Modulation of IGF1R function is critical for the proliferation and survival of many cancer cells. Down-regulation of IGF1R function inhibits the growth and tumorigenicity of various cancer cell lines in vitro and in vivo. Therefore, IGF1R is considered as an attractive therapeutic target for cancer treatment, particularly in combination with other chemotherapeutic drugs. To this end, we designed the murine antibody EM164 and its humanized version AVE1642, which specifically bind to the human IGF1R (Kd ∼0.1 nM), blocking IGF-1 binding, receptor activation and IGF1R-mediated cell growth and survival (Maloney et al. 2003, Cancer Res., 63:5073). Both antibodies have similar IGF-1R affinity and biological activity both in vitro and in vivo. Importantly, EM164 does not bind to the closely related insulin receptor, strongly reducing the risk of metabolic side effects. In vitro, EM164 significantly reduced the growth (>20% inhibition of Thymidine uptake in 10% serum) of approximately 10% of over 90 tumor cell lines tested (colon: HT29, pediatric neuroblastoma: TC-71, RD-ES, SK-N-MC, SK-NF1, sarcoma: Saos-2, NSCLC: H838, H322M, Hop18). In vivo efficacy of EM164 was evaluated in an IGF1R-dependent tumor model. Murine embryo fibroblasts (MEF), expressing the human IGF1R gene under the control of a tetracycline-inducible promoter, formed tumors in NMRInu/nu mice, whereas the parental MEF cells were not tumorigenic. Activity of EM164 (0.4-40 mg/kg/injection, 2x week for 2 weeks) was evaluated in dose response studies on mice bearing established IGF1R-dependent tumors (250 mm3). At the highest dose tested 100% partial regressions and 6/11 complete regressions were obtained. EM164 was profiled against several human xenograft models. 5 out of 27 models were found sensitive including human pancreatic cancer model BxPC-3. In nude mice inoculated with BxPC-3 cells, EM164, administered at 40, 4 and 0.4 mg/kg/IP, 2-3x week for 8 weeks, exhibited anti-tumor activity (log cell kill of 1.9, 1.7 and 1.8 respectively), with tumor escape at the end of therapy. In a tumor metastasis model in which HT-29 cells were implanted in the spleen to obtain liver metastases, treatment with EM164 (40mg/kg/injection, 2x week for 7 weeks) significantly reduced the growth of liver metastases (Mean liver weight of treated vs. vehicle treated mice 1.48g vs. 1.85g, p=0.01). In all tumor xenografts, i.e. both responsive and non-responsive, EM164 treatment (4-40 mg/kg) resulted in a 50-90 % decrease of IGF1R protein level. Taken together, these data showed that by downregulating the IGF1R receptor EM164 effectively inhibited tumor growth of some primary and secondary tumors. These data support the development of AVE1642 for the treatment of cancer patients. Given that only a fraction of tumors appeared responsive to the antibody, further understanding of the tumor characteristics determining susceptibility to the treatment will be important for success.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]