Pancreatic Ductal Adenocarcinoma Targeted Ultrasound Contrast Agent Development

Pancreatic ductal adenocarcinomaPDACis a highly lethal form of cancerIn most patientsdetection is at an advanced stage and the outcome is poorThis project is directed towards development of a molecularly targeted ultrasound contrast agent with potential to detect early stage disease while still curableIn Phase I of this projectwe incorporated the engineered human single chain variable fragmentscFvcontaining a C terminal cysteine into maleimide bearing phospholipid coated perfluoropropane microbubblesMBand in in vivo testing of Thytargeted MB for PDAC detection in transgenic mice detected PDAC tumors andltmm in sizeFurthermoresignal intensity obtained from these MB wasx that obtained from non targeted MB and overx that obtained from non clinically translatable MB prepared by reaction of biotinylated scFv with streptavidin coated MBOverarching HypothesisA clinically translatable Thytargeted MB will improve visualization and detection of PDAC and enable diagnosis at earlier stage disease to ultimately improve survival of PDAC patientsResearch ObjectivesWe will optimize conditions of conjugation chemistry to yield a product that can undergo formal development as a drug candidateWe will scale up production and produce sufficient material for investigational new drugINDenabling studiesWe will perform toxicology studies necessary to support an INDSpecific AimOptimization of preparation of anti ThyscFv to DSPE PEGpurification of the bioconjugateformulation of the phospholipids suspension containing the DSPE PEGMal scFvand in vitro binding evaluation of Thytargeted MB as a drug candidateMilestoneA scFv bioconjugate that binds to Thywith andltnM KD with greater thanpuritySpecific Aimc GMP preparation of Thytargeted MB and validation of drug product in vivoMilestonePreparation of sufficient c GMP Thytargeted MB formulation for IND enabling studiessingle dose MTD similar to control MB and demonstration of in vivo binding ability of Thytargeted MBSpecific AimComplete toxicology studies sufficient to support an INDOutcome of ResearchSuccessful completion of the proposed Aims will yield a Thytargeted MB intended for formal drug development and will allow submission of an IND for testing in first in human clinical trials Pancreatic ductal adenocarcinomaPDACis a highly lethal form of cancerin most patientsdetection is at an advanced stage and the outcome is poorThis project is directed towards development of a molecularly targeted ultrasound contrast agent with potential to detect early stage disease while it is still curableIn Phase I of this projectwe showed feasibility and in this Phase II of the project we will complete studies that would ready the contrast agent for clinical testing