Abstract 3485: MM-111, an ErbB2/ErbB3 bispecific antibody with potent activity in ErbB2-overexpressing cells, positively combines with trastuzumab to inhibit growth of breast cancer cells driven by the ErbB2/ErbB3 oncogenic unit
Authors: Alexandra Huhalov, Sharlene Adams, Violette Paragas, Shinji Oyama, Ryan Overland, Lia Luus, Francis Gibbons, Bo Zhang, Stephanie Nguyen, Ulrik B. Nielsen, Clet Niyikiza, Charlotte F. Mc Donagh, Arthur J. Kudla
Journal: Cancer Research (2010)

Abstract MM-111 is a novel bispecific antibody fusion protein which targets the ErbB2/ErbB3 oncogenic unit, blocking activation of the phosphatidylinositol 3-kinase (PI3K) pro-survival pathway. The anti-ErbB2 arm of MM-111 binds with high affinity to the ErbB2 receptor, which localizes the bispecific molecule to ErbB2 over-expressing tumor cells and promotes binding of the anti-ErbB3 arm to the ErbB3 receptor. MM-111 binding to ErbB3 results in inhibition of ErbB3 signaling by blocking the binding of the ErbB3 physiological ligand heregulin. MM-111 treatment of ErbB2 overexpressing cancer cells inhibits activation of the PI3K pathway with sub-nanomolar potency, blocks cell cycle progression and attenuates tumor cell growth in multiple xenograft models. ErbB2 over-expressing tumor cells are addicted to growth signals provided by the ligand-activated ErbB2/ErbB3 heterodimer. Activation of downstream PI3K pathway signaling also occurs through ligand-independent ErbB2/ErbB2 homodimers and ErbB2/ErbB3 heterodimers. Recently the ErbB2-targeted therapeutic antibody trastuzumab was shown to inhibit basal ErbB3 signaling in the absence of ligand stimulation, purportedly by interrupting ligand-independent ErbB2/ErbB3 heterodimers formed through overexpression of ErbB2. However, in these studies trastuzumab did not effectively block ligand-induced activation of the ErbB2/ErbB3 oncogenic unit. Indeed, there is emerging evidence that ligand-induced ErbB3 activation may have an important role in resistance to trastuzumab. As MM-111 and trastuzumab have distinct and potentially complimentary effects on signaling in cells overexpressing ErbB2, we hypothesized that their combination may synergistically effect inhibition of tumor cell growth driven by the ErbB2/3 signaling network. Our data demonstrate that MM-111 and trastuzumab positively combine to inhibit breast cancer growth in multiple in vitro breast cancer models expressing ErbB2 and ErbB3. Further, in the BT-474 breast cancer xenograft model the combination of MM-111 and trastuzumab results in greater inhibition of tumor growth and an increased number of completely regressed tumors compared to the monotherapy treatment groups. Pharmacodynamic analysis of samples from these studies show that repeated administration of the combined therapeutic agents results in strong inhibition of the ErbB3/PI3K pathway. In conclusion, we show that MM-111 and trastuzumab inhibit the growth of ErbB2 over-expressing breast tumors with distinct mechanisms that act synergistically in combination. Concurrent treatment with MM-111 and trastuzumab may provide a potent therapeutic regimen for ErbB2-overexpressing breast cancer patients and potentially deter acquired resistance to trastuzumab through ErbB3 activation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3485.