DISPOSITION OF CONJUGATE-BOUND AND FREE DOXORUBICIN IN TUMOR-BEARING MICE FOLLOWING ADMINISTRATION OF A BR96-DOXORUBICIN IMMUNOCONJUGATE (BMS-182248)

Purpose: The chimeric BR96-doxorubicin (DOX) immunoconjugate, BMS 1822 48, has induced remissions and cures of human lung adenocarcinoma (L29 87) implanted in athymic mice. The purpose of this study was to evalua te the biodistribution of DOX after BMS 182248 administration to tumor -bearing mice and to evaluate the ability of BMS 182248 to target DOX to tumors. Methods: For this evaluation, L2987-implanted mice were giv en BMS 182248 (5 mg DOX/kg; three doses 4 days apart) and the levels o f both conjugate-bound and free DOX in plasma, tumor, liver and heart were determined. Results: Conjugate-bound DOX comprised the majority o f plasma DOX, with relatively low levels of free DOX present. From pla sma, conjugate-bound DOX distributed to the tissues examined with the order of concentration (per gram of tissue) being tumor > liver > hear t. Free DOX was also detected in liver and heart, but at concentration s lower than those present after an equivalent DOX dose (5 mg/kg; thre e doses 4 days apart). The total exposure of heart to free DOX after B MS 182248 administration was about one-quarter of that found after the administration of DOX alone. The elimination kinetics of both conjuga te-bound and free DOX from heart and liver after BMS 182248 administra tion paralleled those observed from plasma, indicating that equilibriu m had been attained between these nontumor tissues and plasma. The eli mination kinetics of both entities from tumors, however, were differen t from those from plasma, liver and heart. BMS 182248 produced sustain ed levels of both conjugate-bound and free DOX which were present thro ughout the experiment. This suggested that, in contrast to normal tiss ues. tumor tissue retention of BMS 182248 by antigen-promoted binding had occurred and that the kinetics of free DOX in the tumors were cont rolled by the rate of release of DOX from tumor-associated BMS 182248. As a result of this retention, the tumor concentrations of free DOX a fter BMS 182248 administration exceeded those produced by i.v. adminis tration of DOX at the same dose, a finding consistent with the greater antitumor activity of BMS 182248 relative to DOX. BMS 182248 also lib erated DOX upon incubation with rat liver lysosomes and was accumulate d by L2987 cells in culture, with the subsequent intracellular release of DOX. Conclusions: BMS 182248 effectively delivered DOX to L2987 xe nografts implanted in athymic mice and produced higher and more prolon ged tumor concentrations of free DOX than the administration of DOX al one. Following BMS 182248 administration, normal tissues (liver and he art) were exposed to lower overall concentrations of free DOX than wer e produced by administration of an equivalent DOX dose.