DOTA-based pre-targeting of alpha emitters

基于 DOTA 的 α 发射体预定位

• 批准号: 10595416
• 负责人: Sarah Marie Cheal
• 金额: $ 48.92万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-10 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10595416
• 关键词: Actinium; Advanced Malignant Neoplasm; Affinity; Alpha Particles; Animal Model; Animals; Antibodies; Antigens; Apoptosis; Autoradiography; BT 474; Benchmarking; Binding; Biological Assay; Bispecific Antibodies; Blood flow; Breast; Cell Cycle; Cell Death; Cell Proliferation; Characteristics; Chelating Agents; Clinical Trials; Colorectal Cancer; Combined Modality Therapy; Companions; Complex; DNA Binding; DNA Damage; DNA Repair; Data; Detection; Development; Disease; Distributional Activity; Dose; Drug Kinetics; ERBB2 gene; Effectiveness; GPA33 gene; Gene Expression Profiling; Genes; Genetic; Geometry; Goals; Haptens; Heterogeneity; Histology; Human; Hypoxia; Image; Immunohistochemistry; In complete remission; Individual; Isotopes; Kidney; Lanthanoid Series Elements; Liquid substance; Lutetium; Maximum Tolerated Dose; Measurement; Membrane; Methods; Modality; Modeling; Molecular; Monitor; Mus; Normal tissue morphology; Nude Mice; Organ; Ovarian; Palpable; Pathology; Patients; Polyethylene Glycols; Positron-Emission Tomography; Proliferation Marker; Property; Proteus; Radiation; Radiation Dose Unit; Radiation Tolerance; Radiation therapy; Radioactivity; Radiobiology; Radioimmunotherapy; Radioisotopes; Radiolabeled; Radionuclide therapy; Regimen; Series; Serum; Solid; Solid Neoplasm; Specificity; Stomach; Stratification; System; Testing; Therapeutic; Therapeutic Index; Tissue Sample; Tissues; Toxic effect; Toxicology; Trastuzumab; Treatment Efficacy; Treatment Protocols; Treatment outcome; Treatment-related toxicity; Tumor Antigens; Tumor Burden; Tumor Tissue; Tumor-Derived; Weight; Xenograft Model; Xenograft procedure; arm; base; cancer type; density; design; dosimetry; experimental study; human model; image guided; in vivo; kinetic model; malignant breast neoplasm; man; mouse model; multimodality; novel; precision medicine; preclinical study; procaine isothiocyanate; radiation effect; radiation response; resistance mechanism; response; serial imaging; single photon emission computed tomography; stoichiometry; subcutaneous; targeted treatment; theranostics; treatment response; tumor; uptake

Project Summary We have optimized an image-guided, antibody-based method for multi-step targeting (MST) of radiolabeled β- emitting therapeutics (β-MST) to human tumors that has resulted in tumoricidal radiation doses and therapeutic indices (TI) of up to 120-fold between tumor and radiosensitive tissues. In preclinical studies, we have met critical translational landmarks, namely: 1) cure of solid tumors without collateral normal organ toxicity; and 2) detection of tumors of 10 mg or less, by non-invasive in vivo cross-sectional imaging in living mice. We now propose a novel extension of MST to effectively target extremely potent short-range high LET α- emitting isotopes (α-MST) that, if successful, would allow ideal α/β-MST stratification of therapy according to disease characteristics, such as size, tumor geometry, antigen heterogeneity, blood flow, hypoxia, and genetic composition—all features known to impact the effectiveness of radiation therapy to human tumors. In this proposal, we will characterize the efficacy and toxicity of α-MST utilizing a novel carrier for the alpha- emitting isotope actinium-225, which we call “225Ac-proteus-DOTA.” The proposed experimental studies have been designed to assay the parameters responsible for tumor uptake of α-particles during α-MST (specific activity, tumor-antigen density, and antibody-antigen complex internalization), develop an imaging surrogate for dosimetry, and evaluate therapeutic efficacy and toxicity as a single treatment modality, or in combination with β-MST. The methods include serial non-invasive positron emission tomographic (PET) imaging of the individual components of the MST approach, ex vivo radioactivity counting of tissue samples, and assessments of therapeutic response. A single-photon emission computed tomography (SPECT) imaging surrogate is also proposed for companion dosimetry and treatment monitoring. The experimental system is based on three antigen/antibody systems that have been studied extensively in patients: the anti-GPA33 antibody huA33 (colorectal cancer), anti-HER2 antibody trastuzumab (breast, ovarian, gastric), and anti-GD2 antibody hu3F8. Specifically, for α-MST, we will use an MST schema that features novel bi-specific tetravalent anti-tumor antigen/-[M-DOTA] antibody constructs that react with both antigen (A33 or HER2) and radiometal- DOTA with high specificity and binding affinity. These two systems were chosen based on their contrasting membrane antibody-antigen internalization properties; huA33/GPA33 and trastuzumab/HER2 have slow and fast turnover, respectively, which can have significant dosimetry implications for α-MST. This α-MST approach will be studied in three different models in nude mice: a human colorectal cancer (SW1222) xenograft model, a human breast cancer (BT474) xenograft model, and a patient-derived tumor model (GPA33-positive), but importantly, can serve as a treatment guide for additional cancer types for which anti-tumor antigen/-[M-DOTA] antibody constructs are available. We anticipate that α-MST can be applied as a single modality, as well as in combination with β-MST, for highly effective radioimmunotherapy of solid and liquid human tumors.

项目摘要 我们已经优化了一种基于图像引导的基于抗体的方法，用于放射性标记的β-多步靶（MST） 对人类肿瘤的发射治疗（β-MST），导致肿瘤辐射剂量和 肿瘤和放射敏感性组织之间的治疗指数（TI）最多120倍。在临床前研究中，我们 符合关键的翻译地标，即：1）治愈无侧支正常器官的实体瘤 毒性; 2）通过非侵入性体内横截面成像检测10 mg或更少的肿瘤 老鼠。现在，我们提出了MST的新型扩展，以有效地靶向极有效的短距离高点α- 发射同位素（α-MST），如果成功，将允许理想的α/β-MST分层根据 疾病特征，例如大小，肿瘤几何形状，抗原异质性，血流，缺氧和遗传 组成 - 已知影响辐射疗法对人肿瘤的有效性的所有特征。 在此提案中，我们将表征α-MST的效率和毒性，利用新型载体进行α- 发射同位素actacium-225，我们称之为“ 225AC-proteus-dota”。拟议的实验研究具有 旨在主张负责在α-MST期间肿瘤吸收α粒子的参数（特定 活性，肿瘤抗原密度和抗体 - 抗原复合物内在化），为成像替代 剂量法，并评估治疗效率和毒性作为单一治疗方式，或与 β-mst。这些方法包括串行非侵入性正电子发射断层扫描（PET）成像 MST方法的各个组成部分，组织样品的离体放射性计数，以及 评估治疗反应。单光子发射计算机断层扫描（SPECT）成像 还建议替代剂量剂量法和治疗监测。实验系统是 基于已经广泛研究患者的三种抗原/抗体系统：抗GPA33 抗体HUA33（大肠癌），抗HER2抗体曲妥珠单抗（乳腺癌，卵巢，胃）和抗GD2 抗体Hu3f8。特别是对于α-MST，我们将使用具有新型双特异性四维体的MST模式 抗肿瘤抗原/ - [M-DOTA]抗体构建体，与抗原（A33或HER2）和放射线均反应 具有高特异性和结合亲和力的DOTA。这两个系统是根据它们的对比选择的 膜抗体 - 抗原内部化特性； Hua33/gpa33和trastuzumab/her2的速度很慢 快速营业额分别对α-MST具有显着的剂量计。这种α-mst方法 将在裸鼠的三种不同模型中进行研究：人类结直肠癌（SW1222）特征模型，一种 人类乳腺癌（BT474）的色谱模型和患者衍生的肿瘤模型（GPA33阳性），但 重要的是，可以作为抗肿瘤抗原/[M-Dota]的其他癌症类型的治疗指南 提供抗体构建体。我们预计α-mst可以用作单一模态，以及 与β-MST结合，用于固体和液体人类肿瘤的高效放射疗法。