Details

Autor(en) / Beteiligte

• Fitzgerald, Jonathan B
• Johnson, Bryan W
• Baum, Jason
• Adams, Sharlene
• Iadevaia, Sergio
• Tang, Jian
• Rimkunas, Victoria
• Xu, Lihui
• Kohli, Neeraj
• Rennard, Rachel
• Razlog, Maja
• Jiao, Yang
• Harms, Brian D
• Olivier, Jr, Kenneth J
• Schoeberl, Birgit
• Nielsen, Ulrik B
• Lugovskoy, Alexey A

Titel

MM-141, an IGF-IR- and ErbB3-directed bispecific antibody, overcomes network adaptations that limit activity of IGF-IR inhibitors

Ist Teil von

• Molecular cancer therapeutics, 2014-02, Vol.13 (2), p.410-425

Ort / Verlag

United States

Erscheinungsjahr

2014

Quelle

MEDLINE

Beschreibungen/Notizen

• Although inhibition of the insulin-like growth factor (IGF) signaling pathway was expected to eliminate a key resistance mechanism for EGF receptor (EGFR)-driven cancers, the effectiveness of IGF-I receptor (IGF-IR) inhibitors in clinical trials has been limited. A multiplicity of survival mechanisms are available to cancer cells. Both IGF-IR and the ErbB3 receptor activate the PI3K/AKT/mTOR axis, but ErbB3 has only recently been pursued as a therapeutic target. We show that coactivation of the ErbB3 pathway is prevalent in a majority of cell lines responsive to IGF ligands and antagonizes IGF-IR-mediated growth inhibition. Blockade of the redundant IGF-IR and ErbB3 survival pathways and downstream resistance mechanisms was achieved with MM-141, a tetravalent bispecific antibody antagonist of IGF-IR and ErbB3. MM-141 potency was superior to monospecific and combination antibody therapies and was insensitive to variation in the ratio of IGF-IR and ErbB3 receptors. MM-141 enhanced the biologic impact of receptor inhibition in vivo as a monotherapy and in combination with the mTOR inhibitor everolimus, gemcitabine, or docetaxel, through blockade of IGF-IR and ErbB3 signaling and prevention of PI3K/AKT/mTOR network adaptation.