COMPARISON OF 10-TETRAAZACYCLODODECANE-N,N',N'',N'''-TETRAACETIC ACID(DOTA)-PEPTIDE-CHL6, A NOVEL IMMUNOCONJUGATE WITH CATABOLIZABLE LINKER, TO 2-IMINOTHIOLANE-2 [P-(BROMOACETAMIDO)BENZYL]-DOTA-CHL6 IN BREAST-CANCER XENOGRAFTS

Radioimmunotherapy using (131I)-ChL6 antibody has shown promise in pat ients with breast cancer. To enhance this potential, a novel ChL6 immu noconjugate that is catabolizable and tightly binds Y-90 and In-111 wa s developed. The immunoconjugate, 1,4,7,10-tetraazacyclododecane-N,N', N '',N'''-tetraacetic acid (DOTA)-peptide-ChL6, consists of the macroc yclic chelator DOTA linked to ChL6 by a peptide that is preferentially catabolized in the liver. The pharmacokinetic and dosimetric properti es of the radioimmunoconjugates (RICs) In-111- and (90)DOTA-peptide-Ch L6 and In-111- and Y-90-2-iminothiolane (2-IT)-2-[p-(bromoacetamido)be nzyl]-DOTA-ChL6 were compared in athymic mice bearing HBT3477 human br east cancer xenografts. Each of the RICs was stable in vivo and concen trated well in the xenografts. Liver concentration, cumulative radioac tivity (activity over time), and radiation dose of the DOTA-peptide-Ch L6 RICs were one-third to one-half of those of the corresponding 2-IT- 2-[p(bromoacetamido)benzyl]-DOTA-ChL6 RICs. Indium-lll RICs were imper fect tracers for corresponding Y-90 RICs, although their pharmacokinet ics and radiation dosimetries were similar. The resuits of this study were consistent with previously published in vitro data, which indicat ed that the peptide linker of DOTA-peptide-ChL6 was catabolized by cat hepsin B. The cumulative activities and radiation doses to the liver o f DOTA-peptide-ChL6 RICs were one-half of those of corresponding RICs with the 2-IT linker. Preliminary data from pilot studies in patients with breast cancer are in accord with these observations. These novel DOTA-peptide RTCs seem to have excellent clinical potential for radioi mmunotherapy associated with marrow transplantation, for which liver r adiation is likely to be dose limiting for Y-90.