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A Fully-Human Antibody Specifically Targeting a Membrane-Bound Fragment of CADM1 Potentiates the T Cell-Mediated Death of Human Small-Cell Lung Cancer Cells

Small-cell lung cancer (SCLC) is the most aggressive form of lung cancer and the leading cause of global cancer-related mortality. Despite the earlier identification of membrane-proximal cleavage of cell adhesion molecule 1 (CADM1) in cancers, the role of the membrane-bound fragment of CAMD1 (MF-CAD...

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Autores principales: Lee, Ji Hyun, Kim, Ji Woong, Yang, Ha Rim, Song, Seong-Won, Lee, Song-Jae, Jeon, Yeongha, Ju, Anna, Lee, Narim, Kim, Min-Gu, Kim, Minjoo, Hwang, Kyusang, Yoon, Jin Hwan, Shim, Hyunbo, Lee, Sukmook
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9266846/
https://www.ncbi.nlm.nih.gov/pubmed/35805896
http://dx.doi.org/10.3390/ijms23136895
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author Lee, Ji Hyun
Kim, Ji Woong
Yang, Ha Rim
Song, Seong-Won
Lee, Song-Jae
Jeon, Yeongha
Ju, Anna
Lee, Narim
Kim, Min-Gu
Kim, Minjoo
Hwang, Kyusang
Yoon, Jin Hwan
Shim, Hyunbo
Lee, Sukmook
author_facet Lee, Ji Hyun
Kim, Ji Woong
Yang, Ha Rim
Song, Seong-Won
Lee, Song-Jae
Jeon, Yeongha
Ju, Anna
Lee, Narim
Kim, Min-Gu
Kim, Minjoo
Hwang, Kyusang
Yoon, Jin Hwan
Shim, Hyunbo
Lee, Sukmook
author_sort Lee, Ji Hyun
collection PubMed
description Small-cell lung cancer (SCLC) is the most aggressive form of lung cancer and the leading cause of global cancer-related mortality. Despite the earlier identification of membrane-proximal cleavage of cell adhesion molecule 1 (CADM1) in cancers, the role of the membrane-bound fragment of CAMD1 (MF-CADM1) is yet to be clearly identified. In this study, we first isolated MF-CADM1-specific fully human single-chain variable fragments (scFvs) from the human synthetic scFv antibody library using the phage display technology. Following the selected scFv conversion to human immunoglobulin G1 (IgG1) scFv-Fc antibodies (K103.1–4), multiple characterization studies, including antibody cross-species reactivity, purity, production yield, and binding affinity, were verified. Finally, via intensive in vitro efficacy and toxicity evaluation studies, we identified K103.3 as a lead antibody that potently promotes the death of human SCLC cell lines, including NCI-H69, NCI-H146, and NCI-H187, by activated Jurkat T cells without severe endothelial toxicity. Taken together, these findings suggest that antibody-based targeting of MF-CADM1 may be an effective strategy to potentiate T cell-mediated SCLC death, and MF-CADM1 may be a novel potential therapeutic target in SCLC for antibody therapy.
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spelling pubmed-92668462022-07-09 A Fully-Human Antibody Specifically Targeting a Membrane-Bound Fragment of CADM1 Potentiates the T Cell-Mediated Death of Human Small-Cell Lung Cancer Cells Lee, Ji Hyun Kim, Ji Woong Yang, Ha Rim Song, Seong-Won Lee, Song-Jae Jeon, Yeongha Ju, Anna Lee, Narim Kim, Min-Gu Kim, Minjoo Hwang, Kyusang Yoon, Jin Hwan Shim, Hyunbo Lee, Sukmook Int J Mol Sci Article Small-cell lung cancer (SCLC) is the most aggressive form of lung cancer and the leading cause of global cancer-related mortality. Despite the earlier identification of membrane-proximal cleavage of cell adhesion molecule 1 (CADM1) in cancers, the role of the membrane-bound fragment of CAMD1 (MF-CADM1) is yet to be clearly identified. In this study, we first isolated MF-CADM1-specific fully human single-chain variable fragments (scFvs) from the human synthetic scFv antibody library using the phage display technology. Following the selected scFv conversion to human immunoglobulin G1 (IgG1) scFv-Fc antibodies (K103.1–4), multiple characterization studies, including antibody cross-species reactivity, purity, production yield, and binding affinity, were verified. Finally, via intensive in vitro efficacy and toxicity evaluation studies, we identified K103.3 as a lead antibody that potently promotes the death of human SCLC cell lines, including NCI-H69, NCI-H146, and NCI-H187, by activated Jurkat T cells without severe endothelial toxicity. Taken together, these findings suggest that antibody-based targeting of MF-CADM1 may be an effective strategy to potentiate T cell-mediated SCLC death, and MF-CADM1 may be a novel potential therapeutic target in SCLC for antibody therapy. MDPI 2022-06-21 /pmc/articles/PMC9266846/ /pubmed/35805896 http://dx.doi.org/10.3390/ijms23136895 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lee, Ji Hyun
Kim, Ji Woong
Yang, Ha Rim
Song, Seong-Won
Lee, Song-Jae
Jeon, Yeongha
Ju, Anna
Lee, Narim
Kim, Min-Gu
Kim, Minjoo
Hwang, Kyusang
Yoon, Jin Hwan
Shim, Hyunbo
Lee, Sukmook
A Fully-Human Antibody Specifically Targeting a Membrane-Bound Fragment of CADM1 Potentiates the T Cell-Mediated Death of Human Small-Cell Lung Cancer Cells
title A Fully-Human Antibody Specifically Targeting a Membrane-Bound Fragment of CADM1 Potentiates the T Cell-Mediated Death of Human Small-Cell Lung Cancer Cells
title_full A Fully-Human Antibody Specifically Targeting a Membrane-Bound Fragment of CADM1 Potentiates the T Cell-Mediated Death of Human Small-Cell Lung Cancer Cells
title_fullStr A Fully-Human Antibody Specifically Targeting a Membrane-Bound Fragment of CADM1 Potentiates the T Cell-Mediated Death of Human Small-Cell Lung Cancer Cells
title_full_unstemmed A Fully-Human Antibody Specifically Targeting a Membrane-Bound Fragment of CADM1 Potentiates the T Cell-Mediated Death of Human Small-Cell Lung Cancer Cells
title_short A Fully-Human Antibody Specifically Targeting a Membrane-Bound Fragment of CADM1 Potentiates the T Cell-Mediated Death of Human Small-Cell Lung Cancer Cells
title_sort fully-human antibody specifically targeting a membrane-bound fragment of cadm1 potentiates the t cell-mediated death of human small-cell lung cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9266846/
https://www.ncbi.nlm.nih.gov/pubmed/35805896
http://dx.doi.org/10.3390/ijms23136895
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