Blockade of Insulin-Like Growth Factor Type-1 Receptor with Cixutumumab (IMC-A12): A Novel Approach to Treatment for Multiple Cancers

Eric      K. Rowinsky; Jonathan      D. Schwartz; Naseem      Zojwalla; Hagop      Youssoufian; Floyd      Fox; Philippe      Pultar; Ruslan      Novosyadlyy; Jan      Cosaert; Dale      L. Ludwig

doi:10.2174/138945011798829401

Abstract

Insulin-like growth factor type-1 receptor (IGF-1R) plays a central role in cell proliferation and survival and is overexpressed in many tumor types. Notably, IGF-1R – mediated signaling confers resistance to diverse cytotoxic, hormonal, and biologic agents, suggesting that therapies targeting IGF-1R may be effective against a broad range of human malignancies. Cixutumumab (IMC-A12; ImClone Systems) is a fully human immunoglobulin G1 (IgG1) monoclonal antibody that specifically inhibits IGF-1R signaling. Binding of cixutumumab to IGF-1R results in receptor internalization and degradation. Because cixutumumab is an IgG1 monoclonal antibody, it may induce additional cytotoxicity via immune effector mechanisms such as antibody-dependent cellular cytotoxicity. In preclinical studies, cixutumumab monotherapy resulted in growth inhibition of multiple experimental cancers. Moreover, cixutumumab safely enhanced the tumor growth inhibitory and cytotoxic effects of a broad range of chemotherapeutics, and modulated the action of agents that target hormone receptors and signal transduction, which may have implications for cancer therapy. Herein, we review published preclinical and clinical data for cixutumumab and provide a comprehensive overview of selected clinical studies.

Keywords: Cixutumumab, IMC-A12, IGF-IR, insulin-like growth factor receptor type-1, monoclonal antibody, cancer, immunoglobulin, radiotherapy, hormonal therapy, pharmacokinetics