title: A bispecific HER2-targeting FynomAb with superior antitumor activity and novel mode of action.
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.
authors.affiliation: Covagen AG, Wagistrasse, Schlieren, Switzerland.
authors.forename: Simon
authors.initials: S
authors.lastname: Brack
authors.affiliation: Covagen AG, Wagistrasse, Schlieren, Switzerland.
authors.forename: Isabella
authors.initials: I
authors.lastname: Attinger-Toller
authors.affiliation: Covagen AG, Wagistrasse, Schlieren, Switzerland.
authors.forename: Babette
authors.initials: B
authors.lastname: Schade
authors.affiliation: Covagen AG, Wagistrasse, Schlieren, Switzerland.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Mourlane
authors.affiliation: Covagen AG, Wagistrasse, Schlieren, Switzerland.
authors.forename: Kristina
authors.initials: K
authors.lastname: Klupsch
authors.affiliation: Covagen AG, Wagistrasse, Schlieren, Switzerland.
authors.forename: Richard
authors.initials: R
authors.lastname: Woods
authors.affiliation: Covagen AG, Wagistrasse, Schlieren, Switzerland.
authors.forename: Helen
authors.initials: H
authors.lastname: Hachemi
authors.affiliation: Covagen AG, Wagistrasse, Schlieren, Switzerland.
authors.forename: Ulrike
authors.initials: U
authors.lastname: von der Bey
authors.affiliation: Covagen AG, Wagistrasse, Schlieren, Switzerland.
authors.forename: Susann
authors.initials: S
authors.lastname: Koenig-Friedrich
authors.affiliation: Covagen AG, Wagistrasse, Schlieren, Switzerland.
authors.forename: Julian
authors.initials: J
authors.lastname: Bertschinger
authors.affiliation: Covagen AG, Wagistrasse, Schlieren, Switzerland dragan.grabulovski@covagen.com.
authors.forename: Dragan
authors.initials: D
authors.lastname: Grabulovski
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D049109:Cell Proliferation; D006801:Humans; D061986:MCF-7 Cells; D008810:Mice, Inbred C57BL; D021381:Protein Transport; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D015398:Signal Transduction; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D011993:Recombinant Fusion Proteins; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human