Reviews Preclinical Safety and Immune-Modulating Effects of Therapeutic Monoclonal Antibodies to Interleukin-6 and Tumor Necrosis Factor-alpha in Cynomolgus Macaques.
Inhibitors of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) have been shown to be efficacious in a number of autoimmune diseases. In this study, the safety of long-term administration of anti-TNF-alpha and anti-IL-6 monoclonal antibodies (mAbs) was evaluated in cynomolgus macaques. Effects on the immune system were evaluated by analysis of lymphocyte subsets and histopathology of lymphoid tissues. To evaluate the functioning of the immune system, the ability of mAb-treated monkeys to mount a humoral immune response (IgG and IgM) to keyhole limpet hemocyanin (KLH) was evaluated. Treatment with the anti-TNF-alpha mAb produced no histopathological changes in any of the lymphoid tissues examined. There was a small (< 2-fold) elevation in circulating T-and B-lymphocytes during anti-TNF-alpha mAb treatment that was not considered to be toxicologically significant. The antibody response to KLH was unaffected by anti-TNF-alpha mAb treatment. Treatment with anti-IL-6 mAb resulted in a decrease in the size of germinal centers in the spleens of a minority of the animals and a modest but significant decrease in the IgG antibody response to KLH. Weekly intravenous treatment with the anti-IL-6 mAb and twice-weekly subcutaneous treatment with the anti-TNF-alpha mAb for up to 6 months was not associated with any signs of toxicity, and no animal developed an infection throughout the study period. This study demonstrates that the anti-IL-6 and anti-TNF-alpha mAbs produce specific modulating effects on the immune system without rendering the animals immune compromised.
Martin
Pauline L
PL
Centocor, Inc., Malvern, Pennsylvania, USA.
Cornacoff
Joel
J
Prabhakar
Uma
U
Lohr
Thomas
T
Treacy
George
G
Sutherland
Jessica E
JE
Hersey
Sarah
S
Martin
Elise
E