Cixutumumab: Anti-CD221 human monoclonal antibody angiogenesis inhibitor oncolytic

E. K. Rowinsky, J. D. Schwartz, N. Zojwalla, H. Youssoufian, F. Fox, P. Pultar, D. L. Ludwig

Research output: Contribution to journalReview articlepeer-review

Abstract

The use of monoclonal antibodies (mAbs) against cancer targets has been validated as a therapeutic strategy, due in part to the ability of antibodies to induce robust structural and functional perturbations with negligible off-target effects. The insulin-like growth factor I receptor (ICF-I receptor, ICF-IR, CD221), appears to be an ideal target for antibody-directed therapy; the ICF-IR is overexpressed in various cancers and appears to regulate cancer cell proliferation, survival and sensitivity to a wide range of therapeutics. Targeting the ICF-IR with a highly specific mAb may also be desirable to avoid off-target effects. Cixutumumab (IMC-A12; ImClone LLC) is a fully human immunoglobulin G1 (IgG1) mAb that binds to the ICF-IR with high affinity and inhibits ligand-dependent receptor activation and signaling. The antibody exerts its effects via receptor blockade and by mediating efficient receptor internalization and degradation. As an IgG1 construct, cixutumumab may also induce additional cytotoxicity through immune effector mechanisms such as antibody-dependent cellular cytotoxicity. In human tumor xenograft models, IGF-IR blockade occurs following monotherapy with cixutumumab, resulting in significant growth inhibition in various cancers. Moreover, cixutumumab safely enhances many chemotherapeutics and affects agents that modulate hormone receptor activity in hormone-dependent malignancies. A comprehensive overview of preclinical and clinical studies to date is given herein.

Original languageEnglish
Pages (from-to)265-285
Number of pages21
JournalDrugs of the Future
Volume35
Issue number4
DOIs
StatePublished - Apr 2010
Externally publishedYes

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