Ontamalimab

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.

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.

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.

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.

Eighty percent of antibody secreting cells (ASCs) are found in the intestine, where they produce grams of immunoglobulin (Ig) A daily. immunoglobulin A is actively transcytosed into the lumen, where it plays a critical role in modulating the gut microbiota. Although loss of immune tolerance to bacterial antigens is the likely trigger of the dysregulated immune response that characterizes inflammatory bowel disease (IBD), little effort has been placed on understanding the interface between B cells, IgA, and the microbiota during initiation or progression of disease. This may be in part due to the misleading fact that IgA-deficient humans are mostly asymptomatic, likely due to redundant role of secretory (S) IgM. Intestinal B cell recruitment is critically dependent on integrin α4β7-MAdCAM-1 interactions, yet antibodies that target α4β7 (ie, vedolizumab), MAdCAM-1 (ie, ontamalimab), or both β7 integrins (α4β7 and αE [CD103] β7; etrolizumab) are in clinical use or development as IBD therapeutics. The effect of such interventions on the biology of IgA is largely unknown, yet a single dose of vedolizumab lowers SIgA levels in stool and weakens the oral immunization response to cholera vaccine in healthy volunteers. Thus, it is critical to further understand the role of these integrins for the migration of ASC and other cellular subsets during homeostasis and IBD-associated inflammation and the mode of action of drugs that interfere with this traffic. We have recently identified a subset of mature ASC that employs integrin αEβ7 to dock with intestinal epithelial cells, predominantly in the pericryptal region of the terminal ileum. This role for the integrin had not been appreciated previously, nor the αEβ7-dependent mechanism of IgA transcytosis that it supports. Furthermore, we find that B cells more than T cells are critically dependent on α4β7-MAdCAM-1 interactions; thus MAdCAM-1 blockade and integrin-β7 deficiency counterintuitively hasten colitis in interleukin-10-deficient mice. In both cases, de novo recruitment of IgA ASC to the intestinal lamina propria is compromised, leading to bacterial overgrowth, dysbiosis, and lethal colitis. Thus, despite the safe and effective use of anti-integrin antibodies in patients with IBD, much remains to be learned about their various cell targets.