CIA study

Twelve cynomolgus monkeys were assigned to 3 groups (4 animals per group): control and two SL1026-treated groups (1 and 10 mg/kg/dose). Arthritis was induced by collagen treatment as described previously [37]. Bovine type II collagen (K41S type2 collagen, 0.4% solution) was purchased from Collagen Research Center (Tokyo, Japan), diluted to 4 mg/mL and then mixed with an equal volume of complete Freund′s adjuvant (BD Biosciences). Monkeys were immunized on Study Day 0 by intradermal 2 mL injections into the back. Animals received a booster 3 weeks later (day 21) by the same procedure. SL1026 was formulated as described above and intravenous bolus doses (1 mL/kg) were administered into the cephalic vein every 6 h for 11 days starting on the first day of immunization. The control group received vehicle alone following the same dosing schedule. Arthritis scores and general condition scores of monkeys were observed and recorded once a week for 5 weeks, at 6, 12, 20, 27, and 34 days after the first immunization. Clinical assessment was performed according to established methods, which were modified in consideration of joint function [37]. Arthritis scores were evaluated by monitoring the degree of swelling and rigidity at the metacarpophalangeal, proximal interphalangeal, and distal interphalangeal joints, and of the wrist, ankle, elbow, and knee (total 64 joints). Each joint was assessed according to the following evaluation criteria: Score 0, no abnormality; Score 1, swelling not visible, but can be determined by touch; Score 2, swelling slightly visible and can be confirmed by touch; Score 3, swelling clearly visible, but joint can be completely flexed; Score 4, swelling clearly visible, but joint cannot be completely flexed; Score 5, rigid joints. The arthritis score for each animal was designated as the total score of individual joints. General condition scores were evaluated by monitoring behavior and movement of the monkeys. Each monkey was assessed according to the following evaluation criteria: Score 0, No abnormality; Score 1, Difficulty in hanging from the bars of the home cage by the fingers; Score 2, Inability to hang from the bars of the home cage by the fingers (using wrist); Score 3, Movement only by using forelimbs or hindlimbs; Score 4, Crouching; Score 5, Abnormal body position. Arthritis and general condition scores were determined by investigators blind to treatment assignment.