RECOMBINANT ANTI CD33 ANTIBODY FOR AML

用于 AML 的重组抗 CD33 抗体

基本信息

批准号：
2096568
负责人：
DAVID A SCHEINBERG
金额：
$ 21.22万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-09-26 至 1998-06-30
项目状态：
已结题

项目摘要

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.

成人髓系白血病在很大程度上仍然无法治愈。长期目标该计划的主要目标是开发基于单克隆抗体 (mAb) 的治疗药物治疗骨髓性白血病的药物。在过去的 2 1/2 年里，我们在这个 RO1 上构建了新的重组CDR移植人源化抗CD33 mAb （HuMl95）并表征了它们的生物学和生物化学。此次续订拨款建立在先前工作的基础上，并提议开发一种新颖的阿尔法发射HuMl95，单克隆抗体天然免疫功能的研究与细胞因子结合，以及新观察到的探索对 HuM195 构建体的免疫抗性。小鼠临床试验 M195现在已经表明M195快速瞄准、饱和和内化进入身体不同部位的骨髓性白血病细胞低剂量，经放射性标记后，可杀死 99% 以上的白血病细胞即使是白血病负担高（> 1 kg）的难治性患者。鼠类 131I-M195 由于缺乏内在效应子活性而受到限制，，旁观者由于碘 131 的长程 β 以及中和作用，细胞亲和力增强通过人抗小鼠抗体（HAMA）。 HuMl95最近已进入临床研究具有相似的药理学但无免疫原性。这种抗原—— 抗体疾病系统允许测试有效的应用放射性标记的 mAb 构建体和天然 mAb，以消除最小残留疾病： 1. 我们将通过开发一种放射消融策略来实现更可行的α粒子发射HuM 195。第一个目标是基于新配制的 Bismuth-213 放射化学使我们能够纯化可螯合的放射性金属，不具有危险的伽马射线发射。 2. 在在体外，HuMl95 能够介导特异性有效的抗体依赖性针对骨髓性白血病细胞的细胞毒性（ADCC），特别是在低剂量 IL-2 存在的情况下。这样做的第二个目标研究目的是探讨ADCC中HuM 195和细胞因子的相互作用。 3. 我们最近观察到 MDR HL60 细胞也对 HuM 具有交叉耐药性基于 195 的免疫毒素、放射性结合物和补体介导的杀伤。第三个目标是研究和解释这种新的免疫学反抗;将对单个细胞进行电物理研究关于人口。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α粒子发射我们建议开发一种 CD33 阳性、可复制的白血病构建体小鼠模型。