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