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). 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 II application is to examine methods of attaching the most commonly used radionuclide for PET imaging, F-18, to a peptide. The main focus in the first year will be to further develop the novel method of attaching F-18 to a peptide that was disclosed in the Phase I report. Several modifications of the method will be examined with respect to the facile use, yield of product, specific activity, stability and ease of purification. The targeting peptide will carry two HSG haptens to stabilize binding on the tumor cell surface (11). 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 (TF10) 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.
The first goal of this work is to develop a general, simple method of attaching the PET imaging isotope, F-18, to peptides. The second goal of this work is to deliver the F-18 labeled peptide specifically to a tumor while at the same time delivering minimal activity to normal tissues by first administering a novel, genetically engineered, trivalent bispecific antibody that binds specifically to the target tissue of interest (in this case pancreatic cancer), allowing the unbound antibody to clear from the blood (days) and then injecting the F-18 labeled peptide, which contains two groups that bind to the targeted antibody. The injected peptide rapidly localizes to the bispecific antibody on the tumor surface and the portion of the peptide that does not bind to the tumor is rapidly (minutes) cleared from the blood, minimizing uptake in normal tissues thus increasing the contrast between the tumor and normal tissues.
|Laverman, Peter; McBride, William J; Sharkey, Robert M et al. (2014) Al(18) F labeling of peptides and proteins. J Labelled Comp Radiopharm 57:219-23|
|Dijkgraaf, Ingrid; Terry, Samantha Y A; McBride, William J et al. (2013) Imaging integrin alpha-v-beta-3 expression in tumors with an 18F-labeled dimeric RGD peptide. Contrast Media Mol Imaging 8:238-45|
|McBride, William J; D'Souza, Christopher A; Sharkey, Robert M et al. (2012) The radiolabeling of proteins by the [18F]AlF method. Appl Radiat Isot 70:200-4|
|McBride, William J; D'Souza, Christopher A; Karacay, Habibe et al. (2012) New lyophilized kit for rapid radiofluorination of peptides. Bioconjug Chem 23:538-47|
|Laverman, Peter; D'Souza, Christopher A; Eek, Annemarie et al. (2012) Optimized labeling of NOTA-conjugated octreotide with F-18. Tumour Biol 33:427-34|
|D'Souza, Christopher A; McBride, William J; Sharkey, Robert M et al. (2011) High-yielding aqueous 18F-labeling of peptides via Al18F chelation. Bioconjug Chem 22:1793-803|
|McBride, William J; D'Souza, Christopher A; Sharkey, Robert M et al. (2010) Improved 18F labeling of peptides with a fluoride-aluminum-chelate complex. Bioconjug Chem 21:1331-40|
|Laverman, Peter; McBride, William J; Sharkey, Robert M et al. (2010) A novel facile method of labeling octreotide with (18)F-fluorine. J Nucl Med 51:454-61|