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1. (WO2019050458) IMPROVED IMMUNOTHERAPY
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CLAIMS

2. A method for assessing the efficacy of an immunotherapy administered to a patient, said

immunotherapy comprising administration of GAD, comprising the following steps:

- measuring at least one of

GADA IgG subclass distribution;

• GADA levels;

Distribution of cytokines secreted from lymphocytes; and

Lymphocyte proliferation in presence of GAD or CD3/CD28 beads;

in a first blood, plasma or serum sample obtained from said patient at a first point in time and in a second blood, plasma or serum sample obtained from said patient at a second, later, point in time;

- Comparing the so obtained measurements;

wherein an increased relative amount of lgG2, lgG3, and/or IgG-i, or decreased relative amount of IgGi in the GADA IgG subclass distribution; increased GADA levels; an increased relative amount of IL-13 and/or IL-5 or a decreased relative amount of IFNy and/or TNFα in the distribution of cytokines secreted from lymphocytes; and/or reduced lymphocyte proliferation in the presence of GAD or CD3/CD28 beads; as measured in the second sample as compared to as measured in the first sample, is indicative of an effective immunotherapy.

3. The method according to claim 1, wherein at least two, at least three, or four of

GADA IgG subclass distribution;

• GADA levels;

Distribution of cytokines secreted from lymphocytes; and

Lymphocyte proliferation;

are measured in said first and second blood, plasma or serum sample.

4. The method according to claim 1 or 2, wherein the first sample is obtained before or at commencement of the immunotherapy, or 80-100, such as 90, days after commencement of the immunotherapy.

5. The method according to any one of claims 1-3, wherein the second sample is obtained at 160-200 days, such as 180 days; or at 12, 15, 24, 30 or 36 months after commencement of the immunotherapy.

6. The method according to any one of claims 1-3, wherein the second sample is obtained 160- 200 days, such as 180 days; or at 12, 15, 24, 30 or 36 months after the first sample is obtained.

7. The method according to any one of claims 1-5, wherein the immunotherapy comprises daily administration of vitamin D commencing at day 1, and intralymphatic injection of GAD at days 30, 60 and 90.

8. The method according to claim 6, wherein the administration of vitamin D commencing at day 1 extends for 3 months or more, such as 4, 5, or 6 months.

9. The method according to any one of claims 1-7, wherein GADA IgG subclass distribution is measured in said first and second samples and the so obtained measurements are compared, and wherein an increased relative amount of lgG4 in the GADA IgG subclass distribution, as measured in the second sample as compared to as measured in the first sample, is indicative of an effective immunotherapy.

10. The method according to any one of claims 1-8, wherein GADA IgG subclass distribution is measured in said first and second samples and the so obtained measurements are compared, and wherein a decreased relative amount of IgGi in the GADA IgG subclass distribution, as measured in the second sample as compared to as measured in the first sample, is indicative of an effective immunotherapy.

11. The method according to any one of claims 1-9, wherein GADA IgG subclass distribution is measured in said first and second samples and the so obtained measurements are compared, and wherein an increased amount of lgG4 relative to the amount of IgGi in the GADA IgG subclass distribution, as measured in the second sample as compared to as measured in the first sample, is indicative of an effective immunotherapy.

12. The method according to any one of claims 1-10, wherein GADA levels are measured in said first and second samples and the so obtained measurements are compared, wherein increased GADA levels, as measured in the second sample as compared to as measured in the first sample, are indicative of an effective immunotherapy.

13. The method according to any one of claims 1-11, wherein distribution of cytokines secreted from lymphocytes is measured in said first and second samples and the so obtained measurements are compared, wherein increased relative amount of IL-13 and/or IL-5, as measured in the second sample as compared to as measured in the first sample, is indicative of an effective immunotherapy.

14. The method according to any one of claims 1-12, wherein distribution of cytokines secreted from lymphocytes is measured in said first and second samples and the so obtained measurements are compared, wherein an increased amount of IL-13 relative to the amount of IFNy, as measured in the second sample as compared to as measured in the first sample, is indicative of an effective immunotherapy.

15. The method according to any one of claims 1-13, wherein distribution of cytokines secreted from lymphocytes is measured in said first and second samples and the so obtained measurements are compared, wherein decreased relative amount of IFNy and/or TNFα, as measured in the second sample as compared to as measured in the first sample, is indicative of an effective immunotherapy.

16. The method according to any one of claims 1-14, wherein lymphocyte proliferation in

presence of GAD or CD3/CD28 beads is measured in said first and second samples and the so obtained measurements are compared, wherein reduced lymphocyte proliferation in the presence of GAD or CD3/CD28 beads, as measured in the second sample as compared to as measured in the first sample, is indicative of an effective immunotherapy.

17. The method according to any one of claims 1-15, wherein said immunotherapy comprises administration of GAD by means of intralymphatic injection, including injection into a lymph node, intradermal injection, subcutaneous injection, or oral administration.

18. A method for treatment or prevention of type 1 diabetes by means of immunotherapy, comprising the steps of

- administration of GAD to a subject;

- obtaining an assessment of the efficacy of the immunotherapy by a method according to any one of claims 1-16; and

- adjusting the dosage and/or administration route of GAD based on said assessment.

19. The method according to claim 17, wherein if the comparison of the obtained measurements is not indicative of an effective immunotherapy, then the adjustment of the dosage of GAD includes a further administration of GAD by injection into a lymph node.

20. The method according to claim 17, wherein said method comprises

- administration of vitamin D commencing at day 1 and continuing for 3 to 6 months;

- three administrations of GAD into a lymph node of the subject at days 30, 60 and 90, respectively;

- obtaining an assessment of the efficacy of the immunotherapy by a method according to any one of claims 1-16;

and wherein if the comparison of the obtained measurements is not indicative of an effective immunotherapy, then the adjustment of the dosage of GAD includes a fourth administration of GAD into a lymph node at a time between 12 and 18 months after day 1.

21. A method for treatment or prevention of type 1 diabetes in a subject by means of

immunotherapy, comprising the steps of

- administration of vitamin D commencing at day 1 and continuing for 3 to 6 months;

- three administrations of GAD into a lymph node at days 30, 60 and 90, respectively; and

- a fourth administration of GAD into a lymph node at a time between 12 and 18

months after day 1.

22. The method according to any one of claims 17-20, wherein a fourth or further administration is performed if HbAlc and required insulin dose have gone up at 12 to 18 months as compared to levels observed at 5 to 6 months after first GAD-alum injection, and optionally if the IFN/IL-13 ratio has not decreased between the said observations.

23. The method according to any one of claims 17-21, further comprising a further

administration of GAD into a lymph node at 30 months after day 1.

24. The method according to claim 22, wherein the further administration of GAD-alum is

performed if HbAlc and/or required insulin dose for the subject have gone up at 30 months as compared to levels observed at 15 months after first GAD-alum injection, and optionally if the IFN/IL-13 ratio has not decreased between the said observations.

25. The method according to any one of claims 17-23, comprising at least three administrations of GAD into a lymph node of the subject at days 30, 60 and 90, respectively, and wherein at least one further administration into a lymph node is performed if HbAlc levels and/or required insulin dose for the subject at a given time have increased as compared to levels observed 6-24 months prior to said given time.

26. The method according to any one of claims 17-23, comprising at least three administrations of GAD into a lymph node of the subject at days 30, 60 and 90, respectively, and wherein at least one further administration into a lymph node is performed if the relative amount of IL- 13 and/or IL-5 in the distribution of cytokines secreted from lymphocytes is unchanged or decreased at a given time as compared to levels observed 6-24 months prior to said given time.

27. The method according to any one of claims 17-23, comprising at least three administrations of GAD into a lymph node of the subject at days 30, 60 and 90, respectively and wherein at least one further administration into a lymph node is performed if the ratio IFNy/IL-13 in the distribution of cytokines secreted from lymphocytes is unchanged or increased at a given time as compared to a the same ratio observed 6-24 months prior to said given time.

28. The method according to any one of claims 17-23, comprising at least three administrations of GAD into a lymph node of the subject at days 30, 60 and 90, respectively, and wherein at least one further administration into a lymph node is performed if the ratio of lgGl/lgG4 in the population of GAD specific antibodies is unchanged or increased at a given time as compared to the same ratio observed 6-24 months prior to said given time.

29. The method according to any one of claims 17-27, comprising daily administration of vitamin D commencing 0-90 days prior to a fourth or any further administration of GAD into a lymph node.

30. The method according to any one of claims 17-28, wherein vitamin D is administered at a dose of 2000 IU per day.

31. The method according to any one of claims 17-29, wherein vitamin D is administered for 4 months.

32. The method according to any one of claims 17-30, wherein GAD is administered in the form of alum-formulated GAD.

33. GAD for use in a method for treatment according to any one of claims 1-31.

34. Use of GAD in the manufacture of a pharmaceutical composition for use in a method for treatment according to any one of claims 1-31.