First-in-human study of the safety and efficacy of TOL101 induction to prevent kidney transplant rejection.
First-in-human study of the safety and efficacy of TOL101 induction to prevent kidney transplant rejection.
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DOI：
10.1111/ajt.12698
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发表时间：
2014-06
期刊：
影响因子：
--
通讯作者：
Getts DR
中科院分区：
文献类型：
--
作者：
Flechner SM;Mulgoankar S;Melton LB;Waid TH;Agarwal A;Miller SD;Fokta F;Getts MT;Frederick TJ;Herrman JJ;Puisis JP;O'Toole L;Sung R;Shihab F;Wiseman AC;Getts DR
TOL 101是一种靶向αβ TCR的鼠IgM mAb。与其他T细胞靶点不同，αβ TCR没有已知的细胞内信号传导结构域，可能为T细胞失活提供非促有丝分裂靶点。我们报告了TOL 101在肾移植中的6个月2期试验数据。该研究旨在确定导致显著的CD 3 T细胞调节（<25 T细胞/mm 3）的剂量，以检查TOL 101的安全性和耐受性，并获得初步疗效信息。36名患者入组并给予5-10天剂量的TOL 101; 33名患者完成给药，而3名患者在两次给药后由于自限性荨麻疹皮疹而停药。输液调整，抗组胺药，类固醇和剂量递增的TOL 101减少皮疹的发生率。TOL 101的剂量高于28 mg导致延长的CD 3调节，在治疗停止后7天观察到快速恢复。无患者或移植物丢失病例。很少有重大的不良事件报告，与医院获得性肺炎。有五个活检证实的急性细胞排斥反应（13.9%），但是，没有检测到供体特异性抗体。总体而言，TOL 101耐受性良好，支持使用剂量递增21- 28-42-42- 42 mg方案继续进行临床开发。
TOL101 is a murine IgM mAb targeting the αβ TCR. Unlike other T cell targets, the αβ TCR has no known intracellular signaling domains and may provide a nonmitogenic target for T cell inactivation. We report the 6-month Phase 2 trial data testing TOL101 in kidney transplantation. The study was designed to identify a dose that resulted in significant CD3 T cell modulation (<25 T cell/mm3), to examine the safety and tolerability of TOL101 and to obtain preliminary efficacy information. Thirty-six patients were enrolled and given 5–10 daily doses of TOL101; 33 patients completed dosing, while three discontinued after two doses due to a self-limiting urticarial rash. Infusion adjustments, antihistamines, steroids and dose escalation of TOL101 reduced the incidence of the rash. Doses of TOL101 above 28mg resulted in prolonged CD3 modulation, with rapid recovery observed 7 days after therapy cessation. There were no cases of patient or graft loss. Few significant adverse events were reported, with one nosocomial pneumonia. There were five biopsy-confirmed acute cellular rejections (13.9%); however, no donor-specific antibodies were detected. Overall TOL101 was well-tolerated, supporting continued clinical development using the dose escalating 21– 28–42–42–42mg regimen.
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影响因子：
6.2
作者：
Webster, AC;Playford, EG;Craig, JC
通讯作者：
Craig, JC
影响因子：
5.3
作者：
Getts, Daniel R.;Getts, Meghann T.;Miller, Stephen D.
通讯作者：
Miller, Stephen D.
影响因子：
6.2
作者：
Waid, TH;Lucas, BA;Skeeters, LJ
通讯作者：
Skeeters, LJ
影响因子：
2.8
作者：
Getts DR;Shankar S;Chastain EM;Martin A;Getts MT;Wood K;Miller SD
通讯作者：
Miller SD
影响因子：
158.5
作者：
Hanaway, Michael J.;Woodle, E. Steve;Holman, John
通讯作者：
Holman, John