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.

项目概要 我们优化了一种图像引导、基于抗体的方法，用于放射性标记 β- 的多步靶向 (MST) 向人类肿瘤发射治疗剂（β-MST），产生杀肿瘤辐射剂量和 肿瘤和放射敏感组织之间的治疗指数 (TI) 高达 120 倍。在临床前研究中，我们 已达到关键的转化里程碑，即：1）治愈实体瘤，无需附带正常器官 毒性; 2) 通过活体内非侵入性体内横断面成像检测 10 mg 或以下的肿瘤 老鼠。我们现在提出了 MST 的一种新颖扩展，以有效地瞄准极其有效的短程高 LET α- 发射同位素（α-MST），如果成功，将允许根据以下标准进行理想的 α/β-MST 治疗分层 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 成分——已知影响人类肿瘤放射治疗效果的所有特征。 在本提案中，我们将利用新型 α-MST 载体来表征 α-MST 的功效和毒性。 发射同位素 actinium-225，我们称之为“225Ac-proteus-DOTA”。拟议的实验研究 被设计用于测定 α-MST 期间肿瘤摄取 α-粒子的参数（特定 活性、肿瘤抗原密度和抗体-抗原复合物内化），开发成像替代物 剂量测定，并评估作为单一治疗方式或联合治疗的疗效和毒性 β-MST。这些方法包括连续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、组织样本的离体放射性计数，以及 治疗反应的评估。单光子发射计算机断层扫描 (SPECT) 成像 还建议将其替代用于伴随剂量测定和治疗监测。实验系统为 基于已在患者中广泛研究的三种抗原/抗体系统：抗 GPA33 抗体 huA33（结直肠癌）、抗 HER2 抗体曲妥珠单抗（乳腺癌、卵巢癌、胃癌）和抗 GD2 抗体hu3F8。具体来说，对于 α-MST，我们将使用具有新颖双特异性四价特征的 MST 模式 抗肿瘤抗原/-[M-DOTA]抗体构建体与抗原（A33或HER2）和放射性金属发生反应 DOTA具有高特异性和结合亲和力。选择这两个系统是基于它们的对比 膜抗体-抗原内化特性； huA33/GPA33 和曲妥珠单抗/HER2 具有缓慢且 分别快速周转，这可能对 α-MST 具有显着的剂量测定影响。这种 α-MST 方法 将在三种不同的裸鼠模型中进行研究：人类结直肠癌（SW1222）异种移植模型、 人类乳腺癌（BT474）异种移植模型和患者来源的肿瘤模型（GPA33阳性），但是 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 抗体构建体是可用的。我们预计 α-MST 可以作为单一模式应用，也可以应用于 与β-MST组合，对人类实体和液体肿瘤进行高效放射免疫治疗。