Combination of Near-Infrared Photoimmunotherapy Using Trastuzumab and Small Protein Mimetic for HER2-Positive Breast Cancer.

Haruka Yamaguchi,Andreas Evdokiou,Yasuo Okada,Jotaro On,Takamasa Suzuki,Takao Morita,Junya Ono

doi:10.3390/ijms222212213

Abstract

Near-infrared photoimmunotherapy (NIR-PIT) is a promising cancer therapy based on a monoclonal antibody conjugated to a photosensitizer (IR700Dye) that is activated by near-infrared light irradiation. We previously reported on the use of NIR-PIT with a small protein mimetic, the Affibody molecule (6–7 kDa), instead of a monoclonal antibody. In this study, we investigated a combination of NIR-PIT for HER2-positive breast cancer cells (SK-BR3, MDA-MB361, and JIMT1) with HER2 Affibody-IR700Dye conjugate and trastuzumab-IR700Dye conjugate. HER2 Affibody and trastuzumab target different epitopes of the HER2 protein and do not compete. In vitro, the combination of NIR-PIT using both HER2 Affibody-IR700Dye conjugate and trastuzumab-IR700Dye conjugate induced necrotic cell death of HER2-positive breast cancer cells without damage to HER2-negative breast cancer cells (MCF7). It was more efficient than NIR-PIT using either the HER2 Affibody-IR700Dye conjugate alone or the trastuzumab-IR700Dye conjugate alone. Additionally, this combination of NIR-PIT was significantly effective against HER2 low-expressing cancer cells, trastuzumab-resistant cells (JIMT1), and brain metastatic cells of breast cancer (MDA-MB361). Furthermore, in vivo imaging exhibited the strong fluorescence intensity of both HER2 Affibody-IR700Dye conjugates and trastuzumab-Alexa488 conjugates in HER2-positive tumor, indicating that both HER2 Affibody and trastuzumab specifically bind to HER2-positive tumors without competing with each other. In conclusion, the combination of NIR-PIT using both HER2 Affibody and trastuzumab expands the targeting scope of NIR-PIT for HER2-positive breast cancer.

Highlights

In this study, we targeted Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer because HER2-positive expression occurs in about 20% of patients with breast cancer and is generally linked to poor outcomes [1,2]
Various breast cancer cell lines were investigated for human epidermal growth factor receptor 2 (HER2) expression by immunocytochemistry (ICC) and Western blotting analysis
In the Western blotting analysis, a strong band with a molecular weight of 185 kDa corresponding to the HER2 protein was observed in SK-BR3, MDA-MB361, and JIMT1 cells

Summary

Introduction

We targeted HER2-positive breast cancer because HER2-positive expression occurs in about 20% of patients with breast cancer and is generally linked to poor outcomes [1,2]. There are many studies on cancer treatment that target the HER2 protein [3,4,5]. Cancers are heterogeneous, and HER2-positive cancer includes cancer cells with low HER2 expression. A significant number of patients with HER2-positive cancer are either intrinsically resistant or eventually acquire resistance to anti-HER2-based therapy with trastuzumab, which is a major monoclonal antibody used to clinically treat HER2-positive cancer [6]. There is an urgent need for new treatment to break away from the current state of HER2-positive cancer therapy

Methods

Results

Conclusion