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肿瘤之一，由于较晚的诊断和高的可能性