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Acute myeloid leukemia (AML) poses a singular challenge for chimeric antigen receptor (CAR) therapy owing to its phenotypic heterogeneity and similarity to normal hematopoietic stem/progenitor cells (HSPCs). Here we expound a CAR strategy intended to efficiently target AML while minimizing HSPC toxicity. Quantification of target expression in relapsed/refractory patient samples and normal HSPCs reveals a therapeutic window for gated co-targeting of ADGRE2 and CLEC12A: We combine an attenuated ADGRE2-CAR with a CLEC12A-chimeric costimulatory receptor (ADCLEC.syn1) to preferentially engage ADGRE2posCLEC12Apos leukemic stem cells over ADGRE2lowCLEC12Aneg normal HSPCs. ADCLEC.syn1 prevents antigen escape in AML xenograft models, outperforms the ADGRE2-CAR alone and eradicates AML despite proximate myelopoiesis in humanized mice. Off-target HSPC toxicity is similar to that of a CD19-CAR and can be mitigated by reducing CAR T cell-derived interferon-γ. Overall, we demonstrate the ability of target density-adapted cooperative CAR targeting to selectively eliminate AML and potentially obviate the need for hematopoietic rescue.
Pubmed ID: 37802054 RIS Download
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This monoclonal targets IFN-gamma
View all literature mentionsThis monoclonal targets IFNγ
View all literature mentionsThis monoclonal targets CD371 (Clec12A)
View all literature mentionsThis monoclonal targets Human CD312
View all literature mentionsThis monoclonal targets CD123
View all literature mentionsThis monoclonal targets CD33
View all literature mentionsThis monoclonal targets CD90
View all literature mentionsThis monoclonal targets CD71 (Transferrin Receptor)
View all literature mentionsThis monoclonal targets CD45
View all literature mentionsThis monoclonal targets CD45
View all literature mentionsThis monoclonal targets CD38
View all literature mentionsThis monoclonal targets CD34
View all literature mentionsThis monoclonal targets CD25
View all literature mentionsThis monoclonal targets CD19
View all literature mentionsThis monoclonal targets CD16
View all literature mentionsThis monoclonal targets CD8
View all literature mentionsThis monoclonal targets CD14
View all literature mentionsThis monoclonal targets CD3
View all literature mentionsThis monoclonal targets EGFR
View all literature mentionsCell line EL4 is a Cancer cell line with a species of origin Mus musculus (Mouse)
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Mus musculus with name NOD.Cg-Prkdcscid Il2rg
Mus musculus with name NOD.Cg-Prkdcscid Il2rg
Cell line U-937 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line Phoenix-Ampho is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsPublic database with millions of high-resolution images showing the spatial distribution of proteins in different normal human tissues and cancer types, as well as different human cell lines. The data is released together with application-specific validation performed for each antibody, including immunohistochemisty, Western blot analysis and, for a large fraction, a protein array assay and immunofluorescent based confocal microscopy. The database has been developed in a gene-centric manner with the inclusion of all human genes predicted from genome efforts. Search functionalities allow for complex queries regarding protein expression profiles, protein classes and chromosome location. Antibodies included have been analyzed using a standardized protocol in a single attempt without further efforts to optimize the procedure and therefore it cannot be excluded that certain observed binding properties are due to technical rather than biological reasons and that further optimization could result in a different outcome. Submission of antibodies: The Swedish Human Proteome Atlas (HPA) program, invites submission of antibodies from both academic and commercial sources to be included in the human protein atlas. All antibodies will be validated by the HPA-program by a standard procedure and antibodies that are accepted will be use in the tissue- profiling program to generate high-resolution immunohistochemistry images representing a wide spectrum of normal tissues and cancer types.
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