RA Clinical Trial and Future Therapy

What is R-2487?

An oral probiotic to treat RA

What clinical trial phase is R-2487 currently in?

Phase 1 clinical trials, being done by Rise Therapeutics

What is the purpose of R-2487 in treating RA?

R-2487 contains an engineered strain of Lactococcus lactis. The bacteria have been genetically modified to express Colonization Factor Antigen I (CFA/I).

The goal is to use CFA/I to promote regulatory immune responses, particularly the generation of CD4⁺ Tregs and production of anti-inflammatory cytokines such as IL-10, IL-35, and TGF-β.

The rationale is that increasing immune regulation through CFA/I could counteract the autoimmune inflammation of RA.

What is CFA/I and where is it from?

CFA/I is a protein originally identified in an enterotoxigenic strain of E. coli.

For R-2487, scientists introduced the CFA/I gene into L. lactis so that the probiotic can produce CFA/I in the GI tract.

Explain the mechanism of R-2487. How does the drug induce Tregs?

1. R-2487 is administered orally.

2. The engineered L. lactis reaches the GI tract, where they express CFA/I.

3. Soluble CFA/I is taken up by dendritic cells.

4. Dendritic cells process CFA/I and present peptides through MHC class II.

5. Naive CD4⁺ T cells recognize the antigen.

6. Under the regulatory conditions promoted by CFA/I, these CD4⁺ T cells differentiate into Treg cells.

7. Tregs produce anti-inflammatory cytokines, particularly IL-10, IL-35, and TGF-β.

8. These cytokines suppress the excessive RA inflammatory immune responses.

How does increasing Tregs help treat RA?

Tregs normally suppress excessive immune activation.

Tregs increase immune regulation, which decreases autoreactive/inflammatory responses, which decreases RA inflammation.

I.e., Tregs help to restore immune tolerance.

How do IL-10, IL-35, and TGF-β help treat RA?

These cytokines create an anti-inflammatory environment that opposes the excessive immune activation occurring in RA.

Which cytokines do R-2487 affect, and why are they important?

R-2487 leads to reduction in IL-6, IL-17, and IFN-γ, which are inflammatory cytokines.

Ultimately, R-2487 (through the regulatory environment) suppresses the release of inflammatory cytokines.

At what point in RA pathogenesis does R-2487 act on?

R-2487 primarily acts on the immune regulation/inflammation portion of RA pathogenesis.

R-2487 increases Tregs, IL-10, IL-35, and TGF-β. This allows it to suppress Th1, Th17, and inflammatory cytokines.

What is the Antibody-conjugated MSC Drug Delivery System (AcM-DDS), and how is it used to treat RA?

AcM-DDS uses bone-marrow-derived mesenchymal stromal cells (BMSCs) as a delivery vehicle.

The BMSCs are:

• Modified with a CD4 monoclonal antibody (CD4mAb) on their surface.

• Loaded with Cedirogant, a drug that suppresses Th17-mediated inflammation.

The CD4 antibody is intended to help direct the BMSCs toward areas containing CD4⁺ T cells, allowing Cedirogant to be delivered more specifically to inflamed tissue.

Why does AcM-DDS target CD4+ T cells?

CD4⁺ T cells are important drivers of RA inflammation. Several pathogenic helper T-cell populations contribute to RA, particularly Th1 and Th17 cells.

In this future therapy, CD4 serves as a targeting marker that helps the engineered BMSCs localize to areas containing CD4⁺ T cells.

The goal isn't simply to destroy CD4⁺ cells. Instead, the CD4 antibody is being used as a homing/targeting mechanism to deliver the therapeutic payload near pathogenic immune activity.