Association Between Response to Etrolizumab and Expression of Integrin αE and Granzyme A in Colon Biopsies of Patients With Ulcerative Colitis.
Gaik W Tew, Jason A Hackney, Deena Gibbons, Christopher A Lamb, Diana Luca, Jackson G Egen, Lauri Diehl, Jeff Eastham Anderson, Severine Vermeire, John C Mansfield, Brian G Feagan, Julian Panes, Daniel C Baumgart, Stefan Schreiber, Iris Dotan, William J Sandborn, John A Kirby, Peter M Irving, Gert De Hertogh, Gert A Van Assche, Paul Rutgeerts, Sharon O'Byrne, Adrian Hayday, Mary E Keir
Author Information
Gaik W Tew: Genentech Research and Early Development, South San Francisco, California.
Jason A Hackney: Genentech Research and Early Development, South San Francisco, California.
Deena Gibbons: King's College, London, United Kingdom.
Christopher A Lamb: Newcastle University, Newcastle upon Tyne, United Kingdom.
Diana Luca: Genentech Research and Early Development, South San Francisco, California.
Jackson G Egen: Genentech Research and Early Development, South San Francisco, California.
Lauri Diehl: Genentech Research and Early Development, South San Francisco, California.
Jeff Eastham Anderson: Genentech Research and Early Development, South San Francisco, California.
Severine Vermeire: University of Leuven, Leuven, Belgium.
John C Mansfield: Newcastle University, Newcastle upon Tyne, United Kingdom.
Brian G Feagan: University of Western Ontario, London, Ontario, Canada.
Julian Panes: 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.
Daniel C Baumgart: Charité Medical School, Humboldt-University of Berlin, Germany.
Stefan Schreiber: Department of Medicine I, University Hospital Schleswig-Holstein, Christian Albrechts University, Kiel, Germany.
Iris Dotan: Inflammatory Bowel Disease Center, Department of Gastroenterology and Liver Diseases, Tel Aviv Medical Center and Sackler Faculty of Medicine, Tel Aviv, Israel.
William J Sandborn: University of California San Diego, La Jolla, California.
John A Kirby: Newcastle University, Newcastle upon Tyne, United Kingdom.
Peter M Irving: King's College, London, United Kingdom.
Gert De Hertogh: University of Leuven, Leuven, Belgium.
Gert A Van Assche: University of Leuven, Leuven, Belgium; University of Toronto, Toronto, Ontario, Canada.
Paul Rutgeerts: University of Leuven, Leuven, Belgium.
Sharon O'Byrne: Genentech Research and Early Development, South San Francisco, California.
Adrian Hayday: King's College, London, United Kingdom.
Mary E Keir: Genentech Research and Early Development, South San Francisco, California. Electronic address: keir.mary@gene.com.
BACKGROUND & AIMS: 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.
