Induced and pre-existing anti-polyethylene glycol antibody in a trial of every 3-week dosing of pegloticase for refractory gout, including in organ transplant recipients.
Induced and pre-existing anti-polyethylene glycol antibody in a trial of every 3-week dosing of pegloticase for refractory gout, including in organ transplant recipients.
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DOI：
10.1186/ar4500
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发表时间：
2014-03-07
影响因子：
4.9
通讯作者：
Sundy JS
中科院分区：
文献类型：
--
作者：
Hershfield MS;Ganson NJ;Kelly SJ;Scarlett EL;Jaggers DA;Sundy JS
Pegloticase是一种聚乙二醇化重组猪尿酸酶，已被批准用于治疗难治性痛风，剂量为每2周一次静脉内（IV）给药8 mg。然而，在I期试验期间，药代动力学支持较低的给药频率。此外，单剂量pegloticase意外诱导了与聚乙二醇（PEG）结合的抗体（Ab）。我们进行了一项II期试验，以评价每3周给药一次，并进一步确定抗体对pegloticase的应答。包括器官移植受者，因为他们容易发生难以管理的严重痛风，并且因为预防移植物排斥反应的治疗可能影响对pegloticase的免疫反应。在30例患者（包括7例器官移植受者）的5次输注期间监测血浆尿酸酶活性（pUox）、尿酸盐浓度（普阿）和临床反应。根据是否达到并维持普阿<6 mg/dL，将患者分为无（NR）、持续（PR）或短暂（TR）应答者。通过酶联免疫吸附试验监测抗pegloticase和10 kDa mPEG抗体，并进一步确定特异性。我们观察到17例PR，12例TR和1例NR; 21例患者（16例PR，5例TR）接受了所有5次输注。在为期15周的试验中，PR中的普阿平均值为1.0 ± 0.4 mg/dL; pUox的T½约为13天，第5次给药后的曲线下面积比第1次给药后高约30%。PR显示出临床获益，在一些患者中，痛风石消退。在12例TR中，有11例在第2次给药前pUox迅速下降且高尿酸血症复发。在所有TR和NR中，对pegloticase的应答丧失伴随着对PEG的Ab，这在既往未暴露于pegloticase的一半患者中预先存在。无PR，7例器官移植受者中有1例对pegloticase产生持续Ab应答。每3周给药一次是有效的，并且可以增强pegloticase治疗难治性痛风的效用。预先存在或由治疗诱导的抗PEG抗体导致疗效迅速丧失，并增加输注反应的风险。器官移植受者可以从pegloticase中获益，并且可能比非受者更不容易产生抗PEG Ab。研究免疫抑制策略，以尽量减少抗PEG抗体是必要的。ClincalTrials.gov标识符：NCT 00111657
Pegloticase, a PEGylated recombinant porcine uricase, is approved for treating refractory gout at a dose of 8 mg intravenous (IV) every 2 weeks. However, during phase 1 testing, pharmacokinetics supported less frequent dosing. Also, single doses of pegloticase unexpectedly induced antibodies (Ab) that bound to polyethylene glycol (PEG). We have conducted a phase 2 trial to evaluate every 3-week dosing, and to further define the Ab response to pegloticase. Organ transplant recipients were included, as they are prone to severe gout that is difficult to manage, and because treatment to prevent graft rejection might influence the immune response to pegloticase. Plasma uricase activity (pUox), urate concentration (pUA), and clinical response were monitored during up to 5 infusions in 30 patients, including 7 organ transplant recipients. Depending on whether pUA <6 mg/dL was achieved and maintained, patients were classified as non (NR), persistent (PR), or transient (TR) responders. Ab to pegloticase and 10 kDa mPEG were monitored by enzyme linked immunosorbent assay and specificity was further defined. We observed 17 PR, 12 TR, and 1 NR; 21 patients (16 PR, 5 TR) received all 5 infusions. Over the 15-week trial, pUA in PR averaged 1.0 ± 0.4 mg/dL; T½ for pUox was approximately 13 days, and area under the curve after dose 5 was approximately 30% higher than after dose 1. PR showed clinical benefit and in some, tophi resolved. In 11 of 12 TR, pUox fell rapidly and hyperuricemia recurred before dose 2. In all TR and NR, loss of response to pegloticase was accompanied by Ab to PEG, which was pre-existing in half of those who had no prior exposure to pegloticase. No PR, and 1 one out of 7 organ transplant recipients, had a sustained Ab response to pegloticase. Every 3-week dosing is effective and may enhance the utility of pegloticase for treating refractory gout. Ab to PEG, which were pre-existing or induced by treatment, caused rapid loss of efficacy and increased the risk of infusion reactions. Organ transplant recipients can benefit from pegloticase, and may be less prone than non-recipients to developing anti-PEG Ab. Investigation of immunosuppressive strategies to minimize anti-PEG Ab is warranted. ClincalTrials.gov identifier: NCT00111657
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影响因子：
--
作者：
Sundy, John S.;Ganson, Nancy J.;Hershfield, Michael S.
通讯作者：
Hershfield, Michael S.
影响因子：
3.9
作者：
Becker, Michael A.;Schumacher, H. Ralph;Sundy, John S.
通讯作者：
Sundy, John S.
影响因子：
27.4
作者：
Becker MA;Baraf HS;Yood RA;Dillon A;Vázquez-Mellado J;Ottery FD;Khanna D;Sundy JS
通讯作者：
Sundy JS
影响因子：
37.8
作者：
Choi, Hyon K.;Curhan, Gary
通讯作者：
Curhan, Gary
影响因子：
120.7
作者：
Sundy, John S.;Baraf, Herbert S. B.;Becker, Michael A.
通讯作者：
Becker, Michael A.