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| | ==Crystal structure of CD38 with a novel CD38-targeting antibody SAR650984== | | ==Crystal structure of CD38 with a novel CD38-targeting antibody SAR650984== |
| - | <StructureSection load='4cmh' size='340' side='right' caption='[[4cmh]], [[Resolution|resolution]] 1.53Å' scene=''> | + | <StructureSection load='4cmh' size='340' side='right'caption='[[4cmh]], [[Resolution|resolution]] 1.53Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4cmh]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CMH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CMH FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4cmh]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CMH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CMH FirstGlance]. <br> |
| - | </td></tr><tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/NAD(+)_nucleosidase NAD(+) nucleosidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.2.5 3.2.2.5] </span></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.53Å</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4cmh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cmh OCA], [http://pdbe.org/4cmh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4cmh RCSB], [http://www.ebi.ac.uk/pdbsum/4cmh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4cmh ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4cmh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cmh OCA], [https://pdbe.org/4cmh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4cmh RCSB], [https://www.ebi.ac.uk/pdbsum/4cmh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4cmh ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CD38_HUMAN 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. | + | [https://www.uniprot.org/uniprot/CD38_HUMAN 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. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| | + | [[Category: Large Structures]] |
| | [[Category: Mus musculus]] | | [[Category: Mus musculus]] |
| - | [[Category: Bartle, L M]] | + | [[Category: Bartle LM]] |
| - | [[Category: Blanc, V]] | + | [[Category: Blanc V]] |
| - | [[Category: Chiron, M]] | + | [[Category: Chiron M]] |
| - | [[Category: Chittenden, T]] | + | [[Category: Chittenden T]] |
| - | [[Category: Deckert, J]] | + | [[Category: Deckert J]] |
| - | [[Category: Dumontet, C]] | + | [[Category: Dumontet C]] |
| - | [[Category: Ferrari, P]] | + | [[Category: Ferrari P]] |
| - | [[Category: Goldmacher, V]] | + | [[Category: Goldmacher V]] |
| - | [[Category: Lahoute, C]] | + | [[Category: Lahoute C]] |
| - | [[Category: Lejeune, P]] | + | [[Category: Lejeune P]] |
| - | [[Category: Park, P U]] | + | [[Category: Park PU]] |
| - | [[Category: Plesa, A]] | + | [[Category: Plesa A]] |
| - | [[Category: Pouzieux, S]] | + | [[Category: Pouzieux S]] |
| - | [[Category: Skaletskaya, A]] | + | [[Category: Skaletskaya A]] |
| - | [[Category: Vallee, F]] | + | [[Category: Vallee F]] |
| - | [[Category: Wetzel, M C]] | + | [[Category: Wetzel MC]] |
| - | [[Category: ZhouLiu, Q]] | + | [[Category: ZhouLiu Q]] |
| - | [[Category: Hydrolase-immune system complex]]
| + | |
| - | [[Category: Multiple myeloma]]
| + | |
| Structural highlights
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
Purpose: 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 Also
References
- ↑ 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. SAR650984, a novel humanized CD38-targeting antibody, demonstrates potent anti-tumor activity in models of multiple myeloma and other CD38+ hematologic malignancies. Clin Cancer Res. 2014 Jul 1. pii: clincanres.0695.2014. PMID:24987056 doi:http://dx.doi.org/10.1158/1078-0432.CCR-14-0695
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