Pancreatic cancer remains one of the most lethal of cancers, due to a lack of effective early detection methods, complex and invasive surgical treatments, and early spread and metastasis. Clearly, better therapeutic approaches are needed, and in parallel, improved means for detecting and staging pancreatic cancer. Prostate stem cell antigen (PSCA), originally identified as a marker in prostate and bladder cancer, and has also been recognized as highly over expressed in pancreatic adenocarcinoma. Antibodies recognizing PSCA have demonstrated biological activity in prostate cancer and are currently in clinical evaluation for treatment of pancreatic cancer. A humanized, affinity-matured anti-PSCA engineered antibody fragment (minibody;single- chain Fv-CH3 fusion protein, 80 kDa) has been generated with rapid tumor targeting and fast blood clearance optimize for imaging applications, including immunoPET. The PSCA-specific minibody has been scaled up and produced under cGMP conditions for a pilot PET imaging study in patients with metastatic prostate cancer. The overall goal of this Fast Track STTR grant proposal is to translate PSCA-specific minibodies for clinical PET imaging of pancreatic cancer. In Phase I, humanized, affinity-matured PSCA minibody will be produced and purified, radioiodination optimized and binding to recombinant PSCA confirmed, and targeting, biodistribution, clearance, and microPET imaging will be evaluated in mice bearing human pancreatic tumor xenografts. In Phase II, starting with an existing Master Cell Bank, a cGMP production run (>350 mg) of PSCA-specific minibody will be conducted;protein will be purified, vialed and tested. Test radioiodinations withI-124 will be conducted at clinical scale, and an IND application will be prepared. These steps will set the stage for a clinical imaging study in patients with pancreatic adenocarcinoma.
Public Health Relevance: Pancreatic cancer remains one of the most lethal of cancers, with an overall five-year survival rate (all stages) of 5% and only a 20% five-year survival rate for localized disease. Challenges in the field include a lack of effective early detection, complexity of surgical treatment, and early spread and metastasis of pancreatic adenocarcinomas. Clearly, better therapeutic approaches are needed, and in parallel, improved means for detecting and staging pancreatic cancer. Furthermore, as the molecular alterations that underlie the development of pancreatic cancer become more clear, opportunities for novel molecular diagnostics also open up. This proposal describes a novel molecular imaging agent for pancreatic cancer based on an engineered antibody fragment - PSCA minibody - that recognizes a target that is specifically expressed in pancreatic cancer. ImmunoPET imaging using the PSCA minibody can provide an important new tool for diagnosis, staging, and management of pancreatic cancer.
Thesaurus Terms: 125-Iodine;Affinity;Antibodies;Antibody Fragments;Applications Grants;Binding;Binding (Molecular Function);Biodistribution;Biological;Bladder Cancer;Blood;Blood Reticuloendothelial System;Cancer Patient;Cancers;Cell Line;Cell Surface;Cellline;Chimera Protein;Chimeric Proteins;Clinical;Clinical Evaluation;Clinical Protocols;Clinical Testing;Complex;Cyclic Gmp;Detection;Development;Diagnosis;Diagnostic;Early Diagnosis;Early Treatment;Engineering;Evaluation;Flow Cytofluorometries;Flow Cytofluorometry;Flow Cytometry;Flow Microfluorimetry;Flow Microfluorometry;Fusion Protein;Goals;Grant Proposals;Guanosine Cyclic 3',5'-Monophosphate;Guanosine Cyclic Monophosphate;Guanosine, Cyclic 3',5'-(Hydrogen Phosphate);Hplc;Heterograft;Heterologous Transplantation;High Performance Liquid Chromatography;High Pressure Liquid Chromatography;High Speed Liquid Chromatography;Human;I-125;I125 Isotope;Image;Imagery;Immunoglobulin Fragments;In Vitro;Iodine I 125;Loinc Axis 2 Property;Localized Disease;Malignant Bladder Neoplasm;Malignant Neoplasms;Malignant Pancreatic Neoplasm;Malignant Tumor;Malignant Tumor Of The Bladder;Malignant Tumor Of The Prostate;Malignant Neoplasm Of Pancreas;Malignant Neoplasm Of Prostate;Malignant Neoplasm Of Urinary Bladder;Malignant Prostatic Tumor;Man (Taxonomy);Metastasis;Metastasize;Metastatic Neoplasm;Metastatic Prostate Cancer;Metastatic Tumor;Methods;Mice;Mice Mammals;Modern Man;Molecular;Molecular Interaction;Murine;Mus;Neoplasm Metastasis;Operative Procedures;Operative Surgical Procedures;Pet;Pet Scan;Pet Imaging;Petscan;Pett;Psca Antigen;Pancreas;Pancreas Adenocarcinoma;Pancreas Cancer;Pancreas Neoplasms;Pancreas Tumor;Pancreatic;Pancreatic Adenocarcinoma;Pancreatic Cancer;Pancreatic Tumor;Patients;Phase;Phenotype;Positron;Positron Emission Tomography Medical Imaging;Positron Emission Tomography Scan;Positron-Emission Tomography;Preparation;Production;Property;Prostate Ca;Prostate Cancer;Prostate Carcinoma Metastatic;Prostatic Cancer;Proteins;Rad.-Pet;Radioactive Isotopes;Radioactivity;Radioisotopes;Radiolabeled;Radionuclides;Recombinants;Running;Sttr;Secondary Neoplasm;Secondary Tumor;Small Business Technology Transfer Research;Soft Tissue Neoplasms;Soft Tissue Tumor;Staging;Strains Cell Lines;Surgical;Surgical Interventions;Surgical Procedure;Survival Rate;Testing;Therapeutic;Tracer;Translating;Tumor Cell Migration;Urinary Bladder Cancer;Urinary Bladder Malignant Tumor;Visualization;Work;Xenograft;Xenograft Procedure;Xenotransplantation;Antibody Engineering;Base;Cgmp;Cgmp Production;Cancer Imaging;Cancer Metastasis;Cell Bank;Clinical Test;Cultured Cell Line;Developmental;Early Detection;Early Intervention;Early Therapy;Flow Cytophotometry;Gene Product;Guanosine 3'5'monophosphate;Imaging;Immunoreactivity;Improved;In Vivo;Malignancy;Meetings;Molecular Imaging;Mouse Model;Neoplasm/Cancer;Novel;Overexpress;Overexpression;Pancreatic Cancer Cells;Pancreatic Neoplasia;Pancreatic Neoplasm;Pre-Clinical Study;Pre-Clinical Trial;Preclinical Study;Preclinical Trial;Prostate Stem Cell Antigen;Radiolabel;Radiotracer;Research Clinical Testing;Scale Up;Surgery;Tool;Tumor;Tumor Cell Metastasis;Tumor Xenograft;Uptake
