# US 12,215,147 B2 · Methods of selecting, based on polymorphisms, an inflammatory bowel disease subject for treatment with an anti-TL1A antibody > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 12,215,147 B2 - Document ID: US12215147B2 - Status: Granted - Kind: B2 - Application number: 17/409,639 - Filed: 2021-08-23 - Published: 2023-01-19 - Granted: 2025-02-04 - Earliest claimed: 2019-05-14 - Assignees: Prometheus Biosciences, Inc.; Cedars-Sinai Medical Center - Applicants: Prometheus Biosciences, Inc.; Cedars-Sinai Medical Center - Inventors: Laurens Kruidenier; Mahyar Sabripour; Janine Bilsborough; Dermot P. McGovern; Dalin Li - Web page: https://patentgrep.com/patent/US12215147B2 ## CPC - C07K 16/241: {Tumor Necrosis Factors} - A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system - A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants - C07K 16/2875: {against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154 (against NGF C07K16/22, against TNF C07K16/241)} - C12Q 1/6883: for diseases caused by alterations of genetic material - A61K 2039/505: {comprising antibodies} - C12Q 2600/106: Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism - C12Q 2600/156: Polymorphic or mutational markers - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) ## 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. ## Claims ### Claim 1 A method of selecting a subject having inflammatory bowel disease (IBD) for treatment with an anti-tumor necrosis factor-like cytokine 1A (anti-TL1A) antibody or an antigen-binding fragment thereof, the method comprising: (a) providing a biological sample from a subject having IBD to determine presence of three or more polymorphisms selected from the group consisting of: rs1892231, rs56124762, rs6478109, rs2070558, rs2070561, rs11897732, rs6740739, rs17796285, rs7935393, rs12934476, rs12457255, rs2070557, rs4246905, rs10974900, rs12434976, rs16901748, rs2815844, rs889702, rs2409750, rs1541020, rs4942248, rs2297437, rs41309367, rs10733509, rs10750376, rs10932456, rs1326860, rs1528663, rs951279, rs9806914, rs1690492, rs420726, rs7759385, rs2548147, rs7278257, rs11221332, rs11558819, rs2329718, rs2070559, rs2070560, and any proxy polymorphism in linkage disequilibrium with any of the foregoing as determined with an R2 of at least 0.85; (b) selecting a subject determined to have the presence of the three or more polymorphisms in (a), wherein the presence of the three or more polymorphisms is indicative of a positive therapeutic response to a treatment with an anti-TL1A antibody or an antigen-binding fragment thereof with a positive predictive value (PPV) of at least about 70%; and (c) administering a therapeutically effective amount of the anti-TL1A antibody or antigen-binding fragment thereof to the subject selected in (b). ### Claim 2 (depends on 1) The method of claim 1, wherein the presence of the three or more polymorphisms is determined with a method selected from the group consisting of Polymerase Chain Reaction (PCR), automated sequencing, array genotyping, allele-specific hybridization, self-sustained sequence replication, and next-generation sequencing. ### Claim 3 (depends on 2) The method of claim 2, wherein the presence of the three or more polymorphisms is determined with PCR. ### Claim 4 (depends on 3) The method of claim 3, wherein the PCR comprises quantitative polymerase chain reaction (qPCR), reverse transcription PCR (RT-PCR), or a combination thereof. ### Claim 5 (depends on 1) The method of claim 1, wherein the PPV is at least about 75%. ### Claim 6 (depends on 1) The method of claim 1, wherein the presence of the three or more polymorphisms is predictive for responding to the anti-TL1A antibody or antigen-binding fragment thereof with a specificity of at least about 70%. ### Claim 7 (depends on 1) The method of claim 1, wherein the three or more polymorphisms are on a plurality of genes selected from the group consisting of TL1A, THADA Armadillo Repeat Containing (THADA), XK Related 6 (XKR6), Transcription Factor (ETS1), C-Type Lectin Domain Containing 16A (CLEC16A), Suppressor Of Cytokine Signaling 1 (SOCS1), Protein Tyrosine Phosphatase Non-Receptor Type 2 (PTPN2), Inducible T Cell Costimulator Ligand (ICOSLG), Janus Kinase 2 (JAK2), Catenin Delta 2 (CTNND2), Regulator Of G Protein Signaling 7 (RGS7), RNA Binding Fox-1 Homolog 1 (RBFOX1), RNA Binding Motif Protein 17 (RBM17), 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), Ecto-NOX Disulfide-Thiol Exchanger 1 (ENOX1), Coiled-Coil Domain Containing 122 (CCDC122), Regulator Of Telomere Elongation Helicase 1 (RTEL1), TNF Receptor Superfamily Member 6b (TNFRSF6B), GLIS Family Zinc Finger 3 (GLIS3), Solute Carrier Family 1 Member 1 (SLC1A1), IKAROS Family Zinc Finger 2 (IKZF2), Long Intergenic Non-Protein Coding RNA 1031 (LINC01031), Fatty Acyl-CoA Reductase 1 (FAR1), Spondin 1 (SPON1), Long Intergenic Non-Protein Coding RNA 1150 (LINC01150), Pleckstrin Homology, MyTH4 And FERM Domain Containing H2 (PLEKHH2), Plexin A2 (PLXNA2), MIR205 Host Gene (MIR205HG), PR/SET Domain 1 (PRDM1), Autophagy Related 5 (ATG5), Long Intergenic Non-Protein Coding RNA 603 (LINC00603), Prostaglandin E Receptor 4 (PTGER4), and Myotubularin Related Protein 9 (MTMR9), and combinations thereof. ### Claim 8 (depends on 1) The method of claim 1, wherein the three or more polymorphisms comprise rs6478109. ### Claim 9 (depends on 1) The method of claim 1, wherein the three or more polymorphisms comprises a minor allele at rs6478109. ### Claim 10 (depends on 9) The method of claim 9, wherein the minor allele at rs6478109 is Adenine (A) or Thymine (T). ### Claim 11 (depends on 1) The method of claim 1, wherein the three or more polymorphisms are selected from the group consisting of rs6478109, rs7278257, rs2070557, rs7935393, rs9806914, and any proxy polymorphisms that are in linkage disequilibrium with any of the foregoing as determined with an R2 of at least 0.85. ### Claim 12 (depends on 1) The method of claim 1, wherein the three or more polymorphisms are selected from the group consisting of rs6478109, rs7935393, rs9806914, rs16901748, rs2070557, rs7278257, rs2297437, rs1892231, and any proxy polymorphisms that are in linkage disequilibrium with any of the foregoing as determined with an R2 of at least 0.85. ### Claim 13 (depends on 1) The method of claim 1, wherein the three or more polymorphisms are selected from the group consisting of rs6478109, rs16901748, rs2297437, and any proxy polymorphisms that are in linkage disequilibrium with any of the foregoing as determined with an R2 of at least 0.85. ### Claim 14 (depends on 1) The method of claim 1, wherein the three or more polymorphisms are selected from the group consisting of rs6478109, rs2070557, rs7935393, and any proxy polymorphisms that are in linkage disequilibrium with any of the foregoing as determined with an R2 of at least 0.85. ### Claim 15 (depends on 1) The method of claim 1, wherein the three or more polymorphisms are selected from the group consisting of rs6478109, rs7278257, rs7935393, and any proxy polymorphisms that are in linkage disequilibrium with any of the foregoing as determined with an R2 of at least 0.85. ### Claim 16 (depends on 1) The method of claim 1, wherein the three or more polymorphisms are selected from the group consisting of rs6478109, rs9806914, rs1892231, and any proxy polymorphisms that are in linkage disequilibrium with any of the foregoing as determined with an R2 of at least 0.85. ### Claim 17 (depends on 1) The method of claim 1, wherein the three or more polymorphisms are selected from the group consisting of rs6478109, rs7278257, rs16901748, and any proxy polymorphisms that are in linkage disequilibrium with any of the foregoing as determined with an R2 of at least 0.85. ### Claim 18 (depends on 17) The method of claim 17, wherein the proxy polymorphism for rs7278257 is rs56124762. ### Claim 19 (depends on 1) The method of claim 1, wherein the IBD is Crohn's disease (CD). ### Claim 20 (depends on 19) The method of claim 19, wherein the CD is moderate to severe CD. ### Claim 21 (depends on 1) The method of claim 1, wherein the IBD is ulcerative colitis (UC). ### Claim 22 (depends on 21) The method of claim 21, wherein the UC is moderate to severe UC. ### Claim 23 (depends on 1) The method of claim 1, wherein the three or more polymorphisms are 4, 5, 6, 7, or 8 polymorphisms. ### Claim 24 A method comprising: (a) contacting genetic materials in a biological sample obtained from a subject having inflammatory bowel disease (IBD) with one or more nucleic acid primer pairs having forward and reverse primers capable of hybridizing to one or more target nucleic acid sequences, the one or more target nucleic acid sequences collectively comprising chromosome positions of three or more polymorphisms selected from the group consisting of: rs1892231, rs56124762, rs6478109, rs2070558, rs2070561, rs11897732, rs6740739, rs17796285, rs7935393, rs12934476, rs12457255, rs2070557, rs4246905, rs10974900, rs12434976, rs16901748, rs2815844, rs889702, rs2409750, rs1541020, rs4942248, rs2297437, rs41309367, rs10733509, rs10750376, rs10932456, rs1326860, rs1528663, rs951279, rs9806914, rs1690492, rs420726, rs7759385, rs2548147, rs7278257, rs11221332, rs11558819, rs2329718, rs2070559, rs2070560, and any proxy polymorphism in linkage disequilibrium with any of the foregoing as determined with an R2 of at least 0.85; (b) amplifying the target nucleic acid sequences by polymerase chain reactions with the nucleic acid primer pairs of (a); (c) inputting results from (b) into a computer system; and (d) analyzing the results of (b) via the computer system to determine the presence in the target nucleic acid sequences of the three or more polymorphisms of step (a), wherein the presence of the three or more polymorphisms is indicative of a positive therapeutic response to a treatment with an anti-tumor necrosis factor-like cytoking 1A (anti-TL1A) antibody or an antigen-binding fragment thereof with a positive predictive value (PPV) of at least about 70%, and wherein the computer system comprises a storage unit configured to store the three or more polymorphisms. ### Claim 25 (depends on 24) The method of claim 24, further comprising before step (c) contacting the target nucleic acid sequences with a plurality of probes to detect the three or more polymorphisms of step (a). ### Claim 26 (depends on 24) The method of claim 24, wherein the chromosome positions of rs1892231, rs56124762, rs6478109, rs2070558, rs2070561, rs11897732, rs6740739, rs17796285, rs7935393, rs12934476, rs12457255, rs2070557, rs4246905, rs10974900, rs12434976, rs16901748, rs2815844, rs889702, rs2409750, rs1541020, rs4942248, rs2297437, rs41309367, rs10733509, rs10750376, rs10932456, rs1326860, rs1528663, rs951279, rs9806914, rs1690492, rs420726, rs7759385, rs2548147, rs7278257, rs11221332, rs11558819, rs2329718, rs2070559, and rs2070560 are provided in Table 5 and Table 10. ### Claim 27 (depends on 24) The method of claim 24, wherein the PPV is at least about 75%. ### Claim 28 (depends on 24) The method of claim 24, wherein the presence of the three or more polymorphisms is predictive for responding to the anti-TL1A antibody or antigen-binding fragment thereof with a specificity of at least about 70%. ### Claim 29 (depends on 24) The method of claim 24, wherein the three or more polymorphisms are on a plurality of genes selected from the group consisting of TL1A, THADA Armadillo Repeat Containing (THADA), XK Related 6 (XKR6), Transcription Factor (ETS1), C-Type Lectin Domain Containing 16A (CLEC16A), Suppressor Of Cytokine Signaling 1 (SOCS1), Protein Tyrosine Phosphatase Non-Receptor Type 2 (PTPN2), Inducible T Cell Costimulator Ligand (ICOSLG), Janus Kinase 2 (JAK2), Catenin Delta 2 (CTNND2), Regulator Of G Protein Signaling 7 (RGS7), RNA Binding Fox-1 Homolog 1 (RBFOX1), RNA Binding Motif Protein 17 (RBM17), 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), Ecto-NOX Disulfide-Thiol Exchanger 1 (ENOX1), Coiled-Coil Domain Containing 122 (CCDC122), Regulator Of Telomere Elongation Helicase 1 (RTEL1), TNF Receptor Superfamily Member 6b (TNFRSF6B), GLIS Family Zinc Finger 3 (GLIS3), Solute Carrier Family 1 Member 1 (SLC1A1), IKAROS Family Zinc Finger 2 (IKZF2), Long Intergenic Non-Protein Coding RNA 1031 (LINC01031), Fatty Acyl-CoA Reductase 1 (FAR1), Spondin 1 (SPON1), Long Intergenic Non-Protein Coding RNA 1150 (LINC01150), Pleckstrin Homology, MyTH4 And FERM Domain Containing H2 (PLEKHH2), Plexin A2 (PLXNA2), MIR205 Host Gene (MIR205HG), PR/SET Domain 1 (PRDM1), Autophagy Related 5 (ATG5), Long Intergenic Non-Protein Coding RNA 603 (LINC00603), Prostaglandin E Receptor 4 (PTGER4), and Myotubularin Related Protein 9 (MTMR9). ### Claim 30 (depends on 24) The method of claim 24, wherein the three or more polymorphisms comprise rs6478109. ### Claim 31 (depends on 24) The method of claim 24, wherein the three or more polymorphisms comprises a minor allele at rs6478109. ### Claim 32 (depends on 31) The method of claim 31, wherein the minor allele at rs6478109 is Adenine (A) or Thymine (T). ### Claim 33 (depends on 24) The method of claim 24, wherein the three or more polymorphisms are selected from the group consisting of rs6478109, rs7278257, rs2070557, rs7935393, rs9806914, and any proxy polymorphisms that are in linkage disequilibrium with any of the foregoing as determined with an R2 of at least 0.85. ### Claim 34 (depends on 24) The method of claim 24, wherein the three or more polymorphisms are selected from the group consisting of rs6478109, rs7935393, rs9806914, rs16901748, rs2070557, rs7278257, rs2297437, rs1892231, and any proxy polymorphisms that are in linkage disequilibrium with any of the foregoing as determined with an R2 of at least 0.85. ### Claim 35 (depends on 24) The method of claim 24, wherein the three or more polymorphisms are selected from the group consisting of rs6478109, rs16901748, rs2297437, and any proxy polymorphisms that are in linkage disequilibrium with any of the foregoing as determined with an R2 of at least 0.85. ### Claim 36 (depends on 24) The method of claim 24, wherein the three or more polymorphisms are selected from the group consisting of rs6478109, rs2070557, rs7935393, and any proxy polymorphisms that are in linkage disequilibrium with any of the foregoing as determined with an R2 of at least 0.85. ### Claim 37 (depends on 24) The method of claim 24, wherein the three or more polymorphisms are selected from the group consisting of rs6478109, rs7278257, rs7935393, and any proxy polymorphisms that are in linkage disequilibrium with any of the foregoing as determined with an R2 of at least 0.85. ### Claim 38 (depends on 24) The method of claim 24, wherein the three or more polymorphisms are selected from the group consisting of rs6478109, rs9806914, rs1892231, and any proxy polymorphisms that are in linkage disequilibrium with any of the foregoing as determined with an R2 of at least 0.85. ### Claim 39 (depends on 24) The method of claim 24, wherein the three or more polymorphisms are selected from the group consisting of rs6478109, rs7278257, rs16901748, and any proxy polymorphisms that are in linkage disequilibrium with any of the foregoing as determined with an R2 of at least 0.85. ### Claim 40 (depends on 39) The method of claim 39, wherein the proxy polymorphism for rs7278257 is rs56124762. ### Claim 41 (depends on 24) The method of claim 24, wherein the IBD is Crohn's disease (CD). ### Claim 42 (depends on 41) The method of claim 41, wherein the CD is moderate to severe CD. ### Claim 43 (depends on 24) The method of claim 24, wherein the IBD is ulcerative colitis (UC). ### Claim 44 (depends on 43) The method of claim 43, wherein the UC is moderate to severe UC. ### Claim 45 (depends on 24) The method of claim 24, wherein the three or more polymorphisms are 4, 5, 6, 7, or 8 polymorphisms.