Novel Approaches to CD33-Directed Radioimmunotherapy

CD33 定向放射免疫治疗的新方法

• 批准号: 9913021
• 负责人: Roland Bruno Walter
• 金额: $ 68.63万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9913021
• 关键词: Actinium; Acute Myelocytic Leukemia; Address; Alpha Particles; Animals; Antibodies; Antibody Therapy; Antibody-drug conjugates; Antigen Targeting; Antigens; Astatine; Biodistribution; CD69 antigen; Caliber; Cell surface; Cells; Characteristics; Clinic; Clinical; Dangerousness; Daughter; Deposition; Distal; Gemtuzumab Ozogamicin; Genetic Diseases; Glycoproteins; Goals; Half-Life; Hematopoietic; Human; Human Anti-Mouse Antibody; Immune system; Immunization; Immunocompetent; Immunotherapy; Isotopes; Label; Leukemic Cell; Malignant - descriptor; Membrane; Minority Groups; Modeling; Mus; Neoplasms; Normal Cell; Nude Mice; Organ; PTPRC gene; Patients; Production; Property; Radiation; Radiation Tolerance; Radioimmunoconjugate; Radioimmunotherapy; Radioisotopes; Research Personnel; Risk; SET Domain; Safety; Testing; Therapeutic; Therapeutic Studies; Tissues; Toxic effect; Transplantation; Treatment Efficacy; Treatment outcome; Treatment-related toxicity; Variant; Xenograft Model; Xenograft procedure; acute myeloid leukemia cell; arm; base; cell killing; clinical development; conditioning; cost; early phase clinical trial; ethnic minority population; humanized mouse; improved; improved outcome; in vivo; in vivo Model; interest; lead candidate; leukemia; leukemic stem cell; mouse model; multidisciplinary; novel; novel strategies; preclinical study; therapeutic candidate; tumor

Antigen-specific immunotherapies have long been pursued for acute myeloid leukemia (AML). So far most exploited are antibodies targeting the membrane-distal V-set domain of CD33, a glycoprotein displayed on the cell surface of leukemic blasts in almost all cases and possibly leukemia stem cells in some. Improved survival of some patients with gemtuzumab ozogamicin validates this approach but many patients with CD33+ AML do not benefit from this antibody-drug conjugate, prompting interest in developing improved CD33-directed therapeutics. Because AML cells are exquisitely radiosensitive across the entire genetic disease spectrum, a- emitting radionuclides are ideal to arm anti-CD33 antibodies. Unlike b-emitters, they deliver a very high amount of radiation over just a few cell diameters, thereby enabling precise and efficient target cell kill (as few as 10 a- particle hits are sufficient to kill a malignant hematopoietic cell). Early clinical trials with an anti-CD33 antibody labeled with actinium-225 (225Ac-lintuzumab) have been conducted. Besides high cost, however, important shortcomings include the long half-life of 225Ac, leading to freely circulating radionuclide if not retained effectively in target cells, and the release of daughter radionuclides after decay of 225Ac with risk of associated toxicity to healthy tissues. We hypothesize that labeling with astatine-211 (211At), an a-emitter we have focused on because of its shorter half-life and because it decays without production of any long-lived or potentially dangerous daughter isotopes, will provide a novel, superior form of CD33-directed radioimmunotherapy (RIT). Using humanized mice, we have recently generated a panel of fully human antibodies recognizing either the V-set domain or, as the first group, the membrane-proximal C2-set domain of human CD33. Since the V-set but not C2-set domain is missing in some CD33 variants, C2-set domain-directed antibodies can recognize all naturally- occurring variants of CD33 (i.e. are “CD33PAN antibodies”). With these antibodies available, we now plan to optimize CD33-directed RIT for application in AML patients, focusing on 211At. To accomplish this task, we have assembled a multidisciplinary team of investigators with complementary expertise in developing radioimmunoconjugates and other antibody-based therapeutics for AML. Envisioning broad use, we will study 211At-CD33 RIT as “stand-alone” therapy and as augmentation of HCT conditioning, focusing on MHC- haploidentical in vivo models AML. Since many HCT candidates do not have an HLA-matched donor, facilitation of alternative donor HCT remains a critical unmet need, particularly for the extension of this lifesaving option to patients from ethnic minority groups. We expect results from our studies will be readily translatable into the clinic and are anticipated to have an important positive impact as they will provide the groundwork for a new treatment option for patients with AML and other CD33+ neoplasms, for whom current treatment outcomes are unsatisfactory.

抗原特异性免疫疗法长期以来一直被用于治疗急性髓系白血病(AML)。到目前为止大多数 利用的是针对CD33膜远端V-set结构域的抗体，CD33是一种显示在 几乎所有病例的白血病细胞表面都有白血病细胞，部分病例可能有白血病干细胞。提高存活率 在一些getuzumab患者中，ozogamicin验证了这种方法，但许多CD33+AML患者这样做 没有从这种抗体-药物结合物中受益，引发了开发改进的CD33导向的兴趣 治疗学。由于AML细胞在整个遗传疾病谱中都具有极高的辐射敏感性，因此- 发射放射性核素是武装抗CD33抗体的理想选择。与b型发射器不同的是，它们提供了非常高的排放量。 仅在几个细胞直径上的辐射，从而能够精确和有效地杀死目标细胞(低至10a- 粒子撞击足以杀死恶性造血细胞)。抗CD33抗体的早期临床试验 用Ac-225(225Ac-lintuzumab)标记。然而，除了高昂的成本，重要的是 缺点包括225Ac的半衰期很长，如果不能有效保留，就会导致放射性核素自由循环 在靶细胞中，以及225Ac衰变后释放的子体放射性核素有相关毒性的风险 健康的组织。我们假设，用我们关注的a排放物-211(211At)进行标记是因为 它较短的半衰期，因为它腐烂而没有产生任何长寿的或潜在的危险 子代同位素，将提供一种新颖的、优越的CD33导向放射免疫疗法(RIT)。vbl.使用 人源化小鼠，我们最近产生了一组完全人类的抗体，识别V-SET 或者，作为第一组，人CD33的膜近端C2-set结构域。因为V-set，但不是 在一些CD33变异体中缺少C2-SET结构域，C2-SET结构域定向抗体可以识别所有自然- CD33的变异体(即“CD33PAN抗体”)。有了这些抗体，我们现在计划 优化CD33导向的RIT在AML患者中的应用，重点是211At。为了完成这项任务，我们有 组建了一个由多学科调查人员组成的团队，他们在开发方面具有互补的专业知识 放射免疫结合物和其他以抗体为基础的治疗急性髓细胞白血病。展望广泛的用途，我们将研究 211At-CD33RIT作为单独的治疗和作为HCT调节的增强，侧重于MHC- 半相合的体内模型急性髓系白血病。由于许多血细胞移植候选人没有匹配的捐献者， 替代捐献者的血细胞移植仍然是一个关键的未得到满足的需求，特别是将这一挽救生命的选择延长到 少数民族患者。我们希望我们的研究结果可以很容易地应用于临床。 预计将产生重要的积极影响，因为它们将为新的治疗方法奠定基础 AML和其他CD33+肿瘤患者的选择，目前的治疗结果是 不能令人满意。