Novel Approaches to CD33-Directed Radioimmunotherapy

CD33 定向放射免疫治疗的新方法

• 批准号: 10601434
• 负责人: Roland Bruno Walter
• 金额: $ 61.08万
• 依托单位: FRED HUTCHINSON CANCER 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/10601434
• 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; 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; therapeutically effective; 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.

长期以来一直在追求抗原特异性免疫疗法（AML）。到目前为止 被利用的是针对CD33膜偏见的V-stet结构域的抗体，在 在几乎所有情况下，白血病的细胞表面爆炸，有些人可能会在某些情况下进行白血病干细胞。改善生存 在某些患有gemtuzumab ozogamicin的患者中，有许多CD33+ AML的患者DO 这种抗体 - 药物缀合物不受益受 疗法。由于AML细胞在整个遗传疾病谱中完全敏感 发射放射线非常适合手臂抗CD33抗体。与b-emitter不同，他们提供的数量很高 仅在几个细胞直径上的辐射，从而实现精确有效的靶细胞杀伤（只有10个A- 粒子命中足以杀死恶性造血细胞）。抗CD33抗体的早期临床试验 已经进行了用阳式225（225AC-LINTUZUMAB）标记的。但是，除了高昂的成本外，重要的是 缺点包括225AC的长半衰期，如果没有有效保留的话，会导致自由循环放射线 在靶细胞中，腐烂225AC后的女儿放射线释放，与毒性相关的风险 健康的组织。我们假设使用Astatine-211（211AT）标记，我们专注于A-Emitter，因为 它的半衰期较短，并且因为它没有生产任何长期或潜在危险的产生 女儿同位素将提供一种新型的CD33定向放射免疫疗法（RIT）的新型形式。使用 人源化的小鼠，我们最近生成了一组完全人类的抗体，以识别V-stet 域或作为第一组的人类CD33的膜膜C2-set结构域。由于V-stet但不是 在某些CD33变体中缺少C2-set域，C2-set域定向抗体可以自然识别 - 发生CD33的变体（即“ CD33PAN抗体”）。有了这些抗体，我们现在计划 优化CD33指导的RIT用于AML患者，重点是211AT。为了完成这项任务，我们有 组建了一个具有完善专业知识的调查员团队 放射免疫偶联物和其他基于抗体的AML疗法。设想广泛使用，我们将学习 211AT-CD33 RIT作为“独立”疗法和HCT调节的增强，重点是MHC- 单倍型体内模型AML。由于许多HCT候选人没有HLA匹配的捐助者 替代供体HCT仍然是一个关键的未满足需求，尤其是为了扩展这种救生选项 来自少数民族群体的患者。我们预计我们的研究结果将很容易被翻译成诊所 并被预计会产生重要的积极影响，因为它们将为新待遇提供基础 AML和其他CD33+肿瘤患者的选择，目前的治疗结果是 不令人满意。