Background/Purpose:   In a recent Phase 2a clinical trial in patients with rheumatoid arthritis, the novel human anti-IL-20 monoclonal antibody NNC0109-0012 was shown to reduce disease activity (DAS28-CRP) and had a favourable safety/tolerability profile.  In RF-positive and anti-CCP-positive patients it also improved the ACR20/50/70 responses.  Response to anti-IL-20 therapy was rapid, with patients showing significant improvements in DAS scores as early as 1 week after treatment. Expression of IL-20 and its receptor chains IL-20R1, IL-20R2, and IL-22R has previously been demonstrated in synovium from patients with RA. The safety and efficacy data support the hypothesis that anti-IL-20 works locally in the joint without modulating systemic inflammation. To test this hypothesis, human peripheral immune cells from blood and lymphoid tissue were evaluated as IL-20 target cells.

Methods: An extensive collection of immune cell subsets derived from human blood and tonsil were analyzed, both directly after isolation and following ex vivo activation.  Expression of IL-20R1, IL-20R2, and IL-22R was detected by flow cytometry and/or qPCR.  In parallel, cell responsiveness to IL-20 was evaluated by measuring the phosphorylation of STAT3 following treatment of cells with IL-20.  Further functional readouts of IL-20 responsiveness included measurement of proliferation and cytokine production in response to IL-20 treatment.

Results:   The cell types evaluated included B cells, CD8⁺ T cells, CD4⁺ T cell subsets, NK cells, dendritic cells, monocytes, macrophages, mast cells, basophils, eosinophils, and CD34+ hematopoietic stem cells.  The IL-20R2 subunit was detected on several cell types, including monocytes, macrophages, and tonsillar B cells.  However, co-expression of the IL-20 receptor beta chain and one of the two alpha chains, requirements for a functional IL-20 receptor, was not detected on human peripheral immune cells under resting or activated conditions.  Consistent with this, there was a lack of responsiveness to IL-20 as monitored by phosphorylation of STAT3.  Finally, whole blood cultured with IL-20 failed to induce a response as measured by cytokine and chemokine production.  This overall lack of response contrasted to non-immune cell types involved in local inflammation, such as keratinocytes.

Conclusion: The paucity of IL-20 receptor expression and IL-20 responsiveness by peripheral immune cells correlates with the absence of systemic immune suppression in the Phase 2a clinical trial of NNC0109-0012.  In combination with earlier data showing expression of IL-20 in synovial tissues, these data suggest that IL-20 is restricted to acting locally on inflamed synovium in patients with RA. 

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/anti-il-20-targets-local-tissue-inflammation-as-opposed-to-systemic-inflammation/