Tl1a patient selection methods, systems, and devices

Abstract

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.

What is claimed: 
     
         1 . A method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising administering to the subject a therapeutically effective amount of an inhibitor of Tumor necrosis factor-like cytokine 1A (TL1A) activity or expression, provided at least three polymorphisms comprising rs1892231, rs56124762, rs6478109, rs2070558, rs2070561, rs11897732, rs6740739, rs17796285, rs7935393, rs12934476, rs12457255, rs2070557, rs4246905, rs10974900, rs12434976, rs16901748, rs2815844, rs889702, rs2409750, rs1541020, rs4942248, rs12934476, rs12457255, rs2297437, rs41309367, rs10733509, rs10750376, rs10932456, rs1326860, rs1528663, rs951279, rs9806914, rs7935393, rs1690492, rs420726, rs7759385, rs10974900, rs1326860, rs2548147, rs2815844, rs889702, rs9806914, rs7278257, or rs11221332, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2  of at least 0.85, or a combination thereof, are detected in a sample obtained from the subject. 
     
     
         2 . The method of  claim 1 , wherein the at least three polymorphisms are predictive of a positive therapeutic response in the subject to a treatment with the inhibitor of TL1A activity or expression at a positive predictive value of at least about 70%. 
     
     
         3 . The method of  claim 1 , wherein the at least three polymorphisms are predictive of positive therapeutic response in the subject to a treatment with the inhibitor of TL1A activity or expression with a specificity of at least about 70%. 
     
     
         4 . The method of  claim 1 , wherein the at least three polymorphisms comprise:
 (a) rs6478109, rs56124762, and rs1892231;   (b) rs6478109, rs56124762, and rs16901748;   (c) rs6478109, rs1892231, and rs16901748;   (d) rs56124762, rs1892231, and rs16901748;   (e) rs6478109, rs2070558, and rs1892231;   (f) rs6478109, rs2070558, and rs16901748;   (g) rs6478109, rs1892231, and rs16901748;   (h) rs2070558, rs1892231, and rs16901748;   (i) rs6478109, rs2070561, and rs1892231;   (j) rs6478109, rs2070561, and rs16901748;   (k) rs6478109, rs1892231, and rs16901748;   (l) rs2070561, rs1892231, and rs16901748;   (m) rs6478109, rs7935393, and rs1892231;   (n) rs6478109, rs7935393, and rs9806914;   (o) rs6478109, rs7935393, and rs7278257;   (p) rs6478109, rs7935393, and rs2070557;   (q) rs6478109, rs1892231, and rs9806914;   (r) rs6478109, rs1892231, and rs7278257;   (s) rs6478109, rs1892231, and rs2070557;   (t) rs6478109, rs9806914, and rs7278257;   (u) rs6478109, rs9806914, and rs2070557;   (v) rs6478109, rs7278257, and rs2070557;   (w) rs7935393, rs1892231, and rs9806914;   (x) rs7935393, rs1892231, and rs7278257;   (y) rs7935393, rs1892231, and rs2070557;   (z) rs7935393, rs9806914, and rs7278257;   (aa) rs7935393, rs9806914, and rs2070557;   (bb) rs7935393, rs7278257, and rs2070557;   (cc) rs1892231, rs9806914, and rs7278257;   (dd) rs1892231, rs9806914, and rs2070557;   (ee) rs1892231, rs7278257, and rs2070557; or   (ff) rs9806914, rs7278257, and rs2070557.   
     
     
         5 . The method of  claim 1 , wherein the at least three polymorphisms further comprises a fourth polymorphism comprising rs16901748, rs1892231, rs56124762, rs6478109, rs2070558, rs2070561, rs11897732, rs6740739, rs17796285, rs7935393, rs12934476, rs12457255, rs2070557, rs4246905, rs10974900, rs12434976, rs2815844, rs889702, rs2409750, rs1541020, rs4942248, rs12934476, rs12457255, rs2297437, rs41309367, rs10733509, rs10750376, rs10932456, rs1326860, rs1528663, rs951279, rs9806914, rs7935393, rs1690492, rs420726, rs7759385, rs10974900, rs1326860, rs2548147, rs2815844, rs889702, rs9806914, rs7278257, or rs11221332, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2  of at least 0.85, or a combination thereof. 
     
     
         6 . The method of method of  claim 1 , wherein the at least three polymorphisms are detected in the sample by subjecting the sample to an assay configured to detect a presence of at least three nucleotides corresponding to nucleic acid position 501 within at least three of SEQ ID NOS: 1-41, or 57-59. 
     
     
         7 . The method of  claim 1 , wherein the inflammatory, fibrotic, or fibrostenotic disease or condition comprises inflammatory bowel disease, Crohn's disease, obstructive Crohn's disease, ulcerative colitis, intestinal fibrosis, intestinal fibrostenosis, rheumatoid arthritis, or primary sclerosing cholangitis. 
     
     
         8 . The method of  claim 7 , wherein the Crohn's disease is ileal, ileocolonic, or colonic Crohn's disease. 
     
     
         9 . The method of  claim 1 , wherein the subject has, or is at risk for developing, a non-response or loss-of-response to a standard therapy comprising glucocorticosteriods, anti-TNF therapy, anti-a4-b7 therapy, anti-IL12p40 therapy, or a combination thereof. 
     
     
         10 . The method of  claim 1 , wherein the inhibitor of TL1A is an anti-TL1A antibody or antigen-binding fragment. 
     
     
         11 . A method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising:
 (a) determining whether the subject with an inflammatory, a fibrotic, or a fibrostenotic disease or condition is suitable for treatment with an inhibitor of TL1A activity or expression by:
 (i) obtaining or having obtained a sample from the subject; and 
 (ii) subjecting the sample to an assay adapted to detect at least three polymorphisms comprising rs1892231, rs56124762, rs6478109, rs2070558, rs2070561, rs11897732, rs6740739, rs17796285, rs7935393, rs12934476, rs12457255, rs2070557, rs4246905, rs10974900, rs12434976, rs16901748, rs2815844, rs889702, rs2409750, rs1541020, rs4942248, rs12934476, rs12457255, rs2297437, rs41309367, rs10733509, rs10750376, rs10932456, rs1326860, rs1528663, rs951279, rs9806914, rs7935393, rs1690492, rs420726, rs7759385, rs10974900, rs1326860, rs2548147, rs2815844, rs889702, rs9806914, rs7278257, rs11221332, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2  of at least 0.85, or a combination thereof, and 
   (b) treating the subject by administering a therapeutically effective amount of the inhibitor of TL1A activity or expression to the subject.   
     
     
         12 . The method of  claim 11 , wherein the at least three polymorphisms are predictive of a positive therapeutic response in the subject to a treatment with the inhibitor of TL1A activity or expression at a positive predictive value of at least about 70%. 
     
     
         13 . The method of  claim 11 , wherein the at least three polymorphisms are predictive of a positive therapeutic response in the subject to a treatment with the inhibitor of TL1A activity or expression at a specificity of at least about 70%. 
     
     
         14 . The method of  claim 11 , wherein the inflammatory, fibrotic, or fibrostenotic disease or condition comprises inflammatory bowel disease, Crohn's disease, obstructive Crohn's disease, ulcerative colitis, intestinal fibrosis, intestinal fibrostenosis, rheumatoid arthritis, or primary sclerosing cholangitis. 
     
     
         15 . The method of  claim 14 , wherein the Crohn's disease is ileal, ileocolonic, or colonic Crohn's disease. 
     
     
         16 . The method of  claim 11 , wherein the wherein the inhibitor of TL1A activity or expression is an anti-TL1A antibody or antigen-binding fragment. 
     
     
         17 . The method of  claim 11 , wherein the at least three polymorphisms comprise:
 (a) rs6478109, rs56124762, and rs1892231;   (b) rs6478109, rs56124762, and rs16901748;   (c) rs6478109, rs1892231, and rs16901748;   (d) rs56124762, rs1892231, and rs16901748;   (e) rs6478109, rs2070558, and rs1892231;   (f) rs6478109, rs2070558, and rs16901748;   (g) rs6478109, rs1892231, and rs16901748;   (h) rs2070558, rs1892231, and rs16901748;   (i) rs6478109, rs2070561, and rs1892231;   (j) rs6478109, rs2070561, and rs16901748;   (k) rs6478109, rs1892231, and rs16901748;   (l) rs2070561, rs1892231, and rs16901748;   (m) rs6478109, rs7935393, and rs1892231;   (n) rs6478109, rs7935393, and rs9806914;   (o) rs6478109, rs7935393, and rs7278257;   (p) rs6478109, rs7935393, and rs2070557;   (q) rs6478109, rs1892231, and rs9806914;   (r) rs6478109, rs1892231, and rs7278257;   (s) rs6478109, rs1892231, and rs2070557;   (t) rs6478109, rs9806914, and rs7278257;   (u) rs6478109, rs9806914, and rs2070557;   (v) rs6478109, rs7278257, and rs2070557;   (w) rs7935393, rs1892231, and rs9806914;   (x) rs7935393, rs1892231, and rs7278257;   (y) rs7935393, rs1892231, and rs2070557;   (z) rs7935393, rs9806914, and rs7278257;   (aa) rs7935393, rs9806914, and rs2070557;   (bb) rs7935393, rs7278257, and rs2070557;   (cc) rs1892231, rs9806914, and rs7278257;   (dd) rs1892231, rs9806914, and rs2070557;   (ee) rs1892231, rs7278257, and rs2070557; or   (ff) rs9806914, rs7278257, and rs2070557.   
     
     
         18 . The method of  claim 11 , wherein the at least three polymorphisms further comprises a fourth polymorphism comprising rs16901748, rs1892231, rs56124762, rs6478109, rs2070558, rs2070561, rs11897732, rs6740739, rs17796285, rs7935393, rs12934476, rs12457255, rs2070557, rs4246905, rs10974900, rs12434976, rs2815844, rs889702, rs2409750, rs1541020, rs4942248, rs12934476, rs12457255, rs2297437, rs41309367, rs10733509, rs10750376, rs10932456, rs1326860, rs1528663, rs951279, rs9806914, rs7935393, rs1690492, rs420726, rs7759385, rs10974900, rs1326860, rs2548147, rs2815844, rs889702, rs9806914, rs7278257, or rs11221332 or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2  of at least 0.85, or a combination thereof. 
     
     
         19 . The method of  claim 11 , wherein the subject is at risk of developing a non-response or loss-of-response to a standard therapy comprising glucocorticosteriods, anti-TNF therapy, anti-a4-b7 therapy, anti-IL12p40 therapy, or a combination thereof. 
     
     
         20 . A method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising administering to the subject a therapeutically effective amount of an inhibitor of TL1A activity or expression, wherein the subject expresses at least three polymorphisms comprising rs16901748, rs6478109, rs56124762, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R 2  of at least 0.85.