Background/Purpose: Systemic lupus erythematosus (SLE) is a complex, heterogeneous autoimmune disease. There is still a high unmet need to improve current treatment options. The chemokine receptor CXCR4 has been a target for drug discovery for multiple diseases, mainly focused on antagonists, by blocking the CXCR4 chemokine function. However, data have shown that targeting the minor pocket of the receptor selectively induces an immunomodulating profile through downmodulation of key inflammatory cytokines released by CXCR4 expressing innate immune cells. Furthermore, an upregulated expression of CXCR4 on immune cells is correlating with disease progression in SLE. Therefore, the efficacy of ER145, a CXCR4-targeted functionally selective immunomodulator, was evaluated in the pristane-induced murine lupus model.

Methods: Female Balb/C mice received a single intraperitoneal (i.p.) injection of pristane (0.5mL) to induce disease on Day 1. As of study start, mice were treated once daily for 12 weeks with vehicle (PBS, i.p.), ER145 (3, 10 or 30 mg/kg i.p.) or 15 mg/kg prednisolone orally. As of week 4, levels of anti-dsDNA antibody titers were evaluated every 2 weeks. After 12 weeks of treatment, mice were sacrificed, and cytokine levels were determined in serum using ELISA. Furthermore, kidneys were prepared for histopathological scoring using hematoxylin and eosin (H&E) staining.

Results: Daily treatment of mice for 12 weeks with ER145 did not induce any body weight loss, and none of the animals died. Decreased levels of anti-dsDNA antibodies were observed in all ER145 treatment groups compared to vehicle treated group, as of the first timepoint at week 4. Significant differences were shown as of week 6 for the 30 mg/kg ER145 treatment group and as of week 8 for the 10 mg/kg ER145 treatment group. A dose-response effect was maintained until the end of the study. At week 12, significantly decreased levels of IL-1β, IL-6, IL-17 and TNF-α were measured in serum of mice treated with 30 and 10 mg/kg ER145 compared to vehicle treated mice. In the kidneys, mean glomerulus diameters were slightly reduced in ER145 treatment groups compared to vehicle treated mice, although not statistically significant. Interstitial inflammation was significantly reduced in mice treated with 30 mg/kg (44%), 10 mg/kg (38%), and 3 mg/kg (44%) ER145, compared to the vehicle control group. Summed kidney histopathology scores were reduced in mice treated with ER145 (16-23%) compared to the vehicle treated mice.

Conclusion: ER145, a CXCR4-targeted immunomodulator, has shown robust and dose-dependent efficacy upon once daily i.p. treatment for 12 weeks in pristane-induced lupus mice. Treatment rapidly induced decreased levels of anti-dsDNA antibodies, which were maintained, and decreased levels of key pro-inflammatory cytokines in serum at study end. The suppression of kidney interstitial inflammation with ER145 treatment is convincing and suggests that with time, it would have impacted glomerular pathology and tubular cast formation. Based on these promising pharmacological efficacy data with ER145, orally available CXCR4-targeted immunomodulators are currently being developed as a potentially novel and innovative treatment option for SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cxcr4-targeted-functionally-selective-immunomodulator-shows-robust-efficacy-in-pristane-induced-murine-lupus-model/