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.

该赠款提出了第一阶段和第二阶段的试验 重组人性化抗CD33（HUG1-M195）用于治疗骨髓 白血病。 HUG1-M195是一种高亲和力，重组人类单克隆 抗体与CD33反应性，CD33是由脊髓性白血病表达的抗原 细胞。 先前使用鼠M195的临床试验表明M195 迅速靶向，饱和并内化到骨髓性白血病 体内不同隔室的细胞，当放射线标记时，可以 即使在耐火性患者中，杀死超过99％的白血病细胞 白血病负担（> 1公斤）。 鼠131/i-m195受到缺乏的限制 固有效应子活性，由于远距离造成的旁观者细胞杀死 碘-131的β，以及人类抗小鼠抗体中和 （哈马）。 因此，开发了几种人性化的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对急性 髓质白血病细胞，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， 生物分布和与小鼠M195相似的安全性。 在 此外，没有人源化形式可以看到哈马。 因为 M195向白血病细胞的快速，特异性和饱和递送 剂量，这种抗原 - 抗体 - 疾病系统提供了“概念证明” MAB和MAB构建体的两个基本应用的测试：烧蚀 治疗巨大的负担肿瘤和消除最小疾病之后 诱导或延迟疗法。 每个审判都将集中于不同的 重要问题：3种旨在杀死大量细胞的结构将 进行测试。 Beta发射131/i-Hug1-M195将在I/II期中进行测试 骨髓移植前试验。 α发射213/bi-Hug1-M195或 同型二聚体HUG1-M195（HDIGG-M195）（具有增强的生化 标记为131/i的属性将在I期试验中进行测试。 一 旨在杀死患者中少量残留细胞的策略 临床缓解或早期复发也将进行测试：HUG1-M195， 通过IL-2上调的ADCC（HUG1-M195加上低剂量IL-2）的作用，将 在I期试验中进行评估。 在这些研究中，PCR，鱼和流动 将采用最小疾病的细胞仪度量来评估结果 也是如此。 尽管白血病不是最常见的肿瘤，但 该系统的优势应导致可能应用的进步 一般来说。