Abstract 654: MM-111, an ErbB2/ErbB3 bispecific antibody, effectively combines with lapatinib to inhibit growth of ErbB2-overexpressing tumor cells
Authors: Oyama Shinji K. , Paragas Violette , Adams Sharlene , Luus Lia , Huhalov Alexandra , Kudla Arthur J. , Overland Ryan , Nielsen Ulrik B. , Niyikiza Clet , McDonagh Charlotte F. , MacBeath Gavin 
Published: June 2012

The oncogenic receptor ErbB2 (HER2) is frequently overexpressed in a variety of cancer indications, including breast, gastric, bladder, and lung. ErbB3 (HER3), the preferred dimerization partner of ErbB2, is critical for the survival and growth of ErbB2-overexpressing tumors, but is poorly inhibited by current ErbB2-targeted therapies. MM-111 is a novel bispecific antibody designed to specifically inhibit function of the ErbB2/ErbB3 heterodimer in ErbB2-overexpressing tumors. MM-111 binds simultaneously to ErbB2 and ErbB3 and blocks the interaction of ErbB3 with its ligand, heregulin. Inhibiting the ErbB2/ErbB3 heterodimer prevents ligand-induced activation of the phosphotidylinositol 3-kinase (PI3K) pro-survival pathway, altering cell cycle progression and inhibiting tumor growth.

Upregulation of both heregulin and ErbB3 has been observed in tumors that have acquired resistance to the ErbB2-targeted therapies trastuzumab and lapatinib. In addition, ErbB2 and ErbB3 are frequently upregulated in estrogen receptor positive breast cancers that have developed resistance to anti-estrogen therapies. These data indicate that the ErbB2/ErbB3 receptor heterodimer potently activates growth of tumors characterized by ErbB2 overexpression and implicate ErbB3 as a mechanism of resistance to current therapies. Because of its ability to inhibit ErbB3 activity, MM-111 could be effective in combination with ErbB2-targeted therapies by overcoming ErbB3-mediated resistance. Previous data demonstrating that MM-111 acts in concert with trastuzumab to inhibit growth of ErbB2-overexpressing human tumor models support this hypothesis.

We now show that MM-111 effectively combines with lapatinib to inhibit growth of tumors driven by the ErbB2/ErbB3 heterodimer. MM-111, as a single agent, is more effective than lapatinib at inhibiting heregulin-driven activation of ErbB3 and AKT in ErbB2-overexpressing cancer cell lines. In these same cell lines, the combination of MM-111 and lapatinib results in greater AKT inhibition than either treatment alone. In addition, we have demonstrated in ErbB2-overexpressing 3D spheroid cancer models that treatment with the MM-111/ lapatinib combination increases the number of cells in early phase apoptosis as compared to single-drug treatments. Finally, in an ErbB2-overexpressing cancer xenograft model, the combination of MM-111 and lapatinib results in greater inhibition of tumor growth than either therapy alone.

In conclusion, we show that MM-111 and lapatinib positively combine to inhibit the growth of ErbB2-overexpressing tumors. Our results suggest that concurrent treatment with MM-111 and lapatinib may provide a potent therapeutic regimen for cancer patients whose tumors overexpress ErbB2 by deterring ErbB3-mediated resistance to lapatinib.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 654. doi:10.1158/1538-7445.AM2011-654