Evaluation, assays and treatment of PKAL-mediated disorders

一种介导、病症的技术，应用在PKAL-介导的病症的评估、测定和治疗领域，能够解决缓激肽过量产生等问题

Active Publication Date: 2019-09-06
TAKEDA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Hereditary angioedema types I and II are caused by a genetic defect in C1-INH, which leads to overproduction of bradykinin

Method used

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  • Evaluation, assays and treatment of PKAL-mediated disorders
  • Evaluation, assays and treatment of PKAL-mediated disorders
  • Evaluation, assays and treatment of PKAL-mediated disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0258] Example 1. Composite ELISA for Quantification of Functional Cl-INH in Plasma Using Activated Factor XII and / or Plasma Kallikrein

[0259] Dysfunction of the C1 inhibitor, C1-INH, has been demonstrated in hereditary angioedema type II (HAE), which renders the inhibitor ineffective. Type I HAE has low total C1-INH protein levels. Type III HAE is associated with normal C1-INH levels. (“Enzymatic pathways in the pathogenesis of hereditary angioedema: Therole of C1 inhibitor therapy.” Kaplan, A., The Journal of Allergy and Clinical Immunology 126(5):918-25 2010). C1-INH inhibits Factor XIIa, Fragment of Factor XII (XIIf), kallikrein and plasmin. In the absence of C1-INH function, marked activation of the bradykinin formation cascade leads to severe angioedema. Type I HAE is usually characterized by decreased total C1-INH levels. Type II HAE is usually characterized by normal to increased C1-INH levels, however the function of C1-INH is abnormal. The mechanisms leading t...

Embodiment 2

[0265] Example 2. Diagnostic Assay for Hereditary Angioedema Based on Inhibition of Activated Factor XII and / or Plasma Kallikrein

[0266] method

[0267] Patient and Sample Collection: Diagnosis of HAE is made by clinical presentation, low C1-INH protein and / or functional levels (using commercial assays). Citrated plasma from 42 patients with HAE and 23 healthy controls was separated by centrifugation of freshly collected blood at 2000 rpm for 10 minutes at 4°C. All samples were immediately aliquoted and stored at -80°C. Samples were handled similarly at all participating sites (Odense, Denmark; Budapest, Hungary) and shipped overnight on dry ice. The protocol was approved by the Ethics Committee (Ethics Committee) and the Data Protection Agency (Data Protection Agency) of the two participating sites.

[0268] Purified human Factor XIIa and kallikrein were obtained from Enzyme Research Laboratories (South Bend, IN), biotinylation reagents were obtained from Thermo Scientif...

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Abstract

The invention relates to evaluation, assays and treatment of PKAL-mediated disorders. The invention provides assay methods of detecting plasma protease CI inhibitor (Cl-INH) that binds plasma kallikrein, factor XII, or both, and uses thereof for identifying subjects at risk for or suffering from a pKal-mediated 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.

Description

[0001] This application is a divisional application of a Chinese application with a filing date of January 17, 2014, an application number of 2014800169573 (PCT / US2014 / 012090), and an invention title of "Assessment, Measurement and Treatment of PKAL-mediated Diseases". [0002] Cross References to Related Applications [0003] This application claims the benefit of the filing date of US Provisional Application No. 61 / 754,600, filed January 20, 2013. The entire content of this referenced application is incorporated herein by reference. Background technique [0004] Plasma kallikrein (pKal) is the major circulating enzyme that produces bradykinin. Activation of pKal occurs systemically via exposure, which has been linked to disease pathology associated with hereditary angioedema (HAE). Bradykinin is a key mediator of pain, inflammation, edema and angiogenesis. [0005] Plasma protease C1 inhibitors (also known as C1-inhibitors or C1-INH) are protease inhibitors that belong to...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N33/573G01N33/68C07K16/38C12Q1/37
CPCG01N33/6893G01N2333/4706G01N2800/32C12Q1/37C07K16/38G01N33/573A61P1/02A61P1/04A61P1/14A61P11/00A61P13/12A61P17/02A61P19/02A61P19/06A61P25/00A61P25/28A61P27/00A61P29/00A61P35/00A61P37/02A61P7/00A61P7/02A61P7/04A61P7/10A61P9/00A61P9/10A61P9/14A61K38/00C07K14/435C07K16/40C07K2317/21C07K2317/76G01N2333/8121G01N2333/96455G01N2333/96458G01N2800/52G01N2800/70
Inventor K·约瑟夫A·P·卡普兰
Owner TAKEDA PHARMA CO LTD
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