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
Abstract 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 clinica...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-12-01
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| Series: | Journal of Hematology & Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13045-022-01395-0 |
| _version_ | 1797973527125557248 |
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| author | Guangbing Zhang Cuiyu Guo Yan Wang Xianda Zhang Shuang Liu Wen Qu Chunxia Chen Lingli Yan Zhouning Yang Zhixiong Zhang Xiaohua Jiang Xiaofeng Chen Hong Liu Qinhuai Lai Xian Wei Ying Lu Shengyan Zhao Han Deng Yuxi Wang Lin Yu Hongbin Yu Yu Wu Zhaoming Su Pengyu Chen Ziqing Ren Meng Yu Feng Qu Yong Luo Lantu Gou Qing Li Ying Huang Fanxin Ma Jinliang Yang |
| author_facet | Guangbing Zhang Cuiyu Guo Yan Wang Xianda Zhang Shuang Liu Wen Qu Chunxia Chen Lingli Yan Zhouning Yang Zhixiong Zhang Xiaohua Jiang Xiaofeng Chen Hong Liu Qinhuai Lai Xian Wei Ying Lu Shengyan Zhao Han Deng Yuxi Wang Lin Yu Hongbin Yu Yu Wu Zhaoming Su Pengyu Chen Ziqing Ren Meng Yu Feng Qu Yong Luo Lantu Gou Qing Li Ying Huang Fanxin Ma Jinliang Yang |
| author_sort | Guangbing Zhang |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-11T04:05:27Z |
| format | Article |
| id | doaj.art-a39a57a1992548e1beadb485c54a357e |
| institution | Directory Open Access Journal |
| issn | 1756-8722 |
| language | English |
| last_indexed | 2024-04-11T04:05:27Z |
| publishDate | 2022-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Hematology & Oncology |
| spelling | doaj.art-a39a57a1992548e1beadb485c54a357e2023-01-01T12:25:35ZengBMCJournal of Hematology & Oncology1756-87222022-12-011511610.1186/s13045-022-01395-0FTL004, 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 lymphomaGuangbing Zhang0Cuiyu Guo1Yan Wang2Xianda Zhang3Shuang Liu4Wen Qu5Chunxia Chen6Lingli Yan7Zhouning Yang8Zhixiong Zhang9Xiaohua Jiang10Xiaofeng Chen11Hong Liu12Qinhuai Lai13Xian Wei14Ying Lu15Shengyan Zhao16Han Deng17Yuxi Wang18Lin Yu19Hongbin Yu20Yu Wu21Zhaoming Su22Pengyu Chen23Ziqing Ren24Meng Yu25Feng Qu26Yong Luo27Lantu Gou28Qing Li29Ying Huang30Fanxin Ma31Jinliang Yang32State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan UniversityState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan UniversityState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan UniversitySound Biopharmaceuticals Co., Ltd.State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan UniversityDepartment of Clinical Laboratory, Mianyang Central HospitalDepartment of Transfusion, West China Hospital, Sichuan UniversityDepartment of Transfusion, West China Hospital, Sichuan UniversitySound Biopharmaceuticals Co., Ltd.State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan UniversityState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan UniversityState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan UniversityState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan UniversityState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan UniversityState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan UniversityState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan UniversityState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan UniversityState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan UniversityState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan UniversityDepartment of Clinical Laboratory, Mianyang Central HospitalDepartment of Hematology, West China Hospital, Sichuan UniversityDepartment of Hematology, West China Hospital, Sichuan UniversityState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan UniversitySound Biopharmaceuticals Co., Ltd.Sound Biopharmaceuticals Co., Ltd.Sound Biopharmaceuticals Co., Ltd.Sound Biopharmaceuticals Co., Ltd.Department of Head and Neck Oncology, West China Hospital, Sichuan UniversityState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan UniversitySound Biopharmaceuticals Co., Ltd.Sound Biopharmaceuticals Co., Ltd.State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan UniversityState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan UniversityAbstract 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.https://doi.org/10.1186/s13045-022-01395-0Multiple myelomaMonoclonal antibodiesCD38Red blood cellsDirect apoptosis |
| spellingShingle | Guangbing Zhang Cuiyu Guo Yan Wang Xianda Zhang Shuang Liu Wen Qu Chunxia Chen Lingli Yan Zhouning Yang Zhixiong Zhang Xiaohua Jiang Xiaofeng Chen Hong Liu Qinhuai Lai Xian Wei Ying Lu Shengyan Zhao Han Deng Yuxi Wang Lin Yu Hongbin Yu Yu Wu Zhaoming Su Pengyu Chen Ziqing Ren Meng Yu Feng Qu Yong Luo Lantu Gou Qing Li Ying Huang Fanxin Ma Jinliang Yang 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 Journal of Hematology & Oncology Multiple myeloma Monoclonal antibodies CD38 Red blood cells Direct apoptosis |
| 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 | Multiple myeloma Monoclonal antibodies CD38 Red blood cells Direct apoptosis |
| url | https://doi.org/10.1186/s13045-022-01395-0 |
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