Background/Purpose: R-2487 is a novel, orally delivered, synthetic biology-based immunotherapy that utilizes Lactococcus lactis as a carrier vehicle to deliver Colonization Factor Antigen I (CFA/I) to harness immune control via intestinal immune architecture. CFA/I is a recently identified bacterial adhesin, which engages dendritic cells (DCs) and promote systemic regulatory T cell (Treg) expansion. Designed to correct the dysfunctional DC–Treg axis underlying autoimmunity, R-2487 has demonstrated robust immunomodulatory activity and disease protection in the preclinical model of collagen-induced arthritis. These studies showed that oral administration of R-2487 expanded Tregs, reduced inflammatory cytokines, and improved disease outcomes via bystander tolerance in an antigen-independent manner. R-2487 was evaluated in a first-in-human Phase I clinical trial in patients with active Rheumatoid Arthritis (RA). Here, we report preliminary safety, immunological activity, and clinical efficacy data from that clinical study.

Methods: This open-label study enrolled adult patients with RA across three dosing cohorts. Clinical endpoints included DAS28-CRP, CDAI, and RAPID3 scores. Immunophenotyping assessed Treg expansion via flow cytometry. Safety was monitored through adverse event reporting and laboratory values.

Results: R-2487 was well tolerated across all cohorts with no serious adverse events or clinically meaningful laboratory abnormalities. The majority of subjects demonstrated peripheral Treg expansion, confirming the expected mechanism of action. Clinically, patients showed improvement in disease activity as early as 2 weeks post-treatment. Eleven out of 12 subjects reached low disease activity or remission per DAS28-CRP. Among Cohort 2 and 3, all the subjects exhibited robust reduction in CDAI scores (≥6 points) as well as an improvement in the RAPID3 score ( >3.6 points). Upregulation of Treg populations correlated with clinical improvement and supports the hypothesized bystander tolerance mechanism.

Conclusion: Oral administration of R-2487 was safe, well tolerated, and induced meaningful improvements in RA disease activity. The observed peripheral Treg expansion suggests that R-2487 rebalances immune homeostasis through a tolerogenic DC–Treg pathway, illustrating the novel mechanism of action of R-2487. These findings validate the utility of a synthetic biology approach to immune modulation in autoimmune disease, highlight the potential of leveraging microbiome-associated immune control mechanisms, and support continued development of R-2487 in RA.

« Back to ACR Convergence 2025

ACR Meeting Abstracts - https://acrabstracts.org/abstract/r-2487-a-synthetic-biology-based-oral-immunotherapy-promotes-treg-mediated-immune-rebalancing-and-reduces-disease-activity-in-rheumatoid-arthritis-patients/