IMMUNOTHERAPY TRIALS IN LEUKEMIA

白血病的免疫治疗试验

• 批准号: 6269155
• 负责人: DAVID A SCHEINBERG
• 金额: $ 26.93万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-30 至 1998-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6269155
• 关键词: CD antigens; alpha radiation; antileukemic agent; antitumor antibody; beta radiation; cell sorting; cellular immunity; clinical trials; human subject; human therapy evaluation; in situ hybridization; interleukin 2; iodine; lymphokine activated killer cell; monoclonal antibody; myelogenous leukemia; neoplasm /cancer immunotherapy; neoplasm /cancer remission /regression; polymerase chain reaction; recombinant DNA

This grant proposes phase I and II trials of several constructs of recombinant humanized anti-CD33 (HuG1-M195) for therapy of myelogenous leukemia. HuG1-M195 is a high affinity, recombinant human monoclonal antibody reactive with CD33, an antigen expressed by myelogenous leukemia cells. Previous clinical trials with murine M195 have shown that M195 rapidly targets, saturates and internalizes into myelogenous leukemia cells in different compartments of the body and, when radiolabeled, can kill more than 99% of leukemia cells even in refractory patients with high leukemia burden (> 1 kg). Murine 131/I-M195 is limited by lack of intrinsic effector activity, bystander cell kill due to the long range beta of iodine-131, and also neutralization by human anti-mouse antibody (HAMA). Therefore, several humanized M195 constructs were developed to solve these problems. In vitro, HuG1-M195 is capable of mediating specific antibody-dependent cellular cytotoxicity against acute myelogenous leukemia cells, particularly in the presence of low doses of IL-2. A Phase I trial of the HuG1-M195 suggests pharmacology, biodistribution and a safety profile similar to the mouse M195. In addition, no HAMA has been seen with the humanized form. Because of the rapid, specific and saturable delivery of M195 to leukemia cells at low doses, this antigen-antibody-disease system provides "proof of concept" tests of two basic applications of mAb and mAb constructs: Ablative therapy of large burden tumors and elimination of minimal disease after induction or debulking therapy. Each trial will focus on a different important issue: 3 constructs designed to kill large numbers of cells will be tested. Beta emitting 131/I-HuG1-M195 will be tested in a phase I/II trial before bone marrow transplant. Alpha-emitting 213/Bi-HuG1-M195 or a homo-dimeric HuG1-M195 (HdIgG-M195), (with enhanced biochemical properties) labeled with 131/I, will be tested in phase I trials. One strategy designed to kill smaller numbers of residual cells in patients in clinical remission or in early relapse will be tested also: HuG1-M195, that works via IL-2 upregulated ADCC (HuG1-M195 plus low dose IL-2), will be evaluated in a phase I trial. In these studies, PCR, FISH, and flow cytometric measures of minimal disease will be applied to assess outcome as well. Though leukemias are not among the most common neoplasms, the advantages of this system should lead to advances that may be applied generally.

这笔赠款提议对几种结构进行第一期和第二期试验 重组人源化抗 CD33 (HuG1-M195) 用于治疗骨髓性骨髓瘤 白血病。 HuG1-M195 是一种高亲和力的重组人单克隆抗体 与 CD33（骨髓性白血病表达的抗原）反应的抗体 细胞。 之前针对小鼠 M195 的临床试验表明，M195 快速靶向、饱和并内化为骨髓性白血病 身体不同部位的细胞，当进行放射性标记时，可以 即使是高危难治性患者，也能杀死 99% 以上的白血病细胞 白血病负担（>1公斤）。 鼠 131/I-M195 由于缺乏 内在效应器活性，由于远距离而导致旁观者细胞死亡 碘 131 的 beta，也可被人抗小鼠抗体中和 （哈马）。 因此，开发了几种人源化 M195 构建体 解决这些问题。 在体外，HuG1-M195 能够介导 特异性抗体依赖性细胞毒性 骨髓性白血病细胞，特别是在低剂量的情况下 IL-2。 HuG1-M195 的 I 期试验表明药理学， 生物分布和安全性与小鼠 M195 类似。 在 此外，还没有看到人化形式的 HAMA。 因为 将 M195 快速、特异且饱和地递送至白血病细胞 剂量，这种抗原-抗体-疾病系统提供了“概念证明” mAb 和 mAb 构建体的两种基本应用的测试：消融 治疗大负荷肿瘤并消除术后微小疾病 诱导或减瘤治疗。 每个试验将侧重于不同的 重要问题：3种旨在杀死大量细胞的结构将 被测试。 Beta 发射 131/I-HuG1-M195 将在 I/II 阶段进行测试 骨髓移植前进行试验。 α发射 213/Bi-HuG1-M195 或 同源二聚体 HuG1-M195 (HdIgG-M195)，（具有增强的生化 属性）标有 131/I，将在第一阶段试验中进行测试。 一 旨在杀死患者体内少量残留细胞的策略 还将测试临床缓解或早期复发：HuG1-M195， 通过 IL-2 上调 ADCC（HuG1-M195 加低剂量 IL-2）发挥作用，将 在第一阶段试验中进行评估。 在这些研究中，PCR、FISH 和流式细胞术 微小疾病的细胞计数测量将用于评估结果 以及。 尽管白血病不是最常见的肿瘤， 该系统的优点应该会带来可应用的进步 一般来说。