8il3

From Proteopedia

Cryo-EM structure of CD38 in complex with FTL004

Structural highlights

8il3 is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.86Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CD38_HUMAN Synthesizes cyclic ADP-ribose, a second messenger for glucose-induced insulin secretion. Also has cADPr hydrolase activity. Also moonlights as a receptor in cells of the immune system.

Publication Abstract from PubMed

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 mug/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.

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.,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 J Hematol Oncol. 2022 Dec 29;15(1):177. doi: 10.1186/s13045-022-01395-0. PMID:36581954^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ 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. 2022 Dec 29;15(1):177. PMID:36581954 doi:10.1186/s13045-022-01395-0