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.


METHODS
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
Peter J
PJ
Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. peter.houghton@stjude.org
Morton
Christopher L
CL
Gorlick
Richard
R
Kolb
E Anders
EA
Keir
Stephen T
ST
Reynolds
C Patrick
CP
Kang
Min H
MH
Maris
John M
JM
Wu
Jianrong
J
Smith
Malcolm A
MA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D017526:Receptor, IGF Type 1