Novel Approaches to CD33-Directed Radioimmunotherapy

CD33 定向放射免疫治疗的新方法

基本信息

批准号：
10318979
负责人：
Roland Bruno Walter
金额：
$ 14.91万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-15 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10318979
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

项目摘要

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，人们一直在寻求针对急性髓系白血病（AML）的抗原特异性免疫疗法。利用针对 CD33 的膜远端 V 型结构域的抗体，CD33 是一种显示在几乎所有病例中白血病原始细胞的细胞表面都得到改善，并且可能在某些病例中改善了白血病干细胞的存活率。一些使用吉妥珠单抗奥佐米星的患者验证了这种方法，但许多 CD33+ AML 患者没有从这种抗体-药物偶联物中受益，这激发了人们对开发改进的 CD33 导向的兴趣由于 AML 细胞在整个遗传病谱中都具有极高的放射敏感性，a- 与 b 发射体不同，发射放射性核素是武装抗 CD33 抗体的理想选择。辐射仅覆盖几个细胞直径，从而实现精确有效的靶细胞杀伤（低至 10 a- 粒子撞击足以杀死恶性造血细胞）。然而，用actinium-225（225Ac-lintuzumab）标记的方法除了成本高之外，也很重要。缺点包括225Ac的半衰期长，如果不有效保留，会导致放射性核素自由循环靶细胞中的放射性核素，以及 225Ac 衰变后释放的子放射性核素，具有相关毒性的风险我们探索了用 astatine-211 (211At) 进行标记，这是我们关注的 a 发射体，因为其半衰期较短，而且它在衰变时不会产生任何长寿命或潜在危险的物质同位素，将提供一种新型、优越的 CD33 定向放射免疫疗法 (RIT)。人源化小鼠，我们最近生成了一组完全人类抗体，可识别 V 组结构域，或者作为第一组，人 CD33 的近膜 C2 组结构域，但不是 V 组。某些 CD33 变体中缺少 C2 集结构域，C2 集结构域定向抗体可以识别所有天然 - 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，重点关注 211At 为了完成这项任务，我们有。组建了一个多学科研究小组，他们在开发方面具有互补的专业知识我们将研究放射免疫结合物和其他基于抗体的 AML 疗法的广泛应用。 211At-CD33 RIT 作为“独立”疗法和 HCT 调节的增强，重点关注 MHC- 由于许多 HCT 候选者没有 HLA 匹配的供体，因此半相合体内模型 AML 很容易实现。替代捐助者 HCT 的需求仍然是一个未得到满足的关键需求，特别是将这种救生选择扩展到我们希望我们的研究结果能够很容易地转化为临床。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满意。