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: 8649866
• 负责人: Jacob Houghton
• 金额: $ 5.15万
• 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/8649866
• 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; 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(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来开发和应用正电子发射断层扫描(PET)显像剂，用于诊断和分期胰腺癌(PDAC)，胰腺癌是全国第四大癌症死亡原因。目前的诊断方法缺乏有效识别PDAC病变的特异性和敏感性，这种缺乏足够的诊断工具导致了PDAC的高死亡率，这是一个重要的未得到满足的医疗需求。在PET成像中使用抗体是一种获得高灵敏度和选择性的成熟方法，因此，对于开发克服这些缺点的PDAC诊断工具来说，是一个合理的选择。5B1是一种针对唾液酸路易莎(SleA)的全人抗体，SleA是一种表达在PDAC肿瘤细胞表面的抗原，在初步研究中显示出作为免疫PET显像剂的前景。然而，与全长抗体片段相比，抗体片段作为显像剂可以提供一定的优势。利用抗体工程，MabVax Treateutics已经开发出由全人类5b1抗体改造而成的Diabies(5B1Db)，该公司将开发出一种使用模块化放射性标记策略的PET显像剂。为了确定最终临床翻译的最有希望的候选者，将应用两种策略：直接方法和预靶向方法将在BxPC3胰腺癌细胞诱导肿瘤的SCID小鼠中进行评估，以及在胰腺肿瘤中表达SleA的基因工程小鼠模型。在这两种方法中，一系列放射性核素(18F和64Cu)将与5B1Db偶联，以便找到放射性核素和标记策略的最佳组合，以补充5B1Db的药代动力学、药效学和生物分布特性。我们将通过PET成像比较5B1Db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者(S)。在第一种方法中，5B1Db结构将被连接到可能在用于PET成像之前立即被放射性标记的螯合剂上。在第二种方法中，将利用螯合剂偶联的反式环辛烯(TCO)和四嗪(Tz)偶联的5B1Db之间的反向[4+2]环加成反应，在体内实现放射性标记。我们的预靶向方法将包括四个步骤：i)将5b1-TZ片段注射到血流中；ii)抗体片段在肿瘤中积累并伴随着从血液中清除；iii)将放射性标记的TCO结合物注射到血流中；以及iv)将放射性标记的TCO结合物与5b1-TZ片段结合，然后快速清除未结合的放射性物质。这两种方法将提供最好的机会来确定进一步发展的建设。