Activation of LANCL2 by BT-11 Ameliorates IBD by Supporting Regulatory T Cell Stability Through Immunometabolic Mechanisms

Leber, Andrew; Hontecillas, Raquel; Zoccoli-Rodriguez, Victoria; Bassaganya‐Riera, Josep

doi:10.1093/ibd/izy167

Cited by 19 publications

(40 citation statements)

References 54 publications

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“…Additionally, neither BT-11 directly or BT-11-treated Tregs induced greater apoptosis in CD4 + T cells (Supplemental Fig. 4), although previous data support a decrease in proliferation in CD4 + T cells cultured with BT-11-treated Tregs (11).…”

Section: Bt-11 Establishes Changes In Immune Response Through Cell Comentioning

confidence: 76%

“…The effects of LANCL2 activation have been linked to secondary messenger signaling (17), cellular metabolism (18,19), cell survival (20,21), and immune effects (13,14). BT-11 has also been confirmed to modulate cytokine profiles of PBMCs and LPMCs from CD and UC patients, in line with the in vivo effects observed in animal models (11). In addition to efficacy, BT-11 has also been identified to possess a benign safety profile up to tested limit doses of 1000 mg/kg and unique pharmacokinetics with high levels of localization to the GI tract when dosed orally (22).…”

mentioning

confidence: 76%

“…BT-11 is a novel oral, gut-restricted, small-molecule therapeutic for IBD, with limited systemic exposure that targets the LANCL2 pathway. BT-11 is safe and effective (22,24) with a no observed adverse effect level .1000 mg/kg in 3-mo good laboratory practice toxicology studies in rats and dogs and is more effective than current IBD therapeutics in nonclinical models (11). The U.S. Food and Drug Administration has approved BT-11 as an investigational new drug (IND) for CD (IND 128490) and UC (IND 138071), it has successfully completed phase 1 human clinical testing, and it will enter phase II clinical testing in UC and CD in 2019.…”

Section: Discussionmentioning

confidence: 99%

“…This strategy of increased generation and stability of Tregs is one of the proposed mechanisms of BT-11, a novel lanthionine synthetase C-like 2 (LANCL2)-targeting immunometabolic therapeutic (11). BT-11 is an orally active, gut restricted, small-molecule first-in-class therapeutic that is stable in the gastrointestinal (GI) tract and induces immunological changes when dosed orally.…”

mentioning

confidence: 99%

“…BT-11 is an orally active, gut restricted, small-molecule first-in-class therapeutic that is stable in the gastrointestinal (GI) tract and induces immunological changes when dosed orally. Through the LANCL2 pathway, we have previously elucidated that BT-11 modulates late-stage glycolysis in immune cells to bias cellular metabolism toward a profile of increased oxidative phosphorylation and decrease lactate production associated with regulatory function (11). BT-11 was discovered through innovative medical chemistry Landos Biopharma, Inc., Blacksburg, VA 24060 ORCID: 0000-0002-3837-3000 (J.C.).…”

mentioning

confidence: 99%

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Oral Treatment with BT-11 Ameliorates Inflammatory Bowel Disease by Enhancing Regulatory T Cell Responses in the Gut

Leber¹,

Hontecillas²,

Zoccoli-Rodriguez³

et al. 2019

The Journal of Immunology

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Inflammatory bowel disease (IBD) is an expanding autoimmune disease afflicting millions that remains difficult to treat due to the accumulation of multiple immunological changes. BT-11 is an investigational new drug for IBD that is orally active, gut restricted, and targets the lanthionine synthetase C-like 2 immunometabolic pathway. CD25+ FOXP3+ CD4+ T cells are increased locally within the colon of BT-11–treated mice in Citrobacter rodentium and IL-10−/− mouse models of colitis. The maintained efficacy of BT-11 in the absence of IL-10 combined with the loss of efficacy when direct cell–cell interactions are prevented suggest that the regulatory T cell (Treg)–related elements of suppression are cell contact–mediated. When PD-1 is inhibited, both in vitro and in vivo, the efficacy of BT-11 is reduced, validating this assertion. The depletion of CD25+ cells in vivo abrogated the retention of therapeutic efficacy postdiscontinuation of treatment, indicating that Tregs are implicated in the maintenance of tolerance mediated by BT-11. Furthermore, the involvement of CD25 suggested a role of BT-11 in IL-2 signaling. Cotreatment with BT-11 and IL-2 greatly enhances the differentiation of CD25+ FOXP3+ cells from naive CD4+ T cells relative to either alone. BT-11 enhances phosphorylation of STAT5, providing a direct linkage to the regulation of FOXP3 transcription. Notably, when STAT5 is inhibited, the effects of BT-11 on the differentiation of Tregs are blocked. BT-11 effectively enhances the IL-2/STAT5 signaling axis to induce the differentiation and stability of CD25+ FOXP3+ cells in the gastrointestinal mucosa to support immunoregulation and immunological tolerance in IBD.

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Section: Bt-11 Establishes Changes In Immune Response Through Cell Comentioning

confidence: 76%