Anti-CD47 Monoclonal Antibody–Drug Conjugate: A Targeted Therapy to Treat Triple-Negative Breast Cancers

• Main Authors: Yingnan Si, Ya Zhang, Jia-Shiung Guan, Hanh Giai Ngo, Angela Totoro, Ajeet Pal Singh, Kai Chen, Yuanxin Xu, Eddy S. Yang, Lufang Zhou, Runhua Liu, Xiaoguang (Margaret) Liu
• Format: Article
• Language: English
• Published: MDPI AG 2021-08-01
• Series: Vaccines
• Subjects: triple-negative breast cancers; targeted therapy; CD47 receptor; monoclonal antibody; antibody–drug conjugate
• Online Access: https://www.mdpi.com/2076-393X/9/8/882
• ISSN: 2076-393X

Triple-negative breast cancers (TNBCs) are frequently recurrent due to the development of drug resistance post chemotherapy. Both the existing literature and our study found that surface receptor CD47 (cluster of differentiation 47) was upregulated in chemotherapy-treated TNBC cells. The goal of this study was to develop a monoclonal antibody (mAb)-based targeting strategy to treat TNBC after standard treatment. Specifically, a new mAb that targets the extracellular domain of receptor CD47 was developed using hybridoma technology and produced in fed-batch culture. Flow cytometry, confocal microscopy, and in vivo imaging system (IVIS) showed that the anti-CD47 mAb effectively targeted human and mouse TNBC cells and xenograft models with high specificity. The antibody–drug conjugate (ADC) carrying mertansine was constructed and demonstrated higher potency with reduced IC₅₀ in TNBC cells than did the free drug and significantly inhibited tumor growth post gemcitabine treatment in MDA-MB-231 xenograft NSG model. Finally, whole blood analysis indicated that the anti-CD47 mAb had no general immune toxicity, flow cytometry analysis of lymph nodes revealed an increase of CD69⁺ NK, CD11c⁺ DC, and CD4⁺ T cells, and IHC staining showed tumoral infiltration of macrophage in the 4T1 xenograft BALB/cJ model. This study demonstrated that targeting CD47 with ADC has great potential to treat TNBCs as a targeted therapy.