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

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Abstract
Labeling of specific antibodies with bifunctional chelated Actinium-225 (225Ac; an α generator) allows the formation of new, highly potent and selective α-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 225Ac-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 225Ac generator and its daughters in a nude mouse xenograft model of neuroblastoma. The 225Ac-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 225Ac 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 225Ac-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 225Ac-3F8 was studied in a nude rat xenograft model of meningeal carcinomatosis. The 225Ac-3F8 treatment improved survival 2-fold from 16 to 34 days (P = 0.01). In conclusion, in vivo α generators targeted by 3F8 warrant additional study as a possible new approach to the treatment of carcinomatous meningitis.