Browsing by Author "Schmitt, Lisa"

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    Novel EGFR family member binding antibodies as cancer therapeutics
    (2018) Schmitt, Lisa; Kontermann, Roland (Prof. Dr.)
    As conventional anticancer therapeutics often lack specificity and thus lead to toxicities to healthy tissues, monoclonal antibodies implicating specific targeting and low toxicity profiles have become attractive therapeutic drug candidates. ErbB receptors are valuable targets for antibody-mediated tumor therapy. The receptor tyrosine kinase (RTK) HER2 is a well-established tumor antigen whose overexpression is associated with adverse prognosis in breast cancer. The kinase impaired RTK HER3 has only recently emerged as target for antibody-mediated tumor therapy. In this study, a panel of scFv selected by phage display from the naïve human antibody gene libraries HAL7 and HAL8 were characterized. Two novel human monoclonal antibodies, IgG 2-35 and IgG 3-43, were developed from the candidates revealing highest affinity to cell surface expressed HER2 and HER3, respectively. IgG 2-35 bound to HER2 expressing cancer cells with EC50 values between 200 and 330 pM. Furthermore, IgG 2-35 was able to reduce EGF mediated proliferation of two HER2 overexpressing cancer cell lines. IgG 3-43 bound to an epitope conserved between human and mouse HER3. The bivalent IgG bound recombinant bivalent HER3 with subnanomolar affinity (KD = 220 pM) and HER3-expressing tumor cells with EC50 values in the low picomolar range (3 - 30 pM). The antibody competed with heregulin for binding to HER3-expressing cells, efficiently inhibited both, heregulin induced and basal phosphorylation of HER3 as well as downstream signaling, and induced receptor internalization and degradation. Furthermore, IgG 3-43 inhibited heregulin-dependent proliferation of several HER3-positive cancer cell lines. Inhibition of tumor growth and prolonged survival was demonstrated in a FaDu xenograft tumor model in SCID mice. The findings demonstrate that IgG 3-43 efficiently blocks activation of HER3, thereby inhibiting tumor cell growth both in vitro and in vivo.