Preparation and in vivo evaluation of linkers for At-211 labeling of humanized anti-Tac

The syntheses, radiolabeling, antibody conjugation, and in vivo evaluation of new linkers for At-211 labeling of humanized anti-Tac (Hu-anti-Tac), an antibody to the a-chain of the IL-2 receptor (IL-2R alpha) shown to be a us eful target for radioimmunotherapy are described. Synthesis of the organome tallic linker precursors is accomplished by reaction of the corresponding b romo- or iodoaryl esters with bis(tributyltin) in the presence of a palladi um catalyst. Subsequent conversion to the corresponding N-succinimidyl este r and labeling with At-211 of two new linkers, N-succinimidyl 4- [At-211]as tato-3-methylbenzoate and N-succinimidyl N-(4-[At-211]astatophenethyl)succi namate (SAPS), together with the previously reported N-succinimidyl 4- [At- 211]astatobenzoate and N-succinimidyl 3-[At-211]astato-4-methylbenzoate, ar e each conjugated to Hu-anti-Tac. The plasma survival times of these conjug ates are compared to those of directly iodinated (I-125) Hu-anti-Tac. The N -succinimidyl N-(4-[At-211]astatophenethyl)succinamate compound (SAPS) emer ged from this assay as the most viable candidate for At-211-labeling of Hu- anti-Tac. SAPS, along with the directly analogous radio-iodinated reagent, N-succinimidyl N-(4[I-125]astatophenethyl)succinamate (SIPS), are evaluated in a biodistribution study along with directly iodinated (I-125) Hu-anti-T ac. Blood clearance and biological accretion results indicate that SAPS is a viable candidate for further evaluation for radioimmunotherapy of cancer. (C) 2001 Elsevier Science Inc. All rights reserved.