Pretargeted radioimmunotherapy (PRIT) for treatment of non-Hodgkin's lymphoma (NHL): initial phase I/II study results.
Pretargeted radioimmunotherapy (PRIT) for treatment of non-Hodgkin's lymphoma (NHL): initial phase I/II study results.
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用于治疗非霍奇金淋巴瘤 (NHL) 的预靶向放射免疫疗法 (PRIT)：初始 I/II 期研究结果。
DOI：
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发表时间：
2000
影响因子：
3.4
通讯作者：
J. Reno
中科院分区：
文献类型：
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作者：
P. Weiden;H. Breitz;O. Press;J. W. Appelbaum;J. K. Bryan;Sally Gaffigan;Diane M. Stone;D. Axworthy;D. Fisher;J. Reno
研究了非霍奇金淋巴瘤（NHL）患者的预靶向放射免疫治疗（PRIT）。本研究中使用的PRIT方法是一种多步递送系统，其中使用抗体将链霉亲和素靶向肿瘤相关抗原受体，然后使用生物素将90 Y放射性同位素靶向肿瘤定位的链霉亲和素。将一种称为C2 B8或利妥昔单抗的嵌合IgG 1抗CD 20抗体与链霉亲和素（SA）偶联，并给予NHL患者。34小时后，给予清除剂，合成生物素-N-乙酰半乳糖胺，以从循环中清除非局部结合物。最后，给予DOTA-生物素配体，用111 In标记用于成像和/或用90 Y标记用于治疗。10例复发或难治性NHL患者进行了研究。在3例患者中，C2 B8/SA偶联物用痕量186 Re进行放射性标记，以使用伽马照相机成像评估药代动力学和生物分布。7名患者接受了30或50 mCi/m2 90 Y DOTA-生物素。Re-186 C2 B8/SA图像证实缀合物定位于已知的肿瘤部位，并且清除剂从循环中除去> 95%的缀合物。放射性标记的生物素很好地定位于肿瘤。未结合的放射性生物素迅速从全身和正常器官排出。计算的平均肿瘤剂量为29 +/- 23 cGy/mCi 90 Y，平均全身剂量为0.76 +/- 0.3 cGy/mCi 90 Y，导致平均肿瘤与全身剂量比为38：1。仅观察到I/II级非血液学毒性。血液学毒性也不严重;即，接受30或50 mCi/m2的90 Y-DOTA-生物素的7名患者中的5名仅经历短暂的III级（但没有IV级）血液学毒性。虽然10例患者中有6例对链霉亲和素产生了体液免疫应答，但这些应答是延迟和短暂的，因此可能不排除再次治疗。接受30或50 mCi/m2 90 Y治疗的7例患者中有6例实现了客观肿瘤消退，包括3例完全缓解和1例部分缓解。在这些NHL患者中使用PRIT实现的肿瘤与全身剂量比（38：1）的估计值高于使用常规RIT的其他研究中实现的估计值。毒性轻微，肿瘤反应令人鼓舞。PRIT显然值得在NHL患者中进行更多研究。
Pretargeted radioimmunotherapy (PRIT) was investigated in patients with non-Hodgkin's lymphoma (NHL). The PRIT approach used in this study is a multi-step delivery system in which an antibody is used to target streptavidin to a tumor associated antigen receptor, and subsequently biotin is then used to target 90Y radioisotope to the tumor localized streptavidin. A chimeric, IgG1, anti-CD20 antibody, designated C2B8 or Rituximab, was conjugated to streptavidin (SA) and administered to patients with NHL. Thirty-four hours later, a clearing agent, synthetic biotin-N-acetyl-galactosamine, was administered to remove non-localized conjugate from the circulation. Finally, a DOTA-biotin ligand, labeled with 111In for imaging and/or 90Y for therapy was administered. Ten patients with relapsed or refractory NHL were studied. In three patients, the C2B8/SA conjugate was radiolabeled with a trace amount of 186Re in order to assess pharmacokinetics and biodistribution using gamma camera imaging. Seven patients received 30 or 50 mCi/m2 90Y DOTA-biotin. Re-186 C2B8/SA images confirmed that the conjugate localized to known tumor sites and that the clearing agent removed > 95% of the conjugate from the circulation. Radiolabeled biotin localized well to tumor. Unbound radiobiotin was rapidly excreted from the whole body and normal organs. The mean tumor dose calculated was 29 +/- 23 cGy/mCi 90Y and the average whole body dose was 0.76 +/- 0.3 cGy/mCi 90Y, resulting in a mean tumor to whole body dose ratio of 38:1. Only grade I/II non-hematologic toxicity was observed. Hematologic toxicity was also not severe; i.e., five of the seven patients who received 30 or 50 mCi/m2 of 90Y-DOTA-biotin experienced only transient grade III (but no grade IV) hematologic toxicity. Although six of ten patients developed humoral immune responses to the streptavidin, these were delayed and transient and hence may not preclude retreatment. Six of seven patients who received 30 or 50mCi/m2 90Y achieved objective tumor regression, including three complete and one partial response. The estimate of tumor to whole body dose ratio (38:1) achieved with PRIT in these NHL patients is higher than has been achieved in other studies using conventional RIT. Toxicity was mild and tumor response encouraging. PRIT clearly deserves additional study in patients with NHL.