Evaluation, assays and treatment of pKal-mediated disorders
AssigneeTakeda Pharmaceutical Company Limited
InventorsKusumam Joseph, Allen P. Kaplan
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Abstract
The invention provides assay methods of detecting plasma protease CI inhibitor (C1-INH) that binds plasma kallikrein, Factor XII, or both, and uses thereof for identifying subjects at risk for or suffering from a pKal-me-diated or bradykinin-mediated disorder. Provided methods permit analysis of patients with plasma kallikrein-mediated angioedema (KMA), or other diseases mediated by pKal useful in the evaluation and treatment.
Claims20
A method of treating a subject having a plasma kallikrein (pKal)-mediated disorder, the method comprising:
- (i) contacting a sample obtained from the subject containing plasma protease C1 inhibitor (C1-INH) with a capture reagent;
- wherein the capture reagent comprises:
- a) an active form of Factor XII, or a C1-INH binding fragment thereof,
- b) an active form of pKal, or a C1-INH binding fragment thereof, or
- c) a combination of a) and b);
- (ii) measuring a level of the C1-INH in the sample that binds to the capture reagent,
- (iii)—identifying the subject as having a pKal-mediated disorder, wherein the level of the C1-INH obtained in step (i) being reduced relative to the level of the C1-INH in a healthy subject is indicative of occurrence of the pKal-mediated disorder;
- and
- (iv) administering an effective amount of a therapeutic agent to the subject identified in step (iii);
- wherein the therapeutic agent is a plasma kallikrein inhibitor, a bradykinin B2 receptor antagonist or a C1-INH replacement agent;
- and
- wherein the pKal-mediated disorder is selected from the group consisting of rheumatoid arthritis, Crohn's disease, brain ischemia/reperfusion injury, cerebral edema, macular edema, arterial or venous thrombosis, thrombosis associated with ventricular assist devices or stents, heparin-induced thrombocytopenia with thrombosis, thromboembolic disease, intestinal bowel disease, and hereditary angioedema (HAE).
A method for treating a subject having a plasma kallikrein (pKal)-mediated disorder, the method comprising administering to the subject an effective amount of a therapeutic agent,
- wherein the subject has a reduced level of plasma protease C1 inhibitor (C1-INH) that is capable of binding to a capture reagent as compared to a reference value, and
- wherein the capture reagent comprises:
- i) an active form of Factor XII, or a C1-INH-binding fragment thereof;
- ii) an active form of pKal, or a C1-INH-binding fragment thereof, or
- iii) a combination of i) and ii);
- wherein the therapeutic agent is a plasma kallikrein inhibitor, a bradykinin B2 receptor antagonist or a C1-INH replacement agent;
- and
- wherein the pKal-mediated disorder is selected from the group consisting of rheumatoid arthritis, Crohn's disease, brain ischemia/reperfusion injury, cerebral edema, macular edema, arterial or venous thrombosis, thrombosis associated with ventricular assist devices or stents, heparin-induced thrombocytopenia with thrombosis, thromboembolic disease, intestinal bowel disease, and hereditary angioedema (HAE).
Dependencies are inferred from the claim text.