Methods of treating Crohn's disease or ulcerative colitis by administering inhibitors of tumor necrosis factor-like cytokine 1A (TL1A)
Provided are methods, systems, and kits for selecting a patient for treatment with a therapeutic agent based on a presence of a genotype associated with a positive therapeutic response to the therapeutic agent. The therapeutic agent, in some embodiments, is an inhibitor of TL1A activity or expression, such as for example, an anti-TL1A antibody.
1. A method of treating moderately to severely active Crohn's disease or ulcerative colitis in a subject, the method comprising: administering a therapeutically effective amount of an inhibitor of Tumor necrosis factor-like cytokine 1A (TL1A) activity or expression to a subject with moderately to severely active Crohn's disease or ulcerative colitis that tested positive with a test for predicting a positive therapeutic response to the inhibitor of the TL1A activity or expression with a positive predictive value of at least about 70% based, at least in part, on a presence of a combination of genotypes identified in a biological sample obtained from the subject,
wherein the inhibitor of TL1A activity or expression is a protein.
2. The method of claim 1 , wherein the combination of genotypes comprises three or more polymorphisms.
3. The method of claim 1 , wherein the positive predictive value is at least about 75%.
4. The method of claim 1 , wherein the test predicts the positive therapeutic response to the therapeutically effective amount of the inhibitor of the TL1A activity or expression with a specificity of at least about 70%.
5. The method of claim 2 , wherein the three or more polymorphisms comprise rs6478109, rs16901748, and rs2297437, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2 of at least 0.85.
6. The method of claim 2 , wherein the three or more polymorphisms comprise rs6478109, rs2070557, and rs7935393, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2 of at least 0.85.
7. The method of claim 2 , wherein the three or more polymorphisms comprise rs6478109, rs7278257, and rs7935393, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2 of at least 0.85.
8. The method of claim 2 , wherein the three or more polymorphisms comprise rs6478109, rs9806914, and rs1892231, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2 of at least 0.85.
9. The method of claim 2 , wherein the three or more polymorphisms comprise rs6478109, rs7278257, and rs16901748, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2 of at least 0.85.
10. The method of claim 9 , wherein the proxy polymorphism for rs7278257 is rs56124762.
11. The method of claim 1 , wherein the combination of genotypes comprises a combination of single-nucleotide variants.
12. The method of claim 1 , wherein the inhibitor of TL1A activity or expression comprises an anti-TL1A antibody or antigen-binding fragment thereof.
13. A method of treating moderately to severely active Crohn's disease or ulcerative colitis in a subject, the method comprising: administering a therapeutically effective amount of an inhibitor of Tumor necrosis factor-like cytokine 1A (TL1A) activity or expression to a subject selected for treatment based on an allele combination predictive of a positive therapeutic response to the inhibitor of TL1A activity or expression with a positive predictive value of at least about 70%, wherein the allele combination is detected in a biological sample obtained from the subject, and wherein the inhibitor of TL1A activity or expression is a protein.
14. The method of claim 13 , wherein the allele combination comprises at least three variant alleles at three or more polymorphisms.
15. The method of claim 13 , wherein the positive predictive value is at least about 75%.
16. The method of claim 13 , wherein the allele combination is predictive of the positive therapeutic response to the therapeutically effective amount of the inhibitor of the TL1A activity or expression with a specificity of at least about 70%.
17. The method of claim 14 , wherein the three or more polymorphisms comprise rs6478109, rs16901748, and rs2297437, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2 of at least 0.85.
18. The method of claim 14 , wherein the three or more polymorphisms comprise rs6478109, rs2070557, and rs7935393, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2 of at least 0.85.
19. The method of claim 14 , wherein the three or more polymorphisms comprise rs6478109, rs7278257, and rs7935393, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2 of at least 0.85.
20. The method of claim 14 , wherein the three or more polymorphisms comprise rs6478109, rs9806914, and rs1892231, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2 of at least 0.85.
21. The method of claim 14 , wherein the three or more polymorphisms comprise rs6478109, rs7278257, and rs16901748, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2 of at least 0.85.
22. The method of claim 21 , wherein the proxy polymorphism for rs7278257 is rs56124762.
23. The method of claim 10 , wherein the combination of genotypes comprises a combination of single-nucleotide variants.
24. The method of claim 13 , wherein the allele combination comprises a combination of single-nucleotide variants.
25. The method of claim 10 , wherein the inhibitor of TL1A activity or expression comprises an anti-TL1A antibody or antigen-binding fragment thereof.
26. The method of claim 13 , wherein the inhibitor of TL1A activity or expression comprises an anti-TL1A antibody or antigen-binding fragment thereof.
27. A method of treating moderately to severely active Crohn's disease or ulcerative colitis in a subject, the method comprising: administering a therapeutically effective amount of an inhibitor of Tumor necrosis factor-like cytokine 1A (TL1A) activity or expression to a subject with moderately to severely active Crohn's disease or ulcerative colitis that tested positive with a test for predicting a positive therapeutic response to the inhibitor of the TL1A activity or expression with a positive predictive value of at least about 70% based, at least in part, on a presence of a combination of genotypes identified in a biological sample obtained from the subject,
wherein the inhibitor of TL1A activity or expression is a nucleic acid molecule.
28. The method of claim 27 , wherein the combination of genotypes comprises three or more polymorphisms.
29. The method of claim 27 , wherein the positive predictive value is at least about 75%.
30. The method of claim 27 , wherein the test predicts the positive therapeutic response to the therapeutically effective amount of the inhibitor of the TL1A activity or expression with a specificity of at least about 70%.
31. The method of claim 28 , wherein the three or more polymorphisms comprise rs6478109, rs16901748, and rs2297437, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2 of at least 0.85.
32. The method of claim 28 , wherein the three or more polymorphisms comprise rs6478109, rs2070557, and rs7935393, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2 of at least 0.85.
33. The method of claim 28 , wherein the three or more polymorphisms comprise rs6478109, rs7278257, and rs7935393, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2 of at least 0.85.
34. The method of claim 28 , wherein the three or more polymorphisms comprise rs6478109, rs9806914, and rs1892231, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2 of at least 0.85.
35. The method of claim 28 , wherein the three or more polymorphisms comprise rs6478109, rs7278257, and rs16901748, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2 of at least 0.85.
36. The method of claim 35 , wherein the proxy polymorphism for rs7278257 is rs56124762.
37. The method of claim 27 , wherein the combination of genotypes comprises a combination of single-nucleotide variants.
38. The method of claim 36 , wherein the combination of genotypes comprises a combination of single-nucleotide variants.
39. The method of claim 27 , wherein the inhibitor of TL1A activity or expression comprises an siRNA.
40. The method of claim 36 , wherein the inhibitor of TL1A activity or expression comprises an siRNA.
41. A method of treating moderately to severely active Crohn's disease or ulcerative colitis in a subject, the method comprising: administering a therapeutically effective amount of an inhibitor of Tumor necrosis factor-like cytokine 1A (TL1A) activity or expression to a subject selected for treatment based on an allele combination predictive of a positive therapeutic response to the inhibitor of TL1A activity or expression with a positive predictive value of at least about 70%, wherein the allele combination is detected in a biological sample obtained from the subject, and wherein the inhibitor of TL1A activity or expression is a nucleic acid molecule.
42. The method of claim 41 , wherein the allele combination comprises at least three variant alleles at three or more polymorphisms.
43. The method of claim 41 , wherein the positive predictive value is at least about 75%.
44. The method of claim 41 , wherein the allele combination is predictive of the positive therapeutic response to the therapeutically effective amount of the inhibitor of the TL1A activity or expression with a specificity of at least about 70%.
45. The method of claim 42 , wherein the three or more polymorphisms comprise rs6478109, rs16901748, and rs2297437, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2 of at least 0.85.
46. The method of claim 42 , wherein the three or more polymorphisms comprise rs6478109, rs2070557, and rs7935393, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2 of at least 0.85.
47. The method of claim 42 , wherein the three or more polymorphisms comprise rs6478109, rs7278257, and rs7935393, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2 of at least 0.85.
48. The method of claim 42 , wherein the three or more polymorphisms comprise rs6478109, rs9806914, and rs1892231, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2 of at least 0.85.
49. The method of claim 42 , wherein the three or more polymorphisms comprise rs6478109, rs7278257, and rs16901748, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2 of at least 0.85.
50. The method of claim 49 , wherein the proxy polymorphism for rs7278257 is rs56124762.
51. The method of claim 41 , wherein the allele combination comprises a combination of single-nucleotide variants.
52. The method of claim 41 , wherein the inhibitor of TL1A activity or expression comprises an siRNA.
53. The method of claim 50 , wherein the inhibitor of TL1A activity or expression comprises an siRNA.