Initial testing of a monoclonal antibody (IMC-A12) against IGF-1R by the Pediatric Preclinical Testing Program.
BACKGROUND: Many childhood malignancies including sarcomas, neuroblastoma, and Wilms tumor show the presence of both, active, type-1-insulin-like growth factor receptor (IGF-1R), and the autocrine production of its ligands IGF-1/IGF-2. IMC-A12 is a fully human IgG1 antibody that prevents ligand binding to the IGF-1R. PROCEDURES: IMC-A12 was evaluated against the 23 cell lines of the Pediatric Preclinical Testing Program (PPTP) in vitro panel using 96 hr exposure at concentrations ranging from 0.01 nM to 0.1 microM. IMC-A12 was tested in vivo at a dose of 1 mg/mouse administered intraperitoneally twice weekly for 6 weeks. RESULTS: In vitro, IMC-A12-induced T/C values <50% in only three cell lines, a rhabdomyosarcoma cell line (Rh41) and two Ewing sarcoma cell lines (TC-71 and CHLA-9). In vivo, IMC-A12 induced significant differences in EFS distribution compared to control in 24 of 34 (71%) evaluable solid tumor xenografts. Using the PPTP "time to event" activity measure, IMC-A12 induced intermediate (n = 13) or high (n = 1) activity in 33 xenografts evaluable for this activity measure, including 6 of 6 rhabdomyosarcoma xenografts, 3 of 5 osteosarcoma xenografts, 2 of 5 neuroblastoma xenografts, and 1 of 5 Ewing sarcoma xenografts. The only objective response observed was observed in a rhabdomyosarcoma xenograft (Rh28) that achieved a maintained complete response. CONCLUSIONS: IMC-A12 demonstrated broad antitumor activity against the PPTP's in vivo solid tumor panels, with the activity primarily being tumor growth inhibition rather than tumor regression. IMC-A12 showed its greatest activity in vivo against the PPTP's rhabdomyosarcoma xenografts.
Houghton, PJ; Morton, CL; Gorlick, R; Kolb, EA; Keir, ST; Reynolds, CP; Kang, MH; Maris, JM; Wu, J; Smith, MA
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