4cmh | pdb_00004cmh
Crystal structure of CD38 with a novel CD38-targeting antibody SAR650984
Structural highlights
FunctionCD38_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 PubMedPurpose: The CD38 cell surface antigen is expressed in diverse hematologic malignancies including multiple myeloma (MM), B-cell non-Hodgkin lymphoma (NHL), B-cell chronic lymphocytic leukemia (B-CLL), B-cell acute lymphoblastic leukemia (ALL) and T-cell ALL. Here we assessed the anti-tumor activity of the anti-CD38 antibody SAR650984. Experimental Design: Activity of SAR650984 was examined on lymphoma, leukemia and MM cell lines, primary MM samples and MM xenograft models in immunodeficient mice. Results: We identified a humanized anti-CD38 antibody with strong pro-apoptotic activity independent of cross-linking agents, and potent effector functions including complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP), equivalent in vitro to rituximab in CD20+ and CD38+ models. This unique antibody, termed SAR650984, inhibited the ADP-ribosyl cyclase activity of CD38, likely through an allosteric antagonism as suggested by 3D structure analysis of the complex. In vivo, SAR650984 was active in diverse NHL, ALL and MM CD38+ tumor xenograft models. SAR650984 demonstrated single agent activity comparable to rituximab or cyclophosphamide in Daudi or SU-DHL-8 lymphoma xenograft models with induction of the pro-apoptotic marker cleaved capase 7. In addition, SAR650984 had more potent anti-tumor activity than bortezomib in NCI-H929 and Molp-8 MM xenograft studies. Consistent with its mode of action, SAR650984 demonstrated potent pro-apoptotic activity against CD38+ human primary MM cells. Conclusions: These results validate CD38 as a therapeutic target and support the current evaluation of this unique CD38-targeting functional antibody in Phase I clinical trials in patients with CD38+ B-cell malignancies. SAR650984, a novel humanized CD38-targeting antibody, demonstrates potent anti-tumor activity in models of multiple myeloma and other CD38+ hematologic malignancies.,Deckert J, Wetzel MC, Bartle LM, Skaletskaya A, Goldmacher V, Vallee F, Zhou-Liu Q, Ferrari P, Pouzieux S, Lahoute C, Dumontet C, Plesa A, Chiron M, Lejeune P, Chittenden T, Park PU, Blanc V Clin Cancer Res. 2014 Jul 1. pii: clincanres.0695.2014. PMID:24987056[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||
