HARNESSING IN VIVO CLICK CHEMISTRY FOR 211AT-BASED PRETARGETED RADIOIMMUNOTHERAPY

利用体内点击化学进行基于 211AT 的预定位放射免疫治疗

• 批准号: 10679160
• 负责人: Cindy Rodriguez
• 金额: $ 3.24万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-14 至 2025-09-13
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679160
• 关键词: Actinium; Alpha Particles; Animals; Antibodies; Antigen Targeting; Antigens; Astatine; Background Radiation; Biodistribution; Biological; Biological Models; Blood; Chemicals; Chemistry; Circulation; Clinic; Clinical; Colorectal Cancer; Complication; Cyclooctenes; Data; Development; Diels Alder reaction; Dose Rate; Drug Kinetics; Electrons; Evaluation; Excretory function; GPA33 gene; Goals; Half-Life; I131 isotope; Immunoglobulin G; Immunoglobulins; Investigation; Label; Large Intestine Carcinoma; Length; Libraries; Ligation; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Methodology; Modality; Monitor; Monoclonal Antibodies; Mus; Organ; Pathway interactions; Patient-Focused Outcomes; Patients; Performance; Play; Proliferating; Proteins; Radiation; Radiation Dose Unit; Radiation therapy; Radioactivity; Radioimmunoconjugate; Radioimmunotherapy; Radioisotopes; Radiopharmaceuticals; Regimen; Role; Safety; Serum; Site; System; Targeted Radiotherapy; Therapeutic; Tight Junctions; Time; Tissues; Treatment Efficacy; Tumor Tissue; Validation; Variant; Whole Blood; Work; Xenograft Model; Xenograft procedure; cancer therapy; clinical candidate; clinical implementation; clinical translation; cytotoxic; design; dosimetry; effective therapy; efficacy validation; empowerment; experimental study; human model; humanized monoclonal antibodies; improved; improved outcome; in vivo; in vivo evaluation; leukemia/lymphoma; member; mouse model; novel strategies; patient derived xenograft model; radioligand; residence; small molecule; subcutaneous; translational approach; tumor; uptake

PROJECT SUMMARY/ABSTRACT Over the last fifteen years, radioimmunotherapy (RIT) using antibodies labeled with a-emitting radionuclides has shown significant promise for the treatment of cancer. Yet the the multi-day circulation time of monoclonal antibodies means that they must be labeled with an a-emitting radionuclide with a multi-day physical half-life: 225Ac (t1/2 ~ 9.9 d). This unavoidable combination of long biological and physical half-lives can create high radiation dose rates to healthy tissues, a complication that has hampered the clinical proliferation of 225Ac-labeled radioimmunoconjugates. One approach to circumventing this issue lies in pretargeted radioimmunotherapy (PRIT). PRIT is predicated on decoupling the immunoglobulin and radionuclide, injecting the former prior to the latter, and empowering them to recombine at target sites within the body. Labeling the antibody with a fast- moving, small molecule radioligand after it has reached an optimal biodistribution in vivo limits the circulation time of the assembled radioimmunoconjugate in the blood and enables the use of radionuclides with half-lives that are normally incompatible with full-length IgGs. As a result, this approach can produce high activity concentrations in target tissues at only a fraction of the radiation dose to healthy organs produced by traditional, directly-labeled radioimmunoconjugates. This F31 proposal is focused upon creating a novel approach to PRIT that leverages the short-lived, a- emitting radiohalogen astatine-211 (211At; t1/2 ~ 7.2 h) and the in vivo bioorthogonal click ligation between tetrazine (Tz) and trans-cylooctene (TCO). To this end, we will employ a proof-of-concept model system based on the A33 antigen-targeting huA33 antibody as well as murine models of colorectal carcinoma. Specific Aim 1 (SA1) will be focused on the synthesis, characterization, and in vivo evaluation of a library of Tz radioligands labeled with iodine-131 (t1/2 ~ 8.0 d), an inexpensive surrogate for 211At. In Specific Aim 2 (SA2), we will create 211At-labeled variants of the four most promising radioligands identified in SA1. We will then use these 211At- labeled tetrazines and huA33-TCO to perform pretargeted biodistribution studies in a subcutaneous xenograft model of colorectal carcinoma. These biodistribution data will be used to assess the performance of in vivo pretargeting with each 211At-Tz and enable dosimetry calculations designed to elucidate the radiation dose of each strategy to tumor tissue and healthy organs. Finally, Specific Aim 3 (SA3) will be centered on validating the therapeutic efficacy of this approach to 211At-PRIT in subcutaneous, orthotopic, and patient-derived xenograft models of human colorectal carcinoma. Longitudinal PRIT studies will performed with the two most promising 211At-Tz radioligands from SA2 in order to identify a single construct suitable for clinical translation. In the near term, this investigation could lead to the creation of a safer and more effective treatment modality for patients with colorectal cancer. And in the long term, this work could help usher in an era in which 211At-based radiopharmaceuticals play a vital role in the endoradiotherapy of patients with a wide variety of malignancies.

项目摘要/摘要 在过去的15年里，放射免疫治疗（RIT）使用α-放射性核素标记的抗体， 已经显示出治疗癌症的巨大前景。然而，单克隆抗体的多日循环时间 抗体意味着它们必须用具有多日物理半衰期的α-发射放射性核素标记： 225Ac（t1/2 ~ 9.9d）。这种不可避免的长生物和物理半衰期的结合可以产生高浓度的 健康组织的辐射剂量率，这一并发症阻碍了225 Ac标记的 放射免疫结合物。一种解决这个问题的方法是预先靶向放射免疫治疗 （PRIT）。PRIT基于免疫球蛋白和放射性核素的解耦，在免疫球蛋白和放射性核素之间注射前者。 后者，并使它们能够在体内的目标部位重组。把抗体标记上快速- 移动的小分子放射性配体在体内达到最佳生物分布后限制了循环 在血液中组装的放射性免疫缀合物的时间，并且使得能够使用具有半衰期的放射性核素 通常与全长IgG不相容。因此，这种方法可以产生高活性 靶组织中的浓度仅为传统的， 直接标记的放射免疫缀合物。 这个F31提案的重点是创建一种新的PRIT方法，该方法利用了短暂的， 放射性卤代~（211）At; t1/2 ~ 7.2 h）和体内生物正交点击连接 四嗪（Tz）和反式环辛烯（TCO）。为此，我们将采用基于 对靶向A33抗原的huA 33抗体以及结肠直肠癌的鼠模型的作用。具体目标1 (SA1)将集中于Tz放射性配体库的合成、表征和体内评价 碘-131标记（t1/2 ~ 8.0 d）。在具体目标2（SA 2）中，我们将创建 211 At标记的变体的四个最有前途的放射性配体中确定的SA 1。我们会用这些211 At- 标记的四嗪和huA 33-TCO在皮下异种移植物中进行预靶向生物分布研究 结直肠癌模型。这些生物分布数据将用于评估体内 预靶向每个211 At-Tz，并进行剂量测定计算，旨在阐明 每种策略对肿瘤组织和健康器官的影响。最后，具体目标3（SA 3）将集中于验证 该方法对211 At-PRIT在皮下、原位和患者来源的异种移植物中的治疗效果 人结直肠癌模型。纵向PRIT研究将使用两个最有希望的 211 At-Tz放射性配体，以鉴定适合于临床翻译的单一构建体。在不久的 从长远来看，这项研究可能会为患者创造一种更安全，更有效的治疗方式 结直肠癌从长远来看，这项工作可以帮助开创一个新的时代， 放射性药物在各种恶性肿瘤患者的腔内放射治疗中起着至关重要的作用。