A Bispecific HER2-Targeting FynomAb with Superior Antitumor Activity and Novel Mode of Action

Molecular Cancer Therapeutics - Tập 13 Số 8 - Trang 2030-2039 - 2014
Simon Brack1, Isabella Attinger-Toller1, Babette Schade1, Frédéric Mourlane1, Kristina Klupsch1, Richard Woods1, Helen Hachemi1, Ulrike von der Bey1, Susann Koenig-Friedrich1, Julian Bertschinger1, Dragan Grabulovski1
1Authors' Affiliation: Covagen AG, Wagistrasse, Schlieren, Switzerland

Tóm tắt

Abstract Upregulation of HER2 is a hallmark of 20% to 30% of invasive breast cancers, rendering this receptor an attractive target for cancer therapy. Although HER2-targeting agents have provided substantial clinical benefit as cancer therapeutics, there is a need for the development of new agents aiming at circumventing anti-HER2 resistance. On the basis of the approved antibody pertuzumab, we have created a panel of bispecific FynomAbs, which target two epitopes on HER2. FynomAbs are fusion proteins of an antibody and a Fyn SH3–derived binding protein. One bispecific FynomAb, COVA208, was characterized in detail and showed a remarkable ability to induce rapid HER2 internalization and apoptosis in vitro. Moreover, it elicited a strong inhibition of downstream HER2 signaling by reducing HER2, HER3, and EGFR levels in vitro and in vivo. Importantly, COVA208 demonstrated superior activity in four different xenograft models as compared with the approved antibodies trastuzumab and pertuzumab. The bispecific FynomAb COVA208 has the potential to enhance the clinical efficacy and expand the scope of HER2-directed therapies, and delineates a paradigm for designing a new class of antibody-based therapeutics for other receptor targets. Mol Cancer Ther; 13(8); 2030–9. ©2014 AACR.

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Molecular Cancer Therapeutics

Tập 13 Số 8

2030-2039

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