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Development of a Humanized VHH Based Recombinant Antibody Targeting Claudin 18.2 Positive Cancers
Claudin 18.2 (CLDN18.2), a tight junction (TJ) family protein controlling molecule exchange between cells, is frequently over-expressed in gastric cancer, pancreatic adenocarcinomas and in a fraction of non–small cell lung cancer cases. The tumor properties indicate that CLDN18.2 could be an attract...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9273722/ https://www.ncbi.nlm.nih.gov/pubmed/35837391 http://dx.doi.org/10.3389/fimmu.2022.885424 |
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author | Zhong, Weixiang Lu, Yimin Ma, Zhe He, Yinjun Ding, Yongfeng Yao, Gaofeng Zhou, Zhenxing Dong, Jiali Fang, Yongliang Jiang, Weiqin Wang, Weilin Huang, Yanshan |
author_facet | Zhong, Weixiang Lu, Yimin Ma, Zhe He, Yinjun Ding, Yongfeng Yao, Gaofeng Zhou, Zhenxing Dong, Jiali Fang, Yongliang Jiang, Weiqin Wang, Weilin Huang, Yanshan |
author_sort | Zhong, Weixiang |
collection | PubMed |
description | Claudin 18.2 (CLDN18.2), a tight junction (TJ) family protein controlling molecule exchange between cells, is frequently over-expressed in gastric cancer, pancreatic adenocarcinomas and in a fraction of non–small cell lung cancer cases. The tumor properties indicate that CLDN18.2 could be an attractive drug target for gastric and pancreatic cancers. In this study, we present effective strategies for developing anti-CLDN18.2 therapeutic candidates, based on variable domain of heavy chain of heavy chain antibodies (VHHs). CLDN18.2-specific VHHs were isolated by panning a phage display library from an alpaca immunized with a stable cell line highly expressing CLDN18.2. Humanized VHHs fused with human IgG1 Fc, as potential therapeutic candidates, exhibited desirable binding specificity and affinity to CLDN18.2. In vitro experiments showed that hu7v3-Fc was capable of eliciting both antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) on CLDN18.2 positive tumor cells. In the mouse xenograft model, the anti-tumor efficacy of hu7v3-Fc was significantly more potent than Zolbetuximab, the benchmark anti-CLDN18.2 monoclonal antibody. Moreover, in vivo biodistribution using zirconium-89 ((89)Zr) labeled antibodies demonstrated that hu7v3-Fc ((89)Zr-hu7v3-Fc) exhibited a better tumor penetration and a faster tumor uptake than Zolbetuximab ((89)Zr-Zolbetuximab), which might be attributed to its smaller size and higher affinity. Taken together, anti-CDLN18.2 hu7v3-Fc is a promising therapeutic agent for human CLDN18.2 positive cancers. Furthermore, hu7v3 has emerged as a potential module for novel CLDN18.2 related therapeutics. |
format | Online Article Text |
id | pubmed-9273722 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-92737222022-07-13 Development of a Humanized VHH Based Recombinant Antibody Targeting Claudin 18.2 Positive Cancers Zhong, Weixiang Lu, Yimin Ma, Zhe He, Yinjun Ding, Yongfeng Yao, Gaofeng Zhou, Zhenxing Dong, Jiali Fang, Yongliang Jiang, Weiqin Wang, Weilin Huang, Yanshan Front Immunol Immunology Claudin 18.2 (CLDN18.2), a tight junction (TJ) family protein controlling molecule exchange between cells, is frequently over-expressed in gastric cancer, pancreatic adenocarcinomas and in a fraction of non–small cell lung cancer cases. The tumor properties indicate that CLDN18.2 could be an attractive drug target for gastric and pancreatic cancers. In this study, we present effective strategies for developing anti-CLDN18.2 therapeutic candidates, based on variable domain of heavy chain of heavy chain antibodies (VHHs). CLDN18.2-specific VHHs were isolated by panning a phage display library from an alpaca immunized with a stable cell line highly expressing CLDN18.2. Humanized VHHs fused with human IgG1 Fc, as potential therapeutic candidates, exhibited desirable binding specificity and affinity to CLDN18.2. In vitro experiments showed that hu7v3-Fc was capable of eliciting both antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) on CLDN18.2 positive tumor cells. In the mouse xenograft model, the anti-tumor efficacy of hu7v3-Fc was significantly more potent than Zolbetuximab, the benchmark anti-CLDN18.2 monoclonal antibody. Moreover, in vivo biodistribution using zirconium-89 ((89)Zr) labeled antibodies demonstrated that hu7v3-Fc ((89)Zr-hu7v3-Fc) exhibited a better tumor penetration and a faster tumor uptake than Zolbetuximab ((89)Zr-Zolbetuximab), which might be attributed to its smaller size and higher affinity. Taken together, anti-CDLN18.2 hu7v3-Fc is a promising therapeutic agent for human CLDN18.2 positive cancers. Furthermore, hu7v3 has emerged as a potential module for novel CLDN18.2 related therapeutics. Frontiers Media S.A. 2022-06-28 /pmc/articles/PMC9273722/ /pubmed/35837391 http://dx.doi.org/10.3389/fimmu.2022.885424 Text en Copyright © 2022 Zhong, Lu, Ma, He, Ding, Yao, Zhou, Dong, Fang, Jiang, Wang and Huang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Zhong, Weixiang Lu, Yimin Ma, Zhe He, Yinjun Ding, Yongfeng Yao, Gaofeng Zhou, Zhenxing Dong, Jiali Fang, Yongliang Jiang, Weiqin Wang, Weilin Huang, Yanshan Development of a Humanized VHH Based Recombinant Antibody Targeting Claudin 18.2 Positive Cancers |
title | Development of a Humanized VHH Based Recombinant Antibody Targeting Claudin 18.2 Positive Cancers |
title_full | Development of a Humanized VHH Based Recombinant Antibody Targeting Claudin 18.2 Positive Cancers |
title_fullStr | Development of a Humanized VHH Based Recombinant Antibody Targeting Claudin 18.2 Positive Cancers |
title_full_unstemmed | Development of a Humanized VHH Based Recombinant Antibody Targeting Claudin 18.2 Positive Cancers |
title_short | Development of a Humanized VHH Based Recombinant Antibody Targeting Claudin 18.2 Positive Cancers |
title_sort | development of a humanized vhh based recombinant antibody targeting claudin 18.2 positive cancers |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9273722/ https://www.ncbi.nlm.nih.gov/pubmed/35837391 http://dx.doi.org/10.3389/fimmu.2022.885424 |
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