IMMUNOTOXIN PROTOCOLS UNDER THE MEDICINE BRANCH: TARGETED THERAPY OF LYMPHOID NEO

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。随后开始了替代I期，重点是高度纯化的抗CD22结构，每个免疫球蛋白分子有两个去糖基化的蓖麻毒素A链，但不幸的是，这种结构已经无法从供应商处获得。未来的计划是专注于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将在2000财年推出。-免疫治疗，淋巴瘤，-人体受试者和人体组织，液体，细胞等。

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. A replacement Phase I which focused on a highly purified version of the anti- CD22 construct which has two deglycosylated ricin A chains per immunoglobulin molecule was then commenced, but unfortunately this construct has become unavailable from the supplier. 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 will be introduced during FY 2000. - immunotherapy, lymphoma, - Human Subjects & Human Tissues, Fluids, Cells, etc.