Prediction of clinical response to IL23-antagonists using IL23 pathway biomarkers

Patent metadata

Field	Value
Publication number	US-11016099-B2
Application number	US-201615759330-A
Country	US
Kind code	B2
Filing date	Sep 16, 2016
Priority date	Sep 17, 2015
Publication date	May 25, 2021
Grant date	May 25, 2021

Abstract

The present invention relates to the use of components of the IL23 pathway as biomarkers, e.g., IL22, LCN2 and combinations thereof, to stratify or identify populations of patients suffering from IL23-mediated diseases (e.g., Crohn's disease) responsive to treatment with an anti-IL23 antagonist (including, e.g., anti-IL23 antibodies or antigen-binding fragments thereof). Levels of IL23 pathway biomarkers above or below a predetermined threshold can be used, for example, (i) to determine whether a patient with an IL23-mediated disease or disorder such a Crohn's disease is eligible or non-eligible for treatment with a therapeutic agent (e.g., an ant-IL23 antibody), (ii) to determine whether treatment with a certain agent should be commenced, suspended, or modified, (iii) to diagnose whether the IL23-mediated disease is treatable or not treatable with a specific therapeutic agent, or (iv) to predict the outcome of treating the IL23-mediated disease with a specific therapeutic agent.

First claim

What is claimed is:

1. A method of treating Crohn's disease or Inflammatory Bowel Disease in a patient, comprising administering an IL23 antagonist to a patient in an amount and at an interval of:
(a) 15-54 mg every 0.5-1.5 months;
(b) 55-149 mg every 1.5-4.5 months;
(c) 150-299 mg every 4-8 months; or
(d) 300-1100 mg every 4-12 months
if the patient is determined to have (i) a higher or increased level of interleukin-22 (IL22) and/or (ii) a higher or increased level of lipocalin 2 (LCN2) in one or more samples taken from the patient compared to a predetermined IL22 and/or LCN2 threshold level, or compared to a IL22 and/or LCN2 level in one or more control samples, or suspending the administration of an IL23 antagonist to a patient if the patient is determined to have (i) a lower or decreased level of interleukin-22 (IL22) and/or (ii) a lower or decreased level of lipocalin 2 (LCN2) in one or more samples taken from the patient compared to a predetermined IL22 and/or LCN2 threshold level, or compared to a IL22 and/or LCN2 level in one or more control samples.

2. The method according to claim 1 , further comprising measuring the level of IL22 and/or LCN2 in one or more of the samples obtained from the patient or instructing a clinical laboratory or healthcare provider to measure the level of IL22 and/or LCN2 in the sample and/or submitting the one or more samples obtained from the patient to a clinical laboratory or healthcare provider to measure the level of IL22 and/or LCN2 in the sample.

3. The method according to claim 1 further comprising advising a healthcare provider to administer an IL23 antagonist to the patient in an amount and at an interval of:
(a) 15-54 mg every 0.5-1.5 months;
(b) 55-149 mg every 1.5-4.5 months;
(c) 150-299 mg every 4-8 months; or
(d) 300-1100 mg every 4-12 months,
if the patient is determined to have (i) a higher or increased level of IL22 and/or (ii) a higher or increased level of LCN2 in one or more of the samples compared to a predetermined IL22 and/or LCN2 threshold level, or compared to a IL22 and/or LCN2 level in one or more control samples, or to suspend the administration of an IL23 antagonist to the patient if the patient is determined to have (i) a lower or decreased level of IL22 and/or (ii) a lower or decreased level of LCN2 in one or more of the samples compared to a predetermined IL22 and/or LCN2 threshold level, or compared to a IL22 and/or LCN2 level in one or more control samples.

4. The method according to claim 1 , wherein the IL23 antagonist is an anti-IL23 antibody or antigen-binding fragment thereof.

5. The method of claim 4 , wherein the anti-IL23 antibody or antigen-binding fragment thereof binds to the p19 subunit of IL23 (SEQ ID NO: 13), to the p40 subunit of IL23 (SEQ ID NO: 14), or both.

6. The method according to claim 4 , wherein the anti-IL23 antibody or antigen-binding fragment thereof comprises ustekinumab, briakinumab, guselkumab, BI-655066, tildrakinumab, LY-3074828, or an antigen-binding fragment thereof.

7. The method according to claim 4 , wherein the anti-IL23 antibody or antigen-binding fragment thereof comprises (i) a variable region (VH) comprising or consisting of SEQ ID NO: 5 and/or a light chain variable region (VL) comprising or consisting of SEQ ID NO: 6, or (ii) a variable region (VH) comprising or consisting of SEQ ID NO:43 and/or a light chain variable region (VL) comprising or consisting of SEQ ID NO: 44.

8. The method according to claim 4 , wherein the anti-IL23 antibody or antigen-binding fragment thereof comprises six complementarity determining regions selected from SEQ ID NOS: 31-36 or SEQ ID NOS:45-50.

9. The method according to claim 4 , wherein the antibody is administered at a fixed dose.

10. The method according to claim 9 , wherein the fixed dose is between 15 and 1000 mg/dose, is about 210 mg/dose, or is about 700 mg/dose.

11. The method according to claim 1 wherein the patient has been treated before, during, or after the administration of an IL23 antagonist or anti-IL23 antibody or antigen-binding fragment with one or more additional therapies for the treatment of Crohn's disease or Inflammatory Bowel Disease.

12. The method according to claim 1 , wherein the one or more control samples are (i) a sample or samples obtained from normal healthy individuals; (ii) a sample or samples obtained from patients without Crohn's disease or Inflammatory Bowel Disease; or (iii) a combination thereof.

13. The method according to claim 1 , further comprising determining the level of one or more IL23 Pathway Biomarkers selected from the group consisting of CCL20, IL17F, IL17A/F, IL23R, IL12B, IL6, IL21, TNF, CCR6, CCL22, IL1R1, IFN-γ, S100AI2, DEFB-2, DEFB-4, ILI, SERPINB3, PI3/Elafin, LL37, RORy, RORyT, IL26, S100A7, DEFB103B, and GM-CSF.

14. The method according to claim 1 , wherein the predetermined threshold level of IL22 and/or LCN2 is selected from the group consisting of:
(a) about the mean level of IL22 and/or LCN2;
(b) about the median level of IL22 and/or LCN2;
(c) about the 1 st , 2 nd , 3 rd , 4 th , 5 th , 6 th , 7 th , 8 th , or 9 th decile baseline level of IL22 and/or LCN2 as described in TABLES 4 or 5, as measured in the serum using an immunoassay from a plurality of normal healthy patients, patients without Crohn's disease or Inflammatory Bowel Disease, and/or patients with without Crohn's disease or Inflammatory Bowel Disease,
or wherein
(d) the predetermined IL22 threshold level is at least about 7.9 pg/mL to at least about 31.4 pg/mL as measured using an immunoassay;
(e) the predetermined LCN2 threshold level is at least about 143 ng/mL to at least about 261 ng/mL as measured using an immunoassay;
(f) the predetermined IL22 threshold level is about 15.6 pg/mL as measured using an immunoassay; and/or
(g) the predetermined LCN2 threshold level is about 215 ng/mL as measured using an immunoassay.

15. The method according to claim 1 , wherein the patient has Crohn's disease, and wherein the patient is determined to have a level of CRP >5 mg/L and/or a level of FCP >250 μg/g, a level of FCP >20 μg/g, a level of FCP >150 μg/g, a level of FCP >10 μg/g, or a level of FCP at least about 10 μg/g to at least about 250 μg/g in one or more samples taken from the patient.

16. The method according to claim 15 , wherein administration of the IL23 antagonist results in a Crohn's Disease Activity Index (CDAI) response score reduction of at least 10 points and/or a reduction in the total CDAI score to below 150 points after first administering the anti-IL23 antibody or antigen-binding fragment thereof.

17. The method according to claim 16 , wherein the CDAI response score reduction of at least 10 points or reduction in the total CDAI score to below 150 points occurs within 1, 2, 4, 8, 12, 16 or 24 weeks or later after first administering the IL23 antagonist.

18. The method according to claim 16 , wherein the IL23 antagonist is an anti-IL23 antibody or antigen-binding fragment thereof.

19. The method according to claim 17 , wherein the IL23 antagonist is an anti-IL23 antibody or antigen-binding fragment thereof.

20. The method of claim 1 , wherein the amount and interval are:
(a) 15-21 mg every 0.5-1.0 month;
(b) 55-70 mg every 1.5-3.0 months;
(c) 150-260 mg every 4-6 months; or
(d) 300-700 mg every 4-8 months.

21. The method of claim 1 , wherein the amount and interval are:
(a) 21 mg every month;
(b) 70 mg every 3 months;
(c) 210 mg every 6 months; or
(d) 700 mg every 6 months.

Assignees

• Amgen Inc
• Medimmune Llc

Inventors

• Georgantas Iii Robert W
• Morehouse Chris
• Higgs Brandon
• Ranade Koustubh
• Streicher Katie
• Rees William
• Liang Meina
• Faggioni Raffaella
• Li Jing
• Vainshtein Inna
• Lee Yen-Wah
• Chen Jingjing
• Gasser Jr Robert A

Classifications

• C07K16/244 Primary

  Interleukins [IL] · CPC title

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title

• G01N2800/065

  Bowel diseases, e.g. Crohn, ulcerative colitis, IBS · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title