8IL3

Cryo-EM structure of CD38 in complex with FTL004

8IL3 の概要

• エントリーDOI: 10.2210/pdb8il3/pdb
• EMDBエントリー: 35526
• 分子名称: Light chain, Heavy chain, ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 (3 entities in total)
• 機能のキーワード: monoclonal antibody, hydrolase
• 由来する生物種: Homo sapiens; 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 73581.55

構造登録者

Yang, J.,Wang, Y.,Zhang, G. (登録日: 2023-03-01, 公開日: 2023-03-29, 最終更新日: 2024-11-06)

主引用文献

Zhang, G.,Guo, C.,Wang, Y.,Zhang, X.,Liu, S.,Qu, W.,Chen, C.,Yan, L.,Yang, Z.,Zhang, Z.,Jiang, X.,Chen, X.,Liu, H.,Lai, Q.,Wei, X.,Lu, Y.,Zhao, S.,Deng, H.,Wang, Y.,Yu, L.,Yu, H.,Wu, Y.,Su, Z.,Chen, P.,Ren, Z.,Yu, M.,Qu, F.,Luo, Y.,Gou, L.,Li, Q.,Huang, Y.,Ma, F.,Yang, J.
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.
J Hematol Oncol, 15:177-177, 2022

PubMed 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.

PubMed: 36581954
DOI: 10.1186/s13045-022-01395-0

実験手法

ELECTRON MICROSCOPY (3.86 Å)