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Improved in Vivo Stability and Tumor Targeting of Bismuth-labeled Antibody¹

Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 [C. L. R., W. T. A-B., M. S.], and Inorganic and Radioimmune Chemistry Section, Radiation Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892 [M. W. B., S. M., O. A. G.]

We have used a series of bifunctional chelating agents to prepare ²⁰⁶Bilabeled 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-diethylenetriaminepentaacetic 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.

¹ This research was supported in part by Public Health Service Research Grant CA-33470 from the NIH.

² Present address: Stanford Blood Center, 800 Welch Road, Palo Alto, CA 94304.

³ To whom requests for reprints should be addressed.

Received 12/ 5/89. Revised 3/26/90.

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