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（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来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（PDAC）排名为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，并且缺乏足够的诊断工具导致 PDAC 的高死亡率，代表着重大的未满足的医疗需求。在 PET 成像中使用抗体是一种经过验证的方法，可实现高灵敏度和选择性，因此，是开发克服这些缺陷的 PDAC 诊断工具的合理选择。 5B1 是一种全人抗体，针对唾液酸 Lewisa (sLea)（一种在 PDAC 肿瘤细胞表面表达的抗原），在初步研究中已显示出作为免疫 PET 成像剂的前景。然而，与全长对应物相比，抗体片段作为成像剂具有某些优势。 MabVax Therapeutics 利用抗体工程技术，开发了从全人源 5B1 抗体改造而来的双抗体 (5B1Db)，该双抗体将使用模块化放射性标记策略开发为 PET 成像剂。将应用两种策略来确定最有希望进行最终临床转化的候选药物：将在具有 BxPC3 胰腺癌细胞诱导肿瘤的 SCID 小鼠以及表达 BxPC3 的基因工程小鼠模型中评估直接方法和预靶向方法胰腺肿瘤中的sLea。在这两种方法中，一系列放射性核素（18F和64Cu）将与5B1Db结合，以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药物。在第一种方法中，5B1Db 构建体将与螯合剂缀合，螯合剂可在用于 PET 成像之前立即进行放射性标记。在第二种方法中，将使用螯合剂缀合的反式环辛烯 (TCO) 和四嗪 (Tz) 缀合的 5B1Db 之间的逆 [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涉及四个步骤：i）将 5B1-Tz 片段注射到血流中； ii) 抗体片段在肿瘤中积聚并伴随从血液中清除； iii)将放射性标记的TCO缀合物注射到血流中； iv) 放射性标记的 TCO 缀合物与 5B1-Tz 片段结合，然后快速清除未结合的放射性物质。这两种方法将为识别进一步开发的结构提供最佳机会。