Preparation and in vivo evaluation of linkers for 211At labeling of humanized anti-Tac.
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.
Yordanov
A T
AT
Radiation Oncology Branch, Division of Clinical Sciences, National Cancer Institute, Department of Nuclear Medicine, Bethesda, MD 20892, USA.
Garmestani
K
K
Zhang
M
M
Zhang
Z
Z
Yao
Z
Z
Phillips
K E
KE
Herring
B
B
Horak
E
E
Beitzel
M P
MP
Schwarz
U P
UP
Gansow
O A
OA
Plascjak
P S
PS
Eckelman
W C
WC
Waldmann
T A
TA
Brechbiel
M W
MW
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
D000906:Antibodies; D007202:Indicators and Reagents; C444379:N-succinimidyl N-(4-astatophenethyl)succinamate; D019275:Radiopharmaceuticals; D015375:Receptors, Interleukin-2; D013388:Succinimides; D001246:Astatine