In patients with rheumatoid arthritis (RA) there is excessive secretion of CXCL12, a pro-inflammatory chemokine which leads to persistent infiltration of inflammatory immune cells into the joint tissues. This results in chronic inflammation and progressive tissue damage. ACKR3 (also known as CXCR7) functions as a natural scavenger of CXCL12 to prevent excessive increase of CXCL12. However, under pathological conditions, the scavenging capacity of ACKR3 becomes impaired and no longer able to efficiently lower the CXCL12 level to keep it within the normal range.
Discovered and developed by iLeadBMS, IL21120033 is the first compound designed to restore and enhance ACKR3’s function through an Ago-PAM (Dual Agonist and Positive Allosteric Modulator) mechanism. As an Ago-PAM, it not only activates the receptor directly but also enhances the binding affinity of the endogenous ligand CXCL12 with the receptor, thereby significantly improving the overall functional efficiency as a single molecule.
In CXCL12-enriched autoimmune environment, IL21120033 acts as a PAM to promote the binding of ACKR3 to CXCL12 to facilitate its clearance of CXCL12. Conversely, in an environment where tissue repair function is compromised due to low level of CXCL12, IL21120033 acts as an agonist and directly activates ACKR3 to promote angiogenesis and tissue regeneration.
In a Collagen-Induced Arthritis (CIA) mouse model, IL21120033 demonstrated robust therapeutic efficacy across multiple parameters, including disease score, immune cell infiltration, pannus formation, cartilage degradation, and bone erosion. Remarkably, in the high-dose group, IL21120033 treatment led to cartilage regeneration in some animals. When compared to Rinvoq® (upadacitinib), a selective JAK1 inhibitor, IL21120033 showed superior anti-inflammatory and cartilage-protective effects.
Unlike Rinvoq®, which inhibits the JAK/STAT pathway in immune cells but lacks regenerative capability, ACKR3 Ago-PAM provides a dual mechanism of both suppressing inflammation and, promoting tissue repair, highlighting its clearly differentiated therapeutic potential in the autoimmune space. This dual mechanism enabled IL21120033 to deliver a more comprehensive and better efficacy in this animal model.
In addition to RA, iLeadBMS is also investigating the therapeutic potential of IL21120033 in other autoimmune diseases with high unmet needs, such as Inflammatory Bowel Disease (IBD). The compound has shown promising results across multiple autoimmune animal models, and GLP safety studies are currently underway in preparation for the Investigational New Drug (IND) application as the clinical trials are expected to commence next year.
Dr. Yoon-seok (Ivo) Lee, CSO of iLeadBMS stated, "We believe IL21120033 has the potential to become a game-changer in the treatment landscape of autoimmune diseases."
About iLeadBMS
Established in 2020 as a spin-off from Ildong Pharmaceuticals, iLeadBMS specializes in the discovery and development of first-in-class therapeutics for oncology, autoimmune and cardiometabolic diseases. For more information, please visit https://www.ileadbms.com/.
