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Identification and non-clinical characterization of SAR444200, a novel anti-GPC3 T-cell engager for the treatment of GPC3+ solid tumors
Structural highlights
DiseaseGPC3_HUMAN Nephroblastoma;Simpson-Golabi-Behmel syndrome. The disease is caused by variants affecting the gene represented in this entry. FunctionGPC3_HUMAN Cell surface proteoglycan (PubMed:14610063). Negatively regulates the hedgehog signaling pathway when attached via the GPI-anchor to the cell surface by competing with the hedgehog receptor PTC1 for binding to hedgehog proteins (By similarity). Binding to the hedgehog protein SHH triggers internalization of the complex by endocytosis and its subsequent lysosomal degradation (By similarity). Positively regulates the canonical Wnt signaling pathway by binding to the Wnt receptor Frizzled and stimulating the binding of the Frizzled receptor to Wnt ligands (PubMed:16227623, PubMed:24496449). Positively regulates the non-canonical Wnt signaling pathway (By similarity). Binds to CD81 which decreases the availability of free CD81 for binding to the transcriptional repressor HHEX, resulting in nuclear translocation of HHEX and transcriptional repression (By similarity). Inhibits the dipeptidyl peptidase activity of DPP4 (PubMed:17549790). Plays a role in limb patterning and skeletal development by controlling the cellular response to BMP4 (By similarity). Modulates the effects of growth factors BMP2, BMP7 and FGF7 on renal branching morphogenesis (By similarity). Required for coronary vascular development (By similarity). Plays a role in regulating cell movements during gastrulation (By similarity).[UniProtKB:Q6V9Y8][UniProtKB:Q8CFZ4][1] [2] [3] [4] 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[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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