title: Improved in vivo stability and tumor targeting of bismuth-labeled antibody.
abstract: We have used a series of bifunctional chelating agents to prepare 206Bi-labeled monoclonal antibody and have assessed the in vivo stability and tumor targeting of these conjugates in the Rauscher murine erythroleukemia model. Several derivatives of diethylenetriaminepentaacetic acid [the dicyclic dianhydride of diethylenetriaminepentaacetic acid (ca-DTPA), 2-(p-isothiocyanatobenzyl)diethylenetriaminepentaacetic acid (SCNBzDTPA), and 2-(p-isothiocyanatobenzyl)-5(6)-methyl-diethylenetriaminepentaacet ic acid (MxDTPA)], as well as a macrocyclic polyazacycloalkane-N-acetic acid [2-(p-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-N ,N',N",N"'- tetraacetic acid (DOTA)], were conjugated to monoclonal antibody 103A, which is specific for gp70 expressed on Rauscher virus-infected cells. The stability in vivo of 206Bi chelate-103A conjugates was first evaluated in normal mice by determining the levels of 206Bi in blood and kidney, since these were the organs in which free 206Bi, 206Bi-caDTPA-103A, and 35S-103A accumulated. The biodistribution of 206Bi administered as a chelate of caDTPA-103A was virtually indistinguishable from that of free 206Bi, indicating a low degree of in vivo stability of this bismuth chelate when compared to biosynthetically labeled 35S-103A. There was a progressive increase in the 206Bi levels observed in blood when the series of 103A conjugates prepared using SCNBzDTPA, MxDTPA, and DOTA was compared to 206Bi administered free or as a caDTPA-103A chelate. At 1 h after injection into normal mice, the blood level of 206Bi-DOTA-103A was 25-fold greater than that observed for 206Bi-caDTPA-103A and the level in kidney was 6-fold less, values that did not differ significantly from those observed for 35S-103A. Targeting to leukemic spleen was increased by 10-fold when the DOTA conjugate was used; the tumor level was 90% injected dose/g for DOTA, as compared to only 9% injected dose/g for caDTPA-103A at 1 h after injection. Use of the DOTA chelator also reduced by 7-fold the level of uptake by the kidney in the leukemic animals. We, therefore, conclude that the chelator DOTA is a promising reagent for the delivery of 212Bi-antibody conjugates to vascularized tumors under conditions that require targeting via the circulatory system.
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: C L
authors.initials: CL
authors.lastname: Ruegg
authors.forename: W T
authors.initials: WT
authors.lastname: Anderson-Berg
authors.forename: M W
authors.initials: MW
authors.lastname: Brechbiel
authors.forename: S
authors.initials: S
authors.lastname: Mirzadeh
authors.forename: O A
authors.initials: OA
authors.lastname: Gansow
authors.forename: M
authors.initials: M
authors.lastname: Strand
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D001729:Bismuth / Q000493:pharmacokinetics; D002614:Chelating Agents; D005260:Female; D006825:Hybridomas / Q000276:immunology; D007668:Kidney / Q000378:metabolism; D007942:Leukemia, Experimental / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D011868:Radioisotopes; D013154:Spleen / Q000378:metabolism; D013462:Sulfur Radioisotopes; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D002614:Chelating Agents; D011868:Radioisotopes; D013462:Sulfur Radioisotopes; D001729:Bismuth