Bp-Bs, a Novel T-cell Engaging Bispecific Antibody with Biparatopic Her2 Binding, Has Potent Anti-tumor Activities

Jiayu Liu,Xiaoqiong Wu,Limin Lin,Haitao Pan,Yanlan Wang,Yumei Li,Yining Zhao,Zhong Wang

doi:10.1016/j.omto.2019.03.009

Jiayu Liu, Xiaoqiong Wu + Show 6 more

Open Access

https://doi.org/10.1016/j.omto.2019.03.009

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Journal: Molecular Therapy - Oncolytics	Publication Date: Apr 2, 2019
Citations: 10	License type: cc-by

Affiliation: Sun Yat-sen University

Abstract

Patients with Human epidermal growth factor receptor type 2 (Her2) overexpression are associated with aggressive tumor growth and poor clinical outcomes. Bispecific antibodies targeting Her2 have recently exhibited potent effects on Her2 signal inhibition. In this study, a novel biparatopic anti-Her2 bispecific antibody (Bp-Bs) was constructed by linking a single anti-CD3 Fab with two different anti-Her2 single-domain antibodies targeting non-overlapping epitopes of Her2. The Bp-Bs demonstrated strong binding on Her2-positive cells and potent cytotoxicity on Her2-positive tumor cells, even Her2-low expression cells, suggesting that biparatopic bispecific antibodies may have improved therapeutic benefits on broad Her2 patient populations.

Highlights

Human epidermal growth factor receptor type 2 (Her[2], named Her2/neu or ErbB2) is a member of the HER family of transmembrane receptor tyrosine kinases.[1]
The biparatopic anti-Her2 bispecific antibody (Bp-Bs) was formed via the heterodimerization of VH-CH1-VHH2 and VL-CL-VHH1, as anti-Her[2] VHH1 and anti-Her[2] VHH2 bind to different epitopes on Her[2] protein (Figure 1B)
The bivalent anti-Her2 bispecific antibody (Bi-Bs) was formed via the heterodimerization of VH-CH1-VHH1 and VL-CL-VHH1 (Figure 1A)

Summary

Introduction

Human epidermal growth factor receptor type 2 (Her[2], named Her2/neu or ErbB2) is a member of the HER family of transmembrane receptor tyrosine kinases.[1]. The vital role of Her[2] in breast cancer development prompted therapeutic development targeting Her[2]. The development of the anti-Her[2] therapeutics trastuzumab, lapatinib, pertuzumab, and T-DM1 has achieved clinical benefits for Her2-positive patients.[9] low response rates and resistance are associated with current therapeutics. Only 15%–30% of Her2-positive patients respond to trastuzumab therapy due to de novo and acquired resistance.[10,11] Trastuzumab has minimal effects on Her[2] low- or medium-expression cancer cells in vivo and in vitro.[12,13] Poor internalization leads to resistance in T-DM1 treatment of metastatic breast cancer.[10,14,15] new therapeutic options are urgently needed for patients resistant to or with no response to current Her2-targeted therapies

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