DOTA-based pre-targeting of alpha emitters

基于 DOTA 的 α 发射体预定位

• 批准号: 10057369
• 负责人: Sarah Marie Cheal
• 金额: $ 71.77万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 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/10057369
• 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 我们优化了一种图像引导的、基于抗体的多步靶向放射性标记β的方法。 对人类肿瘤的放射治疗(β-MST)已导致杀瘤辐射剂量和 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 遇到了关键的翻译里程碑，即：1)治愈了没有侧枝正常器官的实体肿瘤 毒性；以及2)活体非侵入性横断面成像检测10毫克或以下的肿瘤 老鼠。我们现在提出了一种新的MST扩展，以有效地瞄准极强的短程高LET-α- 发射同位素(α-mst)，如果成功，将允许理想的α/β-mst分层治疗，根据 疾病特征，如大小、肿瘤几何形状、抗原异质性、血流、缺氧和遗传 组合物-所有已知的影响人类肿瘤放射治疗效果的特征。 在这项建议中，我们将利用一种新的载体来表征α-MST的有效性和毒性。 释放出同位素-225，我们称之为“225Ac-Proteus-DOTA”。拟议的实验研究有 旨在分析肿瘤在α-MST期间摄取α-颗粒的相关参数(特异性 活性、肿瘤-抗原密度和抗体-抗原复合体内化)，开发一种用于 剂量测定，并评估作为单一治疗方式的治疗效果和毒性，或与 β-mst.这些方法包括连续的无创正电子发射断层扫描(PET)成像 MST方法的个别组成部分，组织样本的体外放射性计数，以及 治疗反应的评估。单光子发射计算机断层扫描(SPECT)成像 替代物也被建议用于伴生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、胃癌)和抗GD2 抗体hu3F8。具体地说，对于α-mst，我们将使用具有新的双特定四价的mst模式 抗肿瘤抗原/-[M-DOTA]抗体构建可与抗原(A33或HER2)和放射性金属- DOTA具有高度的特异性和结合亲和力。这两个系统是根据它们的对比而选择的 膜抗体-抗原内化特性：huA33/GPA33和曲妥珠单抗/HER2具有缓慢和 快速周转，这可能对α-MST具有显著的剂量学意义。这种α-MST方法 将在三种不同的裸鼠模型中进行研究：人结直肠癌(SW1222)异种移植模型， 人乳腺癌(BT474)异种移植模型和患者来源的肿瘤模型(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 抗体构建体是可用的。我们预计α-MST可以作为一种单一的方式应用，以及在 β-MST联合高效放射免疫治疗人体固体和液体肿瘤