A Novel Fully Human Antibody targeting Extracellular Domain of PSMA Inhibits Tumor Growth in Prostate Cancer.

Jieheng Wu,Guodong Li,Fa Yang,Guoxu Zheng,Pin Xie,Ming Wei,Dian Jiao,Qiang Zhang,Weijun Qin,Donghui Han,Yueheng Han,Aizhi Zhao,Lingling Zhang,Weihong Wen,An-Gang Yang,Shengjia Shi

doi:10.1158/1535-7163.mct-18-1078

Abstract

Prostate cancer is the most commonly diagnosed malignancy in men and the second leading cause of cancer-related death. It is of vital importance to develop new strategies for prostate cancer therapy. PSMA (prostate-specific membrane antigen) is specifically expressed in prostate cancer and the neovasculature of certain cancer types, thus is considered to be an ideal target for cancer therapy. In our previous study, we have obtained a PSMA-specific single-chain variable fragment (scFv), named gy1, from a large yeast display naïve human scFv library. In this study, we reconstructed the PSMA scFv into a fully human antibody (named PSMAb) and evaluated its characterization both in vitro and in vivo We showed that PSMAb can specifically bind with and internalize into PSMA+ cells. The binding affinity of PSMAb is measured to be at nanomolar level, and PSMAb has very good thermostability. In vivo study showed that near IR dye-labeled PSMAb can specifically localize at PSMA+ tumors, and the application of PSMAb in vivo significantly inhibited the growth of PSMA+ tumors, but not PSMA- tumors. At the studied doses, no obvious toxicity was observed when applied in vivo, as shown by the relative normal liver and kidney function and normal structure of important organs, shown by hematoxylin and eosin staining. In addition, PSMAb may inhibit tumor growth through antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity mechanisms. Our results indicated that the novel fully human antibody, PSMAb, deserve further study for PSMA-targeted diagnosis and therapy for prostate cancer and other cancer types with vascular PSMA expression.

Highlights

Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of cancer-related death in men [1]
PSMA has been shown to be expressed in the neovasculature of variable cancer types [12,13,14,15,16,17]
PSMA is considered to be an ideal target for the therapy of prostate cancer, and the cancer types with vascular PSMA expression [18,19,20]

Summary

Introduction

Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of cancer-related death in men [1]. Antibody-based therapy is one of most attractive strategies in cancer therapy, because of the high binding affinity and specificity of an antibody. More than a dozen of PSMA-specific antibodies have been developed and evaluated in the diagnosis and therapy of prostate cancer and other cancer types. Most of these antibodies are mouse mAbs or humanized antibodies, which may bring safety concerns when applied in human. More human PSMA antibodies with high binding affinity or therapeutic efficacy are still needed. We confirmed the specific localization and antitumor effect of PSMAb on PSMAþ tumors in vivo. Our results confirmed that PSMAb deserves further study for PSMAtargeted therapy for prostate cancer and other cancer types with vascular PSMA expression

Materials and Methods

A Novel Fully Human PSMA Antibody Inhibits PCa Tumor Growth

Results

Discussion

Disclosure of Potential Conflicts of Interest