{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Wang L"],"funding":["Japan Agency for Medical Research and Development","Mie University"],"pagination":["734-748"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10928314"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["32(3)"],"pubmed_abstract":["Despite the revolutionary success of chimeric antigen receptor (CAR)-T therapy for hematological malignancies, successful CAR-T therapies for solid tumors remain limited. One major obstacle is the scarcity of tumor-specific cell-surface molecules. One potential solution to overcome this barrier is to utilize antibodies that recognize peptide/major histocompatibility complex (MHCs) in a T cell receptor (TCR)-like fashion, allowing CAR-T cells to recognize intracellular tumor antigens. This study reports a highly specific single-chain variable fragment (scFv) antibody against the MAGE-A4<sub>p230-239</sub>/human leukocyte antigen (HLA)-A∗02:01 complex (MAGE-A4 pMHC), screened from a human scFv phage display library. Indeed, retroviral vectors encoding CAR, utilizing this scFv antibody as a recognition component, efficiently recognized and lysed MAGA-A4<sup>+</sup> tumor cells in an HLA-A∗02:01-restricted manner. Additionally, the adoptive transfer of T cells modified by the CAR-containing glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related receptor (GITR) intracellular domain (ICD), but not CD28 or 4-1BB ICD, significantly suppressed the growth of MAGE-A4<sup>+</sup> HLA-A∗02:01<sup>+</sup> tumors in an immunocompromised mouse model. Of note, a comprehensive analysis revealed that a broad range of amino acid sequences of the MAGE-A4p<sub>230-239</sub> peptide were critical for the recognition of MAGE-A4 pMHC by these CAR-T cells, and no cross-reactivity to analogous peptides was observed. Thus, MAGE-A4-targeted CAR-T therapy using this scFv antibody may be a promising and safe treatment for solid tumors."],"journal":["Molecular therapy : the journal of the American Society of Gene Therapy"],"pubmed_title":["Preclinical evaluation of a novel CAR-T therapy utilizing a scFv antibody highly specific to MAGE-A4&lt;sub&gt;p230-239&lt;/sub&gt;/HLA-A∗02:01 complex."],"pmcid":["PMC10928314"],"funding_grant_id":["JP19ck0106412","JP21ck0106658"],"pubmed_authors":["Shiku H","Miyahara Y","Seo N","Shirakura K","Akahori Y","Kato T","Matsumoto M","Wang L","Katsumoto Y"],"additional_accession":[]},"is_claimable":false,"name":"Preclinical evaluation of a novel CAR-T therapy utilizing a scFv antibody highly specific to MAGE-A4&lt;sub&gt;p230-239&lt;/sub&gt;/HLA-A∗02:01 complex.","description":"Despite the revolutionary success of chimeric antigen receptor (CAR)-T therapy for hematological malignancies, successful CAR-T therapies for solid tumors remain limited. One major obstacle is the scarcity of tumor-specific cell-surface molecules. One potential solution to overcome this barrier is to utilize antibodies that recognize peptide/major histocompatibility complex (MHCs) in a T cell receptor (TCR)-like fashion, allowing CAR-T cells to recognize intracellular tumor antigens. This study reports a highly specific single-chain variable fragment (scFv) antibody against the MAGE-A4<sub>p230-239</sub>/human leukocyte antigen (HLA)-A∗02:01 complex (MAGE-A4 pMHC), screened from a human scFv phage display library. Indeed, retroviral vectors encoding CAR, utilizing this scFv antibody as a recognition component, efficiently recognized and lysed MAGA-A4<sup>+</sup> tumor cells in an HLA-A∗02:01-restricted manner. Additionally, the adoptive transfer of T cells modified by the CAR-containing glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related receptor (GITR) intracellular domain (ICD), but not CD28 or 4-1BB ICD, significantly suppressed the growth of MAGE-A4<sup>+</sup> HLA-A∗02:01<sup>+</sup> tumors in an immunocompromised mouse model. Of note, a comprehensive analysis revealed that a broad range of amino acid sequences of the MAGE-A4p<sub>230-239</sub> peptide were critical for the recognition of MAGE-A4 pMHC by these CAR-T cells, and no cross-reactivity to analogous peptides was observed. Thus, MAGE-A4-targeted CAR-T therapy using this scFv antibody may be a promising and safe treatment for solid tumors.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Mar","modification":"2026-04-08T19:51:06.213Z","creation":"2025-04-04T01:12:03.941Z"},"accession":"S-EPMC10928314","cross_references":{"pubmed":["38243600"],"doi":["10.1016/j.ymthe.2024.01.018"]}}