title: Association Between Response to Etrolizumab and Expression of Integrin αE and Granzyme A in Colon Biopsies of Patients With Ulcerative Colitis.
abstract: OBJECTIVE
  Etrolizumab is a humanized monoclonal antibody against the β7 integrin subunit that has shown efficacy vs placebo in patients with moderate to severely active ulcerative colitis (UC). Patients with colon tissues that expressed high levels of the integrin αE gene (ITGAE) appeared to have the best response. We compared differences in colonic expression of ITGAE and other genes between patients who achieved clinical remission with etrolizumab vs those who did.
  
  
  METHODS
  We performed a retrospective analysis of data collected from 110 patients with UC who participated in a phase 2 placebo-controlled trial of etrolizumab, as well as from 21 patients with UC or without inflammatory bowel disease (controls) enrolled in an observational study at a separate site. Colon biopsies were collected from patients in both studies and analyzed by immunohistochemistry and gene expression profiling. Mononuclear cells were isolated and analyzed by flow cytometry. We identified biomarkers associated with response to etrolizumab. In the placebo-controlled trial, clinical remission was defined as total Mayo Clinic Score ≤2, with no individual subscore >1, and mucosal healing was defined as endoscopic score ≤1.
  
  
  RESULTS
  Colon tissues collected at baseline from patients who had a clinical response to etrolizumab expressed higher levels of T-cell-associated genes than patients who did not respond (P < .05). Colonic CD4(+) integrin αE(+) cells from patients with UC expressed higher levels of granzyme A messenger RNA (GZMA mRNA) than CD4(+) αE(-) cells (P < .0001); granzyme A and integrin αE protein were detected in the same cells. Of patients receiving 100 mg etrolizumab, a higher proportion of those with high levels of GZMA mRNA (41%) or ITGAE mRNA (38%) than those with low levels of GZMA (6%) or ITGAE mRNA (13%) achieved clinical remission (P < .05) and mucosal healing (41% GZMA(high) vs 19% GZMA(low) and 44% ITGAE(high) vs 19% ITGAE(low)). Compared with ITGAE(low) and GZMA(low) patients, patients with ITGAE(high) and GZMA(high) had higher baseline numbers of epithelial crypt-associated integrin αE(+) cells (P < .01 for both), but a smaller number of crypt-associated integrin αE(+) cells after etrolizumab treatment (P < .05 for both). After 10 weeks of etrolizumab treatment, expression of genes associated with T-cell activation and genes encoding inflammatory cytokines decreased by 40%-80% from baseline (P < .05) in patients with colon tissues expressing high levels of GZMA at baseline.
  
  
  CONCLUSIONS
  Levels of GZMA and ITGAE mRNAs in colon tissues can identify patients with UC who are most likely to benefit from etrolizumab; expression levels decrease with etrolizumab administration in biomarker(high) patients. Larger, prospective studies of markers are needed to assess their clinical value.
authors.affiliation: Genentech Research and Early Development, South San Francisco, California.
authors.forename: Gaik W
authors.initials: GW
authors.lastname: Tew
authors.affiliation: Genentech Research and Early Development, South San Francisco, California.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Hackney
authors.affiliation: King's College, London, United Kingdom.
authors.forename: Deena
authors.initials: D
authors.lastname: Gibbons
authors.affiliation: Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Lamb
authors.affiliation: Genentech Research and Early Development, South San Francisco, California.
authors.forename: Diana
authors.initials: D
authors.lastname: Luca
authors.affiliation: Genentech Research and Early Development, South San Francisco, California.
authors.forename: Jackson G
authors.initials: JG
authors.lastname: Egen
authors.affiliation: Genentech Research and Early Development, South San Francisco, California.
authors.forename: Lauri
authors.initials: L
authors.lastname: Diehl
authors.affiliation: Genentech Research and Early Development, South San Francisco, California.
authors.forename: Jeff
authors.initials: J
authors.lastname: Eastham Anderson
authors.affiliation: University of Leuven, Leuven, Belgium.
authors.forename: Severine
authors.initials: S
authors.lastname: Vermeire
authors.affiliation: Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: John C
authors.initials: JC
authors.lastname: Mansfield
authors.affiliation: University of Western Ontario, London, Ontario, Canada.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Feagan
authors.affiliation: Hospital Clinic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain.
authors.forename: Julian
authors.initials: J
authors.lastname: Panes
authors.affiliation: Charité Medical School, Humboldt-University of Berlin, Germany.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Baumgart
authors.affiliation: Department of Medicine I, University Hospital Schleswig-Holstein, Christian Albrechts University, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.affiliation: Inflammatory Bowel Disease Center, Department of Gastroenterology and Liver Diseases, Tel Aviv Medical Center and Sackler Faculty of Medicine, Tel Aviv, Israel.
authors.forename: Iris
authors.initials: I
authors.lastname: Dotan
authors.affiliation: University of California San Diego, La Jolla, California.
authors.forename: William J
authors.initials: WJ
authors.lastname: Sandborn
authors.affiliation: Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: John A
authors.initials: JA
authors.lastname: Kirby
authors.affiliation: King's College, London, United Kingdom.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Irving
authors.affiliation: University of Leuven, Leuven, Belgium.
authors.forename: Gert
authors.initials: G
authors.lastname: De Hertogh
authors.affiliation: University of Leuven, Leuven, Belgium; University of Toronto, Toronto, Ontario, Canada.
authors.forename: Gert A
authors.initials: GA
authors.lastname: Van Assche
authors.affiliation: University of Leuven, Leuven, Belgium.
authors.forename: Paul
authors.initials: P
authors.lastname: Rutgeerts
authors.affiliation: Genentech Research and Early Development, South San Francisco, California.
authors.forename: Sharon
authors.initials: S
authors.lastname: O'Byrne
authors.affiliation: King's College, London, United Kingdom.
authors.forename: Adrian
authors.initials: A
authors.lastname: Hayday
authors.affiliation: Genentech Research and Early Development, South San Francisco, California. Electronic address: keir.mary@gene.com.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Keir
mesh_terms: D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001706:Biopsy; D017322:Clinical Trials, Phase II as Topic; D003093:Colitis, Ulcerative / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D003106:Colon / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D005765:Gastrointestinal Agents / Q000627:therapeutic use*; D020869:Gene Expression Profiling / Q000379:methods; D053804:Granzymes / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D039001:Integrin alpha Chains / Q000235:genetics / Q000378:metabolism*; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000378:metabolism; D016032:Randomized Controlled Trials as Topic; D012074:Remission Induction; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D014945:Wound Healing / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D005765:Gastrointestinal Agents; D039001:Integrin alpha Chains; D012333:RNA, Messenger; C091367:alpha E integrins; D053804:Granzymes; C509212:GZMA protein, human; C559198:etrolizumab
keywords: Anti-Integrin; IBD Drug; Personalized Medicine; Response to Therapy