Initial testing (stage 1) of a monoclonal antibody (SCH 717454) against the IGF-1 receptor by the pediatric preclinical testing program.

摘要

BACKGROUND: SCH 717454 (19D12) is a fully human antibody directed against the insulin-like growth factor 1 receptor (IGF-1R), which is implicated in the growth and metastatic phenotype of a broad range of malignancies. The activity of SCH 717454 was evaluated against the in vitro and in vivo panels of the Pediatric Preclinical Testing Program (PPTP). PROCEDURES: SCH 717454 was tested against the PPTP in vitro panel at concentrations ranging from 0.01 to 100 nM and was tested against the PPTP in vivo panel at a dose of 0.5 mg per mouse administered twice weekly for 4 weeks via intraperitoneal injection. RESULTS: SCH 717454 was ineffective at retarding growth of cell lines in the in vitro panel. In vivo, SCH 717454 significantly increased event-free survival in 20 of 35 (57%) solid tumor xenograft models with tumor regressions in one Ewing sarcoma model (complete response) and 2 osteosarcoma models (maintained complete responses). Using the time to event activity measure, SCH 717454 had intermediate (n =9) or high (n = 1) activity against 31 evaluable solid tumor xenografts, including xenografts from the rhabdoid tumor, Ewing, rhabdomyosarcoma, glioblastoma, neuroblastoma, and osteosarcoma panels. SCH 717454 showed little activity against the 8 xenografts of the acute lymphoblastic leukemia panel. CONCLUSIONS: SCH 717454 demonstrated broad antitumor activity against the PPTP's in vivo solid tumor panels. Further characterization of the molecular predictors of response and of the activity of combinations of SCH 717454 with other anticancer agents are anticipated.