Our primary interest is to develop an imaging method based on bispecific antibody (bsMAb) pretargeting used in combination with F-18 labeled peptides. Such a method would improve the specificity for PET imaging based on the bsMAb's reactivity with either tumor antigens or other markers. This imaging method would take advantage of excellent sensitivity of PET and the high tumor to non-tumor ratios provided by bsMab pretargeting. We have previously described a novel bsMAb pretargeting system based on the hapten binding specificity of an antibody directed to histamine-succinyl-glycine (HSG; 32). Using this system, radiolabeled peptides can be prepared with a variety of radioisotopes for use in imaging and therapy. This pretargeting system has excellent tumor uptake and high tumor/nontumor ratios within 1-3 hours of the peptide injection, and has substantially less renal uptake than directly radiolabeled antibody fragments (e.g., Fab' or scFv). Given the proven success of this pretargeting system, the primary goal of this Phase I application is to examine methods for preparing peptides suitable for use with F-18, the most commonly used radionuclide for PET imaging. The main focus will be to choose a linker to attached the F-18 to a peptide through the F-18 labeled molecule 4-[F-18]fluorobenzaldehyde. Several potential synthetic pathways will be examined with respect to the facile use, yield of product, specific activity, stability, retention of binding to the anti-hapten component of the bsMAb and ease of purification. The targeting peptide will carry two HSG haptens to stabilize binding on the tumor cell surface. Most of the preclinical work has been done with a bsMab that binds to the colo-rectal tumor marker carcinoembryonic antigen and HSG. The proof of principal for this work will be tested using a bsMAb that targets the human pancreatic tumor antigen, MUC1 and HSG. The goal is to help improve the early detection and diagnosis of pancreatic cancer as well as determine the extent of the disease. It is anticipated that following successful synthesis a SBIR Phase II grant would support the optimization, automation and the scale-up of the 4-[F-18]fluorobenzaldehyde conjugation to the peptide to a commercial scale. It would also support the preclinical targeting, synthesis of new peptide derivatives to optimize excretion, serum stablity and safety studies in animals that would be needed before this agent goes into the clinic.
