8ry2: Difference between revisions
New page: '''Unreleased structure''' The entry 8ry2 is ON HOLD Authors: Rondeau, J.M., Wirth, E. Description: Crystal Structure of ANV419, a novel IL-2/anti-IL-2 antibody fusion protein [[Catego... |
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The | ==Crystal Structure of ANV419, a novel IL-2/anti-IL-2 antibody fusion protein== | ||
<StructureSection load='8ry2' size='340' side='right'caption='[[8ry2]], [[Resolution|resolution]] 2.05Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8ry2]] is a 4 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=8RY2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8RY2 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]] 2.05Å</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=8ry2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ry2 OCA], [https://pdbe.org/8ry2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ry2 RCSB], [https://www.ebi.ac.uk/pdbsum/8ry2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ry2 ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Novel engineered IL-2 agonists strive to increase the therapeutic window of aldesleukin (human IL-2) by increasing selectivity toward effector over regulatory T cells and reducing dose-limiting toxicities. Here we describe ANV419, an IL-2/anti-IL2 antibody fusion protein designed for selective IL-2 receptor betagamma (IL-2 Rbetagamma) activation by sterically hindering IL-2 from binding to IL-2 Ralpha. The fusion protein has an IL-2 connected to the light chain complementarity-determining region (CDR) domain of a humanized antibody that binds to IL-2 at the same epitope as IL-2 Ralpha. Optimization of the selectivity and pharmacological properties led to the selection of ANV419. ANV419 preferentially expands CD8(+) T cells and natural killer (NK) cells over T(regs) and can be safely administered at doses that elicit strong pharmacodynamic effects and efficacy in mouse tumor models. Its anti-tumor efficacy was enhanced when combined with programmed cell death protein 1 (PD-1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint inhibitors. ANV419 also enhances the NK cell killing capacity and increases tumor growth inhibition when used alongside trastuzumab in a Her-2(+) xenograft mouse model. In cynomolgus monkeys, the estimated half-life of ANV419 is 24 h, and doses that induced sustained expansion of effector cells were well tolerated without the severe toxicities typically observed with high-dose IL-2. These data support the clinical development of ANV419 in solid tumors and hematological malignancies as monotherapy and in combination with checkpoint inhibitors or agents that induce antibody-dependent cellular cytotoxicity. ANV419 is currently in Phase 1/2 clinical development and may provide cancer patients with a wider therapeutic window than aldesleukin. | |||
Discovery and development of ANV419, an IL-2/anti-IL-2 antibody fusion protein with potent CD8+ T and natural killer cell-stimulating capacity for cancer immunotherapy.,Murer P, Brannetti B, Rondeau JM, Petersen L, Egli N, Popp S, Regnier C, Richter K, Katopodis A, Huber C MAbs. 2024 Jan-Dec;16(1):2381891. doi: 10.1080/19420862.2024.2381891. Epub 2024 , Jul 23. PMID:39041287<ref>PMID:39041287</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 8ry2" style="background-color:#fffaf0;"></div> | ||
[[Category: | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Rondeau JM]] | |||
[[Category: Wirth E]] | |||
Latest revision as of 09:05, 31 July 2024
Crystal Structure of ANV419, a novel IL-2/anti-IL-2 antibody fusion proteinCrystal Structure of ANV419, a novel IL-2/anti-IL-2 antibody fusion protein
Structural highlights
Publication Abstract from PubMedNovel engineered IL-2 agonists strive to increase the therapeutic window of aldesleukin (human IL-2) by increasing selectivity toward effector over regulatory T cells and reducing dose-limiting toxicities. Here we describe ANV419, an IL-2/anti-IL2 antibody fusion protein designed for selective IL-2 receptor betagamma (IL-2 Rbetagamma) activation by sterically hindering IL-2 from binding to IL-2 Ralpha. The fusion protein has an IL-2 connected to the light chain complementarity-determining region (CDR) domain of a humanized antibody that binds to IL-2 at the same epitope as IL-2 Ralpha. Optimization of the selectivity and pharmacological properties led to the selection of ANV419. ANV419 preferentially expands CD8(+) T cells and natural killer (NK) cells over T(regs) and can be safely administered at doses that elicit strong pharmacodynamic effects and efficacy in mouse tumor models. Its anti-tumor efficacy was enhanced when combined with programmed cell death protein 1 (PD-1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint inhibitors. ANV419 also enhances the NK cell killing capacity and increases tumor growth inhibition when used alongside trastuzumab in a Her-2(+) xenograft mouse model. In cynomolgus monkeys, the estimated half-life of ANV419 is 24 h, and doses that induced sustained expansion of effector cells were well tolerated without the severe toxicities typically observed with high-dose IL-2. These data support the clinical development of ANV419 in solid tumors and hematological malignancies as monotherapy and in combination with checkpoint inhibitors or agents that induce antibody-dependent cellular cytotoxicity. ANV419 is currently in Phase 1/2 clinical development and may provide cancer patients with a wider therapeutic window than aldesleukin. Discovery and development of ANV419, an IL-2/anti-IL-2 antibody fusion protein with potent CD8+ T and natural killer cell-stimulating capacity for cancer immunotherapy.,Murer P, Brannetti B, Rondeau JM, Petersen L, Egli N, Popp S, Regnier C, Richter K, Katopodis A, Huber C MAbs. 2024 Jan-Dec;16(1):2381891. doi: 10.1080/19420862.2024.2381891. Epub 2024 , Jul 23. PMID:39041287[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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