title: Pretargeted radioimmunotherapy (RIT) with a novel anti-TAG-72 fusion protein.
abstract: Pretargeted radioimmunotherapy (RIT) increases the dose of radionuclide delivered to tumor sites while limiting radiation to normal tissues. The three components in Pretarget include a streptavidin-containing targeting molecule, a synthetic clearing agent (sCA), and (90)Y and/or (111)In-DOTA-biotin. This trial determined the feasibility and safety of using a genetically engineered fusion protein directed to TAG-72 as the targeting agent. Nine (9) patients with metastatic colorectal cancer (TAG-72+) received 160 mg/m(2) of CC49Fusion protein intravenously (i.v.), followed by the sCA, 45 mg/m(2) i.v. Twenty-four (24) hours later, patients received radiolabeled DOTA-biotin (either 0.65 or 1.3 mg/m(2)). All patients received 5 mCi of (111)In-DOTA-biotin for imaging and dosimetry purposes and patients 4-9 received 10 mCi/m2 of (90)Y-DOTA-biotin as well. The mean plasma T1/2 of CC49Fusion protein was 23 +/- 6 hours. Greater than 95% of the circulating CC49Fusion protein was eliminated from the circulation within 6 hours of sCA administration. The radiolabeled DOTA-biotin rapidly localized to tumor sites while the unbound fraction was rapidly excreted. The mean tumor-to-marrow radiation dose ratio was 139:1 and mean tumor: whole body was 56:1. No infusion-related, renal, hepatic, or hematologic toxicities were noted. CC49Fusion protein performs well in a pretargeted RIT schema, and further study with escalating doses of (90)Y should be pursued. This strategy has the potential to deliver effective radiation tumor doses to TAG- 72+ tumors.
authors.affiliation: Departments of Medicine, Division of Hematology/Oncology University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL 35294-3300, USA. Andres.Forero@ccc.uab.edu
authors.forename: Andres
authors.initials: A
authors.lastname: Forero-Torres
authors.forename: Sui
authors.initials: S
authors.lastname: Shen
authors.forename: Hazel
authors.initials: H
authors.lastname: Breitz
authors.forename: Robert B
authors.initials: RB
authors.lastname: Sims
authors.forename: Don B
authors.initials: DB
authors.lastname: Axworthy
authors.forename: M B
authors.initials: MB
authors.lastname: Khazaeli
authors.forename: Kuang-Ho
authors.initials: KH
authors.lastname: Chen
authors.forename: Ivor
authors.initials: I
authors.lastname: Percent
authors.forename: Stephen
authors.initials: S
authors.lastname: Besh
authors.forename: Albert F
authors.initials: AF
authors.lastname: LoBuglio
authors.forename: Ruby F
authors.initials: RF
authors.lastname: Meredith
mesh_terms: D000230:Adenocarcinoma / Q000628:therapy; D000368:Aged; D000951:Antigens, Neoplasm / Q000627:therapeutic use*; D001710:Biotin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D002986:Clinical Trials as Topic; D015331:Cohort Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015902:Gamma Cameras; D005770:Gastrointestinal Neoplasms / Q000628:therapy; D006023:Glycoproteins / Q000627:therapeutic use*; D006801:Humans; D007205:Indium Radioisotopes; D008113:Liver Neoplasms / Q000556:secondary; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009942:Organometallic Compounds / Q000494:pharmacology; D016499:Radioimmunotherapy / Q000379:methods*; D011868:Radioisotopes; D011874:Radiometry; D019275:Radiopharmaceuticals / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000737:chemistry*; D012211:Rhenium; D019809:Streptavidin / Q000494:pharmacology; D013997:Time Factors; D016896:Treatment Outcome; D015021:Yttrium Radioisotopes / Q000627:therapeutic use
chemical_list: D000951:Antigens, Neoplasm; C405616:DOTA-biotin; D006023:Glycoproteins; D007205:Indium Radioisotopes; D009942:Organometallic Compounds; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D011993:Recombinant Fusion Proteins; D015021:Yttrium Radioisotopes; C047052:tumor-associated antigen 72; D001710:Biotin; D012211:Rhenium; D019809:Streptavidin