GRADUATE STUDENT University of Tennessee health science center Memphis, Tennessee
Administration of human monoclonal antibodies (mAbs) to animals during preclinical drug development may be accompanied by an immunogenic response. This includes development of anti-drug antibodies (ADA) in animals which bind to mAb and may reduce the systemic exposure of the mAb through enhancing its immune complex mediated clearance. ADA formation may thus complicate the accurate assessment of preclinical pharmacokinetics and may prevent toxicity studies from establishing safe exposure ranges of the mAb in study animals. Therefore, we explored the ability of short-term administration of immunosuppressive drug regimens (tacrolimus, sirolimus or methotrexate) to mitigate the immune mediated impact on mAbs in rats Our results showed that a combination of tacrolimus and sirolimus (i) prevents ADA formation to a human mAb in rats, (ii) induces immune tolerance beyond the treatment period with the immunosuppressants, and (ii) maintains mAb serum exposure in treated animals throughout the study period.
Learning Objectives:
To demonstrate the ability of short-term induction treatment with a combination of tacrolimus and sirolimus to induce long-term immune tolerance to a human monoclonal antibody in rats.
To demonstrate that a short term inducton treatment with a combination of tacrolimus and sirolimus is superior to methotrexate in inducing long term tolerance to a human monoclonal antibody in rats.
To demonstrate short term inducton treatment with a combination of tacrolimus and sirolimus prevents ADA formation and thus, maintains monoclonal antibody serum exposure in treated animals throughout the study duration.