DOTA-based pre-targeting of alpha emitters

基于 DOTA 的 α 发射体预定位

• 批准号: 10531612
• 负责人: Sarah Marie Cheal
• 金额: $ 58.21万
• 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 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10531612
• 关键词: Actinium; Advanced Malignant Neoplasm; Affinity; Alpha Particles; Animal Model; Animals; Antibodies; Antigen-Antibody Complex; 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; Reaction; 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; Weight; Xenograft Model; Xenograft procedure; absorption; arm; 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; radiation effect; radiation response; resistance mechanism; response; serial imaging; single photon emission computed tomography; stoichiometry; subcutaneous; 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方法，用于放射性标记的β- 向人类肿瘤发射治疗剂（β-MST），导致肿瘤杀伤辐射剂量， 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 已经达到了关键的转化标志，即：1）治愈实体瘤，无侧支正常器官 毒性;和2）通过活体非侵入性体内横截面成像检测10 mg或更少的肿瘤 小鼠我们现在提出了一种新的MST扩展，以有效地靶向非常有效的短程高LET α- 放射性同位素（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，如大小、肿瘤几何形状、抗原异质性、血流、缺氧和遗传 组成-所有已知影响人类肿瘤放射治疗有效性的特征。 在这项提案中，我们将利用一种新型的α-MST载体来表征α-MST的疗效和毒性。 放射出同位素锕-225，我们称之为“225 Ac-Proteus-DOTA”。拟议的实验研究有 设计用于测定α-MST期间负责α-颗粒的肿瘤摄取的参数（特异性 活性、肿瘤-抗原密度和抗体-抗原复合物内化），开发用于 剂量测定，并评价作为单一治疗方式或与 β-MST。这些方法包括对肿瘤进行连续的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 评估治疗反应。单光子发射计算机断层扫描（SPECT）成像 还提出了用于伴随剂量测定和治疗监测的替代物。了实验系统 基于在患者中广泛研究的三种抗原/抗体系统：抗GPA 33 抗体huA 33（结肠直肠癌）、抗HER 2抗体曲妥珠单抗（乳腺癌、卵巢癌、胃癌）和抗GD 2抗体曲妥珠单抗（乳腺癌、卵巢癌、胃癌）。 抗体hu 3F 8。具体而言，对于α-MST，我们将使用一种MST模式，其特征在于新的双特异性四价 与抗原（A33或HER 2）和放射性金属两者反应的抗肿瘤抗原/-[M-DOTA]抗体构建体， DOTA具有高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; huA 33/GPA 33和曲妥珠单抗/HER 2具有缓慢的， 快速周转，这可能对α-MST具有重要的剂量学意义。这种α-MST方法 将在三种不同的裸鼠模型中进行研究：人结肠直肠癌（SW 1222）异种移植模型， 人乳腺癌（BT474）异种移植物模型和患者来源的肿瘤模型（GPA 33阳性），但是 重要的是，可以作为抗肿瘤抗原/-[M-DOTA] 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，以及在 与β-MST组合，用于人实体和液体肿瘤的高效放射免疫治疗。

项目成果

Intraperitoneal Pretargeted Radioimmunotherapy for Colorectal Peritoneal Carcinomatosis.

• DOI: 10.1158/1535-7163.mct-21-0353
• 发表时间: 2022-01
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7

A Self-Assembling and Disassembling (SADA) Bispecific Antibody (BsAb) Platform for Curative Two-step Pretargeted Radioimmunotherapy.

用于治疗性两步预靶向放射免疫治疗的自组装和拆卸 (SADA) 双特异性抗体 (BsAb) 平台。

• DOI: 10.1158/1078-0432.ccr-20-2150
• 发表时间: 2021-01-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Santich BH;Cheal SM;Ahmed M;McDevitt MR;Ouerfelli O;Yang G;Veach DR;Fung EK;Patel M;Burnes Vargas D;Malik AA;Guo HF;Zanzonico PB;Monette S;Michel AO;Rudin CM;Larson SM;Cheung NK
• 通讯作者: Cheung NK