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

Letter

Author: Yang, Zhouning ; Wang, Yuxi ; Zhang, Zhixiong ; Wei, Xian ; Chen, Xiaofeng ; Yu, Lin ; Yu, Meng ; Liu, Hong ; Lai, Qinhuai ; Li, Qing ; Qu, Wen ; Yang, Jinliang ; Jiang, Xiaohua ; Lu, Ying ; Deng, Han ; Yan, Lingli ; Guo, Cuiyu ; Gou, Lantu ; Su, Zhaoming ; Zhang, Guangbing ; Zhao, Shengyan ; Ren, Ziqing ; Wang, Yan ; Liu, Shuang ; Chen, Pengyu ; Yu, Hongbin ; Qu, Feng ; Zhang, Xianda ; Chen, Chunxia ; Ma, Fanxin ; Huang, Ying ; Wu, Yu ; Luo, Yong

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 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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Indication	Highest Phase	Country/Location	Organization	Date
Multiple Myeloma	Phase 1	CN	Sound Biopharmaceuticals Ltd.	12 Oct 2022

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