Immunotoxin Protocols Under the Medicine Branch: Targeted Therapy of Lymphoid Ne

该项目领域建立在以前的观察结果（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CD 22和抗CD 19决定簇的鼠单克隆抗体可以安全地给予患者，并且在抗CD 22试剂的情况下会产生有意义的反应。我们之前已经完成了一项抗CD 19+抗CD 22免疫毒素联合治疗的I期研究，基于临床前数据，该联合治疗可能更有效。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辐射患者。实验室研究支持CD 19免疫毒素的聚集也可能导致这种现象的概念。临床前研究已经确定了一种安全的储存和解冻程序，可最大限度地减少免疫毒素的聚集。这些研究最近已发表（Clin. Cancer Res.6：1302-1313，2000）。未来的计划是集中在一个高度纯化的“单价”免疫毒素，其中一个A链连接到一个抗体分子作为一个单一的代理。实现这一目标的方案已得到NCI IRB的批准，将于2000年底开始实施。

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 has been approved by the NCI IRB and will commence in late 2000.