9nrj

From Proteopedia

(Difference between revisions)

Current revision

abTCR bound to SAR444200, a novel anti-GPC3 T-cell engager, for the treatment of GPC3+ solid tumors

Structural highlights

9nrj is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.4Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

TRAR1_HUMAN Precursor T-cell acute lymphoblastic leukemia.

Function

TRAR1_HUMAN The alpha chain of TRAV27*01J42*01C*01/TRBV19*01J2S7*01C*02 alpha-beta T cell receptor (TR) clonotype that is specific for HLA-A*02:01-restricted M/matrix protein 1 immunodominant epitope GILGFVFTL of influenza A virus (IAV). Classified as a public TR clonotype, it is preferentially selected in effector memory CD8-positive T cells among multiple HLA-A*02:01 carriers and confers long-lived immunity against IAV infection. Can cross-recognize sporadically emerging IAV variants by molecular mimicry, inducing immunity toward different influenza strains (PubMed:12796775, PubMed:18275829, PubMed:1833769, PubMed:27036003, PubMed:29997621, PubMed:7807026). Antigen recognition initiates TR-CD3 clustering on the cell surface and intracellular activation of LCK that phosphorylates the ITAM motifs of CD3G, CD3D, CD3E and CD247 enabling the recruitment of ZAP70. In turn, ZAP70 phosphorylates LAT, which recruits numerous signaling molecules to form the LAT signalosome. The LAT signalosome propagates signal branching to three major signaling pathways, the calcium, the mitogen-activated protein kinase (MAPK) kinase and the nuclear factor NF-kappa-B (NF-kB) pathways, leading to the mobilization of transcription factors that are critical for gene expression and essential for T cell differentiation into effector/memory T cells (By similarity).[UniProtKB:P01848]^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

T-cell engager (TCE) immunotherapy has demonstrated significant clinical activity in multiple cancers by inducing co-engagement of T-cells and tumor cells, resulting in T-cell activation and T-cell-dependent cellular cytotoxicity (TDCC) against tumor cells. Current-generation TCEs are predominantly composed of antibody-based binding domains targeting the CD3e molecule of the T-cell antigen receptor (TCR)/CD3 complex on T-cells and a tumor-associated antigen on tumor cells. However, limitations of this approach include cytokine release syndrome and a limited therapeutic window. Here, we report the generation and preclinical evaluation of SAR444200, the first NANOBODY(R)-based TCE clinical candidate binding to TCRalphabeta and GPC3 to co-engage T-cells and GPC3+ tumor cells, causing TDCC. SAR444200 bound with nanomolar to picomolar affinity to TCRalphabeta and GPC3 respectively and induced in vitro TDCC against multiple human tumor cell lines with differential GPC3 expression with picomolar potency. In vivo analysis using human cancer cell line-derived (HuH-7 and HepG2) xenografts in immunodeficient mice showed complete tumor regression at doses starting from 0.7 mg/kg. In exploratory non-human primate studies, intravenous administration of SAR444200 was well tolerated up to 8 mg/kg and exhibited greater than dose-proportional clearances and dose-proportional maximum concentrations across the tested dose range. The highly potent and efficacious activity of SAR444200 in diverse models of GPC3+ tumors and the extremely wide tolerated dose range merits further development of this compound. Furthermore, NANOBODY(R)-based TCEs developed using an anti-TCRalphabeta moiety may have specific advantages for the development of TCEs.

Identification and non-clinical characterization of SAR444200, a novel anti-GPC3 NANOBODY(R) T-cell engager, for the treatment of GPC3+ solid tumors.,Meoni P, Vintem APB, Cortez-Retamozo VF, Jacobs J, De Tavernier E, Fiorentini P, Van Hoorick D, Batchelor JD, Svidritskiy E, Qiu Y, Dejonckheere E, Li A, Pao LI, Buyse MA Mol Cancer Ther. 2025 Oct 3. doi: 10.1158/1535-7163.MCT-24-1049. PMID:41041827^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Stewart-Jones GB, McMichael AJ, Bell JI, Stuart DI, Jones EY. A structural basis for immunodominant human T cell receptor recognition. Nat Immunol. 2003 Jul;4(7):657-63. Epub 2003 Jun 8. PMID:12796775 doi:10.1038/ni942
↑ Ishizuka J, Stewart-Jones GB, van der Merwe A, Bell JI, McMichael AJ, Jones EY. The structural dynamics and energetics of an immunodominant T cell receptor are programmed by its Vbeta domain. Immunity. 2008 Feb;28(2):171-82. PMID:18275829 doi:http://dx.doi.org/10.1016/j.immuni.2007.12.018
↑ Moss PA, Moots RJ, Rosenberg WM, Rowland-Jones SJ, Bodmer HC, McMichael AJ, Bell JI. Extensive conservation of alpha and beta chains of the human T-cell antigen receptor recognizing HLA-A2 and influenza A matrix peptide. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):8987-90. doi:, 10.1073/pnas.88.20.8987. PMID:1833769 doi:http://dx.doi.org/10.1073/pnas.88.20.8987
↑ Valkenburg SA, Josephs TM, Clemens EB, Grant EJ, Nguyen TH, Wang GC, Price DA, Miller A, Tong SY, Thomas PG, Doherty PC, Rossjohn J, Gras S, Kedzierska K. Molecular basis for universal HLA-A*0201-restricted CD8+ T-cell immunity against influenza viruses. Proc Natl Acad Sci U S A. 2016 Apr 19;113(16):4440-5. doi:, 10.1073/pnas.1603106113. Epub 2016 Mar 31. PMID:27036003 doi:http://dx.doi.org/10.1073/pnas.1603106113
↑ Sant S, Grzelak L, Wang Z, Pizzolla A, Koutsakos M, Crowe J, Loudovaris T, Mannering SI, Westall GP, Wakim LM, Rossjohn J, Gras S, Richards M, Xu J, Thomas PG, Loh L, Nguyen THO, Kedzierska K. Single-Cell Approach to Influenza-Specific CD8(+) T Cell Receptor Repertoires Across Different Age Groups, Tissues, and Following Influenza Virus Infection. Front Immunol. 2018 Jun 27;9:1453. doi: 10.3389/fimmu.2018.01453. eCollection, 2018. PMID:29997621 doi:http://dx.doi.org/10.3389/fimmu.2018.01453
↑ Lehner PJ, Wang EC, Moss PA, Williams S, Platt K, Friedman SM, Bell JI, Borysiewicz LK. Human HLA-A0201-restricted cytotoxic T lymphocyte recognition of influenza A is dominated by T cells bearing the V beta 17 gene segment. J Exp Med. 1995 Jan 1;181(1):79-91. doi: 10.1084/jem.181.1.79. PMID:7807026 doi:http://dx.doi.org/10.1084/jem.181.1.79
↑ Meoni P, Vintém APB, Cortez-Retamozo VF, Jacobs J, De Tavernier E, Fiorentini P, Van Hoorick D, Batchelor JD, Svidritskiy E, Qiu Y, Dejonckheere E, Li A, Pao LI, Buyse MA. Identification and non-clinical characterization of SAR444200, a novel anti-GPC3 NANOBODY® T-cell engager, for the treatment of GPC3+ solid tumors. Mol Cancer Ther. 2025 Oct 3. PMID:41041827 doi:10.1158/1535-7163.MCT-24-1049

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/9nrj"

Categories: Homo sapiens | Large Structures | Qiu Y | Svidritskiy E | Yanfeng Z

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 9nrj is ON HOLD
+==abTCR bound to SAR444200, a novel anti-GPC3 T-cell engager, for the treatment of GPC3+ solid tumors==
+<StructureSection load='9nrj' size='340' side='right'caption='[[9nrj]], [[Resolution|resolution]] 3.40&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[9nrj]] 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=9NRJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9NRJ FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.4&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=9nrj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9nrj OCA], [https://pdbe.org/9nrj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9nrj RCSB], [https://www.ebi.ac.uk/pdbsum/9nrj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9nrj ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/TRAR1_HUMAN TRAR1_HUMAN] Precursor T-cell acute lymphoblastic leukemia.
+== Function ==
+[https://www.uniprot.org/uniprot/TRAR1_HUMAN TRAR1_HUMAN] The alpha chain of TRAV27*01J42*01C*01/TRBV19*01J2S7*01C*02 alpha-beta T cell receptor (TR) clonotype that is specific for HLA-A*02:01-restricted M/matrix protein 1 immunodominant epitope GILGFVFTL of influenza A virus (IAV). Classified as a public TR clonotype, it is preferentially selected in effector memory CD8-positive T cells among multiple HLA-A*02:01 carriers and confers long-lived immunity against IAV infection. Can cross-recognize sporadically emerging IAV variants by molecular mimicry, inducing immunity toward different influenza strains (PubMed:12796775, PubMed:18275829, PubMed:1833769, PubMed:27036003, PubMed:29997621, PubMed:7807026). Antigen recognition initiates TR-CD3 clustering on the cell surface and intracellular activation of LCK that phosphorylates the ITAM motifs of CD3G, CD3D, CD3E and CD247 enabling the recruitment of ZAP70. In turn, ZAP70 phosphorylates LAT, which recruits numerous signaling molecules to form the LAT signalosome. The LAT signalosome propagates signal branching to three major signaling pathways, the calcium, the mitogen-activated protein kinase (MAPK) kinase and the nuclear factor NF-kappa-B (NF-kB) pathways, leading to the mobilization of transcription factors that are critical for gene expression and essential for T cell differentiation into effector/memory T cells (By similarity).[UniProtKB:P01848]<ref>PMID:12796775</ref> <ref>PMID:18275829</ref> <ref>PMID:1833769</ref> <ref>PMID:27036003</ref> <ref>PMID:29997621</ref> <ref>PMID:7807026</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+T-cell engager (TCE) immunotherapy has demonstrated significant clinical activity in multiple cancers by inducing co-engagement of T-cells and tumor cells, resulting in T-cell activation and T-cell-dependent cellular cytotoxicity (TDCC) against tumor cells. Current-generation TCEs are predominantly composed of antibody-based binding domains targeting the CD3e molecule of the T-cell antigen receptor (TCR)/CD3 complex on T-cells and a tumor-associated antigen on tumor cells. However, limitations of this approach include cytokine release syndrome and a limited therapeutic window. Here, we report the generation and preclinical evaluation of SAR444200, the first NANOBODY(R)-based TCE clinical candidate binding to TCRalphabeta and GPC3 to co-engage T-cells and GPC3+ tumor cells, causing TDCC. SAR444200 bound with nanomolar to picomolar affinity to TCRalphabeta and GPC3 respectively and induced in vitro TDCC against multiple human tumor cell lines with differential GPC3 expression with picomolar potency. In vivo analysis using human cancer cell line-derived (HuH-7 and HepG2) xenografts in immunodeficient mice showed complete tumor regression at doses starting from 0.7 mg/kg. In exploratory non-human primate studies, intravenous administration of SAR444200 was well tolerated up to 8 mg/kg and exhibited greater than dose-proportional clearances and dose-proportional maximum concentrations across the tested dose range. The highly potent and efficacious activity of SAR444200 in diverse models of GPC3+ tumors and the extremely wide tolerated dose range merits further development of this compound. Furthermore, NANOBODY(R)-based TCEs developed using an anti-TCRalphabeta moiety may have specific advantages for the development of TCEs.
-Authors: Svidritskiy, E., Qiu, Y., Yanfeng, Z.
+Identification and non-clinical characterization of SAR444200, a novel anti-GPC3 NANOBODY(R) T-cell engager, for the treatment of GPC3+ solid tumors.,Meoni P, Vintem APB, Cortez-Retamozo VF, Jacobs J, De Tavernier E, Fiorentini P, Van Hoorick D, Batchelor JD, Svidritskiy E, Qiu Y, Dejonckheere E, Li A, Pao LI, Buyse MA Mol Cancer Ther. 2025 Oct 3. doi: 10.1158/1535-7163.MCT-24-1049. PMID:41041827<ref>PMID:41041827</ref>
-Description: abTCR bound to SAR444200, a novel anti-GPC3 T-cell engager, for the treatment of GPC3+ solid tumors
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Svidritskiy, E]]
+<div class="pdbe-citations 9nrj" style="background-color:#fffaf0;"></div>
-[[Category: Yanfeng, Z]]
+== References ==
-[[Category: Qiu, Y]]
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Qiu Y]]
+[[Category: Svidritskiy E]]
+[[Category: Yanfeng Z]]

9nrj

From Proteopedia

Current revision

abTCR bound to SAR444200, a novel anti-GPC3 T-cell engager, for the treatment of GPC3+ solid tumors

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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