IMMUNOTOXIN PROTOCOLS--TARGETED THERAPY OF LYMPHOID NEOPLASMS

“这个项目领域建立在以前的观察基础上 （Blood 85：3457，1995和Blood 88：1188，1996）， 用去糖基化蓖麻毒素A链构建的免疫毒素， 抗CD 22和抗CD 19的鼠单克隆抗体 决定因素分别可以安全地给予患者， 抗CD 22试剂的情况下引起有意义的反应。 在本报告所述期间，我们完成了第一阶段 抗-CD 19+抗-CD 22的组合的研究 免疫毒素，基于临床前数据， 可能会更有效。不幸的是，我们遇到了 剂量限制性毒性，与剂量无关。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 也可能是造成这种现象的原因。临床前研究 已经定义了一个安全的储存和解冻程序， 免疫毒素的聚集。目前第一阶段的重点是 高度纯化形式的抗CD 22构建体，其具有两个 每个免疫球蛋白分子的去糖基化蓖麻毒素A链。这是 在双A链的情况下， 分子，并在化疗的情况下与化疗组合， 单蓖麻毒素A链加合物。"

"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. During the period covered by this report, we 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 current Phase I is now focusing on highly purified versions of the anti- CD22 construct which has two deglycosylated ricin A chains per immunoglobulin molecule. This is being studied as a single agent in the case of the double A chain molecule, and in combination with chemotherapy in the case of the mono-ricin A chain adduct."