CD38+ cell depletion with TAK-079 reduces arthritis in a cynomolgus collagen-induced arthritis (CIA) model

Abstract

Abstract TAK-079 is a fully human, cytolytic IgG1 mAb against human CD38. We tested the ability of TAK-079 to treat arthritis using a monkey CIA model with features of symmetrical small joint polyarthritis resembling human RA. Monkeys were injected with bovine collagen type II in complete Freund’s adjuvant on Day 0 and Day 21 to induce arthritis. 1 monkey was used as a disease-free, age-matched control (naïve). In monkeys with CIA, the prophylactic group (n=8; 3 mg/kg, QW, iv) started treatment on Day 7 and continued for 8 weeks. The therapeutic treatment groups were randomized, after progression to overt disease, to 1 of 3 treatments: Vehicle (n=5; QW, iv), TAK-079 (n=7; 3 mg/kg, QW, iv), or dexamethasone (Dex; n=4; 0.1 mg/kg QD, po) and treated for 5 weeks. Prophylactic treatment with TAK-079 inhibited arthritis induction and therapeutic treatment reduced arthritic disease to a similar extent as Dex. TAK-079 treatment reduced CD38+ cells in the blood and spleen vs. naïve animal. After the first dose, blood monocytes, B and T cells were each reduced ≤ 55%, but reduction of monocyte and T cell counts were transient despite continued dosing. NK cells showed almost complete depletion. Neutrophil and platelet counts, elevated due to active arthritis, appeared normalized by TAK-079 vs. the naïve animal. TAK-079 treatment reduced systemic and local inflammation. Treated animals suffered less weight loss, and had reduced CRP and ALP levels and increased albumin levels. TAK-079 treatment reduced cartilage degradation and bone resorption in the IP and MCP joints based on radiology findings and confirmed by qualitative histological grading. TAK-079 was effective in treating CIA, supporting its continued investigation for the treatment of autoimmune disease.