A novel JAK3 and Syk-Inhibitor, R348, for prevention of chronic airway allograft rejection
Jeffrey Velotta1, Vanessa Taylor2, Esteban Masuda2, Gary Park2, David Carroll2, Robert Robbins1, Sonja Schrepfer1; 1Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA; 2Rigel Pharmaceuticals, South San Francisco, CA
Comment on this Abstract
Objective: This is the first study to investigate the role of a novel JAK3 and Syk inhibitor, R348, in the prevention of chronic airway allograft rejection. Both kinases are vital for cytokine signal transduction and immune cell differentiation.
Methods: Trachea from Brown-Norway donors were heterotopically transplanted in the greater omentum of Lewis rats. Recipients were treated for 28 days with R348 (10, 20, 40, or 80 mg/kg) or rapamycin (0.75 or 3 mg/kg) or left untreated. Grafts were harvested and tracheal segments were processed for histological evaluation by computer morphometry determining degree of luminal obliteration and percentage of respiratory epithelium coverage. Thymus and spleen weights were quantified and compared between all groups. Side effects of R348 and rapamycin were assessed using animal weights calculated every week. Plasma levels of R348 and R333, its active metabolite, were quantified by high-power liquid chromatography and pharmacokinetics were determined.
Results: R348 at 20, 40, and 80 mg/kg significantly inhibited luminal obliteration (69±20%, 20±13%, 15±7%; p=0.003 vs. no medication). Rapamycin in both concentrations significantly inhibited luminal obliteration (37±15%, 11±6%; p<0.001 vs. no medication) similarly to R348 at 40 and 80 mg/kg and was more effective than R348 at 10 and 20 mg/kg (37±15%, 11±6% vs. 94±10%, 69±20%; p=0.003). R348 at 40 and 80 mg/kg significantly preserved respiratory epithelium compared to R348 at 10 and 20 mg/kg (49±35%, 76±27% vs. 0±0, 3±7%; p=0.004) and was superior to rapamycin in luminal preservation (49±35%, 76±27% vs. 27±17%, 36±15%; p=0.01). All R348 treated recipient thymus and spleen weights were significantly lower compared to the non-treated group (p=0.001). Animal weight gain over 28 days was similar between all groups with the exception that recipients treated with 80 mg/kg of R348 had significantly reduced weight gain compared to the rest (p<0.0001). Plasma levels of R333 were more stable (6000 ng/ml at 2 hours, 6500 ng/ml at 8 hours) than R348 and showed a slower decrease.
Conclusion: R348 effectively prevented the development of obliterative airway disease (OAD) and significantly preserved respiratory epithelium with 40 mg/kg being the optimal dose. Rapamycin significantly inhibited luminal obliteration with minimal effects on respiratory epithelium preservation. R348 occupies a favorable pharmacokinetic profile compared to rapamycin and is highly effective at precluding chronic airway allograft rejection.
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