ANTIDISIALOGANGLIOSIDE RICIN A-CHAIN IMMUNOTOXINS SHOW POTENT ANTITUMOR EFFECTS IN-VITRO AND IN A DISSEMINATED HUMAN NEUROBLASTOMA SEVERE COMBINED IMMUNODEFICIENCY MOUSE MODEL

Several monoclonal antibodies (mAbs) were screened on different neurob lastoma cell lines to evaluate ricin A-chain immunotoxins for possible use against human neuroblastoma. Pour mAbs were identified that exhib ited high antitumor activity against neuroblastoma cell lines as measu red in an indirect cytotoxicity assay. These mAbs, including 14G2a (an tidisialoganglioside), ch14.18 (a humanized switch variant), BW704 (an tidisialoganglioside), and chCE7 (anti-glycoprotein of M(r) 190,000), were subsequently linked via the bivalent linker rbonyl-alpha-methyl-a lpha-(2-piridyldithio)toluene to deglycoslyated ricin A chain. The mos t potent immunotoxin, 14G2a.dgA, inhibited the protein synthesis of ne uroblastoma cell lines IMR5 and NMB by 50% at concentrations of 6 x 10 (-12) M. To test the antitumor efficacy of these immunotoxins in vivo, we developed a disseminated human neuroblastoma model in severe combi ned immunodeficiency mice. Treatment of tumor-bearing mice with 14G2a. dgA 12 days after tumor challenge resulted in a significant prolongati on of survival as compared with phosphate-buffered saline-treated cont rols (16.8 versus 6.5 weeks). We conclude that ricin A-chain immunotox ins might be of potential use in the treatment of human neuroblastoma.