Gaik W Tew1, Jason A Hackney1, Deena Gibbons2, Christopher A Lamb3, Diana Luca1, Jackson G Egen1, Lauri Diehl1, Jeff Eastham Anderson1, Severine Vermeire4, John C Mansfield3, Brian G Feagan5, Julian Panes6, Daniel C Baumgart7, Stefan Schreiber8, Iris Dotan9, William J Sandborn10, John A Kirby3, Peter M Irving2, Gert De Hertogh4, Gert A Van Assche11, Paul Rutgeerts4, Sharon O'Byrne1, Adrian Hayday2, Mary E Keir12. 1. Genentech Research and Early Development, South San Francisco, California. 2. King's College, London, United Kingdom. 3. Newcastle University, Newcastle upon Tyne, United Kingdom. 4. University of Leuven, Leuven, Belgium. 5. University of Western Ontario, London, Ontario, Canada. 6. 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. 7. Charité Medical School, Humboldt-University of Berlin, Germany. 8. Department of Medicine I, University Hospital Schleswig-Holstein, Christian Albrechts University, Kiel, Germany. 9. Inflammatory Bowel Disease Center, Department of Gastroenterology and Liver Diseases, Tel Aviv Medical Center and Sackler Faculty of Medicine, Tel Aviv, Israel. 10. University of California San Diego, La Jolla, California. 11. University of Leuven, Leuven, Belgium; University of Toronto, Toronto, Ontario, Canada. 12. Genentech Research and Early Development, South San Francisco, California. Electronic address: keir.mary@gene.com.
Abstract
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.
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.
Authors: Jonathan L Digby-Bell; Raja Atreya; Giovanni Monteleone; Nick Powell Journal: Nat Rev Gastroenterol Hepatol Date: 2019-11-25 Impact factor: 46.802
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Authors: Mark T Osterman; Kelli L VanDussen; Ilyssa O Gordon; Elisabeth M Davis; Katherine Li; Kate Simpson; Matthew Ciorba; Sarah C Glover; Bincy Abraham; Xueyan Guo; Eric U Yee; Felicia D Allard; Jacqueline G Perrigoue; Brian Claggett; Bo Shen; Thaddeus S Stappenbeck; Julia J Liu Journal: Inflamm Bowel Dis Date: 2021-04-15 Impact factor: 5.325