Ixekizumab, a novel anti–IL-17A antibody, exhibits low immunogenicity during long-term treatment in patients with psoriasis

Abstract

388 Ixekizumab, a novel anti-IL-17A antibody, exhibits low immunogenicity during long-term treatment in patients with psoriasis A Blauvelt, R Langley, C Leonardi, K Gordon, T Luger, M Ohtsuki, B Nickoloff, L Kerr, L Mallbris and K Reich 1 Oregon Medical Research Center, Portland, OR, 2 Dalhousie University, Halifax, NS, Canada, 3 Saint Louis University, St. Louis, MO, 4 Northwestern University Feinberg School of Medicine, St. Louis, MO, 5 University of Munster, Munster, Germany, 6 Jichi Medical University, Shimotsuke, Japan, 7 Eli Lilly and Company, Indianapolis, IN and 8 Dermatologikum Hamburg and SCIderm Research Institute, Hamburg, Germany The potential association of treatment-emergent anti-drug antibodies (TE-ADAs) with efficacy and safety in patients treated with ixekizumab (IXE), a high binding affinity monoclonal antibody that selectively targets interleukin-17A, was evaluated. TE-ADAs were evaluated in patients randomized to 80 mg IXE either every 2 weeks (IXE Q2W; N1⁄41150) or 4 weeks (IXE Q4W; N1⁄41143) for up to 12 weeks following a 160-mg starting dose. IXE responders at Week 12 were re-randomized to IXE Q4W (N1⁄4397) or IXE Q12W (N1⁄4382) until Week 60. A highaffinity capture elution screening assay was used to assess ADA serum trough levels. Serum TE-ADAs were divided into four titer groups (negative, low, moderate, and high). At 12 weeks, the majority of patients were TE-ADA negative (IXE Q2W: 91.0%; IXE Q4W: 86.6%). TE-ADE titers at 12 weeks for IXE Q2W and IXE Q4W patients were, respectively, 5.7% and 8.0% (low), 1.6% and 3.0% (moderate), and 1.7% and 2.4% (high). IXE Q2W patients with high TEADA titers had reduced PASI responses versus TE-ADA negative patients; 12-week mean percent PASI improvement was 91.7% (negative), 85.7% (low), 88.7% (moderate), and 53.5% (high); 12-week PASI 75 response rates were 90.7% (negative), 84.8% (low), 83.3% (moderate), and 36.8% (high). Mean percent improvement from baseline to 60 weeks PASI was 94.3% (negative), 97.0% (low), and 100% (moderate) for TE-ADA titer patients. IXE Q4W data were similar. No safety findings were correlated to TE-ADAs. TE-ADA levels in IXE patients did not affect maintenance of response and safety up to 60 weeks among initial IXE responders. 389 The extravesicular miRNome of senescent human fibroblasts and its impact on keratinocyte functionality L Terlecki-Zaniewicz, V Pils, J Schwestka, J Latreille, I Lammermann, R Weinmullner, I Berlin, M Hackl, F Morizot and J Grillari 1 Dept. of Biotechnology, BOKU University Vienna, Austria, Christian Doppler Laboratory for Biotechnology of Skin Aging, Vienna, Austria, 2 CE.R.I.E.S. (Research Centre on Human Skin of CHANEL), Neuilly sur Seine, France and 3 TAmiRNA GmbH, Vienna, Austria In aged skin up to 25% of senescent cells are present and supposed to impair tissue homeostasis and regeneration resulting in a gradual loss of juvenile appearance and functionality, while transiently the presence of senescent cells might be beneficial for cutaneous wound healing. The senescence associated secretory phenotype (SASP) is one pivotal hallmark of senescent cells, whereby proinflammtory cytokines, chemokines and metalloproteases are secreted and alter the tissue microenvironment. Recently, micro RNAs (miRNAs) packaged into extracellular vesicles (EV) have been found as part of SASP (miRSASP). Here, we report the identification of EV-miRNAs as part of the human dermal skin fibroblasts’ SASP. For this purpose, stress induced premature senescence was triggered by repeated low doses of H2O2 in cells of 3 donors and EV of senescent and control cells were harvested by ultracentrifugation for miRNomics and functional biological studies. We identified differentially secreted miRNAs by qPCR arrays and correlated their extracellular and intracellular abundance. Based on that, we have confirmed selected prominent, highly secreted miRNAs to be more abundant in EVs of senescent cells. Furthermore, by nanoparticle tracking analysis we observed that senescent fibroblasts secrete more vesicles than controls. In order to test if EV-miRNAs might be part of a paracrine cross-talk between dermal fibroblasts and epidermal keratinocytes, we confirmed uptake of cel-miR-39 enclosed in fibroblast derived EV by keratinocytes in monolayers and in full thickness skin-equivalents. To summarize, our data indicate that extravesicular miRNAs of senescent fibroblasts are bona fide members of the SASP and that they contribute to the communication between fibroblasts and keratinocytes in 2D and 3D human skin models.