TOXINS TARGETED TO THE CELL MEMBRANE--DISRUPTION OF SIGNAL TRANSDUCTION

该项目寻求开发通过靶向细胞来发挥作用的制剂。 B细胞淋巴瘤负性调节细胞的表面成分 通过对细胞信号转导的影响而生长。这些实体 作为单一药物或与靶向脱糖基联合使用 蓖麻毒素-A链免疫毒素将被开发为新的治疗药物。 有待探索的假设是，联合治疗与 靶向毒素和负生长调节分子将导致 与任何一种药物相比，改善了治疗指数 独自一人。在本报告所述期间，该项目完成了 针对CD19的毒素IgG-HD37-SMPT-DGA的I期临床试验。 治疗10例，OCR 1例，PR 1例，MR 2例，SD 2例，PD 4例，NE 1例， 一种迄今未见报道的毒性，即肢端青紫，是免疫球蛋白HD37-SMPT-DGA 被认可了。有趣的是，在相关的实验室研究中，我们观察到 用于构建毒素的抗体HD37的活性与 免疫毒素对CD19淋巴瘤细胞增殖的抑制作用 细胞系。对HD37抗体的研究表明，在12小时内 除了指数级生长的细胞外，pRb的低磷酸化 观察到，随着G1的积累。这一结果表明 抗体HD37与Ig G-RFB4-SMPT-DGA的结合策略 临床活性免疫毒素。联合应用的第一阶段试验 Ig G-RFB4-SMPT-DGA和Ig G-HD37-SMPT-DGA正在进行中，将提供 比较抗体加治疗指数的依据 免疫毒素组合。

This project seeks to develop agents which act by targeting a cell surface component of B-cell lymphomas which can negatively regulate cell growth by an effect on cellular signal transduction. These entities either as single agents or in combination with targeted deglycosylated ricin-A chain immunotoxins will be developed as novel therapeutic agents. The hypothesis to be explored is that the combined therapy with a targeted toxin and the negative growth regulatory molecule will lead to improved therapeutic index in comparison to that achieved by either agent alone. During the period of this report, this project has completed a Phase I clinical trial of IgG-HD37-SMPT-dgA, a toxin targeted at CD19. Of 10 patients treated, there were OcR, 1 PR, 2 MR, 2 SD, 4 PD, 1 NE, and a hitherto unreported toxicity, acral cyanosis, of IgG-HD37-SMPT-dgA was recognized. Interestingly, in correlative laboratory studies we observed that the antibody used to construct the toxin, HD37, was as active as the immunotoxin in decreasing cell proliferation in a CD 19-bearing lymphoma cell line. Studies with HD37 antibody reveal that within 12 hr of addition to exponentially growing cells, hypophosphorylation of pRb was observed, along with accumulation in G1. This result suggests the strategy of combining the antibody HD37 with IgG-RFB4-SMPT-dgA, a clinically active immunotoxin. A Phase I trial of the combination of IgG-RFB4-SMPT-dgA and IgG-HD37-SMPT-dgA is in progess and will provide the basis for comparing therapeutic index of the antibody plus immunotoxin combination.