Anti-IGF-IR antibody h10H5 induces a unique transcriptional profile in SK-N-AS human neuroblastoma xenograft tumor

The insulin-like growth factor (IGF) system consists of two ligands (IGF-I and IGF-II), which both signal through type I IGF receptor (IGF-IR) to stimulate proliferation and inhibit apoptosis, with activity contributing to malignant growth of many types of human cancers. We have developed a humanized, affinity-matured anti-human IGF-IR monoclonal antibody (h10H5), which binds with high affinity and specificity to the extracellular domain. h10H5 inhibits IGF-IR-mediated signaling by blocking IGF-I and IGF-IIbinding and by inducing cell surface receptor down-regulation via internalization and degradation. In vitro, h10H5 exhibits anti-proliferative effects on cancer cell lines. In vivo, h10H5 demonstrates single-agent anti-tumor efficacy in human SK-N-AS neuroblastoma and SW527 breast cancer xenograft models, and even greater efficacy in combination with the chemotherapeutic agent Docetaxel or an anti-VEGF antibody. Anti-tumor activity of h10H5 is associated with decreased AKT activation and glucose uptake, and a 316-gene transcription profile with significant changes involving DNA metabolic and cell cycle machineries. These data support the clinical testing of h10H5 as a biotherapeutic for IGF-IR-dependent human tumors.

8

Shang Y, Mao Y, Batson J, Scales SJ, Phillips G, Lackner MR, Totpal K, Williams S, Yang J, Tang Z, Modrusan Z, Tan C, Liang WC, Tsai SP, Vanderbilt A, Kozuka K, Hoeflich K, Tien J, Ross S, Li C, Lee SH, Song A, Wu Y, Stephan JP, Ashkenazi A, Zha J