Superior Antitumor Activity of a Novel Bispecific Antibody Cotargeting Human Epidermal Growth Factor Receptor 2 and Type I Insulin-like Growth Factor Receptor

Abstract

The humanized anti-HER2 monoclonal antibody (mAb) trastuzumab (Herceptin; Genentech) effectively inhibits human epidermal growth factor receptor 2 (HER2)-positive breast tumors. However, many patients responding to treatment often develop resistance. Cross-talk between type I insulin-like growth factor receptor (IGF-IR) and HER2 and elevated IGF-IR signaling have been implicated in tumor cell resistance to trastuzumab therapy. Previously, we reported that the anti-IGF-IR mAb m590 inhibits proliferation and migration of breast cancer MCF-7 cells in vitro. Here, we generated a "knobs-into-holes" bispecific antibody (Bi-Ab) against HER2 and IGF-IR by engineering trastuzumab and m590. We compared the effects of Bi-Ab treatment in vitro and in SKOV-3 HER2-and IGF-IR-overexpressing cancer xenograft mouse model with those of m590 and trastuzumab treatment alone or in combination. Bi-Ab effectively inhibited proliferation of HER2-and IGF-IR-overexpressing ovarian cancer SKOV-3 cells in vitro by ablating receptor phosphorylation and downstream PI3K/Akt and mitogen-activated protein kinase signaling. Bi-Ab more effectively inhibited cancer growth in SKOV-3 HER2-and IGF-IR-overexpressing cancer xenograft mouse model than m590 and trastuzumab alone or in combination. Mice bearing SKOV-3 HER2-and IGF-IR-overexpressing xenografts showed extensive and sustainable tumor regression when treated with Bi-Ab. Our results suggest that Bi-Ab has superior antitumor activity compared with monospecific antibodies, and cotargeting HER2 and IGF-IR may be clinically beneficial in minimizing the acquired resistance to trastuzumab therapy. Mol Cancer Ther; 13(1); 90-100. Ó2013 AACR.

Role of IGF1R in Breast Cancer Subtypes, Stemness, and Lineage Differentiation

“…In trastuzumab-resistant cells, IGF1R-promoted ERBB2 phosphorylation and IGF1R-induced invasion are mediated by Src and FoxM1 ( 98 ). Co-targeting ERBB2 and IGF1R reduces Erk/AKT activation, cell proliferation, in vitro invasion, and xenograft tumor growth to a greater extent than targeting either receptor individually ( 98 , 99 ). Interestingly, treating trastuzumab-resistant cells with metformin re-sensitizes cells by disrupting the ERBB/IGF1R complexes ( 97 ), again strongly suggesting that a combined therapy would hold promise for patients with ERBB2 + breast tumors.…”

IGF-1R peptide vaccines/mimics inhibit the growth of BxPC3 and JIMT-1 cancer cells and exhibit synergistic antitumor effects with HER-1 and HER-2 peptides

“…50 Co-targeting HER-2 and IGF-1R with trastuzumab and heat-induced expression of dominant-negative IGF-1 receptor (486/STOP) has been shown to synergistically inhibited human breast cancer cells. 16 Further, synergistic antitumor effects were reported with the combination of trastuzumab and the IGF-1R kinase inhibitor NVP-AEW541 preferentially in human breast cancer cells that are HER-2-dependent.…”

“…For example, a preclinical study indicated that combined treatment with IGF-1R-and HER-2-targeted therapies resulted in synergistic growth inhibition 22 of breast cancers, findings that have encouraged the development of a novel HER-2:IGF-1R bispecific antibody. 23 Further, we previously showed that IGF-1R-targeting improves trastuzumab sensitivity in cells that have acquired trastuzumab resistance. 17 Thus, targeting the IGF-1R signaling axis is a promising strategy, partly because it has the potential to bypass multiple mechanisms that promote resistance to currently employed targeted therapies against breast cancer.…”

Mechanisms of action of therapeutic antibodies for cancer

“…Chen et al developed an antibody bispecific for HER2 and IGF-1R[63]. They demonstrated that this construct inhibits tumor growth in mouse models.…”