Session Information
Session Type: Abstract Session
Session Time: 3:00PM-4:30PM
Background/Purpose: Current standard of care chronic inflammatory disease therapies are designed to suppress inflammation and are not optimized for inflammation resolution and restoration of tissue homeostasis and function. This unmet need requires a new class of therapeutics that complement anti-inflammatory treatments to enable potentially curative responses. Stimulating inflammation resolution and tissue repair by tissue resident immune cells may increase tissue function recovery and potentially increase remission rates. Macrophages are key drivers of tissue homeostasis and repair after inflammatory insult. Therapies inducing tissue macrophages expansion and reprogramming may synergize with existing cytokine blockade agents to enhance inflammation resolution and tissue function renewal.
Methods: Variants of human recombinant CSF-1 (rhCSF-1) conjugated to PEG polymers with diverse molecular sizes and conjugation chemistries were screened in vitro for CSF-1R affinity by SPR and target engagement potency in vitro in myeloid cells in mouse and human blood. In vivo screening for reduced clearance, sustained CSF-1R agonism and tissue macrophage inflammation resolution and tissue repair markers in blood and liver tissue were conducted in wildtype c57Bl/6 and Balb/c mice. Target engagement potency and duration were measured by flow cytometry of phosphorylated ERK (pERK) and Akt (pAkt). Phenotypic characterization of blood and liver tissue monocytes and macrophages in vivo was conducted by flow cytometry of inflammation resolution pathways and metalloprotease activity markers. Single agent efficacy was tested in a mouse model of DSS induced colitis and synergy with TNFa blockade (Enbrel) was evaluated in rat collagen induced arthritis (CIA) model.
Results: In vitro and in vivo screening of rhCSF-1 polymer conjugates identified a CSF-1R agonist with a differentiated PK/PD profile compared to the native CSF-1 cytokine. In vivo treatment with the CSF-1R agonist showed significantly reduced target mediated clearance, sustained target engagement and proliferation and expansion of tissue resident macrophages with minimal off-target effects of monocyte infiltration and production of monocyte-derived macrophages. Tissue macrophages induced the expression of inflammation resolution and tissue repair markers including increasing IL-4Ra and IL-10Ra cell surface expression, efferocytosis receptor MerTK upregulation and metalloproteases activation. Single agent treatment showed efficacy in mouse DSS colitis model accelerating disease reduction in the resolution phase after peak inflammation. Combination treatment with TNFa blockade showed enhancement of cytokine blockade efficacy accelerating paw volume reduction after starting treatment at the peak of inflammation in a rat CIA model.
Conclusion: We have designed a novel CSF-1R agonist optimized for sustained receptor activation and tissue macrophages reprogramming to promote expression of inflammation resolution and tissue remodeling functions. Tissue macrophages activation was decoupled from pro-inflammatory monocytes tissue infiltration induction that may be a beneficial property for the treatment of chronic inflammatory conditions.
To cite this abstract in AMA style:
Kivimae S, Mukherjee S, Quach P, Pena R, Zemska O, Olszewski M, Huang J, Labson M, Walker D, Maiti M, Tripathi C, Chang T, Adapala S, Hamel D, Brendza K, Miyazaki T, Zalevsky J. A Novel Therapeutically Active CSF-1R Agonist Promotes Tissue Macrophages Inflammation Resolution and Induces Tissue Repair Pathways [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/a-novel-therapeutically-active-csf-1r-agonist-promotes-tissue-macrophages-inflammation-resolution-and-induces-tissue-repair-pathways/. Accessed .« Back to ACR Convergence 2024
ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-novel-therapeutically-active-csf-1r-agonist-promotes-tissue-macrophages-inflammation-resolution-and-induces-tissue-repair-pathways/