Metabolite biomarkers for diseases associated with the contact activation system

Patent metadata

Field	Value
Publication number	US-11340237-B2
Application number	US-201716333101-A
Country	US
Kind code	B2
Filing date	Sep 15, 2017
Priority date	Sep 16, 2016
Publication date	May 24, 2022
Grant date	May 24, 2022

Abstract

Provided herein are methods and kits for analyzing a biological sample obtained from a subject having, suspected of having, or being at risk for a disease associated with the contact activation system.

First claim

What is claimed is:

1. A method, comprising:
(i) providing a biological sample obtained from a subject having, suspected of having, or being at risk for hereditary angioedema (HAE)
(ii) measuring the level of a metabolite biomarker or metabolite biomarker set selected from the group consisting of serotonin; tryptophan; indolelactate; indolepropionate, gamma-/beta-tocopherol; ascorbate; palmitic amide; oleamide; linoleamide; 9-hydroxyoctadecadienoic acid (9-HODE); 13-hydroxyoctadecadienoic acid (13-HODE); 9,10-di-hydroxy-12Z-octadecenoic acid (9,10-DiHOME); 12,13-dihydroxy-9Z-octadecenoic acid (12,13-DiHOME); 19,20-dihydroxy-4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid (19,20 DiHDPA); N-acetylmethionine; methionine sulfone; S-adenosylhomocysteine; cysteine; cysteine sulfinic acid, pregnenolone sulfate; 5 alpha-pregnan-3beta,20beta-diol monosulfate; pregnen-diol disulfate; pregn steroid monosulfate; pregnanediol-3-glucuronide; corticosterone; cortisone; dehydroisoandrosterone sulfate (DHEA-S); 16a-hydroxy DHEA 3-sulfate; epiandrosterone sulfate; androsterone sulfate; 4-androsten-3beta, 17beta-diol monosulfate; 4-androsten-3alpha, 17alpha-diol monosulfate; 4-androsten-3beta, 17beta-diol disulfate; 5alpha-androstan-3alpha,17alpha-diol monosulfate; 5alpha-androstan-3beta,17-beta-diol disulfate; andro steroid monosulfate; etiocholanolone glucuronide; pregnanolone/alloprenanolone sulfate; eicosapentaenoate, mead acid, stearidonate, nicotinamide, and pantothenate;
(iii) identifying the subject as having HAE or being at risk of for HAE if the level of the metabolite biomarker or metabolite biomarker set in the biological sample obtained from the subject is at least 1.1-fold higher or at least 1.1-fold lower than the level of a corresponding metabolite biomarker set of a control subject; and
(iv) administering to the subject identified as having HAE or being at risk for HAE an effective amount of a therapeutic agent for treating HAE.

2. The method of claim 1 , wherein the subject is a human patient.

3. The method of claim 2 , wherein the human patient has a history of HAE.

4. The method of claim 2 , wherein the biological sample is a serum sample or a plasma sample obtained from the human patient.

5. The method of claim 1 , wherein therapeutic agent is a plasma kallikrein (pKal) inhibitor, a bradykinin 2 receptor (B2R) inhibitor, and/or a C1 esterase inhibitor.

6. The method of claim 5 , wherein the pKal inhibitor is an anti-pKal antibody or an inhibitory peptide.

7. The method of claim 6 , wherein the therapeutic agent is lanadelumab, ecallantide, icatibant, or human plasma-derived C1-INH.

8. The method of claim 1 , wherein the HAE is type I HAE or type II HAE.

9. The method of claim 1 , wherein the level of the metabolite biomarker or metabolite biomarker set of the subject is at least 1.5-fold higher or at least 1.5-fold lower than the level of the corresponding metabolite biomarker set obtained from a control subject.

10. The method of claim 1 , wherein the biomarker set consists of 2-10 metabolite biomarkers.

11. The method of claim 1 , wherein the at least one metabolite biomarker is serotonin.

12. The method of claim 1 , wherein the at least one metabolite biomarker is a metabolite associated with fatty acid amide hydrolase activity.

13. The method of claim 12 , wherein the metabolite associated with fatty acid amide hydrolase activity is palmitic acid, oleamide, or linoleamide.

14. The method of claim 1 , wherein the at least one metabolite biomarker is a lipid peroxide.

15. The method of claim 14 , wherein the lipid peroxide is 9-hydroxyoctadecadienoic acid (9-HODE), 13-hydroxyoctadecadienoic acid (13-HODE), 9,10-di-hydroxy-12Z-octadecenoic acid (9,10-DiHOME), 12,13-dihydroxy-9Z-octadecenoic acid (12,13-DiHOME), or 19,20-dihydroxy-4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid (19,20 DiHDPA).

16. The method of claim 1 , wherein the at least one metabolite biomarker is a metabolite involved in sulfur metabolism.

17. The method of claim 16 , wherein the metabolite involved in sulfur metabolism is N-acetylmethionine, methionine sulfone, S-adenosylhomocysteine, cystine, or cysteine sulfinic acid.

18. The method of claim 1 , wherein the at least one metabolite biomarker is a metabolite involved in steroid metabolism.

19. The method of claim 18 , wherein the metabolite involved in steroid metabolism is pregnenolone sulfate; 5 alpha-pregnan-3beta,20beta-diol monosulfate; pregnen-diol disulfate; pregn steroid monosulfate; pregnanediol-3-glucuronide; corticosterone; cortisone; dehydroisoandrosterone sulfate (DHEA-S); 16a-hydroxy DHEA 3-sulfate; epiandrosterone sulfate; androsterone sulfate; 4-androsten-3beta, 17beta-diol monosulfate; 4-androsten-3alpha, 17alpha-diol monosulfate; 4-androsten-3beta, 17beta-diol disulfate; 5alpha-androstan-3alpha,17alpha-diol monosulfate; 5alpha-androstan-3beta,17-beta-diol disulfate; andro steroid monosulfate, etiocholanolone glucuronide; or pregnanolone/alloprenanolone sulfate.

20. The method of claim 1 , wherein the at least one metabolite biomarker is a fatty acid.

21. The method of claim 20 , wherein the fatty acid is eicosapentaenoate (EPA), mead acid, or stearidonate.

22. The method of claim 1 , wherein the at least one metabolite biomarker is a cofactor precursor.

23. The method of claim 22 , wherein the cofactor precursor is nicotinamide or pantothenate.

24. A method, comprising:
(i) providing a biological sample obtained from a subject having, suspected of having, or being at risk for hereditary angioedema (HAE);
(ii) measuring the level of a metabolite biomarker or metabolite biomarker set, which comprises at least one metabolite biomarker selected from the group consisting of corticosterone, eicosapentaenoate, mead acid, stearidonate, nicotinamide, and pantothenate;
(iii) identifying the subject as being at risk of HAE attack if the level of the metabolite biomarker or metabolite biomarker set in the biological sample obtained from the subject is at least 1.1-fold higher or at least 1.1-fold lower than the level of a corresponding metabolite biomarker or metabolite biomarker set of a control subject or significantly differs from the level of the corresponding metabolite biomarker or metabolite biomarker set of a biological sample previously obtained from the subject; and
(iv) administering to the subject at risk of HAE attack an effective amount of a therapeutic agent for treating HAE.

25. The method of claim 1 , wherein the at least one metabolite biomarker is tryptophan, indolelactate, indoleproprionate, gamma-/beta-tocopherol, or ascorbate.

26. The method of claim 24 , wherein the level of the metabolite biomarker or metabolite biomarker set of the subject is at least 1.5-fold higher or at least 1.5-fold lower than the level of the corresponding metabolite biomarker set previously obtained from the subject.

Assignees

• Takeda Pharmaceuticals Co

Inventors

• Sexton Daniel J
• Viswanathan Malini
• Faucette Ryan
• Gaur Tripti

Classifications

• G01N2800/50

  Determining the risk of developing a disease · CPC title

• G01N33/743 Primary

  Steroid hormones · CPC title

• G01N33/6893 Primary

  related to diseases not provided for elsewhere · CPC title

• G01N33/942

  Serotonin, i.e. 5-hydroxy-tryptamine · CPC title

• G01N33/6806

  Determination of free amino acids · CPC title