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1. WO2013158585 - BIOMARKERS FOR MONITORING INTERVENTION THERAPIES FOR DIABETES

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WHAT IS CLAIMED:

1. A method of determining the efficacy of an anti-diabetic therapy or treatment comprising:

(a) determining the N-glycan composition of a serum sample obtained from an individual or patient at a time following the start of the anti-diabetic therapy or treatment; and

(b) comparing the N-glycan composition of the serum sample to the N-glycan composition of a serum sample obtained from the individual or patient at a time before the start of the anti-diabetic therapy or treatment,

wherein a difference between the N-glycan composition of the serum sample obtained from the individual or patient at a time following the start of the anti-diabetic therapy or treatment and the N-glycan composition of the serum sample obtained from the individual or patient at a time before the start of the anti-diabetic therapy or treatment indicates that the antidiabetic therapy or treatment is efficacious.

2. The method of claim 1, wherein the difference in the N-glycan composition is a decrease in the amount of at least one high mannose N-glycan, hybrid N-glycan, complex N-glycan, or O-acetylated N-glycan in the N-glycan composition of the serum sample obtained from the serum sample obtained from the individual or patient at a time following the start of the anti-diabetic therapy or treatment compared to the amount of the corresponding N-glycan in the serum sample obtained from the individual or patient before the start of the antidiabetic therapy or treatment.

3. The method of claim 1, wherein the N-glycan composition is determined by separating the N-glycans from the proteins in the serum sample to provide a composition of N-glycans and determining the relative amounts of N-glycans in the composition by Matrix Adsorption Laser Desorption/Ionization-Time-Of-Flight (MALDI-TOF).

4. A method of determining the efficacy of an anti-diabetic therapy or treatment comprising:

(a) providing a first serum sample obtained from an individual or patient at time before the start of the anti-diabetic therapy or treatment and a second serum sample obtained from the individual from a time following the start of the anti-diabetic therapy or treatment;

(b) determining the N-glycan composition of the first serum sample to obtain a first N-linked glycosylation profile and determining the N-glycan composition of the second serum sample to obtain a second N-linked glycosylation profile; and

(c) comparing the first and second N-linked glycosylation profiles, wherein a difference between the first and second N-linked glycosylation profiles indicates that the antidiabetic therapy or treatment is efficacious.

5. The method of claim 4, wherein a decrease in the amount of at least one high mannose N-glycan, hybrid N-glycan, complex N-glycan, or O-acetylated N-glycan in the second N-linked glycosylation profile compared to the amount of the corresponding N-glycan in the first N-linked glycosylation profile indicates that the anti-diabetic therapy or treatment is efficacious.

6. The method of claim 4, wherein the N-glycan composition is determined by separating the N-glycans from the proteins in the serum sample to provide a composition of

N-glycans and determining the relative amounts of N-glycans in the composition by Matrix Adsorption Laser Desorption/Ionization-Time-Of-Flight (MALDI-TOF).

7. The method of claim 5, wherein the high mannose N-glycan is

Man9GlcNAc2 (920000), Man8GlcNAc2 (820000), Man7GlcNAc2 (720000), Man6GlcNAc2 (620000), or Man5GlcNAc2 (520000).

8. The method of claim 5, wherein the hybrid N-glycans is SiaGalGlcNAcMan3 GlcNAc2 (430010), SiaGalGlcNAcMan4GlcNAc2 (530010), or

SiaGalGlcNAcMan5GlcNAc2 (630010), wherein Sia is Neu5Ac or Neu5Gc.

9 The method of claim 5, wherein the O-acetylated (O-Ac) N-glycan is Sia2Gal2GlcNAc2Man3GlcNAc2(1 Oc -Ac) (540021), Sia2Gal2GlcNAc2Man3GlcNAc2(2 O-Ac) (540022), Sia3Gal2GlcNAc2Man3GlcNAc2(1 O-Ac) (540031), or

Sia3Gal2GlcNAc2Man3GlcNAc2(2 O-Ac) (540032), wherein Sia is Neu5Ac or Neu5Gc.

10. The method of claim 5, wherein the complex N-glycan is Sia2Gal2GlcNAc2Man3GlcNAc2 (540020), wherein Sia is Neu5Ac or Neu5Gc.

11. The method of claim 5, wherein the N-glycan composition obtained from the individual or patient at a time following the start of the therapy or treatment comprises an increase in the amount of one or more fucosylated N-glycans compared to the amount of the corresponding fucosylated N-glycan in the N-glycan composition obtained from the individual or patient before the start of the anti-diabetic therapy or treatment.

12. The method of claim 1 1, wherein the fucosylated N-glycan is Sia3Gal3GlcNAc3Man3GlcNAc2(Fuc) (651030), Sia3Gal3GlcNAc3Man3GlcNAc2(Fuc)(1 O-Ac) (651031), or Sia4Gal4GlcNAc4Man3GlcNAc2(Fuc) (761040), wherein Sia is Neu5Ac or Neu5Gc.

13. The method of claim 4, wherein the difference in the N-linked glycosylation profile comprises (i) a decrease in one or more N-glycans selected from the group consisting of Man9GlcNAc2 (920000), Man8GlcNAc2 (820000), Man7GlcNAc2 (720000), Man6GlcNAc2 (620000), and Man5GlcNAc2 (520000); and (ii) a decrease one or more N-glycans selected from the group consisting of SiaGalGlcNAcMan3GlcNAc2 (430010),

SiaGalGlcNAcMan4GlcNAc2 (530010), and SiaGalGlcNAcMan5GlcNAc2 (630010), wherein Sia is Neu5Ac or Neu5Gc.

14. The method of claim 4, wherein the difference in the N-linked glycosylation profile comprises (i) a decrease in one or more N-glycans selected from the group consisting of Man9GlcNAc2 (920000), Man8GlcNAc2 (820000), Man7GlcNAc2 (720000), Man6GlcNAc2 (620000), and Man5GlcNAc2 (520000); (ii) a decrease one or more N-glycans selected from the group consisting of SiaGalGlcNAcMan3GlcNAc2 (430010),

SiaGalGlcNAcMan4GlcNAc2 (530010), and SiaGalGlcNAcMan5GlcNAc2 (630010), wherein Sia is Neu5Ac or Neu5Gc; and (iii) a decrease in one or more N-glycans selected from the group consisting of Sia2Gal2GlcNAc2Man3GlcNAc2(1 O-Ac) (540021),

Sia2Gal2GlcNAc2Man3GlcNAc2(2 O-Ac) (540022), Sia3Gal2GlcNAc2Man3GlcNAc2(1 O-Ac) (540031), and Sia3Gal2GlcNAc2Man3GlcNAc2(2 O-Ac) (540032), wherein Sia is Neu5Ac or Neu5Gc.

15. The method of claim 4, wherein the difference in the N-linked glycosylation profile comprises (i) a decrease in one or more N-glycans selected from the group consisting of Man9GlcNAc2 (920000), Man8GlcNAc2 (820000), Man7GlcNAc2 (720000), Man6GlcNAc2 (620000), and Man5GlcNAc2 (520000); (ii) a decrease one or more N-glycans selected from the group consisting of SiaGalGlcNAcMan3GlcNAc2 (430010),

SiaGalGlcNAcMan4GlcNAc2 (530010), and SiaGalGlcNAcMan5GlcNAc2 (630010), wherein Sia is Neu5Ac or Neu5Gc; (iii) a decrease in one or more N-glycans selected from the group consisting of Sia2Gal2GlcNAc2Man3GlcNAc2(1 O-Ac) (540021),

Sia2Gal2GlcNAc2Man3GlcNAc2(2 O-Ac) (540022), Sia3Gal2GlcNAc2Man3GlcNAc2(1 O-Ac) (540031), and Sia3Gal2GlcNAc2Man3GlcNAc2(2 O-Ac) (540032), wherein Sia is Neu5Ac or Neu5Gc; and (iv) a decrease in a complex N-glycan such as Sia2Gal2GlcNAc2Man3GlcNAc2 (540020), wherein Sia is Neu5Ac or Neu5Gc.

16. The method of claim 4, wherein the difference in the N-linked glycosylation profile comprises (i) a decrease in one or more N-glycans selected from the group consisting of Man9GlcNAc2 (920000), Man8GlcNAc2 (820000), Man7GlcNAc2 (720000), Man6GlcNAc2 (620000), and Man5GlcNAc2 (520000); (ii) a decrease one or more N-glycans selected from the group consisting of SiaGalGlcNAcMan3GlcNAc2 (430010),

SiaGalGlcNAcMan4GlcNAc2 (530010), and SiaGalGlcNAcMan5GlcNAc2 (630010), wherein Sia is Neu5Ac or Neu5Gc; and (iii) a decrease in a complex N-glycan such as

Sia2Gal2GlcNAc2Man3GlcNAc2 (540020), wherein Sia is Neu5Ac or Neu5Gc.

17. The method of claim 4, wherein the one or more serum samples were obtained from the individual or patient from a time selected from 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, and 21 days following the start of the therapy or treatment.

18. The method of claim 4, wherein the anti-diabetic therapy or treatment comprises insulin, an insulin sensitizer, insulin secretagogue, alpha-glucosidase inhibitor, incretin or incretin mimetic, dipetidyl peptidase 4 (DPP4) inhibitor, amylin or amylin analog, GLP-1 receptor agonist.

19. A biomarker for determining the efficacy of a treatment for diabetes which comprises the N-linked glycosylation profile of the proteins in plasma serum.

20. Use of an N-linked glycosylation profile of a serum sample from an individual or patient in which an anti-diabetic therapy or treatment has been initiated as a predictive biomarker for determining efficacy of the therapy or treatment for diabetes.

21. Use of the amount of one or more high mannose N-glycans, hybrid N-glycans, O-acetylated N-glycans, complex N-glycans, fucosylated N-glycans, or combinations thereof in a serum sample obtained from an individual or patient in which an anti-diabetic therapy or treatment has been initiated as a predictive biomarker for determining efficacy of the therapy or treatment for diabetes.