Engineered anti-PSCA antibodies for immunoPET and targeted therapy of pancreatic cancer

用于免疫PET和胰腺癌靶向治疗的工程化抗PSCA抗体

• 批准号: 10343450
• 负责人: Anna M Wu
• 金额: $ 73万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10343450
• 关键词: Address; Affinity; Alpha Particles; Animal Model; Antibodies; Antigen Targeting; Beta Particle; Biodistribution; Bioreactors; Blood; Bone Marrow; Cause of Death; Cell Line; Cell Surface Proteins; Cells; Clinical; Clinical Trials; Detection; Development; Diagnosis; Disease; Dose; Dose Fractionation; Dose-Limiting; Drug Kinetics; Effectiveness; Engineering; Exhibits; FCGR2B gene; Fostering; Future; Hepatic; Hepatobiliary; Human; I131 isotope; Image; ImmunoPET; Immunoglobulin Fragments; Injections; Investigational New Drug Application; KPC model; Kidney; Knock-in; Knock-in Mouse; Label; Liver; Malignant Neoplasms; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Modeling; Molecular Target; Monitor; Mus; Mutation; Neuroendocrine Tumors; Normal tissue morphology; Nude Mice; Operative Surgical Procedures; Organ; Pancreas; Pancreatic Adenocarcinoma; Patients; Positron; Positron-Emission Tomography; Probability; Process; Production; Property; Proteins; Radiation; Radiation Dose Unit; Radiation Tolerance; Radioactivity; Radioimmunotherapy; Radioisotopes; Radiolabeled; Radionuclide Imaging; Radionuclide therapy; Route; Safety; Solid Neoplasm; Staging; Targeted Radiotherapy; Testing; Therapeutic; Time; Tissues; Toxic effect; Tumor Antigens; Variant; Vial device; Xenograft Model; Xenograft procedure; advanced disease; advanced pancreatic cancer; antibody engineering; base; cGMP production; cancer therapy; cell bank; design; dosimetry; effective therapy; expectation; first-in-human; imaging study; improved; improved outcome; mouse model; mutant; novel; novel strategies; overexpression; pancreatic cancer cells; pancreatic cancer model; pancreatic cancer patients; pancreatic neoplasm; preclinical efficacy; preclinical study; prostate stem cell antigen; research clinical testing; subcutaneous; success; targeted imaging; targeted treatment; theranostics; tumor; tumor xenograft; uptake

Pancreatic cancer remains among the most lethal of solid tumors, due to late diagnosis and a high probability of metastatic spread. Effective new systemic treatments are needed in order to improve outcomes in patients. Targeted radionuclide therapy has demonstrated effectiveness cancer therapy, notably with the success of 177Lu- dotatate in neuroendocrine tumors including those of the pancreas. Prostate Stem Cell Antigen (PSCA) is upregulated in 60-80% of pancreatic adenocarcinomas, making it a promising target for antibody-directed therapy. An engineered antibody fragment, the A2 scFv-Fc2 DM has been specifically designed for optimized delivery of therapeutic radionucides in pancreatic cancer. It is based on a humanized, high-affinity anti-PSCA antibody, and contains Fc mutations engineered to foster rapid blood clearance via the hepatobiliary route. As a result, radiation dose to key organs/tissues (bone marrow and kidney) is minimized, enabling effective delivery of an alpha- or beta-emitting radionuclide to tumors. In Aim 1, biodistribution studies will be undertaken in mouse models, in order to confirm the expected tumor targeting and hepatic clearance. Formal dose estimations will be made for the scFv-Fc2 DM radiolabeled with either 177Lu or 225Ac for therapy. Aim 2 will explore the potential efficacy of the anti-PSCA scFv-Fc2 DM in mouse models of pancreatic cancer, including subcutaneous xenografts of human pancreatic tumor cells, a syngeneic model of KPC-PSCA tumors in huPSCA knock-in mice, and patient-derived pancreatic tumor xenograft models. The relative efficacies and toxicities of the alpha-emitter 225Ac and beta-emitter 177Lu will be analyzed in order to prepare for future clinical therapy studies. In Aim 3, clinical production and conjugation of the anti-PSCA scFv-Fc2 DM will be performed, testing conducted, and an IND filed. Finally, in Aim 4 we will conduct a first-in-human imaging study using 64Cu-DOTA-anti-PSCA scFv- Fc2 DM in patients with advanced pancreatic cancer, to evaluate the targeting, and clearance properties and potential radiation dose delivery of this novel engineered antibody fragment. Results from this clinical immunoPET study will be central to guiding future development of a radioimmunotherapy agent that can be implemented in a theranostic approach to pancreatic cancer.

胰腺癌仍然是最致命的实体瘤之一，因为诊断较晚并且发生癌症的可能性很高。 转移性扩散。为了改善患者的预后，需要有效的新系统治疗。 靶向放射性核素治疗已证明癌症治疗的有效性，特别是 177Lu- dotatate 治疗神经内分泌肿瘤，包括胰腺肿瘤。前列腺干细胞抗原 (PSCA) 是 在 60-80% 的胰腺腺癌中表达上调，使其成为抗体导向的有希望的靶点 治疗。 A2 scFv-Fc2 DM 是一种工程抗体片段，专为优化 在胰腺癌中输送治疗性放射性核素。它基于人源化、高亲和力的抗 PSCA 抗体，并含有经过改造的 Fc 突变，可通过肝胆途径促进快速血液清除。作为一个 结果，对关键器官/组织（骨髓和肾脏）的辐射剂量降至最低，从而实现有效输送 α或β发射放射性核素对肿瘤的影响。在目标 1 中，将在小鼠中进行生物分布研究 模型，以确认预期的肿瘤靶向和肝脏清除。正式的剂量估计将是 用于用 177Lu 或 225Ac 放射性标记的 scFv-Fc2 DM 进行治疗。目标2将探索潜力 抗 PSCA scFv-Fc2 DM 在小鼠胰腺癌模型（包括皮下注射）中的功效 人胰腺肿瘤细胞的异种移植物，huPSCA 敲入小鼠中 KPC-PSCA 肿瘤的同基因模型， 和患者来源的胰腺肿瘤异种移植模型。 α发射体的相对功效和毒性 225Ac和β-发射体177Lu将被分析，以便为未来的临床治疗研究做好准备。在目标 3 中， 将进行抗 PSCA scFv-Fc2 DM 的临床生产和缀合，进行测试，并 IND 提交。最后，在目标 4 中，我们将使用 64Cu-DOTA-anti-PSCA scFv- 进行首次人体成像研究 Fc2 DM 在晚期胰腺癌患者中的作用，以评估靶向性和清除特性 这种新型工程抗体片段的潜在辐射剂量传递。本次临床结果 免疫PET研究对于指导放射免疫治疗剂的未来开发至关重要，该治疗剂可以 在胰腺癌的治疗诊断方法中实施。