In-vivo study of KSP/QRH heptapeptide dimer for detection of biliary intra-epithelial neoplasia

Project Summary In this Direct to Phase 2 SBIR proposal, IVMT, LLC aims to perform a Phase 2 multi-center study to advance the clinical utility of a targeted image contrast agent. This small business start-up has been formed to commercialize highly sensitive cancer-specific imaging agents. A near-infrared (NIR) fluorescently-labeled peptide heterodimer specific for EGFR and ErbB2 will be topically administered in the biliary tract to distinguish the benign versus malignant etiology of indeterminant biliary strictures. Current methods used to image the bile ducts can visualize non-specific anatomical features, but do not reveal the underlying molecular properties that drive malignancy. The heterodimer is a novel biochemical structure that arranges two unique peptide ligands that bind with high specificity to cell surface targets that stimulate epithelial cell growth, proliferation, and differentiation. These targets are highly overexpressed by cancers that obstruct the biliary tract to form indeterminant strictures. The peptide monomers are separated by a PEG linker with a unique length to match the physiological spacing between the two targets to bind concurrently. This innovative configuration generates synergistic target-ligand interactions that can substantially improve binding performance compared with individual monomer peptides. Cancer is a heterogeneous process, thus the detection of multiple targets may be needed to achieve optimal imaging performance. Quantified results from the peptide heterodimer binding to transformed cells in vitro showed a substantial increase in fluorescence intensity by comparison with that for either target individually, and the binding affinity was found to improve by >3-fold versus that of either monomer peptide. Increased sensitivity occurs from simultaneous detection of two unique targets. Greater specificity arises from the bivalent structure binding to a larger combined region of the target. Using this approach, early targets can be detected at lower levels of expression, and may identify malignant biliary strictures at an early stage. The specific aims are as follows. The IRDye800-labeled peptide heterodimer will be synthesized using Good Manufacturing Practices, aliquoted in single use vials, and distributed to n = 6 clinical sites. Stability will be monitored over the duration of the study. A single IRB will perform ethical review and regulatory oversight. The peptide heterodimer will be administered topically to at least n = 20 patients with indeterminant biliary strictures at each site. NIR fluorescence images will be collected in vivo using a multi- modal scanning fiber cholangioscope. A deep learning algorithm will be developed to evaluate the in vivo images by calculating a target-to-background ratio from regions of NIR fluorescence. Clinical evidence will be collected to demonstrate efficacy for a peptide heterodimer to distinguish malignant from benign indeterminant biliary strictures in a diverse population and broad range of etiologies. A clinical network of academic medical centers will be established over a national geographic distribution to perform the multi-center study.