Composition and method for treatment of reperfusion injury and tissue damage
Inventors
Heffernan, Mark • O'Neill, Luke • Mcguirk, Peter • Keogh, Brian • Locher, Christopher • De Kleijn, Dominique • Arslan, Fatih • Pasterkamp, Gerard
Assignees
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Publication Number
US-8734788-B2
Publication Date
2014-05-27
Expiration Date
Abstract
The present invention provides compounds and methods for the treatment and prophylaxis of ischemia reperfusion injury. In particular the invention provides compounds which function to suppress Toll-like Receptor 2 biological function or expression.
Core Innovation
The described invention relates to targeting Toll-like receptor 2 (TLR2) in a subject to treat or prevent a reperfusion induced cardiac inflammatory condition associated with ischemia/reperfusion injury. The invention uses an antibody or an antigen-binding fragment thereof that is an antagonist of the function of TLR2. Suppressing TLR2 activity and/or expression reduces downstream pro-inflammatory signaling, including NF-kappaB signaling.
The invention provides methods in which administration of a TLR2 antagonist is carried out as treatment or as prophylaxis, including timing relative to a subject undergoing reperfusion-associated events. In particular, the invention includes administration before, during, or after surgical procedures selected from angioplasty, cardiac bypass surgery, thrombolysis, endarterectomy, heart transplantation and coronary artery bypass grafting (CABG). The invention further includes embodiments that administer the TLR2 antagonist together with a therapeutically effective secondary immunosuppressant and/or secondary therapeutic compounds.
The described invention is supported by experimental evidence in a mouse LAD ischemia/24h reperfusion model showing reduced infarct size with an anti-TLR2 monoclonal antibody OPN-301. The invention also includes evidence for a role of TLR2 on circulating immune cells, including blood versus organ TLR2 knockout chimeras, associated with changes in macrophage influx and preserved cardiac function at 28 days. The invention further includes cross-species binding/potency considerations for pig, rabbit, monkey, rhesus, and cynomolgus, and includes screening assays and device concepts such as stent coating with a TLR2 antagonistic compound.
Claims Coverage
Independent claim coverage includes two methods: one for treatment and one for prophylaxis of reperfusion induced cardiac inflammatory conditions, each centered on administering a TLR2 antagonist antibody or antigen-binding fragment. The independent claims collectively emphasize antagonizing TLR2 function and peri-procedural timing tied to a defined set of cardiac surgeries/procedures.
Antagonist antibody to treat reperfusion induced cardiac inflammation
A method for the treatment of a reperfusion induced cardiac inflammatory condition comprising administering a therapeutically effective amount of an antibody or an antigen-binding fragment thereof that is an antagonist of the function of Toll-like Receptor 2 (TLR2) to a subject in need of such treatment.
Peri-procedural prophylactic TLR2 antagonist administration
A method for the prophylaxis of a reperfusion induced cardiac inflammatory condition comprising administering a therapeutically effective amount of an antibody or an antigen-binding fragment thereof that is an antagonist of the function of Toll-like Receptor 2 (TLR2) to a subject in need of such treatment, wherein the antibody or antigen-binding fragment is administered prior to, during or following the subject undergoing a surgical procedure selected from angioplasty, cardiac bypass surgery, thrombolysis, endarterectomy, heart transplantation and coronary artery bypass grafting (CABG).
The claim set focuses on inhibiting TLR2 function using an antagonist antibody or antigen-binding fragment, with peri-procedural timing for both treatment and prophylaxis around specified reperfusion-associated surgeries.
Stated Advantages
Reduced infarct size in a mouse LAD ischemia/24h reperfusion model with the anti-TLR2 monoclonal antibody OPN-301.
Macrophage influx is reduced or changed in embodiments involving circulating immune cell TLR2 activity, with preserved cardiac function at 28 days.
Documented Applications
Treatment and prophylaxis of reperfusion induced cardiac inflammatory conditions associated with ischemia/reperfusion injury, including myocardial/cardiovascular inflammatory conditions.
Use in connection with peri-event timing around angioplasty, cardiac bypass surgery, thrombolysis, endarterectomy, heart transplantation, and coronary artery bypass grafting (CABG).
Application to transplantation rejection / immunological rejection.
Application to stent coating using a TLR2 antagonistic compound.
Use in experimental models including a mouse LAD ischemia/24h reperfusion model and blood versus organ TLR2 knockout chimeras, with assessment of infarct size and cardiac function at 28 days.
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