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Plant-Derived Anti-Human Epidermal Growth Factor Receptor 2 Antibody Suppresses Trastuzumab-Resistant Breast Cancer with Enhanced Nanoscale Binding.

ABSTRACT: Traditional monoclonal antibodies such as Trastuzumab encounter limitations when treating Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer, particularly in cases that develop resistance. This study introduces plant-derived anti-HER2 variable fragments of camelid heavy chain domain (VHH) fragment crystallizable region (Fc) KEDL(K) antibody as a potent alternative for overcoming these limitations. A variety of biophysical techniques, in vitro assays, and in vivo experiments uncover the antibody's nanoscale binding dynamics with transmembrane HER2 on living cells. Single-molecule force spectroscopy reveals the rapid formation of two robust bonds, exhibiting approximately 50 pN force resistance and bond lifetimes in the second range. The antibody demonstrates a specific affinity for HER2-positive breast cancer cells, including those that are Trastuzumab-resistant. Moreover, in immune-deficient mice, the plant-derived anti-HER2 VHH-FcK antibody exhibits superior antitumor activity, especially against tumors that are resistant to Trastuzumab. These findings underscore the plant-derived antibody's potential as an impactful immunotherapeutic strategy for treating Trastuzumab-resistant HER2-positive breast cancer.

SUBMITTER: Park C

PROVIDER: S-EPMC11210341 | biostudies-literature | 2024 Jun

REPOSITORIES: biostudies-literature

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Plant-Derived Anti-Human Epidermal Growth Factor Receptor 2 Antibody Suppresses Trastuzumab-Resistant Breast Cancer with Enhanced Nanoscale Binding.

Park Chanyong C Kim Kibum K Kim Yerin Y Zhu Rong R Hain Lisa L Seferovic Hannah H Kim Min-Hyeok MH Woo Hyun Joo HJ Hwang Hyunju H Lee Seung Ho SH Kim Sangmin S Lee Jeong Eon JE Hinterdorfer Peter P Ko Kisung K Park Sungsu S Oh Yoo Jin YJ

ACS nano 20240519 25

Traditional monoclonal antibodies such as Trastuzumab encounter limitations when treating Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer, particularly in cases that develop resistance. This study introduces plant-derived anti-HER2 variable fragments of camelid heavy chain domain (VHH) fragment crystallizable region (Fc) KEDL(K) antibody as a potent alternative for overcoming these limitations. A variety of biophysical techniques, <i>in vitro</i> assays, and <i>in vivo</i> ...[more]

PMID: 38764224

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Project description:Trastuzumab resistance is a severe problem in the treatment of ErbB2-amplified cancer. Although trastuzumab plus pertuzumab is able to partly overcome trastuzumab resistance in ErbB2-overexpressing cancer, its antitumor efficacy remains limited. The present study investigated the antitumor activity of the combination of trastuzumab with H2-18, which is an antibody targetinsg ErbB2 domain I. Cell proliferation and inhibition experiments indicated that H2-18 and trastuzumab synergistically inhibited the proliferation of both the trastuzumab-sensitive gastric cancer cell line, NCI-N87 and the trastuzumab-resistant gastric cancer cell line, NCI-N87-TraRT. Furthermore, H2-18 plus trastuzumab inhibited the growth of NCI-N87-TraRT cells more effectively than trastuzumab plus pertuzumab, both in vitro and in vivo. Compared with trastuzumab plus pertuzumab, H2-18 plus trastuzumab had a potent ability to inhibit NCI-N87-TraRT cells to form colonies. Notably, H2-18 plus trastuzumab was more effective in inducing cell death than trastuzumab plus pertuzumab. The in vivo studies demonstrated that H2-18 plus trastuzumab effectively inhibited the growth of both NCI-N87 and NCI-N87-TraRT xenograft tumors. Further experiments revealed that in NCI-N87-TraRT cells, H2-18 plus trastuzumab was comparable to trastuzumab plus pertuzumab in the inhibition of phosphorylated (p-)HER3, p-AKT and p-ERK. However, compared with trastuzumab plus pertuzumab, H2-18 plus trastuzumab effectively activated ROS production and the phosphorylation of JNK and c-jun in NCI-N87-TraRT cells. Therefore, the superior antitumor efficacy of H2-18 plus trastuzumab over trastuzumab plus pertuzumab may be mainly attributable to the potent cell death-inducing activity. In addition, the in vitro and in vivo antitumor effect of the combination of H2-18, trastuzumab and pertuzumab were further investigated. The results revealed that H2-18 plus trastuzumab plus pertuzumab exhibited a maximal antitumor effect among all the anti-ErbB2 monoclonal antibody combinations tested. In summary, H2-18 plus trastuzumab may have potential as an effective strategy to overcome the resistance to trastuzumab in ErbB2-amplified gastric cancer cell lines.

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Dataset Information

Plant-Derived Anti-Human Epidermal Growth Factor Receptor 2 Antibody Suppresses Trastuzumab-Resistant Breast Cancer with Enhanced Nanoscale Binding.

Publications

Plant-Derived Anti-Human Epidermal Growth Factor Receptor 2 Antibody Suppresses Trastuzumab-Resistant Breast Cancer with Enhanced Nanoscale Binding.

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