Differential Effects of Ontamalimab Versus Vedolizumab on Immune Cell Trafficking in Intestinal Inflammation and Inflammatory Bowel Disease

Schulze L, Becker E, Dedden M, Liu L, Van Passen C, Mohamed Abdou M, Müller T, Wiendl M, Ullrich K, Atreya I, Leppkes M, Ekici AB, Kirchner P, Stürzl M, Sexton D, Palliser D, Atreya R, Siegmund B, Neurath M, Zundler S (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Journal of Crohns & Colitis Elsevier

Book Volume: 17

Pages Range: 1817-1832

Journal Issue: 11

DOI: 10.1093/ecco-jcc/jjad088

Abstract

Background and Aims: The anti-MAdCAM-1 antibody ontamalimab demonstrated efficacy in a phase II trial in ulcerative colitis and results of early terminated phase III trials are pending, but its precise mechanisms of action are still unclear. Thus, we explored the mechanisms of action of ontamalimab and compared it to the anti-α4β7 antibody vedolizumab. Methods: We studied MAdCAM-1 expression with RNA sequencing and immunohistochemistry. The mechanisms of action of ontamalimab were assessed with fluorescence microscopy, dynamic adhesion and rolling assays. We performed in vivo cell trafficking studies in mice and compared ontamalimab and vedolizumab surrogate [-s] antibodies in experimental models of colitis and wound healing. We analysed immune cell infiltration under anti-MAdCAM-1 and anti-α4β7 treatment by single-cell transcriptomics and studied compensatory trafficking pathways. Results: MAdCAM-1 expression was increased in active inflammatory bowel disease. Binding of ontamalimab to MAdCAM-1 induced the internalization of the complex. Functionally, ontamalimab blocked T cell adhesion similar to vedolizumab, but also inhibited L-selectin-dependent rolling of innate and adaptive immune cells. Despite conserved mechanisms in mice, the impact of ontamalimab-s and vedolizumab-s on experimental colitis and wound healing was similar. Single-cell RNA sequencing demonstrated enrichment of ontamalimab-s-treated lamina propria cells in specific clusters, and in vitro experiments indicated that redundant adhesion pathways are active in these cells. Conclusions: Ontamalimab has unique and broader mechanisms of action compared to vedolizumab. However, this seems to be compensated for by redundant cell trafficking circuits and leads to similar preclinical efficacy of anti-α4β7 and anti-MAdCAM-1 treatment. These results will be important for the interpretation of pending phase III data.

Authors with CRIS profile

Lisa Schulze Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Emily Becker Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Mark Dedden Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Lijuan Liu Lehrstuhl für Innere Medizin I Chiara Van Passen Department of Surgery Mariam Mohamed Abdou Department of Surgery Tanja Müller Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Maximilian Wiendl Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Karen Ullrich Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Imke Atreya Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Moritz Leppkes Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Arif Bülent Ekici Lehrstuhl für Humangenetik Michael Stürzl Professur für Molekulare und Experimentelle Chirurgie Raja Atreya Professur für Translationale Immunforschung bei chronisch entzündlichen Darmerkrankungen (Heisenberg-Professur) Markus Neurath Lehrstuhl für Innere Medizin I Sebastian Zundler Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology

Involved external institutions

Takeda Pharmaceutical Company Limited JP Japan (JP) Charité - Universitätsmedizin Berlin DE Germany (DE)

How to cite

APA:

Schulze, L., Becker, E., Dedden, M., Liu, L., Van Passen, C., Mohamed Abdou, M.,... Zundler, S. (2023). Differential Effects of Ontamalimab Versus Vedolizumab on Immune Cell Trafficking in Intestinal Inflammation and Inflammatory Bowel Disease. Journal of Crohns & Colitis, 17(11), 1817-1832. https://doi.org/10.1093/ecco-jcc/jjad088

MLA:

Schulze, Lisa, et al. "Differential Effects of Ontamalimab Versus Vedolizumab on Immune Cell Trafficking in Intestinal Inflammation and Inflammatory Bowel Disease." Journal of Crohns & Colitis 17.11 (2023): 1817-1832.

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