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Advances in Antibody-Drug Conjugates in the Treatment of HER2-Positive Breast Cancer.

ABSTRACT: Although targeted drugs improved the therapeutic effect of HER2-positive breast cancer, the long-term prognosis was still poor. In this regard, the research and development of antibody-drug conjugates (ADCs) came into being and made a lot of progress. ADCs had the characteristics of both chemotherapeutic agents and targeted agents by combining chemotherapeutic agents and targeted agents through a linker. It not only had a strong anti-tumor effect on HER2-positive breast cancer, but also had certain anti-tumor effects on HER2-low and even HER2-negative patients. In addition, the clinical researches of ADCs combined with immune checkpoint inhibitors (ICIs) therapy had also made a great breakthrough. This review aimed to summarize the clinical progress of ADCs, in particular the two drugs approved by the US Food and Drug Administration (FDA) for HER2-positive metastatic breast cancer as well as to summarize the current status of ADCs in combination with ICIs.

SUBMITTER: Yu Y

PROVIDER: S-EPMC9747846 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Advances in Antibody-Drug Conjugates in the Treatment of HER2-Positive Breast Cancer.

Yu Yongchao Y Wang Jin J Liao Dongying D Zhang Dou D Li Xiaojiang X Jia Yingjie Y Kong Fanming F

Breast cancer (Dove Medical Press) 20221209

Although targeted drugs improved the therapeutic effect of HER2-positive breast cancer, the long-term prognosis was still poor. In this regard, the research and development of antibody-drug conjugates (ADCs) came into being and made a lot of progress. ADCs had the characteristics of both chemotherapeutic agents and targeted agents by combining chemotherapeutic agents and targeted agents through a linker. It not only had a strong anti-tumor effect on HER2-positive breast cancer, but also had cert ...[more]

PMID: 36532256

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Project description:Chemotherapeutic drugs suffer from non-specific binding, undesired toxicity, and poor blood circulation which contribute to poor therapeutic efficacy. In this study, antibody-drug nanoparticles (ADNs) are engineered by synthesizing pure anti-cancer drug nanorods (NRs) in the core of nanoparticles with a therapeutic monoclonal antibody, Trastuzumab on the surface of NRs for specific targeting and synergistic treatments of human epidermal growth factor receptor 2 (HER2) positive breast cancer cells. ADNs were designed by first synthesizing ~ 95 nm diameter × ~ 500 nm long paclitaxel (PTX) NRs using the nanoprecipitation method. The surface of PTXNRs was functionalized at 2' OH nucleophilic site using carbonyldiimidazole and conjugated to TTZ through the lysine residue interaction forming PTXNR-TTZ conjugates (ADNs). The size, shape, and surface charge of ADNs were characterized using scanning electron microscopy (SEM), SEM, and zeta potential, respectively. Using fluorophore labeling and response surface analysis, the percentage conjugation efficiency was found > 95% with a PTX to TTZ mass ratio of 4 (molar ratio ≈ 682). In vitro therapeutic efficiency of PTXNR-TTZ was evaluated in two HER2 positive breast cancer cell lines: BT-474 and SK-BR-3, and a HER2 negative MDA-MB-231 breast cancer cell using MTT assay. PTXNR-TTZ inhibited > 80% of BT-474 and SK-BR-3 cells at a higher efficiency than individual PTX and TTZ treatments alone after 72 h. A combination index analysis indicated a synergistic combination of PTXNR-TTZ compared with the doses of single-drug treatment. Relatively lower cytotoxicity was observed in MCF-10A human breast epithelial cell control. The molecular mechanisms of PTXNR-TTZ were investigated using cell cycle and Western blot analyses. The cell cycle analysis showed PTXNR-TTZ arrested > 80% of BT-474 breast cancer cells in the G2/M phase, while > 70% of untreated cells were found in the G0/G1 phase indicating that G2/M arrest induced apoptosis. A similar percentage of G2/M arrested cells was found to induce caspase-dependent apoptosis in PTXNR-TTZ treated BT-474 cells as revealed using Western blot analysis. PTXNR-TTZ treated BT-474 cells showed ~ 1.3, 1.4, and 1.6-fold higher expressions of cleaved caspase-9, cytochrome C, and cleaved caspase-3, respectively than untreated cells, indicating up-regulation of caspase-dependent activation of apoptotic pathways. The PTXNR-TTZ ADN represents a novel nanoparticle design that holds promise for targeted and efficient anti-cancer therapy by selective targeting and cancer cell death via apoptosis and mitotic cell cycle arrest.

Dataset Information

Advances in Antibody-Drug Conjugates in the Treatment of HER2-Positive Breast Cancer.

Publications

Advances in Antibody-Drug Conjugates in the Treatment of HER2-Positive Breast Cancer.

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