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FTL004, an anti-CD38 mAb with negligible RBC binding and enhanced pro-apoptotic activity, is a novel candidate for treatments of multiple myeloma and non-Hodgkin lymphoma

Anti-CD38 monoclonal antibodies (mAbs), daratumumab, and isatuximab have represented a breakthrough in the treatment of multiple myeloma (MM). Recently, CD38-based mAbs were expected to achieve increasing potential beyond MM, which encouraged us to develop new anti-CD38 mAbs to meet clinical needs....

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Autores principales: Zhang, Guangbing, Guo, Cuiyu, Wang, Yan, Zhang, Xianda, Liu, Shuang, Qu, Wen, Chen, Chunxia, Yan, Lingli, Yang, Zhouning, Zhang, Zhixiong, Jiang, Xiaohua, Chen, Xiaofeng, Liu, Hong, Lai, Qinhuai, Wei, Xian, Lu, Ying, Zhao, Shengyan, Deng, Han, Wang, Yuxi, Yu, Lin, Yu, Hongbin, Wu, Yu, Su, Zhaoming, Chen, Pengyu, Ren, Ziqing, Yu, Meng, Qu, Feng, Luo, Yong, Gou, Lantu, Li, Qing, Huang, Ying, Ma, Fanxin, Yang, Jinliang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9798557/
https://www.ncbi.nlm.nih.gov/pubmed/36581954
http://dx.doi.org/10.1186/s13045-022-01395-0
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author Zhang, Guangbing
Guo, Cuiyu
Wang, Yan
Zhang, Xianda
Liu, Shuang
Qu, Wen
Chen, Chunxia
Yan, Lingli
Yang, Zhouning
Zhang, Zhixiong
Jiang, Xiaohua
Chen, Xiaofeng
Liu, Hong
Lai, Qinhuai
Wei, Xian
Lu, Ying
Zhao, Shengyan
Deng, Han
Wang, Yuxi
Yu, Lin
Yu, Hongbin
Wu, Yu
Su, Zhaoming
Chen, Pengyu
Ren, Ziqing
Yu, Meng
Qu, Feng
Luo, Yong
Gou, Lantu
Li, Qing
Huang, Ying
Ma, Fanxin
Yang, Jinliang
author_facet Zhang, Guangbing
Guo, Cuiyu
Wang, Yan
Zhang, Xianda
Liu, Shuang
Qu, Wen
Chen, Chunxia
Yan, Lingli
Yang, Zhouning
Zhang, Zhixiong
Jiang, Xiaohua
Chen, Xiaofeng
Liu, Hong
Lai, Qinhuai
Wei, Xian
Lu, Ying
Zhao, Shengyan
Deng, Han
Wang, Yuxi
Yu, Lin
Yu, Hongbin
Wu, Yu
Su, Zhaoming
Chen, Pengyu
Ren, Ziqing
Yu, Meng
Qu, Feng
Luo, Yong
Gou, Lantu
Li, Qing
Huang, Ying
Ma, Fanxin
Yang, Jinliang
author_sort Zhang, Guangbing
collection PubMed
description Anti-CD38 monoclonal antibodies (mAbs), daratumumab, and isatuximab have represented a breakthrough in the treatment of multiple myeloma (MM). Recently, CD38-based mAbs were expected to achieve increasing potential beyond MM, which encouraged us to develop new anti-CD38 mAbs to meet clinical needs. In this study, we developed a novel humanized anti-CD38 antibody, FTL004, which exhibited enhanced pro-apoptotic ability and negligible binding to red blood cells (RBCs). FTL004 presented a better ability to induce direct apoptosis independent of Fc-mediated cross-linking against lymphoma and MM cell lines as well as primary myeloma cells derived from MM patients. For instance, FTL004 induced RPMI 8226 cells with 55% early apoptosis cells compared with 20% in the isatuximab-treated group. Of interest, FTL004 showed ignorable binding to CD38 on human RBCs in contrast to tumor cells, even at concentrations up to 30 μg/mL. Furthermore, with an engineered Fc domain, FTL004 displayed stronger antibody-dependent cellular cytotoxicity (ADCC) against CD38+ malignant cells. In vivo MM and non-Hodgkin lymphoma tumor xenograft models showed that FTL004 possessed an effective anti-tumor effect. Cryo-electron microscopy structure resolved two epitope centers of FTL004 on CD38: one of which was unique while the other partly overlapped with that of isatuximab. Taken together, FTL004 distinguishes it from other CD38 targeting mAbs and represents a potential candidate for the treatment of MM and non-Hodgkin lymphoma.
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spelling pubmed-97985572022-12-30 FTL004, an anti-CD38 mAb with negligible RBC binding and enhanced pro-apoptotic activity, is a novel candidate for treatments of multiple myeloma and non-Hodgkin lymphoma Zhang, Guangbing Guo, Cuiyu Wang, Yan Zhang, Xianda Liu, Shuang Qu, Wen Chen, Chunxia Yan, Lingli Yang, Zhouning Zhang, Zhixiong Jiang, Xiaohua Chen, Xiaofeng Liu, Hong Lai, Qinhuai Wei, Xian Lu, Ying Zhao, Shengyan Deng, Han Wang, Yuxi Yu, Lin Yu, Hongbin Wu, Yu Su, Zhaoming Chen, Pengyu Ren, Ziqing Yu, Meng Qu, Feng Luo, Yong Gou, Lantu Li, Qing Huang, Ying Ma, Fanxin Yang, Jinliang J Hematol Oncol Correspondence Anti-CD38 monoclonal antibodies (mAbs), daratumumab, and isatuximab have represented a breakthrough in the treatment of multiple myeloma (MM). Recently, CD38-based mAbs were expected to achieve increasing potential beyond MM, which encouraged us to develop new anti-CD38 mAbs to meet clinical needs. In this study, we developed a novel humanized anti-CD38 antibody, FTL004, which exhibited enhanced pro-apoptotic ability and negligible binding to red blood cells (RBCs). FTL004 presented a better ability to induce direct apoptosis independent of Fc-mediated cross-linking against lymphoma and MM cell lines as well as primary myeloma cells derived from MM patients. For instance, FTL004 induced RPMI 8226 cells with 55% early apoptosis cells compared with 20% in the isatuximab-treated group. Of interest, FTL004 showed ignorable binding to CD38 on human RBCs in contrast to tumor cells, even at concentrations up to 30 μg/mL. Furthermore, with an engineered Fc domain, FTL004 displayed stronger antibody-dependent cellular cytotoxicity (ADCC) against CD38+ malignant cells. In vivo MM and non-Hodgkin lymphoma tumor xenograft models showed that FTL004 possessed an effective anti-tumor effect. Cryo-electron microscopy structure resolved two epitope centers of FTL004 on CD38: one of which was unique while the other partly overlapped with that of isatuximab. Taken together, FTL004 distinguishes it from other CD38 targeting mAbs and represents a potential candidate for the treatment of MM and non-Hodgkin lymphoma. BioMed Central 2022-12-29 /pmc/articles/PMC9798557/ /pubmed/36581954 http://dx.doi.org/10.1186/s13045-022-01395-0 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Correspondence
Zhang, Guangbing
Guo, Cuiyu
Wang, Yan
Zhang, Xianda
Liu, Shuang
Qu, Wen
Chen, Chunxia
Yan, Lingli
Yang, Zhouning
Zhang, Zhixiong
Jiang, Xiaohua
Chen, Xiaofeng
Liu, Hong
Lai, Qinhuai
Wei, Xian
Lu, Ying
Zhao, Shengyan
Deng, Han
Wang, Yuxi
Yu, Lin
Yu, Hongbin
Wu, Yu
Su, Zhaoming
Chen, Pengyu
Ren, Ziqing
Yu, Meng
Qu, Feng
Luo, Yong
Gou, Lantu
Li, Qing
Huang, Ying
Ma, Fanxin
Yang, Jinliang
FTL004, an anti-CD38 mAb with negligible RBC binding and enhanced pro-apoptotic activity, is a novel candidate for treatments of multiple myeloma and non-Hodgkin lymphoma
title FTL004, an anti-CD38 mAb with negligible RBC binding and enhanced pro-apoptotic activity, is a novel candidate for treatments of multiple myeloma and non-Hodgkin lymphoma
title_full FTL004, an anti-CD38 mAb with negligible RBC binding and enhanced pro-apoptotic activity, is a novel candidate for treatments of multiple myeloma and non-Hodgkin lymphoma
title_fullStr FTL004, an anti-CD38 mAb with negligible RBC binding and enhanced pro-apoptotic activity, is a novel candidate for treatments of multiple myeloma and non-Hodgkin lymphoma
title_full_unstemmed FTL004, an anti-CD38 mAb with negligible RBC binding and enhanced pro-apoptotic activity, is a novel candidate for treatments of multiple myeloma and non-Hodgkin lymphoma
title_short FTL004, an anti-CD38 mAb with negligible RBC binding and enhanced pro-apoptotic activity, is a novel candidate for treatments of multiple myeloma and non-Hodgkin lymphoma
title_sort ftl004, an anti-cd38 mab with negligible rbc binding and enhanced pro-apoptotic activity, is a novel candidate for treatments of multiple myeloma and non-hodgkin lymphoma
topic Correspondence
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9798557/
https://www.ncbi.nlm.nih.gov/pubmed/36581954
http://dx.doi.org/10.1186/s13045-022-01395-0
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