding fragment thereof which antagonizes the function of Toll-like Receptor 2 to a subject in need of such treatment; and administering to the subject an immunosuppressant compound selected from anti-CD20 antibody, anti-TNF antibody, interleukin-1 blocker, blocker of T cell activation, non-steroidal anti-inflammatory agent, organic gold derivative, D-penicillamine, 4-aminoquinoline, azathioprine, methotrexate, cyclosporine, angiogenesis inhibitor, monoclonal antibody with binding specificity to T cells, monoclonal antibody with binding specificity to an adhesion molecule, and monoclonal antibody with binding specificity to a cytokine or a growth factor.
Combination approach using TLR2 antagonism with formulation components plus an immunosuppressant selected from specified agents
A method for the treatment of rheumatoid arthritis comprising administering a therapeutically effective amount of an antibody or binding fragment thereof which antagonizes the function of Toll-like Receptor 2 and one or more compounds selected from a pharmaceutically acceptable carrier, a diluent, a solubilizer, an emulsifier, a preservative and an adjuvant to a subject in need of such treatment; and administering to the subject an immunosuppressant compound selected from anti-CD20 antibody, anti-TNF antibody, interleukin-1 blocker, blocker of T cell activation, non-steroidal anti-inflammatory agent, organic gold derivative, D-penicillamine, 4-aminoquinoline, azathioprine, methotrexate, cyclosporine, angiogenesis inhibitor, monoclonal antibody with binding specificity to T cells, monoclonal antibody with binding specificity to an adhesion molecule, and monoclonal antibody with binding specificity to a cytokine or a growth factor.
Across the independent claims, rheumatoid arthritis treatment is defined by administering a therapeutically effective amount of an antibody or binding fragment that antagonizes Toll-like Receptor 2 function, optionally formulated with pharmaceutically acceptable carrier, diluent, solubilizer, emulsifier, preservative, or adjuvant. Additional independent claims further require administering an immunosuppressant selected from specified agents or classes after the TLR2 antagonistic administration.
Stated Advantages
Reduces or inhibits TLR2 biological activities in TLR2-expressing synovium cells or tissues [procedural detail omitted for safety].
Documented Applications
Treating and/or preventing rheumatoid arthritis by antagonizing Toll-like Receptor 2 (TLR2).
Supporting context for rheumatoid arthritis includes using synovial fluid and synovial tissue biopsy explants to evaluate cytokine expression profiles modulated by a TLR2 agonist and a TLR2 antagonist.
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