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Lipolysis-stimulated lipoprotein receptor-targeted antibody-drug conjugate demonstrates potent antitumor activity against epithelial ovarian cancer

BACKGROUND: Epithelial ovarian cancer (EOC) is a lethal malignant tumor, for which new treatment options are urgently required. Lipolysis-stimulated lipoprotein receptor (LSR) is widely expressed in EOC, and it is associated with poor prognosis. In this study, we developed an antibody-drug conjugate...

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Autores principales: Kanda, Mizuki, Serada, Satoshi, Hiramatsu, Kosuke, Funauchi, Masashi, Obata, Kengo, Nakagawa, Satoshi, Ohkawara, Tomoharu, Murata, Okinori, Fujimoto, Minoru, Chiwaki, Fumiko, Sasaki, Hiroki, Ueda, Yutaka, Kimura, Tadashi, Naka, Tetsuji
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Neoplasia Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9679668/
https://www.ncbi.nlm.nih.gov/pubmed/36413881
http://dx.doi.org/10.1016/j.neo.2022.100853
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author Kanda, Mizuki
Serada, Satoshi
Hiramatsu, Kosuke
Funauchi, Masashi
Obata, Kengo
Nakagawa, Satoshi
Ohkawara, Tomoharu
Murata, Okinori
Fujimoto, Minoru
Chiwaki, Fumiko
Sasaki, Hiroki
Ueda, Yutaka
Kimura, Tadashi
Naka, Tetsuji
author_facet Kanda, Mizuki
Serada, Satoshi
Hiramatsu, Kosuke
Funauchi, Masashi
Obata, Kengo
Nakagawa, Satoshi
Ohkawara, Tomoharu
Murata, Okinori
Fujimoto, Minoru
Chiwaki, Fumiko
Sasaki, Hiroki
Ueda, Yutaka
Kimura, Tadashi
Naka, Tetsuji
author_sort Kanda, Mizuki
collection PubMed
description BACKGROUND: Epithelial ovarian cancer (EOC) is a lethal malignant tumor, for which new treatment options are urgently required. Lipolysis-stimulated lipoprotein receptor (LSR) is widely expressed in EOC, and it is associated with poor prognosis. In this study, we developed an antibody-drug conjugate (ADC) targeting LSR as a new therapeutic approach to EOC. METHODS: We, herein, developed novel anti-LSR monoclonal antibodies (mAbs) and an LSR-ADC by conjugating monomethyl auristatin E as a payload. We subsequently evaluated the in vitro and in vivo (on xenograft models) antitumor effect of the LSR-ADC. RESULTS: An overexpression of LSR was observed not only in the primary EOC tumor but also in its lymph node and omental metastases. The EOC cell lines NOVC7-C and OVCAR3 strongly expressed LSR (as compared to ES2 cells). Both the anti-LSR mAb and the LSR-ADC were able to specifically bind to LSR-positive cells and were rapidly internalized and trafficked to the lysosomes. The LSR-ADC demonstrated a potent antitumor effect against NOVC-7C and OVCAR3, but little activity against ES2 cells. In vitro, the LSR-ADC exhibited a potent antitumor effect against NOVC-7C and OVCAR3. Moreover, in the OVCAR3 xenograft models as well as in the patient-derived xenograft models of LSR-positive EOC, the LSR-ADC significantly inhibited tumor growth. The LSR-ADC also suppressed the omental/bowel metastases in OVCAR3-Luc xenografts and improved the median survival. CONCLUSION: The developed LSR-ADC demonstrated a significant antitumor activity against LSR-positive EOC cell lines and tumors. Our preclinical data support the use of the LSR-ADC as a novel therapy for patients with LSR-positive ovarian cancer.
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spelling pubmed-96796682022-11-25 Lipolysis-stimulated lipoprotein receptor-targeted antibody-drug conjugate demonstrates potent antitumor activity against epithelial ovarian cancer Kanda, Mizuki Serada, Satoshi Hiramatsu, Kosuke Funauchi, Masashi Obata, Kengo Nakagawa, Satoshi Ohkawara, Tomoharu Murata, Okinori Fujimoto, Minoru Chiwaki, Fumiko Sasaki, Hiroki Ueda, Yutaka Kimura, Tadashi Naka, Tetsuji Neoplasia Original Research/Original Research Article BACKGROUND: Epithelial ovarian cancer (EOC) is a lethal malignant tumor, for which new treatment options are urgently required. Lipolysis-stimulated lipoprotein receptor (LSR) is widely expressed in EOC, and it is associated with poor prognosis. In this study, we developed an antibody-drug conjugate (ADC) targeting LSR as a new therapeutic approach to EOC. METHODS: We, herein, developed novel anti-LSR monoclonal antibodies (mAbs) and an LSR-ADC by conjugating monomethyl auristatin E as a payload. We subsequently evaluated the in vitro and in vivo (on xenograft models) antitumor effect of the LSR-ADC. RESULTS: An overexpression of LSR was observed not only in the primary EOC tumor but also in its lymph node and omental metastases. The EOC cell lines NOVC7-C and OVCAR3 strongly expressed LSR (as compared to ES2 cells). Both the anti-LSR mAb and the LSR-ADC were able to specifically bind to LSR-positive cells and were rapidly internalized and trafficked to the lysosomes. The LSR-ADC demonstrated a potent antitumor effect against NOVC-7C and OVCAR3, but little activity against ES2 cells. In vitro, the LSR-ADC exhibited a potent antitumor effect against NOVC-7C and OVCAR3. Moreover, in the OVCAR3 xenograft models as well as in the patient-derived xenograft models of LSR-positive EOC, the LSR-ADC significantly inhibited tumor growth. The LSR-ADC also suppressed the omental/bowel metastases in OVCAR3-Luc xenografts and improved the median survival. CONCLUSION: The developed LSR-ADC demonstrated a significant antitumor activity against LSR-positive EOC cell lines and tumors. Our preclinical data support the use of the LSR-ADC as a novel therapy for patients with LSR-positive ovarian cancer. Neoplasia Press 2022-11-19 /pmc/articles/PMC9679668/ /pubmed/36413881 http://dx.doi.org/10.1016/j.neo.2022.100853 Text en © 2022 The Authors. Published by Elsevier Inc. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Research/Original Research Article
Kanda, Mizuki
Serada, Satoshi
Hiramatsu, Kosuke
Funauchi, Masashi
Obata, Kengo
Nakagawa, Satoshi
Ohkawara, Tomoharu
Murata, Okinori
Fujimoto, Minoru
Chiwaki, Fumiko
Sasaki, Hiroki
Ueda, Yutaka
Kimura, Tadashi
Naka, Tetsuji
Lipolysis-stimulated lipoprotein receptor-targeted antibody-drug conjugate demonstrates potent antitumor activity against epithelial ovarian cancer
title Lipolysis-stimulated lipoprotein receptor-targeted antibody-drug conjugate demonstrates potent antitumor activity against epithelial ovarian cancer
title_full Lipolysis-stimulated lipoprotein receptor-targeted antibody-drug conjugate demonstrates potent antitumor activity against epithelial ovarian cancer
title_fullStr Lipolysis-stimulated lipoprotein receptor-targeted antibody-drug conjugate demonstrates potent antitumor activity against epithelial ovarian cancer
title_full_unstemmed Lipolysis-stimulated lipoprotein receptor-targeted antibody-drug conjugate demonstrates potent antitumor activity against epithelial ovarian cancer
title_short Lipolysis-stimulated lipoprotein receptor-targeted antibody-drug conjugate demonstrates potent antitumor activity against epithelial ovarian cancer
title_sort lipolysis-stimulated lipoprotein receptor-targeted antibody-drug conjugate demonstrates potent antitumor activity against epithelial ovarian cancer
topic Original Research/Original Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9679668/
https://www.ncbi.nlm.nih.gov/pubmed/36413881
http://dx.doi.org/10.1016/j.neo.2022.100853
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