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.
Highlights
Since the introduction of trastuzumab (Herceptin, Roche) for the treatment of HER2-positive metastatic breast cancer in 1998, HER2-targeted therapies have transformed the clinical practice of HER2-positive tumor treatment
The binding site of Fynomer C12 on HER2 was mapped to five amino acid residues on the surface of domain I, representing an epitope distinct from pertuzumab within the dimerization domain II [3] or from trastuzumab within domain IV (21; Supplementary Fig. S1E)
All four C12-pertuzumab FynomAbs termed COVA201, COVA202, COVA207, and COVA208 could be purified as described in Materials and Methods at comparable yields as the parental antibody pertuzumab
Summary
Since the introduction of trastuzumab (Herceptin, Roche) for the treatment of HER2-positive metastatic breast cancer in 1998, HER2-targeted therapies have transformed the clinical practice of HER2-positive tumor treatment. 1), an antibody which binds to domain II of HER2 and blocks its dimerization [2, 3], and the antibody drug conjugate ado-trastuzumab emtansine 4), multiple therapeutic options for patients with HER2-positive breast cancer have become available. The vast majority of patients with metastatic breast cancer relapse after treatment with the currently available HER2-targeted therapies, and there remains a significant medical need for better treatment regimens [5]. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).
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