title: Treatment of neuroblastoma meningeal carcinomatosis with intrathecal application of alpha-emitting atomic nanogenerators targeting disialo-ganglioside GD2.
abstract: Labeling of specific antibodies with bifunctional chelated Actinium-225 ((225)Ac; an alpha generator) allows the formation of new, highly potent and selective alpha-emitting anticancer drugs. We synthesized and evaluated a radioimmunoconjugate based on 3F8, an IgG(3) antibody that specifically binds to ganglioside GD2, which is overexpressed by many neuroectodermal tumors including neuroblastoma. The (225)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 (225)Ac generator and its daughters in a nude mouse xenograft model of neuroblastoma. The (225)Ac-3F8 showed an IC(50) 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 (225)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 (225)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 (225)Ac-3F8 was studied in a nude rat xenograft model of meningeal carcinomatosis. The (225)Ac-3F8 treatment improved survival 2-fold from 16 to 34 days (P = 0.01). In conclusion, in vivo alpha generators targeted by 3F8 warrant additional study as a possible new approach to the treatment of carcinomatous meningitis.
authors.affiliation: Departments of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
authors.forename: Matthias
authors.initials: M
authors.lastname: Miederer
authors.forename: Michael R
authors.initials: MR
authors.lastname: McDevitt
authors.forename: Paul
authors.initials: P
authors.lastname: Borchardt
authors.forename: Ira
authors.initials: I
authors.lastname: Bergman
authors.forename: Kim
authors.initials: K
authors.lastname: Kramer
authors.forename: Nai-Kong V
authors.initials: NK
authors.lastname: Cheung
authors.forename: David A
authors.initials: DA
authors.lastname: Scheinberg
mesh_terms: D000186:Actinium / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology*; D005732:Gangliosides / Q000378:metabolism*; D000882:Haplorhini; D006801:Humans; D018796:Immunoconjugates; D007074:Immunoglobulin G / Q000276:immunology* / Q000627:therapeutic use*; D007278:Injections, Spinal; D008577:Meningeal Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology*; D051381:Rats; D011923:Rats, Nude; D016019:Survival Analysis; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
chemical_list: C419226:3F8 antibody; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D005732:Gangliosides; D018796:Immunoconjugates; D007074:Immunoglobulin G; C019403:ganglioside, GD2; D000186:Actinium