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A novel antibody-drug conjugate, HcHAb18-DM1, has potent anti-tumor activity against human non-small cell lung cancer.

Biochemical and biophysical research communications (2019-04-24)
Muren Huhe, Jiaxin Lou, Yumeng Zhu, Yu Zhao, Ying Shi, Bo Wang, Xiuxuan Sun, Xiaoqin Zhang, Yang Zhang, Zhi-Nan Chen
ABSTRACT

Cluster of differentiation 147 (CD147), a transmembrane protein of the immunoglobulin superfamily, is a potential target of treatment against human non-small cell lung cancer (NSCLC). Although there have been exciting advances in epidermal growth factor receptor (EGFR)-targeted therapy for NSCLC in recent years, additional novel targeted agents are needed to improve the efficiency and to offer more options for patients. Antibody-drug conjugates (ADCs) utilize a chemical linker to conjugate cytotoxic drugs to a monoclonal antibody to maximize the delivery to target cells and minimize the delivery to other normal cells. The aim of this study was to prepare a novel anti-CD147 conjugate and examine the tumoricidal effect on NSCLC in vitro and in vivo. HcHAb18 was conjugated to the drug maytansinoid 1 (DM1) via a non-cleavable thioether linker (SMCC) to prepare HcHAb18-DM1 with an appropriate drug-antibody ratio (DAR). NSCLC cell lines expressing different levels of CD147 were tested in vitro to determine internalization, cell cycle arrest and cytotoxicity. In vivo efficacy and safety of HcHAb18-DM1 were evaluated in NSCLC xenograft mouse models. We found that HcHAb18-DM1 displayed an impressive potency in vitro and in vivo with a favorable safety profile. Upon binding to CD147, HcHAb18 could be internalized and delivered the payload DM1 to disturb mitotic spindle formation by microtubules. Target cells were arrested at G2/M phase and HcHAb18-DM1 exerted antiproliferative activity in vitro. Antigen-antibody binding and target cells with high growth rate were two integral prerequisites for exerting anti-tumor activity of HcHAb18-DM1. Therefore, we suggest HcHAb18-DM1 is a promising CD147-targeted therapeutic for NSCLC.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
DAPI, for nucleic acid staining
Sigma-Aldrich
Anti-α-Tubulin−FITC antibody, Mouse monoclonal, clone DM1A, purified from hybridoma cell culture
Sigma-Aldrich
Monoclonal Anti-Human IgG1−FITC antibody produced in mouse, clone 8c/6-39, purified immunoglobulin, buffered aqueous solution

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