8IL3
Cryo-EM structure of CD38 in complex with FTL004
Summary for 8IL3
| Entry DOI | 10.2210/pdb8il3/pdb |
| EMDB information | 35526 |
| Descriptor | Light chain, Heavy chain, ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 (3 entities in total) |
| Functional Keywords | monoclonal antibody, hydrolase |
| Biological source | Homo sapiens More |
| Total number of polymer chains | 3 |
| Total formula weight | 73581.55 |
| Authors | |
| Primary citation | 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 Cited by 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: 36581954DOI: 10.1186/s13045-022-01395-0 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.86 Å) |
Structure validation
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