Bispecific antibody simultaneously targeting PD1 and HER2 inhibits tumor growth via direct tumor cell killing in combination with PD1/PDL1 blockade and HER2 inhibition

Chang-Ling Gu,Wei Xu,Zhen-Ping Zhu,Le Zhao,Hai-Xia Zhu,Hao-Min Huang,Lan Deng,Xiao-Qing Meng,Yue-Qin Liu,Kai Li

doi:10.1038/s41401-021-00683-8

Abstract

Immune checkpoint blockade has shown significant clinical benefit in multiple cancer indications, but many patients are either refractory or become resistant to the treatment over time. HER2/neu oncogene overexpressed in invasive breast cancer patients associates with more aggressive diseases and poor prognosis. Anti-HER2 mAbs, such as trastuzumab, are currently the standard of care for HER2-overexpressing cancers, but the response rates are below 30% and patients generally suffer relapse within a year. In this study we developed a bispecific antibody (BsAb) simultaneously targeting both PD1 and HER2 in an attempt to combine HER2-targeted therapy with immune checkpoint blockade for treating HER2-positive solid tumors. The BsAb was constructed by fusing scFvs (anti-PD1) with the effector-functional Fc of an IgG (trastuzumab) via a flexible peptide linker. We showed that the BsAb bound to human HER2 and PD1 with high affinities (EC50 values were 0.2 and 0.14 nM, respectively), and exhibited potent antitumor activities in vitro and in vivo. Furthermore, we demonstrated that the BsAb exhibited both HER2 and PD1 blockade activities and was effective in killing HER2-positive tumor cells via antibody-dependent cellular cytotoxicity. In addition, the BsAb could crosslink HER2-positive tumor cells with T cells to form PD1 immunological synapses that directed tumor cell killing without the need of antigen presentation. Thus, the BsAb is a new promising approach for treating late-stage metastatic HER2-positive cancers.

Highlights

The HER2/neu oncogene encodes an epidermal growth factor receptor (EGFR)-related receptor, HER2, an orphan receptor whose ligand has not yet been identified
The anti-HER2×Programmed death-1 (PD1) bispecific antibody (BsAb) exhibited ADCC toward HER2overexpressing tumor cells but not T cells ADCC plays an important role in trastuzumab-mediated tumor cell killing
The BsAb comprises a full trastuzumab IgG with two copies of anti-PD1 (609A) scFvs symmetrically fused to the C-terminus of the heavy chains

Summary

INTRODUCTION

The HER2/neu oncogene encodes an epidermal growth factor receptor (EGFR)-related receptor, HER2, an orphan receptor whose ligand has not yet been identified. The objective response rates to trastuzumab monotherapy range between 12% and 34% and the majority of patients who initially responded to trastuzumab generally develop resistance or relapse after a year [8] To this end, alternative anti-HER2 antibody-based therapeutics including antibody-drug conjugates, such as T-DM1 and DS8201s, and bispecific antibodies (BsAbs) are being actively developed and have shown significant clinical benefits in several cancer indications [9,10,11,12]. The BsAb exhibited superior tumor cell killing activity in the presence of peripheral blood mononuclear cells (PBMCs) or activated T cells relative to combination of the two parental mAbs. our anticonjugated goat anti-human IgG (Jackson, Cat.#109-095-003) at 4 °C for 1 h.

MATERIALS AND METHODS

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Findings

DISCUSSION