提示: 手机请竖屏浏览!

抗唾液酸结合性免疫球蛋白样凝集素-8(Siglec-8)抗体治疗嗜酸细胞性胃炎和十二指肠炎
Anti–Siglec-8 Antibody for Eosinophilic Gastritis and Duodenitis


Evan S. Dellon ... 其他 • 2020.10.22
相关阅读
• 嗜酸细胞性胃炎和十二指肠炎的新疗法

摘要


背景

嗜酸细胞性胃炎和十二指肠炎的特征包括胃肠道黏膜嗜酸性粒细胞增多、慢性症状、生活质量下降和缺乏适当疗法。肥大细胞活性可能对疾病的发病机制有促进作用。AK002(lirentelimab)是抗Siglec-8抗体,可减少嗜酸性粒细胞和抑制肥大细胞,并且已在动物模型中表现出治疗嗜酸细胞性胃炎和十二指肠炎的潜力。

 

方法

在这项2期试验中,我们以1∶1∶1的比例将有症状的嗜酸细胞性胃炎、嗜酸细胞性十二指肠炎或者这两种疾病的成人患者随机分组,三组分别以每月1次的频率接受4次小剂量AK002、大剂量AK002或安慰剂输入。主要终点是胃肠道嗜酸性粒细胞计数从基线至末次给药后2周的变化;为了提高统计学功效,我们在安慰剂组与合并AK002组鼻尖比较了这一终点。次要终点包括对治疗产生应答(症状总分降低>30%并且胃肠道嗜酸性粒细胞计数减少>75%)和症状总分的变化。

 

结果

在被随机分组的65例患者中,43例被分配接受AK002治疗,22例被分配接受安慰剂治疗。在合并AK002组中,胃肠道嗜酸性粒细胞计数的平均变化百分比为-86%,而安慰剂组为9%(最小二乘均值差异,-98个百分点;95%置信区间[CI],-121~-76;P<0.001)。63%接受AK002治疗的患者和5%接受安慰剂治疗的患者对治疗产生了应答(差异,58个百分点;95% CI,36~74;P<0.001)。在AK002组和安慰剂组中,症状总分的平均变化分别为-48%和-22%(最小二乘均值差异,-26个百分点;95% CI,-44~-9;P=0.004)。AK002组的不良事件与安慰剂组的不良事件相似,唯一例外的是AK002组中发生轻度至中度输液相关反应的患者百分比较高(合并AK002组和安慰剂组的发生率分别为60%和23%)。

 

结论

在嗜酸细胞性胃炎或十二指肠炎患者中,AK002减少了胃肠道嗜酸性粒细胞,并减轻了症状。AK002组的输液相关反应发生率高于安慰剂组(由Allakos资助,ENIGMA在ClinicalTrials.gov注册号为NCT03496571)。





作者信息

Evan S. Dellon, M.D., M.P.H., Kathryn A. Peterson, M.D., Joseph A. Murray, M.D., Gary W. Falk, M.D., Nirmala Gonsalves, M.D., Mirna Chehade, M.D., M.P.H., Robert M. Genta, M.D., John Leung, M.D., Paneez Khoury, M.D., Amy D. Klion, M.D., Sabine Hazan, M.D., Michael Vaezi, M.D., Adam C. Bledsoe, M.D., Sandy R. Durrani, M.D., Chao Wang, Ph.D., Camilla Shaw, B.S.N., R.N., Alan T. Chang, B.S., Bhupinder Singh, M.D., Amol P. Kamboj, M.D., Henrik S. Rasmussen, M.D., Ph.D., Marc E. Rothenberg, M.D., Ph.D., and Ikuo Hirano, M.D.
From the University of North Carolina, Chapel Hill (E.S.D.); the University of Utah, Salt Lake City (K.A.P.); Mayo Clinic Rochester, Rochester, MN (J.A.M., A.C.B.); the University of Pennsylvania Perelman School of Medicine, Philadelphia (G.W.F.); Northwestern University, Chicago (N.G., I.H.); the Icahn School of Medicine at Mount Sinai, New York (M.C.); Baylor College of Medicine, Houston (R.M.G.); Tufts University, Boston (J.L.); the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (P.K., A.D.K.); Ventura Clinical Trials, Ventura (S.H.), and Allakos, Redwood City (C.S., A.T.C., B.S., A.P.K., H.S.R.) — both in California; Vanderbilt University, Nashville (M.V.); the Division of Allergy and Immunology, Cincinnati Children’s Hospital, University of Cincinnati College of Medicine, Cincinnati (S.R.D., M.E.R.); and Pharma Data Associates, Piscataway, NJ (C.W.). Address reprint requests to Dr. Dellon at CB #7080, Bioinformatics Bldg., 130 Mason Farm Rd., Chapel Hill, NC 27599-7080, or at edellon@med.unc.edu.

 

参考文献

1. Gonsalves N. Eosinophilic gastrointestinal disorders. Clin Rev Allergy Immunol 2019;57:272-285.

2. Egan M, Furuta GT. Eosinophilic gastrointestinal diseases beyond eosinophilic esophagitis. Ann Allergy Asthma Immunol 2018;121:162-167.

3. Fleischer DM, Atkins D. Evaluation of the patient with suspected eosinophilic gastrointestinal disease. Immunol Allergy Clin North Am 2009;29:53-63.

4. Caldwell JM, Collins MH, Stucke EM, et al. Histologic eosinophilic gastritis is a systemic disorder associated with blood and extragastric eosinophilia, TH2 immunity, and a unique gastric transcriptome. J Allergy Clin Immunol 2014;134:1114-1124.

5. Youngblood BA, Brock EC, Leung J, et al. AK002, a humanized sialic acid-binding immunoglobulin-like lectin-8 antibody that induces antibody-dependent cell-mediated cytotoxicity against human eosinophils and inhibits mast cell-mediated anaphylaxis in mice. Int Arch Allergy Immunol 2019;180:91-102.

6. Hsu Blatman KS, Gonsalves N, Hirano I, Bryce PJ. Expression of mast cell-associated genes is upregulated in adult eosinophilic esophagitis and responds to steroid or dietary therapy. J Allergy Clin Immunol 2011;127(5):1307.e3-1308.e3.

7. Abonia JP, Blanchard C, Butz BB, et al. Involvement of mast cells in eosinophilic esophagitis. J Allergy Clin Immunol 2010;126:140-149.

8. Bolton SM, Kagalwalla AF, Arva NC, et al. Mast cell infiltration is associated with persistent symptoms and endoscopic abnormalities despite resolution of eosinophilia in pediatric eosinophilic esophagitis. Am J Gastroenterol 2020;115:224-233.

9. Niranjan R, Mavi P, Rayapudi M, Dynda S, Mishra A. Pathogenic role of mast cells in experimental eosinophilic esophagitis. Am J Physiol Gastrointest Liver Physiol 2013;304:G1087-G1094.

10. Dellon ES, Chen X, Miller CR, et al. Tryptase staining of mast cells may differentiate eosinophilic esophagitis from gastroesophageal reflux disease. Am J Gastroenterol 2011;106:264-271.

11. Reed CC, Genta RM, Youngblood BA, Wechsler JB, Dellon ES. Mast cell and eosinophil counts in gastric and duodenal biopsies from patients with and without eosinophilic gastroenteritis. Clin Gastroenterol Hepatol 2020 August 12 (Epub ahead of print).

12. Pesek RD, Reed CC, Muir AB, et al. Increasing rates of diagnosis, substantial co-occurrence, and variable treatment patterns of eosinophilic gastritis, gastroenteritis, and colitis based on 10-year data across a multicenter consortium. Am J Gastroenterol 2019;114:984-994.

13. Reed C, Woosley JT, Dellon ES. Clinical characteristics, treatment outcomes, and resource utilization in children and adults with eosinophilic gastroenteritis. Dig Liver Dis 2015;47:197-201.

14. Ko HM, Morotti RA, Yershov O, Chehade M. Eosinophilic gastritis in children: clinicopathological correlation, disease course, and response to therapy. Am J Gastroenterol 2014;109:1277-1285.

15. Talley NJ, Shorter RG, Phillips SF, Zinsmeister AR. Eosinophilic gastroenteritis: a clinicopathological study of patients with disease of the mucosa, muscle layer, and subserosal tissues. Gut 1990;31:54-58.

16. Chang JY, Choung RS, Lee RM, et al. A shift in the clinical spectrum of eosinophilic gastroenteritis toward the mucosal disease type. Clin Gastroenterol Hepatol 2010;8:669-675.

17. Jensen ET, Martin CF, Kappelman MD, Dellon ES. Prevalence of eosinophilic gastritis, gastroenteritis, and colitis: estimates from a national administrative database. J Pediatr Gastroenterol Nutr 2016;62:36-42.

18. Alhmoud T, Hanson JA, Parasher G. Eosinophilic gastroenteritis: an underdiagnosed condition. Dig Dis Sci 2016;61:2585-2592.

19. Chehade M, Gehman LT, Singh B, Rasmussen HS. The tortuous path to diagnosis (Dx) of eosinophilic gastritis and eosinophilic gastroenteritis (EG/EGE) in the United States: a real-world, population-based study. Allergy 2019;74(S106):375-375. abstract.

20. Licari A, Votto M, Scudeller L, et al. Epidemiology of nonesophageal eosinophilic gastrointestinal diseases in symptomatic patients: a systematic review and meta-analysis. J Allergy Clin Immunol Pract 2020;8(6):1994.e2-2003.e2.

21. Hiremath G, Kodroff E, Strobel MJ, et al. Individuals affected by eosinophilic gastrointestinal disorders have complex unmet needs and frequently experience unique barriers to care. Clin Res Hepatol Gastroenterol 2018;42:483-493.

22. Bedell A, Taft T, Craven MR, Guadagnoli L, Hirano I, Gonsalves N. Impact on health-related quality of life in adults with eosinophilic gastritis and gastroenteritis: a qualitative assessment. Dig Dis Sci 2018;63:1148-1157.

23. Kiwamoto T, Kawasaki N, Paulson JC, Bochner BS. Siglec-8 as a drugable target to treat eosinophil and mast cell-associated conditions. Pharmacol Ther 2012;135:327-336.

24. Youngblood BA, Brock EC, Leung J, et al. Siglec-8 antibody reduces eosinophils and mast cells in a transgenic mouse model of eosinophilic gastroenteritis. JCI Insight 2019;4(19):e126219-e126219.

25. Legrand F, Cao Y, Wechsler JB, et al. Sialic acid-binding immunoglobulin-like lectin (Siglec) 8 in patients with eosinophilic disorders: receptor expression and targeting using chimeric antibodies. J Allergy Clin Immunol 2019;143(6):2227.e10-2237.e10.

26. Kikly KK, Bochner BS, Freeman SD, et al. Identification of SAF-2, a novel Siglec expressed on eosinophils, mast cells, and basophils. J Allergy Clin Immunol 2000;105:1093-1100.

27. Altrichter S, Staubach P, Pasha M, et al. Clinical activity of AK002, an anti-Siglec-8 antibody, in multiple forms of uncontrolled chronic urticaria. Ann Allergy Asthma Immunol 2019;123:Suppl:S27-S28. abstract.

28. Levine T, Tauber J, Nguyen Q, et al. Clinical activity of AK002, an anti-Siglec-8 antibody, in severe allergic conjunctivitis and comorbid atopic diseases. Ann Allergy Asthma Immunol 2019;123:Suppl:S17-S17. abstract.

29. Collins MH. Histopathologic features of eosinophilic esophagitis and eosinophilic gastrointestinal diseases. Gastroenterol Clin North Am 2014;43:257-268.

30. Patient-reported outcome measures: use in medical product development to support labeling claims: guidance for industry. Silver Spring, MD: Food and Drug Administration, December 2009.

31. Chan IS, Zhang Z. Test-based exact confidence intervals for the difference of two binomial proportions. Biometrics 1999;55:1202-1209.

32. Busse WW, Katial R, Gossage D, et al. Safety profile, pharmacokinetics, and biologic activity of MEDI-563, an anti-IL-5 receptor alpha antibody, in a phase I study of subjects with mild asthma. J Allergy Clin Immunol 2010;125(6):1237.e2-1244.e2.

33. Levin AS, Otani IM, Lax T, Hochberg E, Banerji A. Reactions to rituximab in an outpatient infusion center: a 5-year review. J Allergy Clin Immunol Pract 2017;5(1):107.e1-113.e1.

34. Siewert E, Lammert F, Koppitz P, Schmidt T, Matern S. Eosinophilic gastroenteritis with severe protein-losing enteropathy: successful treatment with budesonide. Dig Liver Dis 2006;38:55-59.

35. Tan AC, Kruimel JW, Naber TH. Eosinophilic gastroenteritis treated with non-enteric-coated budesonide tablets. Eur J Gastroenterol Hepatol 2001;13:425-427.

36. Foroughi S, Foster B, Kim N, et al. Anti-IgE treatment of eosinophil-associated gastrointestinal disorders. J Allergy Clin Immunol 2007;120:594-601.

37. Prussin C, James SP, Huber MM, Klion AD, Metcalfe DD. Pilot study of anti-IL-5 in eosinophilic gastroenteritis. J Allergy Clin Immunol 2003;111:Suppl 1:S275-S275. abstract.

38. Ramsay DB, Stephen S, Borum M, Voltaggio L, Doman DB. Mast cells in gastrointestinal disease. Gastroenterol Hepatol (N Y) 2010;6:772-777.

服务条款 | 隐私政策 | 联系我们