Advanced
ovarian cancer is largely incurable, but initially it is frequently confined to the i.p. space. We explored i.p.
radioimmunotherapy in a mouse model of human
ovarian cancer. Use of a targeted
actinium-225 ((225)Ac) in vivo generator of alpha particles exploits the extreme, selective cytotoxicity of alpha particles, while providing a feasible half-life to enable delivery to
tumor. (225)Ac chelated with 2-(p-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10 tetraacetic
acid was conjugated to
trastuzumab, an anti-HER-2/neu antibody. The
radioimmunoconjugate was tested for immunoreactivity, internalization, and cytotoxicity using a human ovarian
carcinoma cell line, SKOV3. (225)Ac-labeled
trastuzumab retained immunoreactivity (50-90%), rapidly internalized into cells (50% at 2 h), and had an ED(50) of 1.3 nCi/ml after 4 days of incubation in vitro. i.p. administered (225)Ac- or (111)In-labeled
trastuzumab behaved similarly with high
tumor uptake [56-60% injected dose per gram (% ID/g) at 4 h, which increased to 65-70% ID/g at 24 h].
Tumor uptake was 3-5-fold higher than liver and spleen, the normal organs with the highest uptake. i.v. administration of (111)In-labeled
trastuzumab produced slightly higher normal organ uptake compared with i.p.-administered (111)In-labeled
trastuzumab. However,
tumor uptake was low, 5%-26% ID/g.
Therapy was examined with native
trastuzumab and 220, 330, and 450 nCi of (225)Ac-labeled
trastuzumab or (225)Ac-labeled control antibody at different dosing schedules.
Therapy was initiated 9 days after
tumor seeding. Groups of control mice and those administered native
trastuzumab had median survivals of 33 and 37 or 44 days, respectively. Median survival was 52-126 days with (225)Ac-labeled
trastuzumab at various doses and schedules, and 48-64 days for (225)Ac-labeled control the same schedules. Deaths from toxicity occurred with the highest activity levels. In conclusion, i.p. administration with a (225)Ac-labeled internalizing anti-HER-2/neu antibody can extend survival significantly in a nude mouse model of human
ovarian cancer at levels that produce no apparent gross toxicity.