Combining anti-ERBB3 antibodies specific for domain I and domain III enhances the anti-tumor activity over the individual monoclonal antibodies.

Jimson W D’Souza,Irina Shchaveleva,Matthew K Robinson,Lisa E Goldsmith,Smitha Reddy,James D Marks,Samuel Litwin

doi:10.1371/journal.pone.0112376

Jimson W D’Souza, Irina Shchaveleva + Show 5 more

Open Access

https://doi.org/10.1371/journal.pone.0112376

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Abstract

BackgroundInappropriate signaling through the epidermal growth factor receptor family (EGFR1/ERBB1, ERBB2/HER2, ERBB3/HER3, and ERBB4/HER4) of receptor tyrosine kinases leads to unregulated activation of multiple downstream signaling pathways that are linked to cancer formation and progression. In particular, ERBB3 plays a critical role in linking ERBB signaling to the phosphoinositide 3-kinase and Akt signaling pathway and increased levels of ERBB3-dependent signaling is also increasingly recognized as a mechanism for acquired resistance to ERBB-targeted therapies.MethodsWe had previously reported the isolation of a panel of anti-ERBB3 single-chain Fv antibodies through use of phage-display technology. In the current study scFv specific for domain I (F4) and domain III (A5) were converted into human IgG1 formats and analyzed for efficacy.ResultsTreatment of cells with an oligoclonal mixture of the A5/F4 IgGs appeared more effective at blocking both ligand-induced and ligand-independent signaling through ERBB3 than either single IgG alone. This correlated with improved ability to inhibit the cell growth both as a single agent and in combination with other ERBB-targeted therapies. Treatment of NCI-N87 tumor xenografts with the A5/F4 oligoclonal led to a statistically significant decrease in tumor growth rate that was further enhanced in combination with trastuzumab.ConclusionThese results suggest that an oligoclonal antibody mixture may be a more effective approach to downregulate ERBB3-dependent signaling.

Highlights

The ERBB family of receptor tyrosine kinases (RTKs) is comprised of the epidermal growth factor receptor (EGFR/ ERBB1), ERBB2/HER2, ERRB3/HER3, and ERBB4/HER4
EGFR and ERBB2 have been the focus of extensive drug development efforts and are the targets of both small-molecule tyrosine kinase inhibitors (TKIs) and antibodybased therapies that are FDA-approved for treating a variety of indications, including breast (BrCa), lung, colorectal, head and neck, and gastric cancers (GCa) [2]
We previously identified a panel of scFv specific for the extracellular domain (ECD) of ERBB3 by panning a naıve human phage display library [26]

Summary

Introduction

The ERBB family of receptor tyrosine kinases (RTKs) is comprised of the epidermal growth factor receptor (EGFR/ ERBB1), ERBB2/HER2, ERRB3/HER3, and ERBB4/HER4. In normal epithelial-derived tissues, signaling through this family of RTKS is regulated through ligand-driven homo- and heterodimerization. Unregulated and/ or inappropriate signaling through EGFR and ERBB2, as a consequence of protein overexpression or mutation, is linked to both formation and progression of a variety of epithelial-derived tumors [1]. Inappropriate signaling through the epidermal growth factor receptor family (EGFR1/ERBB1, ERBB2/HER2, ERBB3/HER3, and ERBB4/HER4) of receptor tyrosine kinases leads to unregulated activation of multiple downstream signaling pathways that are linked to cancer formation and progression. ERBB3 plays a critical role in linking ERBB signaling to the phosphoinositide 3-kinase and Akt signaling pathway and increased levels of ERBB3-dependent signaling is increasingly recognized as a mechanism for acquired resistance to ERBB-targeted therapies

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Conclusion