Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: Oncostatin M (OSM) is a pleiotropic member of the gp130/IL-6 cytokine family involved in pathological processes of fibrosis, inflammation and vasculopathy. Diffuse cutaneous systemic sclerosis (DcSSc) subjects have increased OSM serum levels and OSM/OSM-related genes are upregulated in DcSSc skin biopsies (Feeney 2016). A previous monoclonal antibody developed for the treatment of RA was discontinued due to lack of efficacy likely associated to poor binding affinity (Choy 2013). A novel IgG1 Mab (GSK2330811), with approximately (~) >10 fold increased binding affinity in-vitro, is being developed for the treatment of DcSSc. We aimed to assess target engagement in the target tissue (skin) and to determine the antibody in-vivo affinity using physiology-based pharmacokinetic modelling (PBPK) in a first time in human study (Study 201246).
Methods: Healthy males and females of non-child bearing potential aged 18 to 65 received single ascending subcutaneous doses of GSK2330811 (0.1-6mg/kg) or placebo. Skin suction blisters were raised on the volar surface of the forearm by applying suction for 4 hours followed by collection of the blister fluid. Validated immunoassays were used to measure target engagement (free and total OSM) and GSK2330811 concentrations in blood and skin. A combined PBPK and target mediated drug disposition model (TMDD) was developed to assess in-vivo affinity of GSK2330811 (Cao, 2014).
Results: 30 Subjects received GSK2330811 and 10 placebo. GSK2330811 showed a favourable safety and tolerability profile compared to placebo. Skin suction blisters were well tolerated. The PK of GSK2330811 was consistent with IgG1 Mab against a soluble target. The typical apparent distribution volume was 11.5 l (95% CI: 10.2-13.1) and the typical apparent systemic clearance was 14.1 ml/hr (95% CI: 12.7-15.6). The mean terminal half-life was ~3 weeks. GSK2330811 ratio between skin and plasma concentration was ~ 20-30%. Estimated in-vivo affinity was ~ 0.6 nM. A rapid (~ 30 min) OSM target turnover was estimated based on total OSM data. Free OSM levels were below the limit of quantitation after drug administration in both serum and blister fluid indicating substantial OSM inhibition. At the top dose level ~ 90% of target engagement is predicted in serum, while slightly lower values (~70-80%) are predicted in the skin blister fluid.
Conclusion: This study demonstrates that GSK2330811 has sufficient affinity to achieve high target engagement in systemic circulation and target tissue. Skin blister analysis provided valuable data to inform the mechanistic target engagement model. These data support progression of GSK2330811. A proof of mechanism study in subjects with DcSSc is being developed. References: Feeney M, et al. Arthritis Rheumatol 2015;67(suppl 10) Choy EH, et al. Arthritis Res Ther 2013 Sep 24;15 (5):R132 Cao Y & Jusko WJ. J Pharmacokinet Pharmacodyn 2014;41(4):375-387
To cite this abstract in AMA style:Reid J, Zamuner S, Edwards K, Rumley S, Sully K, Feeney M, Kumar S, Fernando D, Wisniacki N. Targeting Oncostatin M in the Target Tissue: Assessment of in-Vivo Affinity and Target Engagement of an Anti-OSM Monoclonal Antibody By Combining Blood and Skin Blister Fluid Data [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/targeting-oncostatin-m-in-the-target-tissue-assessment-of-in-vivo-affinity-and-target-engagement-of-an-anti-osm-monoclonal-antibody-by-combining-blood-and-skin-blister-fluid-data/. Accessed November 28, 2020.
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