title: Preparation and in vivo evaluation of linkers for 211At labeling of humanized anti-Tac.
abstract: The syntheses, radiolabeling, antibody conjugation, and in vivo evaluation of new linkers for 211At labeling of humanized anti-Tac (Hu-anti-Tac), an antibody to the alpha-chain of the IL-2 receptor (IL-2Ralpha) shown to be a useful target for radioimmunotherapy are described. Synthesis of the organometallic linker precursors is accomplished by reaction of the corresponding bromo- or iodoaryl esters with bis(tributyltin) in the presence of a palladium catalyst. Subsequent conversion to the corresponding N-succinimidyl ester and labeling with 211At of two new linkers, N-succinimidyl 4-[211At]astato-3-methylbenzoate and N-succinimidyl N-(4-[211At]astatophenethyl)succinamate (SAPS), together with the previously reported N-succinimidyl 4-[211At]astatobenzoate and N-succinimidyl 3-[211At]astato-4-methylbenzoate, are each conjugated to Hu-anti-Tac. The plasma survival times of these conjugates are compared to those of directly iodinated (125I) Hu-anti-Tac. The N-succinimidyl N-(4-[211At]astatophenethyl)succinamate compound (SAPS) emerged from this assay as the most viable candidate for 211At-labeling of Hu-anti-Tac. SAPS, along with the directly analogous radio-iodinated reagent, N-succinimidyl N-(4-[125I]astatophenethyl)succinamate (SIPS), are evaluated in a biodistribution study along with directly iodinated (125I) Hu-anti-Tac. Blood clearance and biological accretion results indicate that SAPS is a viable candidate for further evaluation for radioimmunotherapy of cancer.
authors.affiliation: Radiation Oncology Branch, Division of Clinical Sciences, National Cancer Institute, Department of Nuclear Medicine, Bethesda, MD 20892, USA.
authors.forename: A T
authors.initials: AT
authors.lastname: Yordanov
authors.forename: K
authors.initials: K
authors.lastname: Garmestani
authors.forename: M
authors.initials: M
authors.lastname: Zhang
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.forename: Z
authors.initials: Z
authors.lastname: Yao
authors.forename: K E
authors.initials: KE
authors.lastname: Phillips
authors.forename: B
authors.initials: B
authors.lastname: Herring
authors.forename: E
authors.initials: E
authors.lastname: Horak
authors.forename: M P
authors.initials: MP
authors.lastname: Beitzel
authors.forename: U P
authors.initials: UP
authors.lastname: Schwarz
authors.forename: O A
authors.initials: OA
authors.lastname: Gansow
authors.forename: P S
authors.initials: PS
authors.lastname: Plascjak
authors.forename: W C
authors.initials: WC
authors.lastname: Eckelman
authors.forename: T A
authors.initials: TA
authors.lastname: Waldmann
authors.forename: M W
authors.initials: MW
authors.lastname: Brechbiel
mesh_terms: D000818:Animals; D000906:Antibodies / Q000737:chemistry; D001246:Astatine; D002851:Chromatography, High Pressure Liquid; D005260:Female; D007202:Indicators and Reagents; D007553:Isotope Labeling; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008819:Mice, Nude; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D013388:Succinimides; D014018:Tissue Distribution
chemical_list: D000906:Antibodies; D007202:Indicators and Reagents; C444379:N-succinimidyl N-(4-astatophenethyl)succinamate; D019275:Radiopharmaceuticals; D015375:Receptors, Interleukin-2; D013388:Succinimides; D001246:Astatine