IMC-A12 is a fully human IgG1 monoclonal antibody that binds with high affinity to IGF-IR, inhibiting ligand-dependent receptor activation and downstream signaling. IMC-A12 also mediates internalization and degradation of the IGF-IR [22
]. IMC-A12 demonstrated relatively modest activity against the PPTP cell line panel where 50 percent growth inhibition was determined in only 3 (sarcoma) of 23 lines. As discussed previously [15
], conditions of in vitro
growth use high serum, which probably circumvents the effect of IGF-1R inhibition.
, IMC-A12, a species-specific antibody, demonstrated virtually no toxicity, but had broad-spectrum antitumor activity inducing significant differences in EFS distribution compared to control in 24 of 34 (71%) evaluable solid tumor xenografts. Significant differences in EFS distribution (treated to control) were observed in one or more xenografts for each histotype tested, with the exception of the medulloblastoma panel. 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 Wilms tumor panel and the medulloblastoma panel showed only low activity for the EFS T/C activity measure. The only objective response induced by IMC-A12 was observed in a rhabdomyosarcoma xenograft (Rh28) that achieved a maintained complete response. Two other alveolar rhabdomyosarcoma xenografts, Rh10, and Rh41 were also amongst the most sensitive to IMC-A12 treatment, consistent with the observation that the normally imprinted allele of the IGF2
gene is activated in alveolar rhabdomyosarcoma [23
]. PD2 (progressive disease with growth delay) responses were observed in an additional 16 xenografts.
Clinically, weekly doses of IMC-A12 ranging from 3 to 10 mg/kg have been well tolerated with no consistent adverse effects [22
]. In adults, the plasma half-life values at the 3 and 6 mg/kg dose levels averaged 148 and 209 hours, while maximal IMC-A12 plasma concentrations were 333 and 415 μg/mL, respectively. Of importance to the current study, target trough concentrations of IMC-A12, as determined from preclinical studies in human tumor xenograft models, were achieved at the 6 mg/kg dose [22
The PPTP previously evaluated another IGF-1R-targeted antibody [15
]. Twenty-three in vivo
models are common to both studies. Based on growth inhibition, similar activity for IMC-A12 and SCH717454 was observed in 13 models. Compared to the other antibody, IMC-A12 was superior in 5 models and inferior in 5 models. While the overall patterns of response were similar, there were differences. For example, IMC-A12 had greater activity against 3 of 5 rhabdomyosarcoma xenografts, but less activity in 2 of 4 Ewing sarcomas and 2 of 5 osteosarcoma xenografts. Of interest is that rhabdomyosarcomas are predominantly IGF-2-driven whereas Ewing sarcomas and many osteosarcomas primarily secrete IGF-1. Reference to the PPTP Affymetrix expression profiles (pptp.stjude.org/affyData.php
) showed that 4/5 Ewing sarcoma xenografts had high expression of IGF-1 ligand, whereas all 8 rhabdomyosarcomas and 7/8 neuroblastomas had high level expression of IGF-2 ligand. The osteosarcoma models were evenly divided into those with high IGF-1 or high IGF-2 expression. IGF-2 expression was strong in 5/14 brain tumors, but only a single line (BT-41) expressed IGF-1. Only 3/10 ALL xenografts expressed IGF-2 ligand, and none expressed IGF-1 signal. Thus, there is no apparent correlation between expression of ligand and tumor sensitivity to IMC-A12.
Several strategies for inhibiting IGF-1R-mediated signaling are in clinical or preclinical development. These include small molecule inhibitors of IGF-1R, receptor-binding antibodies such as IMC-A12, and antibodies that directly bind ligands. Results presented here, and previously [15
] indicate that the predominant effect of antibodies that block ligand binding to IGF-1R is to slow tumor progression, rather than induce a high frequency of tumor regressions. IGF’s act as survival factors for numerous cellular stresses, including cytotoxic agents used in treatment of childhood cancer. Consequently, for pediatric cancer one rational use of agents such as IMC-A12 is to combine these agents with current curative chemotherapy. A second approach will be to evaluate IMC-A12 in combination with other signaling inhibitors, such as rapamycin (sirolimus), against the PPTP in vivo panel
. Combinations of IMC-A12 with standard chemotherapy agents and with molecularly targeted agents (e.g., cetuximab, erlotinib, temsirolimus) are being studied in clinical trials for adults with cancer and pediatric evaluations of IMC-A12 have been initiated.