Development of CD46 theranostics for imaging and treatment of multiple myeloma

用于多发性骨髓瘤成像和治疗的 CD46 治疗诊断学的开发

基本信息

批准号：
10539684
负责人：
Robert Richard Flavell
金额：
$ 67.02万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10539684
关键词：
Animal Model Antibody-drug conjugates Antigens Award Binding Biodistribution CD46 Antigen CRISPR interference Cells Characteristics Chromosomes Clinical Trials Combined Modality Therapy Data Detection Development Disease Dose Eligibility Determination Epitopes Genes Genomics Goals Human Image Immunoglobulin G Isotopes Length Magnetic Resonance Imaging Malignant Neoplasms Maximum Tolerated Dose Methods Modeling Molecular Target Morbidity - disease rate Multiple Myeloma Mus PET/CT scan Patient Care Patients Performance Phase I Clinical Trials Physicians Pilot Projects Population Positron Positron-Emission Tomography Pre-Clinical Model Preclinical Testing Protocols documentation Radiolabeled Radionuclide therapy Radiopharmaceuticals Recording of previous events Refractory Relapse Scanning Signal Transduction Site Surface Techniques Testing Therapeutic Therapeutic Agents Tissues Toxic effect Xenograft Model base clinical translation cold agglutinins experience fluorodeoxyglucose fluorodeoxyglucose positron emission tomography genome-wide human model imaging agent imaging scientist imaging study improved in vivo in vivo evaluation molecular imaging mortality neoplastic cell new therapeutic target novel novel diagnostics novel strategies novel therapeutic intervention pomalidomide pre-clinical screening standard of care targeted agent targeted treatment theranostics translational study treatment strategy tumor

Animal Model Antibody-drug conjugates Antigens Award Binding Biodistribution CD46 Antigen CRISPR interference Cells Characteristics Chromosomes Clinical Trials Combined Modality Therapy Data Detection Development Disease Dose Eligibility Determination Epitopes Genes Genomics Goals Human Image Immunoglobulin G Isotopes Length Magnetic Resonance Imaging Malignant Neoplasms Maximum Tolerated Dose Methods Modeling Molecular Target Morbidity - disease rate Multiple Myeloma Mus PET/CT scan Patient Care Patients Performance Phase I Clinical Trials Physicians Pilot Projects Population Positron Positron-Emission Tomography Pre-Clinical Model Preclinical Testing Protocols documentation Radiolabeled Radionuclide therapy Radiopharmaceuticals Recording of previous events Refractory Relapse Scanning Signal Transduction Site Surface Techniques Testing Therapeutic Therapeutic Agents Tissues Toxic effect Xenograft Model base clinical translation cold agglutinins experience fluorodeoxyglucose fluorodeoxyglucose positron emission tomography genome-wide human model imaging agent imaging scientist imaging study improved in vivo in vivo evaluation molecular imaging mortality neoplastic cell new therapeutic target novel novel diagnostics novel strategies novel therapeutic intervention pomalidomide pre-clinical screening standard of care targeted agent targeted treatment theranostics translational study treatment strategy tumor

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项目摘要

PROJECT SUMMARY AND ABSTRACT The primary goal of this proposal is to develop novel theranostic agents targeting CD46 for imaging and treatment of multiple myeloma (MM). CD46 is a novel therapeutic target, with a cognate antibody-drug conjugate, FOR46, now in phase 1 clinical trials. Our preliminary data demonstrate high expression of CD46 in MM. In this proposal, we develop and implement [89Zr]DFO-YS5 and [225Ac]DOTA-YS5 as imaging and therapeutic agents targeting MM. The central hypothesis of this proposal is that CD46 is an effective target for molecular imaging and therapy of MM. In this proposal we test this hypothesis in preclinical models, and in a pilot study of patients with MM. In order to test this hypothesis, we have assembled an experienced team of chemists, biologists, imaging scientists, physicists, and physicians to evaluate this method in preclinical models and in patients. In specific aim 1, we will develop [89Zr]DFO-YS5 and [225Ac]DOTA-YS5 as PET imaging and therapeutic agents for MM. In specific aim 2, we will develop new co-treatment approaches to maximize CD46 expression, and use these to augment [89Zr]DFO-YS5 PET and [225Ac]DOTA-YS5 treatment. In aim 3, we perform a pilot [89Zr]DFO-YS5 PET imaging study in patients with MM, and analyze the data to determine its sensitivity for detecting sites of disease. The methods developed in this proposal will ultimately be used to develop novel diagnostic and therapeutic approaches in MM, to help reduce morbidity and mortality for this disease.

项目摘要和摘要该提案的主要目的是开发针对CD46进行成像和治疗的新型治疗剂多发性骨髓瘤（mm）。 CD46是一个新型的治疗靶标，具有同源抗体 - 药物结合物，for46，现在正在第1阶段临床试验中。我们的初步数据表明CD46在MM中的高表达。在此提案中，我们开发和实施[89ZR] DFO-YS5和[225AC] DOTA-YS5作为成像和治疗剂的靶向毫米。该提议的中心假设是CD46是分子成像和治疗的有效靶标 mm。在此提案中，我们在临床前模型中检验了这一假设，以及对MM患者的试点研究。为了检验这一假设，我们组建了一支经验丰富的化学家，生物学家，成像团队科学家，物理学家和医生在临床前模型和患者中评估这种方法。在特定目标中 1，我们将开发[89ZR] DFO-YS5和[225AC] DOTA-YS5作为MM的PET成像和治疗剂。在具体目的2，我们将开发新的共同处理方法来最大化CD46表达，并将其用于增强[89ZR] DFO-YS5 PET和[225AC] dota-ys5处理。在AIM 3中，我们执行飞行员[89ZR] DFO-YS5 PET 对患有MM的患者进行成像研究，并分析数据以确定其检测疾病部位的敏感性。该提案中开发的方法最终将用于开发新颖的诊断和治疗性在MM中的方法，以帮助降低该疾病的发病率和死亡率。