Serotherapy of B-cell neoplasms with anti-B4-blocked ricin: a phase I trial of daily bolus infusion.
Serotherapy of B-cell neoplasms with anti-B4-blocked ricin: a phase I trial of daily bolus infusion.
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DOI：
10.1182/blood.v79.3.576.bloodjournal793576
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发表时间：
1992
期刊：
影响因子：
20.3
通讯作者：
M. Grossbard;Arnold;Freedman;Jérôme;F. Coral;Victor;Goldmacher;L. Eliseo;N. Spector;K. Dear;J. Lambert;Walter;Blattler;James;Taylor;L. Nadler
中科院分区：
文献类型：
--
作者：
M. Grossbard;Arnold;Freedman;Jérôme;F. Coral;Victor;Goldmacher;L. Eliseo;N. Spector;K. Dear;J. Lambert;Walter;Blattler;James;Taylor;L. Nadler
抗B4封闭蓖麻毒素（Anti-B4-bR）是由抗B4单克隆抗体（MoAb）和蛋白毒素“封闭蓖麻毒素”组成的免疫毒素。“抗B4单克隆抗体针对在超过95%的正常和肿瘤B细胞上表达的B系限制性CD 19抗原。封闭蓖麻毒素是一种改变的蓖麻毒素衍生物，其通过化学封闭B链的半乳糖结合结构域来消除其非特异性结合。体外细胞毒性研究表明，抗B4-bR的IC 37为2 x 10（-11）mol/L，而天然蓖麻毒素为4 x 10（-12）mol/L。在25例难治性B细胞恶性肿瘤患者中进行了I期剂量递增临床试验。抗B4-bR通过每日1小时推注给药，连续5天，剂量范围为1 μ g/kg/d至60 μ g/kg/d。在接受最大耐受剂量50 μ g/kg/d治疗5天（总剂量为250 μ g/kg）的大多数患者中，血清水平一过性高于1 nmol/L。剂量限制性毒性定义为肝转氨酶一过性、可逆性3级升高，但不损害肝脏合成功能。轻微毒性包括一过性低白蛋白血症、血小板减少症和发热。9例患者检测到人抗鼠抗体和人抗蓖麻毒素抗体。观察到1例完全缓解、2例部分缓解和8例混合或一过性缓解。这些结果显示了抗B4-bR的体外和体内细胞毒性，并表明该免疫毒素可每日推注给药5天，具有可耐受的可逆毒性。
Anti-B4-blocked Ricin (Anti-B4-bR) is an immunotoxin comprised of the anti-B4 monoclonal antibody (MoAb) and the protein toxin "blocked ricin." The anti-B4 MoAb is directed against the B-lineage-restricted CD19 antigen expressed on more than 95% of normal and neoplastic B cells. Blocked ricin is an altered ricin derivative that has its nonspecific binding eliminated by chemically blocking the galactose binding domains of the B chain. In vitro cytotoxicity studies demonstrate that the IC37 of Anti-B4-bR is 2 x 10(-11) mol/L compared with 4 x 10(-12) mol/L for native ricin. A phase I dose escalation clinical trial was conducted in 25 patients with refractory B-cell malignancies. Anti-B4-bR was administered by daily 1-hour bolus infusion for 5 consecutive days at doses ranging from 1 microgram/kg/d to 60 micrograms/kg/d. Serum levels above 1 nmol/L were achieved transiently in the majority of patients treated at the maximum tolerated dose of 50 micrograms/kg/d for 5 days for a total dose of 250 micrograms/kg. The dose-limiting toxicity was defined by transient, reversible grade 3 elevations in hepatic transaminases, without impaired hepatic synthetic function. Minor toxicities included transient hypoalbuminemia, thrombocytopenia, and fevers. Human antimouse antibody and human anti-ricin antibody were detected in nine patients. One complete response, two partial responses, and eight mixed or transient responses were observed. These results show the in vitro and in vivo cytotoxicity of Anti-B4-bR and indicate that this immunotoxin can be administered as a daily bolus infusion for 5 days with tolerable, reversible toxicity.