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TitleFTL004, 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, issue, pagesJ Hematol Oncol, Vol. 15, Issue 1, Page 177, Year 2022
Publish dateDec 29, 2022
AuthorsGuangbing 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 /
PubMed AbstractAnti-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 ...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.
External linksJ Hematol Oncol / PubMed:36581954 / PubMed Central
MethodsEM (single particle)
Resolution3.86 Å
Structure data

35526

8il3

EMDB-35526, PDB-8il3:
Cryo-EM structure of CD38 in complex with FTL004
Method: EM (single particle) / Resolution: 3.86 Å

Source
  • homo sapiens (human)
KeywordsHYDROLASE / monoclonal antibody

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