Atypical hemolytic uremic syndrome (ahus) biomarker proteins

A biomarker, hemolytic technology, applied in the direction of anti-animal/human immunoglobulin, biological test, immunoglobulin, etc.

Active Publication Date: 2019-03-29
ALEXION PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite the eventual availability of useful drugs for the treatment of aHUS patients, there remains a need for diagnosing aHUS patients and monitoring the progression and resolution of aHUS

Method used

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  • Atypical hemolytic uremic syndrome (ahus) biomarker proteins
  • Atypical hemolytic uremic syndrome (ahus) biomarker proteins
  • Atypical hemolytic uremic syndrome (ahus) biomarker proteins

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0282] Example 1. Materials and Methods

[0283] urine sample

[0284] Mix freshly collected urine immediately with protease inhibitors. Concentrations of several analytes including NGAL, cystatin C, clusterin, TIMP-1, β2-microglobulin, C5b9, C5a, and creatinine.

[0285] NGAL levels were measured in urine with a commercially available kit (R&D Systems, Minneapolis, MN; product number: DLCN20). Briefly, urine samples were diluted 1:3 with the calibration diluent RD5-24 provided in the kit. Add 50 μL of each sample or kit standard control (NSO-expressed recombinant human lipocalin-2) to the wells of the assay plate in duplicate, each well containing 100 μL of the assay diluent RD1- 52. After two hours of incubation at 4°C in the refrigerator, the wells were washed 4 times with 200 μL of wash solution per well. 200 μL of anti-NGAL conjugate labeled with an enzyme (horseradish peroxidase) was added to each well and incubated in the refrigerator at 4°C for two hours. The...

Embodiment 2

[0307] Example 2: Results

[0308] ongoing complement activation markers

[0309] As summarized in Table 2 below, plasma concentrations of the complement components Ba and sC5b9 and urine concentrations of C5a and sC5b-9 were elevated in most aHUS patients relative to concentrations in biological fluid samples from healthy volunteers. see also Figures 1A-1F .

[0310] Table 2

[0311] aHUS biomarker protein

Increased n / N(%) from baseline

P-value

Plasma Ba

35 / 35(100.0)

<0.0001

plasma sC5b-9

37 / 38(97.4)

<0.0001

Urine C5a

26 / 29(89.7)

0.0007

urine sC5b-9

23 / 27(85.2)

0.0025

[0312] *"N" indicates the total number of patients for which a given biomarker was assessed, while "n" indicates the number of those "N" patients with elevated biomarker protein levels.

[0313] These results suggest a significant ongoing systemic alternative pathway complement activation in aHUS patients.

[0314] The mean ...

Embodiment 3

[0387] Example 3: Baseline levels of selected aHUS biomarker proteins in aHUS patients

[0388] At baseline, before eculizumab treatment, significant complement activation, vascular inflammation / injury, and parenchymal signs of organ damage were observed in aHUS patients, regardless of use of plasmapheresis / transfusion or platelet count, Hp or Normal laboratory value of LDH. As demonstrated by the data shown in Table 11, the concentrations of aHUS biomarkers of complement activity, vascular inflammation, endothelial activation and injury, coagulation, and renal injury were significantly elevated in aHUS patients compared to healthy subjects of.

[0389] Table 11

[0390]

[0391]

[0392] NHV means the normal human value or concentration of a given aHUS biomarker protein reported in the table.

[0393] "creat" means creatinine, the concentration of which was used to normalize some of the biomarker concentrations reported in the table.

[0394] CAP means alternative...

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Abstract

The invention provides biomarker proteins whose concentration or activity level changes correlate with atypical hemolytic uremic syndrome (aHUS) or clinically meaningful treatment of aHUS with a complement inhibitor. The invention also provides compositions and methods for interrogating the concentration and / or activity of one or more of said biomarker proteins in a biological fluid. Among other aspects, the compositions and methods are useful for assessing the risk of developing aHUS, diagnosing aHUS, determining whether a subject is experiencing a first acute episode of aHUS, monitoring the progression or resolution of aHUS, and / or monitoring the effects of The response to treatment with complement inhibitors or the optimization of such treatment may be useful.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Application Nos. 61 / 913,180 and 61 / 863,299, filed December 6, 2013, and August 7, 2013, respectively. The entire contents of the above applications and any patents, patent applications and references cited throughout this specification are hereby incorporated by reference in their entirety. technical field [0003] The fields of the invention are medicine, immunology, molecular biology, and protein chemistry. Background of the invention [0004] Hemolytic uremic syndrome (HUS) is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. HUS is classified into one of two categories: diarrhea-associated (D+HUS; also known as Shiga toxin-producing Escherichia coli (STEC)-HUS or typical HUS) and nondiarrheal or atypical HUS (aHUS). D+HUS is the most common form, accounting for more than 90% of cases, and is caused by prior disease w...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): G01N33/68
CPCA61K2039/505C07K16/18C07K2317/21C07K2317/24C07K2317/54C07K2317/55C07K2317/622C07K2317/626C07K2317/76G01N33/6863G01N33/6893G01N2333/4716G01N2333/485G01N2333/522G01N2333/5412G01N2333/5421G01N2333/5434G01N2333/545G01N2333/57G01N2333/70503G01N2333/70525G01N2333/70539G01N2333/7151G01N2333/745G01N2333/7452G01N2333/75G01N2333/775G01N2333/8139G01N2333/8146G01N2333/974G01N2800/226G01N2800/347G01N2800/50G01N2800/52A61P13/12A61P43/00Y02A50/30
Inventor S·F·麦克奈特R·科费尔A·库克雷亚K·A·贝达德Y·严
Owner ALEXION PHARMA INC
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