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(12) United States Patent (10) Patent No.: US 9.482,672 B2 Gong Et Al

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(12) United States Patent (10) Patent No.: US 9.482,672 B2 Gong Et Al USOO9482672B2 (12) United States Patent (10) Patent No.: US 9.482,672 B2 Gong et al. (45) Date of Patent: Nov. 1, 2016 (54) METHODS FOR DIAGNOSING IRRITABLE 2002fO197661 A1 12/2002 Niles et al. BOWEL, SYNDROME 2003,022903.0 A1 12/2003 Theoharides 2008.OO57590 A1 3/2008 Urdea et al. (71) Applicant: NESTEC S.A., Vevey (CH) 2008/0085524 A1 4/2008 Lois (72) Inventors: Hua Gong, San Diego, CA (US); Shui FOREIGN PATENT DOCUMENTS Long Wang, San Diego, CA (US); JP 2000-065820 A 3, 2000 Sharat Singh, Rancho Santa Fe, CA JP 2003-277378. A 10, 2003 (US) JP 2007-506100 A 3, 2007 JP 2007-1864.57 A 7/2007 JP 2008-521817. A 6, 2008 (73) Assignee: Nestec S.A., Vevey (CH) JP 2008-530537 A 8, 2008 JP 2009-52.1690 A 6, 2009 (*) Notice: Subject to any disclaimer, the term of this WO O3.011812 A1 2, 2003 patent is extended or adjusted under 35 WO 2005/O29091 A2 3, 2005 U.S.C. 154(b) by 0 days. WO 2007/076411 A1 7/2005 WO 2006/06877O A1 6, 2006 WO 2006/084.299 A2 8, 2006 (21) Appl. No.: 14/222,531 WO 2008/O14414 A2 1, 2008 WO 2008/022177 A2 2, 2008 (22) Filed: Mar. 21, 2014 WO 2009,045291 A2 4/2009 (65) Prior Publication Data OTHER PUBLICATIONS US 2014/O1997.09 A1 Jul. 17, 2014 Jones et al. The Lancet, vol. 320, Issue 8308, pp. 1115-1172, Nov. 20, 1982, Abstract Only.* Related U.S. Application Data Thevarajah et al. (Practical Gastroenterology, May 2005, p. 62-74).* J.D. Wood (Gut, 2006, vol. 55, pp. 445-447, Commentaries).* (60) Division of application No. 13/352.225, filed on Jan. Gittlen et al. (Gut, 1990, vol. 31, pp. 96-99).* 17, 2012, now Pat. No. 8,709,733, which is a division Barbara, G. et al. “Activated Mast Cells in Proximity to Colonic of application No. 12/862,707, filed on Aug. 24, 2010, Nerves Correlate with Abdominal Pain in Irritable Bowel Syn now Pat. No. 8,114,616, which is a continuation of drome.” American Gastroenterological Association, 2004, vol. 126, pp. 693-702. application No. PCT/US2010/039866, filed on Jun. Clarke, G. et al., “Irritable bowel syndrome: towards biomarker 24, 2010. identification,” Trends in Molecular Medicine, Elsevier Current Trends, GB, vol. 15, No. 10, Oct. 1, 2009, pp. 478-479. (60) Provisional application No. 61/220,525, filed on Jun. Clarke, G. et al., “W2034 Polyunsaturated Fatty Acids Contribute to 25, 2009, provisional application No. 61/252,094, the Inflammatory Phenotype in Irritable Bowel Syndrome.” Gas filed on Oct. 15, 2009. troenterology, Elsevier, Philadelphia, PA. vol. 136, No. 5, May 1, 2009, pp. A-777. (51) Int. Cl. Gittlen, S.D. et al., “Raised histamine concentrations in chronic GOIN 33/53 (2006.01) cholestatic liver disease,” Gut, 1990, vol. 31, pp. 96-99. GOIN 3L/00 (2006.01) Guilarte, M. et al., “Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum.” Gut, 56(2), 203-209, GOIN 33/573 (2006.01) 2007. GOIN 33/68 (2006.01) Lembo, A.J. et al., “Use of serum biomarkers in a diagnostic test for GOIN 33/74. (2006.01) irritable bowel syndrome.” Alimentary Pharmacology & Therapeu (52) U.S. Cl. tics, vol. 29, No. 8, Apr. 1, 2009, pp. 834-842. Patnaik, Mrinal et al., “Systemic mastocytosis—A concise clinical CPC ........ G0IN 33/573 (2013.01); G0IN 33/6893 and laboratory review.” Archives of Pathology & Laboratory Medi (2013.01); G0IN 33/74 (2013.01); G0IN cine, 131(5), 784-791, 2007. 2800/065 (2013.01); G0IN 2800/56 (2013.01); Samineni, Sridhar et al., “Optimization, Comparison, and Applica Y10S 436/809 (2013.01); Y10T 436/147777 tion of Colorimetric vs. Chemiluminescence Based Indirect Sand (2015.01) wich ELISA for Measurement of Human IL-23,” Journal of (58) Field of Classification Search Immunoassay & Immunochemistry, 2006, vol. 27, pp. 183-193. CPC. A61K 38/00; A61K 39/00; G01N 33/582: (Continued) G01N 33/6893; G01N 33/54366; C07K 5700; C07K 14/705; C07K 16/18 Primary Examiner — Lisa Cook See application file for complete search history. (74) Attorney, Agent, or Firm — Kilpatrick Townsend & Stockton LLP (56) References Cited (57) ABSTRACT The invention provides an ELISA assay for the determina U.S. PATENT DOCUMENTS tion of serum mast cell B-tryptase levels using rabbit anti 5,744,319 A 4, 1998 Niles et al. tryptase as the capture antibody and alkaline phosphatase 6,867,197 B1 3/2005 Davis et al. conjugated G3 as the detecting antibody. Luminescent Sub 8, 114,616 B2 * 2/2012 Gong ................... GO1N 33,573 strate CPSD was used to enhance the assay sensitivity. Also 427/287 provided are methods for aiding in the diagnosis of irritable 8,624,002 B2 * 1/2014 Gu ......................... CO7K 16,26 bowel syndrome by detecting the serum level of B-tryptase, 530,387.1 8,709,733 B2 * 4/2014 Gong ................... GO1N 33,573 histamine and/or prostaglandin E. 435/287.9 21 Claims, 13 Drawing Sheets US 9,482.672 B2 Page 2 (56) References Cited Wang. Sherman et al., “Evaluation on the diagnostic utility of serum tryptase level in irritable bowel syndrome.” Am. J. Gastroenterol OTHER PUBLICATIONS ogy, 104(Suppl 3); S498, 2009. Taira, M. et al., "Serum B12 tryptase level as a marker of allergic Wood, J.D., "Histamine, mast cells, and the enteric nervous system airway inflammation in asthma,” Journal of Asthma, Asthma Pub- in the irritable bowel syndrome, enteritis, and food allergies.” Gut, lications Society, Ossining, New York. 39(4), 315-322, 2002. Thevarajah, Sharmela et al., “Gastrointestinal Tract and Irritable 2006, vol. 55, pp. 445-447. Bowel Syndrome.” Practical Gastroenterology, May 2005, pp. 62-74. * cited by examiner U.S. Patent Nov. 1, 2016 Sheet 1 of 13 US 9,482.672 B2 Optimize the Coating Ab Dose Response Curve of Human Tryptase with Different Amount of Coating Antibody 11000 is 4 ug/ml 10000 A 2 ug/ml 9000 V 1 lug/ml 8000 0 0.5 g/ml 7000 6000 0.03371 5000 0.07571 4000 Log Tryptase uglml FIG. 1 U.S. Patent Nov. 1, 2016 Sheet 2 of 13 US 9,482.672 B2 Optimize the Detecting Ab Dose Response Curve of Tryptase with Different Dilutions of Detecting Ab AP-G3 20000 15000 0.05956 0.1236 Log Tryptase uglml FIG. 2 U.S. Patent Nov. 1, 2016 Sheet 3 of 13 US 9,482.672 B2 Development of Sensitive Human Tryptase ELISA for the Detection of Tryptase in Human Serum Standard Curve of Tryptase ELISA 10000 7500 STD 5000 EC50 2500 0.06455 -5 -4 -3 -2 -1 O 1 Log Tryptase ng/ml) FIG. 3 U.S. Patent Nov. 1, 2016 Sheet 4 of 13 US 9,482.672 B2 Human Tryptase Concentration in Serum from Gil Control (71), IBS-C (61), and IBS-D (203) Patients. Values are expressed as mean (SEM). *p = 0.0019 for IBS-D; Mann Whitney U test. FIG. 4 U.S. Patent Nov. 1, 2016 Sheet 5 of 13 US 9,482.672 B2 Tryptase Log Value Distribution 1 3. 2) 25 Q4 6 (38 & 1 & 8 8 BSD BSA FIG. 5 U.S. Patent Nov. 1, 2016 Sheet 6 of 13 US 9,482.672 B2 Density Analysis for Tryptase Data O6BSO3 COhorts c BS) --no BSC MMM ESA, on EATY e e FIG. 6 U.S. Patent Nov. 1, 2016 Sheet 7 of 13 US 9,482.672 B2 Human tryptase concentration in serum from healthy control (n=156), IBS-D (n=209), IBS-C (n=119), and IBS-A (n=57) Values are expressed as mean (SEM), p<0.05 for IBS-D, Mann Whitney U test 8& && FIG. 7 U.S. Patent Nov. 1, 2016 Sheet 8 of 13 US 9,482.672 B2 Standard Curve of Human Tryptase 10000 8000 6000 4000 2000 O N N N N N N Q SS S. Q Log Tryptase lug/ml FIG. 8 U.S. Patent Nov. 1, 2016 Sheet 10 of 13 US 9,482.672 B2 FIG. 10 U.S. Patent Nov. 1, 2016 Sheet 11 of 13 US 9,482.672 B2 009 009), 0001, ?uffida) O O O o 009), o O u/fd eulueSH U.S. Patent Nov. 1, 2016 Sheet 12 of 13 US 9,482.672 B2 U.S. Patent Nov. 1, 2016 Sheet 13 of 13 US 9,482.672 B2 1. 200 FIG. 13 US 9,482,672 B2 1. 2 METHODS FOR DIAGNOSING RRTABLE are considered important contributors to symptom patho BOWEL, SYNDROME genesis (Quigley, Scand. J. Gastroenterol. 38(Suppl. 237): 1-8 (2003); Mayer et al., Gastroenterol., 122:2032-2048 CROSS-REFERENCES TO RELATED (2002)), this condition is now generally viewed as a disorder APPLICATIONS of the brain-gut axis. Recently, roles for enteric infection and intestinal inflammation have also been proposed. Studies This application is a divisional application of U.S. patent have documented the onset of IBS following bacteriologi application Ser. No. 13/352.225, filed Jan. 17, 2013, now cally confirmed gastroenteritis, while others have provided U.S. Pat. No. 8,709,733 B2, which application is a divisional evidence of low-grade mucosal inflammation (Spiller et al., of U.S. patent application Ser. No. 12/862,707, filed Aug. 10 Gut, 47:804-811 (2000); Dunlop et al., Gastroenterol. 125: 24, 2010, now U.S. Pat. No. 8,114,616 B2, which applica 1651-1659 (2003); Cumberland et al., Epidemiol. Infect. tion is a continuation of PCT/US2010/039866, which appli 130:453-460 (2003)) and immune activation (Gwee et al., cation claims priority to U.S.
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