Immunotoxin Protocols Under the Medicine Branch: Targete

该项目领域建立在先前的观察（Blood 85: 3457, 1995和Blood 88:1188, 1996）的基础上，即用去糖基化蓖麻毒素A链构建的免疫毒素和分别针对抗cd22和抗cd19决定因子的小鼠单克隆抗体可以安全地给予患者，并且在抗cd22试剂的情况下会引起有意义的反应。我们之前已经完成了抗cd19 +抗cd22免疫毒素联合的I期研究，基于临床前数据，该联合可能更有效。不幸的是，我们遇到了与剂量无关的剂量限制性毒性。这包括血管渗漏综合征和溶血性尿毒症综合征在以前的放疗患者。实验室研究支持CD19免疫毒素的聚集也可能导致这种现象的观点。临床前研究已经确定了一种安全的储存和解冻程序，可以最大限度地减少免疫毒素的聚集。这些研究最近已发表（克林）。癌症，6:1302-1313,2000)。未来的计划是专注于一种高度纯化的“单价”免疫毒素，其中一个a链作为单一剂连接到一个抗体分子上。实现这一目标的协议是开放的。一项对蓖麻毒素A链免疫毒素的系统回顾显示，在接受过放射治疗的患者中，与这些药物相关的不良事件有很强的相关性（临床癌症研究7:255,2001）。这已纳入当前方案的资格标准。

This project area builds on previous observations (Blood 85: 3457, 1995 and Blood 88:1188, 1996) that immunotoxins constructed with deglycosylated ricin A chain and murine monoclonal antibodies directed to anti-CD22 and anti-CD19 determinants respectively could be given safely to patients and in the case of the anti-CD22 reagent cause meaningful responses. We had previously completed a Phase I study of the combination of the anti-CD19 + anti-CD22 immunotoxins, based on pre clinical data that the combination might be more effective. Unfortunately, we encountered dose-limiting toxicity in a way that did not correlate with dose. This consisted of vascular leak syndrome and a hemolytic-uremic syndrome in previously irradiated patients. Laboratory studies support the concept that aggreggation of the CD19 immunotoxin also may have contributed to this phenomenon. Preclinical studies have defined a safe storage and thawing procedure that minimizes aggregation of immunotoxin. These studies have recently been published(Clin. Cancer Res. 6:1302-1313, 2000). The future plan is to focus on a highly purified "monovalent" immunotoxin where one A chain is joined to one antibody molecule as a single agent. The protocol to accomplish this is open for accual. A systematic review of experience with ricin A chain immunotoxins has revealed a strong association of adverse events related to these agents in patients with prior radiation therapy(Clinical Cancer Research 7: 255, 2001). This has been incorporated into the eligibility criteria for the current protocol.