Treatment of hepatocellular carcinoma with a GPC3-targeted bispecific T cell engager.

Yanyu Bi,Xianming Kong,Zonghai Li,Bo Song,Hua Jiang,Huamao Wang,Peng Wang

doi:10.18632/oncotarget.17905

Abstract

There are limited strategies for the treatment of hepatocellular carcinoma (HCC). In this study, we prepared a Bispecific T cell engager (BiTE) targeting Glypican 3 (GPC3) and CD3. The GPC3/CD3 BiTE was prepared by fusing the single-chain variable fragment (scFv) of the humanized anti-GPC3 antibody (9F2) with the scFv of the anti-CD3 antibody (OKT3). The in vitro and in vivo cytotoxic activities of the GPC3/CD3 BiTE were evaluated against various HCC cell lines. The GPC3/CD3 BiTE could efficiently mediate the T cell killing of GPC3-positive HCC in vitro, which was dependent on GPC3 expression on the surface of HCC cells. Moreover, our study indicates that, in the presence of the GPC3/CD3 BiTE, T cells could efficiently destroy GPC3-positive human HCC cells in vitro and in vivo. Additionally, our study further proved that GPC3 is not expressed in normal tissues. Thus, GPC3 may be a cancer-specific antigen. Collectively, these findings suggest that this anti-GPC3 BiTE might be a promising anti-tumor reagent for patients with GPC3-positive HCC.

Highlights

Hepatocellular carcinoma is the sixth most common cancer in the world, and the third most frequent cause of cancer-related death [1,2]
Glypican 3 (GPC3)/CD3 Bispecific T cell engager (BiTE) effectively binds to Peripheral blood mononuclear cells (PBMCs) and GPC3+ hepatocellular carcinoma (HCC) cells
FACS analysis revealed that GPC3/CD3 BiTE strongly bound to SK-Hep1-GPC3 (GPC3-transfected SK-Hep-1 cell line), HepG2, Huh-7 and Hep3B cells, barely bound to SK-Hep-1 cells and weakly bound to PLC/PRF/5 cells (Figure 2C)

Summary

Introduction

Hepatocellular carcinoma is the sixth most common cancer in the world, and the third most frequent cause of cancer-related death [1,2]. The incidence of HCC is quickly increasing in both Asian and Western countries [3]. Surgery is the most effective treatment for HCC. Tumor recurrence after a curative liver resection is very high and there is only a 10% 5-year survival rate [4]. The majority of patients with HCC are diagnosed at a late stage when potentially curative therapies, including chemotherapy, chemoembolization, ablation, and proton beam therapy, are least effective. Sorafenib (Nexavar), the first clinically approved targeted drug therapy for HCC, could only extend overall survival by 2–3 months [4,5]. Many patients permanently withdraw from treatment because of severe skin toxicity [6]. There remains an unmet need for tolerable, life-prolonging strategies for patients in the management of HCC

Methods

Results

Conclusion