(1125) - Selective Activation of Naturally Occurring Regulatory T Cells (Tregs) by the Monoclonal Antibody (mAb) BT-061. Markers of Clinical Activity and Early Phase II Results in Patients with Rheumatoid Arthritis (RA)

Naturally occurring Tregs are essential for maintaining normal immune homeostasis in healthy individuals. In patients with autoimmune diseases reduced numbers or functional impairment of Tregs has been observed. A humanized agonistic mAb, BT-061 selectively activates Tregs. It binds to a unique epitope of the CD4 molecule, leading to induction of Treg specifi c signaling events. While freshly isolated and resting Tregs do not inhibit T cell proliferation, pre-treatment of Tregs with BT-061 leads to suppression of CD4 and CD8 T effector cell proliferation, reduction of pro-infl ammatory cytokines and a moderate increase in the anti-infl ammatory cytokine TGF-beta. To further assess the potential of BT-061 to modulate immune responses, in vitro studies with synovial fl uid derived mononuclear cells from patients with active RA were performed. Addition of BT-061 at concentrations between 0.01 and 50 micro g/mL to isolated CD4-positive cells derived from the highly infl ammatory milieu of RA synovial fl uid suppressed proliferation as well as IFN-gamma production following antigen-specifi c stimulation. In a Phase I/IIa trial in patients with psoriasis, a single dose of BT-061 resulted in PASI 50/75 responses for up to 90 days at doses of 0.5, 2.5, 10, 20 mg i.v. and 12.5, 25 mg s.c. A Phase IIa, multicenter, randomized placebo-controlled trial with BT-061 monotherapy was performed in 96 patients with active RA and inadequate responses to one or more traditional DMARD despite 3 months or more of treatment. Patients were randomized to 12 treatment groups: from 1.25-100 mg s.c, or 0.5-25 mg i.v, once weekly for 6 weeks: 6 patients received BT-061 and 2 received placebo in each group. Patients with any AEs (%) 8 (57%) 6 (60%) 4 (67%) 6 (100%) 2 (33%) 3 (50%) 3 (50%) 4 (67%) 4 (67%) 3 (50%) 3 (50%) 6 (100%) 4 (67%) 1 (17%) Patients with serious AEs 0 1 (10%) 0 2 (33%) 0 0 0 0 0 0 0 0 0 0 Patients withdrawing due to AE 2 (14%) 3 (30%) 0 0 0 0 0 1 (17%) 1 (17%) 0 0 0 0 0 100