8g2m: Difference between revisions
New page: '''Unreleased structure''' The entry 8g2m is ON HOLD Authors: Williams, J.C., Williams, J.C. Description: The tumor activated anti-CTLA-4 monoclonal antibody XTX101 demonstrates tumor-... |
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The | ==The tumor activated anti-CTLA-4 monoclonal antibody XTX101 demonstrates tumor-growth inhibition and tumor-selective pharmacodynamics in mouse models of cancer== | ||
<StructureSection load='8g2m' size='340' side='right'caption='[[8g2m]], [[Resolution|resolution]] 1.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8g2m]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus] and [https://en.wikipedia.org/wiki/Peptide_display_vector_fth1 Peptide display vector fth1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8G2M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8G2M 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]] 1.8Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</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=8g2m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8g2m OCA], [https://pdbe.org/8g2m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8g2m RCSB], [https://www.ebi.ac.uk/pdbsum/8g2m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8g2m ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
INTRODUCTION: The clinical benefit of the anti-CTLA-4 monoclonal antibody (mAb) ipilimumab has been well established but limited by immune-related adverse events, especially when ipilimumab is used in combination with anti-PD-(L)1 mAb therapy. To overcome these limitations, we have developed XTX101, a tumor-activated, Fc-enhanced anti-CTLA-4 mAb. METHODS: XTX101 consists of an anti-human CTLA-4 mAb covalently linked to masking peptides that block the complementarity-determining regions, thereby minimizing the mAb binding to CTLA-4. The masking peptides are designed to be released by proteases that are typically dysregulated within the tumor microenvironment (TME), resulting in activation of XTX101 intratumorally. Mutations within the Fc region of XTX101 were included to enhance affinity for FcgammaRIII, which is expected to enhance potency through antibody-dependent cellular cytotoxicity. RESULTS: Biophysical, biochemical, and cell-based assays demonstrate that the function of XTX101 depends on proteolytic activation. In human CTLA-4 transgenic mice, XTX101 monotherapy demonstrated significant tumor growth inhibition (TGI) including complete responses, increased intratumoral CD8+T cells, and regulatory T cell depletion within the TME while maintaining minimal pharmacodynamic effects in the periphery. XTX101 in combination with anti-PD-1 mAb treatment resulted in significant TGI and was well tolerated in mice. XTX101 was activated in primary human tumors across a range of tumor types including melanoma, renal cell carcinoma, colon cancer and lung cancer in an ex vivo assay system. CONCLUSIONS: These data demonstrate that XTX101 retains the full potency of an Fc-enhanced CTLA-4 antagonist within the TME while minimizing the activity in non-tumor tissue, supporting the further evaluation of XTX101 in clinical studies. | |||
XTX101, a tumor-activated, Fc-enhanced anti-CTLA-4 monoclonal antibody, demonstrates tumor-growth inhibition and tumor-selective pharmacodynamics in mouse models of cancer.,Jenkins KA, Park M, Pederzoli-Ribeil M, Eskiocak U, Johnson P, Guzman W, McLaughlin M, Moore-Lai D, O'Toole C, Liu Z, Nicholson B, Flesch V, Qiu H, Clackson T, O'Hagan RC, Rodeck U, Karow M, O'Neil J, Williams JC J Immunother Cancer. 2023 Dec 12;11(12):e007785. doi: 10.1136/jitc-2023-007785. PMID:38164757<ref>PMID:38164757</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Williams | <div class="pdbe-citations 8g2m" style="background-color:#fffaf0;"></div> | ||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Mus musculus]] | |||
[[Category: Peptide display vector fth1]] | |||
[[Category: Williams JC]] | |||
Latest revision as of 14:57, 30 October 2024
The tumor activated anti-CTLA-4 monoclonal antibody XTX101 demonstrates tumor-growth inhibition and tumor-selective pharmacodynamics in mouse models of cancerThe tumor activated anti-CTLA-4 monoclonal antibody XTX101 demonstrates tumor-growth inhibition and tumor-selective pharmacodynamics in mouse models of cancer
Structural highlights
Publication Abstract from PubMedINTRODUCTION: The clinical benefit of the anti-CTLA-4 monoclonal antibody (mAb) ipilimumab has been well established but limited by immune-related adverse events, especially when ipilimumab is used in combination with anti-PD-(L)1 mAb therapy. To overcome these limitations, we have developed XTX101, a tumor-activated, Fc-enhanced anti-CTLA-4 mAb. METHODS: XTX101 consists of an anti-human CTLA-4 mAb covalently linked to masking peptides that block the complementarity-determining regions, thereby minimizing the mAb binding to CTLA-4. The masking peptides are designed to be released by proteases that are typically dysregulated within the tumor microenvironment (TME), resulting in activation of XTX101 intratumorally. Mutations within the Fc region of XTX101 were included to enhance affinity for FcgammaRIII, which is expected to enhance potency through antibody-dependent cellular cytotoxicity. RESULTS: Biophysical, biochemical, and cell-based assays demonstrate that the function of XTX101 depends on proteolytic activation. In human CTLA-4 transgenic mice, XTX101 monotherapy demonstrated significant tumor growth inhibition (TGI) including complete responses, increased intratumoral CD8+T cells, and regulatory T cell depletion within the TME while maintaining minimal pharmacodynamic effects in the periphery. XTX101 in combination with anti-PD-1 mAb treatment resulted in significant TGI and was well tolerated in mice. XTX101 was activated in primary human tumors across a range of tumor types including melanoma, renal cell carcinoma, colon cancer and lung cancer in an ex vivo assay system. CONCLUSIONS: These data demonstrate that XTX101 retains the full potency of an Fc-enhanced CTLA-4 antagonist within the TME while minimizing the activity in non-tumor tissue, supporting the further evaluation of XTX101 in clinical studies. XTX101, a tumor-activated, Fc-enhanced anti-CTLA-4 monoclonal antibody, demonstrates tumor-growth inhibition and tumor-selective pharmacodynamics in mouse models of cancer.,Jenkins KA, Park M, Pederzoli-Ribeil M, Eskiocak U, Johnson P, Guzman W, McLaughlin M, Moore-Lai D, O'Toole C, Liu Z, Nicholson B, Flesch V, Qiu H, Clackson T, O'Hagan RC, Rodeck U, Karow M, O'Neil J, Williams JC J Immunother Cancer. 2023 Dec 12;11(12):e007785. doi: 10.1136/jitc-2023-007785. PMID:38164757[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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