title: Establishment of the In Vivo Efficacy of Pretargeted Radioimmunotherapy Utilizing Inverse Electron Demand Diels-Alder Click Chemistry.
abstract: The pretargeting system based on the inverse electron demand Diels-Alder reaction (IEDDA) between trans-cyclooctene (TCO) and tetrazine (Tz) combines the favorable pharmacokinetic properties of radiolabeled small molecules with the affinity and specificity of antibodies. This strategy has proven to be an efficient method for the molecularly targeted delivery of pharmaceuticals, including isotopes for radiological imaging. Despite encouraging results from in vivo PET imaging studies, this promising system has yet to be thoroughly evaluated for pretargeted radioimmunotherapy (PRIT). Toward that end, we synthesized two novel177Lu-labeled tetrazine-bearing radioligands. Next, we compared the usefulness of our ligands for PRIT when paired with TCO-modified 5B1-a human, anti-CA19.9 mAb-in preclinical murine models of pancreatic cancer. The exemplary ligand,177Lu-DOTA-PEG7-Tz, showed rapid (4.6 ± 0.8% ID/g at 4 hours) and persistent (16.8 ± 3.9% ID/g at 120 hours) uptake in tumors while concurrently clearing from blood and nontarget tissues. Single-dose therapy studies using 5B1-TCO and varying amounts of177Lu-DOTA-PEG7-Tz (400, 800, and 1,200 μCi) showed that our system elicits a dose-dependent therapeutic response in mice bearing human xenografts. Furthermore, dosimetry calculations suggest that our approach is amenable to clinical applications with its excellent dosimetric profile in organs of clearance (i.e., liver and kidneys) as well as in dose-limiting tissues, such as red marrow. This study established that a pretargeted methodology utilizing the IEDDA reaction can rapidly and specifically deliver a radiotherapeutic payload to tumor tissue, thus illustrating its excellent potential for clinical translation. Mol Cancer Ther; 16(1); 124-33. ©2016 AACR.
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.|Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jacob L
authors.initials: JL
authors.lastname: Houghton
authors.affiliation: Department of Chemistry, Hunter College and the Graduate Center of the City University of New York, New York, New York.|Ph.D. Program in Chemistry of the Graduate Center of the City University of New York, New York, New York.
authors.forename: Rosemery
authors.initials: R
authors.lastname: Membreno
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.|Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Dalya
authors.initials: D
authors.lastname: Abdel-Atti
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Cunanan
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Sean
authors.initials: S
authors.lastname: Carlin
authors.affiliation: MabVax Therapeutics, San Diego, California.
authors.forename: Wolfgang W
authors.initials: WW
authors.lastname: Scholz
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Pat B
authors.initials: PB
authors.lastname: Zanzonico
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.|Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York.|Weill Cornell Medical College, New York, New York.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Lewis
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York. bz102@hunter.cuny.edu.|Department of Chemistry, Hunter College and the Graduate Center of the City University of New York, New York, New York.|Ph.D. Program in Chemistry of the Graduate Center of the City University of New York, New York, New York.|Weill Cornell Medical College, New York, New York.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Zeglis
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D057930:Click Chemistry; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000473:pathology; D011092:Polyethylene Glycols / Q000737:chemistry; D049268:Positron-Emission Tomography; D016499:Radioimmunotherapy; D011874:Radiometry; D019275:Radiopharmaceuticals / Q000737:chemistry* / Q000494:pharmacology*; D014018:Tissue Distribution; D047368:Tumor Burden / Q000187:drug effects / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019275:Radiopharmaceuticals; D011092:Polyethylene Glycols