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: C L Ruegg, W T Anderson-Berg, M W Brechbiel, S Mirzadeh, O A Gansow, M Strand
• Journal: Cancer research (Cancer Res) Vol. 50 Issue 14 Pg. 4221-6 (Jul 15 1990) ISSN: 0008-5472 [Print] United States
• PMID: 2364380 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Chelating Agents
• Radioisotopes
• Sulfur Radioisotopes
• Bismuth

Topics

• Animals
• Antibodies, Monoclonal
• Bismuth (pharmacokinetics)
• Chelating Agents
• Female
• Hybridomas (immunology)
• Kidney (metabolism)
• Leukemia, Experimental (metabolism)
• Mice
• Mice, Inbred BALB C
• Radioisotopes
• Spleen (metabolism)
• Sulfur Radioisotopes
• Tissue Distribution