Aims: Janus-kinase-(JAK)3 is crucial for signal transduction in immune cells. This is the
first report on the novel JAK3 inhibitor R348 for prevention of acute and chronic
rejection.
Methods: Pharmacokinetic and in vitro enzyme inhibition assays were performed to characterize
the drug. Heterotopic BN-Lew heart (n=108) and tracheal transplantations (n=48) were
performed to study acute cardiac allograft rejection and the development of chronic
obliterative airway disease (OAD), respectively. Immunosuppressive efficacy and drug
toxicity of R348 (10–80mg/kg) was compared to tacrolimus (1–4mg/kg) and rapamycin
(0.75–3mg/kg).
Results: Plasma levels of R348's active metabolite R333 sustained high several hours, and
in vitro enzyme assays showed selective inhibition of JAK3-dependent pathways.
Acute rejection study: R348 40mg/kg was effective to preserve cardiac allograft function,
significantly reduced early mononuclear graft infiltration, and decreased histologic
rejection scores on day 5, similar to rapamycin 3mg/kg. R348 40mg/kg and rapamycin
3mg/kg were similarly effective to reduce the host cellular Th1/Th2 responsiveness
and similarly suppressed intragraft IFN-gamma, MIP3-alpha, and IL-6 expression. Prolongation
of allograft survival with R348 20–40mg/kg was similar to that of tacrolimus 2mg/kg
or rapamycin 2mg/kg. R348 demonstrated highly beneficial synergistic interactions
with tacrolimus.
OAD study: R348 40mg/kg and rapamycin 3mg/kg similarly inhibited tracheal OAD development
and inhibited donor-specific antibody production by day 28. However, only R348 preserved
airway morphology and physiologic gene expression. R348 was subtherapeutic at 10mg/kg
and toxic at 80mg/kg.
Conclusions: R348 highly effectively diminishes acute cellular rejection and OAD development with
favorable pharmakokinetics and biological activity and is suitable for combination
regimens with tacrolimus.
