IMMUNOTHERAPY TRIALS IN LEUKEMIA

该补助金提出了几种结构的I期和II期试验， 用于治疗骨髓性白血病的重组人源化抗-CD 33（HuG 1-M195） 白血病 HuG 1-M195是一种高亲和力的重组人单克隆抗体， 与髓细胞白血病表达的抗原CD 33反应的抗体 细胞 先前的小鼠M195临床试验表明，M195 快速靶向、饱和并内化为骨髓性白血病 细胞在身体的不同隔室，当放射性标记，可以 杀死超过99%的白血病细胞，即使在高浓度的难治性患者中也是如此。 白血病负荷（> 1 kg）。 小鼠131/I-M195由于缺乏 内在效应物活性，由于长距离的旁观者细胞杀伤 β碘-131，以及人抗小鼠抗体中和 （HAMA）. 因此，开发了几种人源化M195构建体， 解决这些问题。 在体外，HuG 1-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 IL-2。 HuG 1-M195的I期试验表明药理学， 生物分布和安全性与小鼠M195相似。 在 此外，在人源化形式中没有观察到HAMA。 因为 M195在低浓度下向白血病细胞的快速、特异性和可饱和递送 剂量，这种抗原-抗体-疾病系统提供了“概念证明” mAb和mAb构建体的两种基本应用的测试：消融 治疗大负荷肿瘤和消除微小疾病后， 诱导或减积治疗。 每次审判都将集中在一个不同的 重要问题：3种设计用于杀死大量细胞的结构将 得到考验 β发射131/I-HuG 1-M195将在I/II阶段进行测试 骨髓移植前的临床试验 α-发射213/Bi-HuG 1-M195或 同源二聚体HuG 1-M195（HdIgG-M195），（具有增强的生物化学活性， 特性）标记的131/I，将在I期试验中进行测试。 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：HuG 1-M195， 通过IL-2上调ADCC（HuG 1-M195加低剂量IL-2）发挥作用， 在I期试验中进行评估。 在这些研究中， 将应用微小病变的细胞计数测量来评估结果 也 虽然白血病不是最常见的肿瘤， 该系统的优点应导致可应用的进步 一般来说。

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.