FRI0170 Pharmacodynamic biomarkers demonstrate overlapping and distinct biological pathways for lymphotoxin-alpha and tumor necrosis factor-alpha in patients with rheumatoid arthritis
Authors: A. E. Herman, W. P. Kennedy, M. Townsend, M. Williams, J. Grogan, S. Fischer, S. Iyer, A. Song, J. C. Davis
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Lymphotoxin (LT)-α, a member of the TNF superfamily, is required for lymph node development and recruitment of B and T cells into lymph nodes via induction of CXCL13 and CCL19 (1). LTα has been implicated in the development of ectopic lymphoid tissue found in rheumatoid arthritis (RA) synovium (2). In pre-clinical xenograft models, the anti-LTα antibody pateclizumab (PTZ) inhibited the binding of soluble LTα<sub>3</sub> to TNF receptors and membrane-bound LTα<sub>1</sub>β<sub>2</sub> to LTβ receptor, and depleted LT-expressing T and B cells (3). In a Phase 1 study, patients treated with PTZ had decreased circulating CXCL13 levels (4). <h3>Objectives</h3> PTZ and the anti-TNFα antibody adalimumab (ADA) target distinct and overlapping pathways; thus, pharmacodynamic (PD) biomarkers representative of each pathway were assessed to understand contributions of each to disease and therapeutic response. <h3>Methods</h3> A Phase 2 study was conducted in DMARD-IR RA patients. Patients received PTZ (360 mg), ADA (40 mg), or placebo, SC every 2 weeks for 10 weeks. All patients remained on background DMARDs. Serum was collected to assess PD biomarkers on Day 1 (pre-dose), and at multiple timepoints thereafter. Chemokines, cytokines, adhesion molecules, matrix metalloproteases (MMPs), and inflammatory markers were measured using quantitative immunoassay methods. Statistical assessments were performed using the Wilcoxon rank sum test to compare the change in biomarker levels to placebo at Week 12. <h3>Results</h3> ADA had superior efficacy to PTZ in DMARD-IR RA patients (5). Circulating levels of CXCL13 and CCL19 were reduced in PTZ treated patients, demonstrating target engagement in the LTα pathway. ADA also blocked CXCL13, but not CCL19, suggesting a unique role for LTα (likely as LTα1β2) in CCL19 production. Blockade of the TNFα pathway via ADA down-regulated several additional biomarkers involved in TNF biology. These included MMP-1, MMP-3, and IL-6; and the inflammatory markers CRP, ESR, and S100A8. In contrast, PTZ did not induce changes in inflammatory markers or MMPs. Although PTZ was expected to inhibit the interaction of soluble LTα<sub>3</sub> with TNFRs, TNFR-driven biological activity remained apparent in PTZ-treated patients. <h3>Conclusions</h3> Blockade of TNFα vs. LTα in DMARD-IR RA patients demonstrated distinct and overlapping patterns in downstream biomarkers of disease activity. TNFα blockade led to decreases in multiple biomarkers related to TNFR signaling. LTα blockade demonstrated significant reduction in levels of CCL19, as well as CXCL13, suggesting an impact on T and B cell migration and/or lymphogenesis. However, the decrease in chemokines observed with LTα blockade was associated with only modest reduction in clinical activity (5). <h3>References</h3> Ngo VN et al. 1999 JEM 189:403. Grogan JL &amp; Ouyang W. 2012 EJI 42:2255. Chiang EY et al. 2012 PLoS One 7:e33106. Emu et al. 2012 Arthritis Res Ther 14:R6. Kennedy WP et al. EULAR 2013 (submitted). <h3>Disclosure of Interest</h3> A. Herman Employee of: Genentech, Inc., W. Kennedy Employee of: Genentech, Inc., M. Townsend Employee of: Genentech, Inc., M. Williams Employee of: Genentech, Inc., J. Grogan Employee of: Genentech, Inc., S. Fischer Employee of: Genentech, Inc., S. Iyer Employee of: Genentech, Inc., A. Song Employee of: Genentech, Inc., J. Davis Jr Employee of: Genentech, Inc.