6t3j: Difference between revisions
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The | ==Dual Epitope Targeting by Anti-DR5 Antibodies== | ||
<StructureSection load='6t3j' size='340' side='right'caption='[[6t3j]], [[Resolution|resolution]] 3.05Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6t3j]] is a 10 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6T3J OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6T3J FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.05Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></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=6t3j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6t3j OCA], [https://pdbe.org/6t3j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6t3j RCSB], [https://www.ebi.ac.uk/pdbsum/6t3j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6t3j ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Higher order DR5 clustering can induce tumor cell death, however therapeutic compounds targeting DR5 have achieved limited clinical efficacy. We describe HexaBody-DR5/DR5, an equimolar mixture of two DR5-specific IgG1 antibodies with an Fc-domain mutation that augments antibody hexamerization after cell surface target binding. The two antibodies do not compete for binding to DR5 as demonstrated using binding competition studies, and binding to distinct epitopes in the DR5 extracellular domain was confirmed by crystallography. The unique combination of dual epitope targeting and increased IgG hexamerization resulted in potent DR5 agonist activity by inducing efficient DR5 outside-in signaling and caspase-mediated cell death. Preclinical studies in vitro and in vivo demonstrated that maximal DR5 agonist activity could be achieved independent of Fcgamma receptor-mediated antibody crosslinking. Most optimal agonism was observed in the presence of complement complex C1, although without inducing complement-dependent cytotoxicity. It is hypothesized that C1 may stabilize IgG hexamers that are formed after binding of HexaBody-DR5/DR5 to DR5 on the plasma membrane, thereby strengthening DR5 clustering and subsequent outside-in signaling. We observed potent anti-tumor activity in vitro and in vivo in large panels of patient-derived xenograft models representing various solid cancers. The results of our preclinical studies provided the basis for an ongoing clinical trial exploring the activity of HexaBody-DR5/DR5 (GEN1029) in patients with malignant solid tumors. | |||
Dual epitope targeting and enhanced hexamerization by DR5 antibodies as a novel approach to induce potent anti-tumor activity through DR5 agonism.,Overdijk MB, Strumane K, Beurskens FJ, Ortiz Buijsse A, Vermot-Desroches C, Vuillermoz BS, Kroes T, Jong B, Hoevenaars N, Hibbert RG, Lingnau A, Forssmann U, Schuurman J, Parren PWHI, de Jong RN, Breij ECW Mol Cancer Ther. 2020 Aug 26. pii: 1535-7163.MCT-20-0044. doi:, 10.1158/1535-7163.MCT-20-0044. PMID:32847982<ref>PMID:32847982</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6t3j" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Antibody 3D structures|Antibody 3D structures]] | |||
*[[TRAIL|TRAIL]] | |||
*[[Tumor necrosis factor receptor 3D structures|Tumor necrosis factor receptor 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Augustin M]] | |||
[[Category: Breij ECW]] | |||
[[Category: Hibbert RG]] | |||
[[Category: Krapp S]] | |||
[[Category: Overdijk MB]] | |||
[[Category: Tauchert MJ]] | |||
Latest revision as of 11:21, 17 October 2024
Dual Epitope Targeting by Anti-DR5 AntibodiesDual Epitope Targeting by Anti-DR5 Antibodies
Structural highlights
Publication Abstract from PubMedHigher order DR5 clustering can induce tumor cell death, however therapeutic compounds targeting DR5 have achieved limited clinical efficacy. We describe HexaBody-DR5/DR5, an equimolar mixture of two DR5-specific IgG1 antibodies with an Fc-domain mutation that augments antibody hexamerization after cell surface target binding. The two antibodies do not compete for binding to DR5 as demonstrated using binding competition studies, and binding to distinct epitopes in the DR5 extracellular domain was confirmed by crystallography. The unique combination of dual epitope targeting and increased IgG hexamerization resulted in potent DR5 agonist activity by inducing efficient DR5 outside-in signaling and caspase-mediated cell death. Preclinical studies in vitro and in vivo demonstrated that maximal DR5 agonist activity could be achieved independent of Fcgamma receptor-mediated antibody crosslinking. Most optimal agonism was observed in the presence of complement complex C1, although without inducing complement-dependent cytotoxicity. It is hypothesized that C1 may stabilize IgG hexamers that are formed after binding of HexaBody-DR5/DR5 to DR5 on the plasma membrane, thereby strengthening DR5 clustering and subsequent outside-in signaling. We observed potent anti-tumor activity in vitro and in vivo in large panels of patient-derived xenograft models representing various solid cancers. The results of our preclinical studies provided the basis for an ongoing clinical trial exploring the activity of HexaBody-DR5/DR5 (GEN1029) in patients with malignant solid tumors. Dual epitope targeting and enhanced hexamerization by DR5 antibodies as a novel approach to induce potent anti-tumor activity through DR5 agonism.,Overdijk MB, Strumane K, Beurskens FJ, Ortiz Buijsse A, Vermot-Desroches C, Vuillermoz BS, Kroes T, Jong B, Hoevenaars N, Hibbert RG, Lingnau A, Forssmann U, Schuurman J, Parren PWHI, de Jong RN, Breij ECW Mol Cancer Ther. 2020 Aug 26. pii: 1535-7163.MCT-20-0044. doi:, 10.1158/1535-7163.MCT-20-0044. PMID:32847982[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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