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Developing an Anti-sialyl-Lewisa Diabody for ImmunoPET Imaging of Pancreas Cancer

开发用于胰腺癌免疫 PET 成像的抗唾液酸化 Lewisa 双抗体

基本信息

批准号：
9098651
负责人：
Jacob Houghton
金额：
$ 1.67万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2016-10-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9098651
关键词：
Affinity Alder plant Animal Model Antibodies Antigens Binding Biodistribution Biological Markers Blood Blood Circulation Cancer Etiology Cancerous Carbohydrates Cells Chelating Agents Chemistry Clinical Complement Detection Development Diagnosis Diagnostic Diagnostic Imaging Disadvantaged Discipline of Nuclear Medicine Disease Drug Kinetics Engineering Evaluation Future Genetically Engineered Mouse Goals Health Human Image Imaging Device Immunoglobulin Fragments Injection of therapeutic agent Label Laboratories Lead Length Lesion Malignant Neoplasms Malignant neoplasm of pancreas Medical Membrane Mentors Methodology Methods Mus Neoplasm Metastasis Non-Malignant Oncologist Pancreatic Adenocarcinoma Parents Pharmacodynamics Positron-Emission Tomography Property Radioactive Radioimmunoconjugate Radioisotopes Radiolabeled Reaction Research Research Personnel Research Project Grants SCID Mice Sensitivity and Specificity Series Specificity Staging Surface Therapeutic Training Translations Tumor Antigens antibody engineering base cancer cell clinical practice cycloaddition disease diagnosis experience human monoclonal antibodies imaging agent improved in vivo laboratory experience mortality mouse model neoplastic cell novel oncology pancreatic neoplasm pre-clinical radiotracer research study tool tumor tumor metabolism uptake

项目摘要

DESCRIPTION (provided by applicant): The goal of the proposed research project is to develop and apply modular strategies to the development and application of positron emission tomography (PET) imaging agents for the diagnosis and staging of pancreatic adenocarcinoma (PDAC), which ranks as the fourth leading cause of cancer mortality nationally. Current diagnostic methodology lacks the specificity and sensitivity to efficiently identify PDAC lesions, and this lack of adequate diagnostic tools contributes to the high mortality of PDAC, representing a significant unmet medical need. The use of antibodies in PET imaging is a proven method for achieving high sensitivity and selectivity, and, thus, is a logical choice for th development of a diagnostic tool for PDAC that overcomes those shortfalls. 5B1, a fully-human antibody that targets an sialyl Lewisa (sLea), an antigen that is expressed on the surface of PDAC tumor cells, has shown promise in initial studies as an immunoPET imaging agent. However, antibody fragments can offer certain advantages as imaging agents, compared to their full-length counterparts. Using antibody engineering, diabodies (5B1Db) engineered from the fully-human 5B1 antibody have been developed by MabVax Therapeutics, which will be developed as a PET imaging agent using a modular radiolabeling strategy. Two strategies will be applied in order to identify the most promising candidate for eventual clinical translation: a direct approach and a pre-targeting approach will be assessed in SCID mice with tumors induced by BxPC3 pancreas cancer cells as well as a genetically engineered mouse model expressing sLea in pancreatic tumors. In both approaches, series of radionuclides (18F and 64Cu) will be conjugated to 5B1Db in order to find the best combination of radionuclide and labeling strategy that complement the pharmacokinetic, pharmacodynamics, and biodistribution properties of 5B1Db. We will compare tumor uptake and biodistribution of the combinations of 5B1Db via PET imaging in order to identify one optimal candidate(s) for further pre-clinical development. In the first approach, 5B1Db constructs will be conjugated to chelators that may be radiolabeled immediately prior to use in PET imaging. In the second approach, radiolabeling will be achieved in vivo, using the inverse [4+2] cycloaddition reaction between a chelator-conjugated trans-cylcooctene (TCO) and a tetrazine (Tz)-conjugated 5B1Db. Our pre-targeted method will involve four steps: i) the injection into the bloodstream of 5B1-Tz fragment; ii) accumulation of the antibody fragment in the tumor and concomitant clearance from the blood; iii) the injection into the bloodstream of the radiolabeled TCO conjugate; and iv) the binding of the radiolabeled TCO conjugate to the 5B1-Tz fragment followed by the rapid clearance of unbound radioactive material. These two approaches will provide the best chance of identifying a construct for further development.

描述（由申请人提供）：拟议研究项目的目标是开发和应用模块化策略，以开发和应用正电子发射断层扫描（PET）成像剂，用于胰腺癌（PDAC）的诊断和分期，胰腺癌是全国癌症死亡率的第四大原因。目前的诊断方法缺乏有效识别PDAC病变的特异性和敏感性，并且缺乏足够的诊断工具导致PDAC的高死亡率，这代表了显著未满足的医疗需求。在PET成像中使用抗体是一种经过验证的实现高灵敏度和选择性的方法，因此是开发克服这些不足的PDAC诊断工具的合理选择。5 B1是一种靶向唾液酸化Lewisa（sLea）的全人抗体，sLea是PDAC肿瘤细胞表面表达的抗原，在初步研究中显示出作为免疫PET成像剂的前景。然而，与其全长对应物相比，抗体片段可以提供作为成像剂的某些优点。使用抗体工程，由全人5 B1抗体工程化的双抗体（5 B1 Db）已由MabVax Therapeutics开发，其将使用模块化放射性标记策略开发为PET成像剂。将应用两种策略以确定最终临床转化的最有希望的候选物：将在具有由BxPC 3胰腺癌细胞诱导的肿瘤的SCID小鼠以及在胰腺肿瘤中表达sLea的基因工程小鼠模型中评估直接方法和预靶向方法。在这两种方法中，一系列放射性核素（18 F和64 Cu）将与5 B1 Db缀合，以找到补充5 B1 Db的药代动力学、药效学和生物分布特性的放射性核素和标记策略的最佳组合。我们将通过PET成像比较5 B1 Db组合的肿瘤摄取和生物分布，以确定进一步临床前开发的最佳候选药物。在第一种方法中，5 B1 Db构建体将与螯合剂缀合，所述螯合剂可以在用于PET成像之前立即进行放射性标记。在第二种方法中，放射性标记将在体内实现，使用螯合剂缀合的反式环辛烯（TCO）和四嗪（Tz）缀合的5 B1 Db之间的逆[4+2]环加成反应。我们的预靶向方法将涉及四个步骤：i）将5 B1-Tz片段注射到血流中; ii）抗体片段在肿瘤中的积累和伴随的从血液中的清除; iii）将放射性标记的TCO缀合物注射到血流中;和iv）放射性标记的TCO缀合物与5 B1-Tz片段结合，随后快速清除未结合的放射性物质。这两种方法将为进一步开发提供最佳的机会。