RECOMBINANT ANTI CD33 ANTIBODY FOR AML

用于 AML 的重组抗 CD33 抗体

• 批准号: 2443005
• 负责人: DAVID A SCHEINBERG
• 金额: $ 22.59万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-26 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2443005
• 关键词: CD antigens; acidity /alkalinity; acute myelogenous leukemia; antileukemic agent; antitumor antibody; athymic mouse; bismuth; cell mediated cytotoxicity; cell type; drug resistance; human subject; immune tolerance /unresponsiveness; immunochemistry; immunoconjugates; laboratory mouse; membrane potentials; minimal residual disease; multidrug resistance; neoplasm /cancer immunotherapy; neoplasm /cancer pharmacology; neoplasm /cancer radionuclide therapy; radionuclides; radiopharmacology; tissue /cell culture

Myeloid leukemias of adults remain largely incurable. The long term goals of this program are to develop monoclonal antibody (mAb)-based therapeutic agents for myeloid leukemia. Over the last 2 1/2 years on this RO1, we have constructed new recombinant CDR grafted humanized antiCD33 mAb (HuMl95) and characterized their biology and biochemistry. This renewal grant builds on the prior work and proposes development of a novel alpha emitting HuMl95, study of the native immune function of the mAb in conjunction with cytokines, as well as an exploration of newly observed immunological resistance to HuM195 constructs. Clinical trials with murine M195 have now shown that M195 rapidly targets, saturates and internalizes into myelogenous leukemia cells in different compartments of the body at low doses and, when radiolabeled, can kill more than 99% of leukemia cells even in refractory patients with high leukemia burden (> 1 kg). Murine 131I-M195 is limited by lack of intrinsic effector activity,, bystander cell kin due to the long range beta of iodine-131, and also neutralization by human anti-mouse antibody (HAMA). HuMl95 has recently entered clinical study with similar pharmacology but without immunogenicity. This antigen- antibody-disease system allows tests of applications of potent radiolabeled mAb constructs and native mAb to eliminate minimal residual disease: 1. We will approach the radio-ablative strategy by developing a more feasible alpha-particle emitting HuM 195. This first aim is based on newly formulated Bismuth-213 radiochemistry that allows us to purify a chelatable radiometal that does not have dangerous gamma emissions. 2. In vitro, HuMl95 is capable of mediating specific potent antibody-dependent cellular cytotoxicity (ADCC) against myelogenous leukemia cells, particularly in the presence of low doses of IL-2. A second aim of this study is to explore the interaction of HuM 195 and cytokines in ADCC. 3. We recently observed that MDR HL60 cells were also cross- resistant to HuM 195-based immunotoxins, radioconjugates, and complement-mediated killing. A third aim proposes to study and explain this new immunological resistance; electrophysical studies will be done on individual cells and on populations. This may have wide implications for immunotherapy. 4. Finally, in order to more quickly study the novel alpha particle emitting constructs we propose to develop a CD33 positive, reproducible leukemia model in mice.

成年人的髓样白血病在很大程度上无法治愈。长期目标 该程序的基于单克隆抗体（MAB）的治疗 髓样白血病的特工。在过去的2 1/2年中，我们 已经构建了新的重组CDR接枝的人源化抗D33 mAb （Huml95）并描述了它们的生物学和生物化学。这个更新 格兰特以先前的工作为基础，并提议开发新颖的alpha 发射HUML95，研究mAb的天然免疫功能 与细胞因子的结合以及对新观察的探索 对HUM195结构的免疫抗性。鼠的临床试验 M195现在已经表明M195迅速靶向饱和并内在化 进入身体不同隔室的骨髓性白血病细胞 低剂量，当放射性标记时会杀死超过99％的白血病细胞 即使在白血病高负担（> 1 kg）的难治性患者中。鼠 131i-M195受到固有效应活性的限制，旁观者 细胞亲戚由于碘131的远距离beta而引起的，并且也中和 人类抗小鼠抗体（Hama）。 HUML95最近进入了临床 具有相似药理的研究，但没有免疫原性。这个抗原 - 抗体 - 疾病系统允许测试有效的应用 放射标记的mAb构建体和天然mAb，以消除最小残留物 疾病：1。我们将通过开发一个 更可行的α粒子发出嗡嗡声195。这个第一个目标是基于 新配制的BiSmuth-213放射化学，使我们能够净化一个 没有危险的伽玛排放的可切除辐射量。 2。in 体外，HUML95能够介导特定的有效抗体依赖性 针对脊髓性白血病细胞的细胞细胞毒性（ADCC）， 特别是在低剂量的IL-2的情况下。第二个目标 研究是为了探索ADCC中HUM 195和细胞因子的相互作用。 3。 我们最近观察到MDR HL60细胞也具有交叉抗性 基于195的免疫毒素，放射性轭物和补体介导的杀戮。 第三个目标建议研究和解释这种新的免疫学 反抗;电物理研究将在单个细胞上进行，并 关于人口。这可能对免疫疗法具有广泛的影响。 4。 最后，为了更快地研究新型的α粒子发射 我们建议开发CD33阳性，可再生性白血病的结构 小鼠模型。