Treatment of Neuroblastoma Meningeal Carcinomatosis with Intrathecal Application of -Emitting Atomic Nanogenerators Targeting Disialo-Ganglioside GD2

Labeling of specific antibodies with bifunctional chelated Actinium-225 (Ac; an generator) allows the formation of new, highly potent and selective -emitting anticancer drugs. We synthesized and evaluated a radioimmunoconjugate based on 3F8, an IgG3 antibody that specifically binds to ganglioside GD2, which is overexpressed by many neuroectodermal tumors including neuroblastoma. The Ac-1,4,7,10-tetra-azacylododecane (DOTA)-3F8 construct was evaluated for radiochemical purity and sterility, immunoreactivity, cytotoxicity in vitro, induction of apoptosis on GD2-positive cells, as well as for pharmacological biodistribution and metabolism of the Ac generator and its daughters in a nude mouse xenograft model of neuroblastoma. The Ac-3F8 showed an IC50 of 3 Bq/ml (80 pCi/ml) on the neuroblastoma cell line, NMB7, in vitro. Apoptosis of these cells was not observed. Biodistribution in mice showed specific targeting of a subcutaneous tumor; there was redistribution of the Ac daughter nuclides mainly from blood to kidneys and to small intestine. Toxicity was examined in cynomolgus monkeys. Monkeys injected with 1 to 3 doses of intrathecal Ac-3F8 radioimmunoconjugate (80 to 150 kBq/kg total dose) did not show signs of toxicity based on blood chemistry, complete blood counts, or by clinical evaluations. Therapeutic efficacy of intrathecal Ac-3F8 was studied in a nude rat xenograft model of meningeal carcinomatosis. The Ac-3F8 treatment improved survival 2-fold from 16 to 34 days (P 0.01). In conclusion, in vivo generators targeted by 3F8 warrant additional study as a possible new approach to the treatment of carcinomatous meningitis.