Session Type: Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: Systemic lupus erythematosus (SLE) is a complex, heterogeneous autoimmune disease. There is still a high unmet need to improve current treatment options. Type 1 interferon (IFN) has recently been validated as clinical target for SLE.
CXCR4 antagonist IT1t has shown to selectively induce an immunomodulating profile through downmodulation of IFN-α release by plasmacytoid dendritic cells (pDCs)1. Functionally selective immunomodulators derived from IT1t, with low/no CXCR4 antagonism and increased immunomodulating activity, not limited to the control of type 1 IFN, have been discovered and may represent a novel therapeutic approach for interferonopathies, like SLE.
In vivo efficacy of one representative compound, ER000145 was evaluated in (NZB x NZW) F1 mice. This spontaneous lupus mouse model is sharing several pathophysiological features of human SLE, with clear kidney development starting around 22 weeks of age.
Methods: As of 24 weeks of age female (NZB x NZW) F1 mice received daily intraperitoneal (ip) administrations of ER000145 at either 3, 10 or 30 mg/kg for 16 weeks. Cyclophosphamide was administered once a week at 50 mg/kg ip as positive control. Body weight was recorded twice per week and proteinuria were measured weekly up to week 40 of age. At week 40 of age, kidney function readouts were performed by assessing the levels of blood urea nitrogen (BUN) and creatinine. At week 24, 34 and 40 of age, anti-dsDNA antibody titers were evaluated by ELISA. After 16 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 for assessment of nephritis. In addition, spleen and bone pathology was performed to assess potential for immunosuppression using haematological and histological endpoints.
Results: Daily treatment of mice for 16 weeks with ER000145 did not show compound-induced body weight loss. Significant dose-dependent decreases in proteinuria, BUN levels and anti-ds DNA antibody titers were shown at week 40 of age for the 10 mg/kg and 30 mg/kg ER000145 treatment groups versus the vehicle control group. Despite overall low systemic cytokine levels, a reduction of serum TNF-α and IL-6 was observed for mice treated with ER000145. Histopathological analysis of the kidney confirmed a significant dose-dependent reduction of glomerular and tubular scores upon ER000145 treatment versus the vehicle control group at week 40 of age, confirming the inhibition of nephritis development. Haematology and histopathology of lymphoid organs showed no overt cell atypia nor cell depletion, a histological profile consistent with an absence of immunosuppression as opposed to the cyclophosphamide-treated group.
Conclusion: ER000145 showed robust and dose-dependent efficacy upon once daily ip treatment for 16 weeks in (NZB x NZW) F1 lupus-prone mice. No signs of immunosuppression were detected.
Based on these promising efficacy data obtained in vivo with ER000145, orally available functionally selective immunomodulators are currently being developed as a potentially novel and innovative treatment option for SLE.
1 Smith et al. Sci Adv. 2019 ;5(7)eaav9019
To cite this abstract in AMA style:ASNAGLI H, TESSIER S, FOSTER M, DENIES S, HOEBEN E, CROUZET J, VAN DER AA A. Functionally Selective Immunomodulator Shows Robust Efficacy in Spontaneous Lupus Mouse Model [abstract]. Arthritis Rheumatol. 2023; 75 (suppl 9). https://acrabstracts.org/abstract/functionally-selective-immunomodulator-shows-robust-efficacy-in-spontaneous-lupus-mouse-model/. Accessed .
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/functionally-selective-immunomodulator-shows-robust-efficacy-in-spontaneous-lupus-mouse-model/