9nrj | pdb_00009nrj
abTCR bound to SAR444200, a novel anti-GPC3 T-cell engager, for the treatment of GPC3+ solid tumors
Structural highlights
DiseaseTRAR1_HUMAN Precursor T-cell acute lymphoblastic leukemia. FunctionTRAR1_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 PubMedT-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
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