Session Information
Session Type: Abstract Submissions (ACR)
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.
Disclosure:
A. L. Blasius,
Novo Nordisk,
3;
J. N. Beilke,
Novo Nordisk,
3;
H. Blumberg,
Novo Nordisk,
3;
J. Bui,
Novo Nordisk,
3;
J. H. Cox,
Novo Nordisk,
3;
T. Cox,
Novo Nordisk,
3;
H. J. Jessup,
Novo Nordisk,
3;
P. L. Kong,
Novo Nordisk,
3;
S. D. Levin,
Novo Nordisk,
3;
V. H. Odegard,
Novo Nordisk,
3;
J. A. Stucky,
Novo Nordisk,
3;
E. P. Thomas,
Novo Nordisk,
3;
J. A. Wahle,
Novo Nordisk,
3;
J. Rømer,
Novo Nordisk,
3.
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