MM-141, an IGF-IR– and ErbB3-Directed Bispecific Antibody, Overcomes Network Adaptations That Limit Activity of IGF-IR Inhibitors

Abstract

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. Mol Cancer Ther; 13(2); 410-25. Ó2013 AACR.

A Combination of Structural and Empirical Analyses Delineates the Key Contacts Mediating Stability and Affinity Increases in an Optimized Biotherapeutic Single-chain Fv (scFv)

“…Each drop contained 0.15 l of E10 and 0.15 l of reservoir solution containing 100 mM Tris, pH 8.5, and 2000 mM (NH 4 )2SO 4 . The crystals appeared after 2 weeks, reaching a final size of 0.05 ϫ 0.07 ϫ 0.1 mm 3 . The concentration of E10-CXCL13 was 8.7 mg/ml in TBS buffer.…”

Combination therapy approaches to target insulin-like growth factor receptor signaling in breast cancer

“…Similar to the bispecific antibodies that target both IGF1R and EGFR (Dong et al 2011, Croasdale et al 2012), a tetravalent bispecific antibody, MM-141, has been developed that targets both IGF1R and erbB3 (HER3), preventing IGF-1 and IGF-2 ligand binding to IGF1R and heregulin binding to erbB3, subsequent ligand-induced receptor phosphorylation, and p-AKT downstream signaling (Fitzgerald et al 2014). MM-141 is more effective in reducing p-AKT than antibodies that target IGF1R and erbB3 individually and can enhance the antitumor effects of the chemotherapeutic agent, docetaxel, in DU145 prostate cancer xenografts (Table 2) (Fitzgerald et al 2014).…”

Cross-arm binding efficiency of an EGFR x c-Met bispecific antibody

“…10 Over 50 molcular formats have been engineered for the creation of bispecific molecules, which attests to the excitement and potential therapeutic development opportunities offered by these designs. 11,12 Among them, bispecific antibodies (BsAbs), a family of engineered antibody derivatives that recognize two different target antigens (e.g., HER2xHER3, 13 HER3xIGF-1R 14 and EGFRxHER3 15 for pathway blockage, or EpCAMxCD3 16 and CD3xCD19 17 for immune effector cell re-direction), are of particular interest. BsAbs can be generated by a variety of approaches.…”