IMMUNOTHERAPY TRIALS IN LEUKEMIA

这笔赠款建议对几个结构进行第一和第二阶段的试验 重组人源化抗CD33(HuG1-M195)治疗骨髓性白血病 白血病。HuG1-M195是一株高亲和力的重组人单抗 与髓系白血病表达的抗原CD33的抗体反应 细胞。之前对小鼠M195的临床试验表明，M195 快速靶向、饱和并内化为髓系白血病 位于身体不同隔室的细胞，当被放射性标记时，可以 即使在难治性高白血病患者中也能杀死99%以上的白血病细胞 白血病负担(&gt；1公斤)。小鼠131/I-M195细胞缺乏 内在效应器活性，旁观者细胞因长距离杀伤 碘-131的β，以及人抗鼠抗体的中和作用 (哈马)。因此，几个人性化的M195结构被开发为 解决这些问题。在体外，HuG1-M195能够介导 抗急性白血病的特异性抗体依赖的细胞毒作用 髓系白血病细胞，特别是在低剂量的 IL-2。HUG1-M195的I期试验表明， 生物分布和类似于小鼠M195的安全性。在……里面 此外，人性化的形式还没有看到哈马。因为 快速、特异、可饱和的M195低分子转导白血病细胞 剂量，这个抗原-抗体-疾病系统提供了“概念证明” 单抗和单抗构建的两种基本应用的测试：消融 大负担肿瘤的治疗与术后微小病变的消除 诱导或脱髓疗法。每一次审判都将侧重于不同的 重要问题：设计用于杀死大量细胞的3种结构将 接受测试。发射131/I-HuG1-M195的测试版将在I/II阶段进行测试 骨髓移植前的试验。阿尔法发射213/BiHuG1-M195或 一种均二聚体HuG1-M195(HdIg G-M195)，(具有增强的生化 标有131/I的药物)将在第一阶段试验中进行测试。一 旨在杀死患者体内较小数量残留细胞的策略 临床缓解或早期复发也将进行测试：HuG1-M195， 这是通过IL-2上调的ADCC(HuG1-M195加低剂量IL-2)起作用的，Will 在第一阶段试验中进行评估。在这些研究中，聚合酶链式反应、FISH和Flow 微小疾病的细胞学测量将被应用于评估结果 也是。虽然白血病不是最常见的肿瘤，但 这一系统的优点应该会带来可以应用的进步 一般说来。

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.