Background/Purpose: Systemic sclerosis (SSc) a complex and rare immune-mediated connective tissue disorder characterized by microvascular damage, inflammatory cell infiltration, and excessive deposition of extracellular matrix proteins (ECMs) resulting in fibrosis of the skin and internal organs. Like for many chronic inflammatory diseases dysfunctional macrophage activity is linked to the failure of initiating the resolution of inflammation programs and with that a main disease driver and a central part of disease progression in affected organs. The objective of our preclinical analysis, was to evaluate the therapeutic activity of an innovative secretome drug candidate Resolvix, which was developed from experimentally induced resolution type macrophages, in experimental models of SSc.

Methods: Two established inducible preclinical models of SSc (bleomycin (BLM) and HOCl) were used to monitor the impact of Resolvix on skin (thickness and collagen deposition), lung (leucocyte infiltration and alveolar macrophage efferocytosis) and lymphoid organs (Tregs) as well as selected plasma proteins. A single treatment at predetermined therapeutic activity or respective controls were administrated intra-venously at 3 weeks post disease induction and mice were monitored daily and sacrificed for analysis after 3 weeks post treatment.

Results: In both models we could show a significant reduction of skin thickening and collagen deposition in skin samples after a single administration of Resolvix when compared to controls. Leucocyte infiltrates particularly evident in the HOCl model were significantly reduced by the Resolvix treatment in skin and lung tissues. Furthermore, Resolvix treatment restored the efferocytosis activity in alveolar macrophages collected from broncho-alveolar lavage (BAL) fluids that were significant reduced in these models as sign of uncontrolled ongoing chronic inflammation and recently reported in SSc patients. Efferocytosis capacities were restored to comparable levels as detected in healthy mice.

Conclusion: Collectively our preclinical data demonstrate that the pro-resolution factors harnessed from these specialized macrophages are able to durably revert skin fibrosing, control inflammatory cell infiltration and restore defective macrophage efferocytosis and function as a novel and advanced therapeutic approach in SSc. Resolvix may be considered as a next generation cell-free and disease modifying biological drug candidate for further development for the treatment of SSc.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-novel-therapeutic-opportunity-in-systemic-sclerosis-the-fibrolytic-activities-of-a-specialized-macrophage-secretome/