A HER2-specific Modified Fc Fragment (Fcab) Induces Antitumor Effects Through Degradation of HER2 and Apoptosis

Kin-Mei Leung,Sarah Batey,Robert Rowlands,Samine J Isaac,Phil Jones,Victoria Drewett,Joana Carvalho,Miguel Gaspar,Sarah Weller,Melanie Medcalf,Mateusz M Wydro,Robert Pegram,Geert C Mudde,Anton Bauer,Kevin Moulder,Max Woisetschläger,Mihriban Tuna,John S Haurum,Haijun Sun

doi:10.1038/mt.2015.127

Abstract

FS102 is a HER2-specific Fcab (Fc fragment with antigen binding), which binds HER2 with high affinity and recognizes an epitope that does not overlap with those of trastuzumab or pertuzumab. In tumor cells that express high levels of HER2, FS102 caused profound HER2 internalization and degradation leading to tumor cell apoptosis. The antitumor effect of FS102 in patient-derived xenografts (PDXs) correlated strongly with the HER2 amplification status of the tumors. Superior activity of FS102 over trastuzumab or the combination of trastuzumab and pertuzumab was observed in vitro and in vivo when the gene copy number of HER2 was equal to or exceeded 10 per cell based on quantitative polymerase chain reaction (qPCR). Thus, FS102 induced complete and sustained tumor regression in a significant proportion of HER2-high PDX tumor models. We hypothesize that the unique structure and/or epitope of FS102 enables the Fcab to internalize and degrade cell surface HER2 more efficiently than standard of care antibodies. In turn, increased depletion of HER2 commits the cells to apoptosis as a result of oncogene shock. FS102 has the potential of a biomarker-driven therapeutic that derives superior antitumor effects from a unique mechanism-of-action in tumor cells which are oncogenically addicted to the HER2 pathway due to overexpression.

Highlights

HER2 is an oncoprotein in the ERBB receptor family
Activation of this receptor family induces potent signaling through the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways which promote tumor cell growth and survival.[1]
Selection and production of an anti-HER2 Fcab Experimental and computational stability studies were performed to assess the effects of randomization of distinct regions within

Summary

INTRODUCTION

HER2 is an oncoprotein in the ERBB receptor family. Activation of this receptor family induces potent signaling through the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways which promote tumor cell growth and survival.[1]. The engineering of the Fcab has been described previously by replacing amino acid sequences in the human IgG1 Fc fragment located at the C-terminal structural loops in the CH3 domain to generate antigen binding sites (Figure 1a).[11] The Fcab scaffold typically retains effector functions as well as the long halflife comparable to wild-type (WT) Fcab (the unmodified corresponding sequence of the constant region of human IgG1) at one third of the size of an IgG. Such properties set the Fcab apart from other antibody scaffolds of similar or smaller size.

RESULTS

DISCUSSION

MATERIALS AND METHODS