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

• 批准号: 8893777
• 负责人: Jacob Houghton
• 金额: $ 5.42万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8893777
• 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; 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; Modeling; Mus; Neoplasm Metastasis; Non-Malignant; Oncologist; Pancreatic Adenocarcinoma; Parents; Pharmacodynamics; Positron-Emission Tomography; Property; Radioactive; Radioimmunoconjugate; Radioisotopes; Radiolabeled; Reaction; Relative (related person); 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; mortality; mouse model; neoplastic cell; novel; oncology; pancreatic neoplasm; pre-clinical; public health relevance; radiotracer; research study; tool; tumor; tumor metabolism; uptake

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）：拟议的研究项目的目的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，以诊断和分期胰腺腺癌（PDAC），这是癌症死亡率的第四个主要原因。当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有助于PDAC的高死亡率，这代表了巨大的未满足医疗需求。在PET成像中使用抗体是实现高灵敏度和选择性的一种经过验证的方法，因此，是开发PDAC诊断工具的逻辑选择，该工具克服了这些不足。 5B1是一种完全人类的抗体，该抗体靶向siAllyl Lewisa（SLEA），一种在PDAC肿瘤细胞表面表达的抗原，在初步研究中作为免疫图成像剂表现出了希望。但是，与其全长对应物相比，抗体片段可以作为成像剂具有某些优势。使用抗体工程，Mabvax Therapeicats开发了从完全人类5B1抗体设计的Diabodies（5B1DB），该抗体将使用模块化放射性标记策略开发为宠物成像剂。将采用两种策略，以确定最终临床翻译的最有希望的候选者：直接方法和靶向方法将在SCID小鼠中评估使用BXPC3胰腺癌细胞诱导的肿瘤以及在胰腺肿瘤中表达SLEA的基因工程小鼠模型的肿瘤。在这两种方法中，一系列放射性核素（18F和64CU）将共轭到5B1DB，以找到相互补充5B1DB的药代动力学，药态动力学和生物分布特性的放射性核素和标记策略的最佳组合。我们将比较5B1DB通过PET成像的肿瘤吸收和生物分布，以确定一个最佳候选者（S）以进行进一步的临床前发育。在第一种方法中，5B1DB构建体将与螯合剂共轭，这些螯合剂可能会在PET成像中使用之前立即进行放射性标记。在第二种方法中，使用螯合剂偶联的反甲辛烯（TCO）和四嗪（TZ）结合的5B1DB之间的逆[4+2]环加成反应，将在体内实现放射性标记。我们先进的方法将涉及四个步骤：i）注射5B1-TZ片段的血液； ii）在肿瘤中积累抗体片段和血液中伴随清除； iii）注射放射性标记的TCO结合物的血液； iv）放射性标记的TCO偶联物与5B1-TZ片段的结合，然后快速清除未结合的放射性材料。这两种方法将为确定进一步发展的结构提供最佳机会。