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Inhibition of tumor cell growth and cancer stem cell expansion by a 4 bispecific antibody targeting EGFR and HER3 5

The frequent activation of HER3 signaling as a resistance mechanism to EGFR-targeted 33 therapy has motivated the development of combination therapies that block more than one 34 receptor tyrosine kinase. Here, we have developed a novel tetravalent, bispecific single- 35 chain diabody-Fc fusion protein targeting EGFR and HER3 (also known als ErbB3) that 36 integrates the antigen-binding sites of a humanized version of Cetuximab as well as a 37 recently developed anti-HER3 antibody, IgG 3-43. This bispecific antibody combines the 38 binding and neutralizing properties of the parental antibodies, as observed in biochemical 39 and in vitro 2D and 3D cell culture assays, and gave rise to long-lasting growth suppression 40 in a s.c. xenograft head-and-neck tumor model. In triple-negative breast cancer (TNBC) cell 41 lines, treatment with the bispecific antibody inhibited the proliferation and oncosphere 42 formation efficiency driven by HER3 signaling. In an orthotopic MDA-MB-468 tumor model, 43 this translated into antitumor effects superior to those obtained by the parental antibodies 44 alone or in combination and was associated with a reduced number of cells with stem-like 45 properties. These findings demonstrate that the bispecific antibody efficiently blocks not only 46 TNBC proliferation but also the survival and expansion of the cancer stem cell population, 47 holding promise for further preclinical development. 48