Bispecific killer cell engagers(BiKEs)are a powerful tool to incite the killing power of natural killer(NK)cells.Here,we posited that the BiKE technology could be utilized to deplete activated immune cells expressing ...Bispecific killer cell engagers(BiKEs)are a powerful tool to incite the killing power of natural killer(NK)cells.Here,we posited that the BiKE technology could be utilized to deplete activated immune cells expressing programmed death-1(PD-1^(+)cells),and hence treat autoimmune diseases since these cells drive the disorders.We designed and generated PD-1 BiKE that targets an activating NK cell receptor,CD16,and PD-1.PD-1 BiKE showed specific binding to PD-1^(+)cells and engaged CD16 simultaneously.PD-1 BiKE enhanced NK cell-mediated apoptosis and depletion of PD-1^(+)Raji cells,but not PD-1-Raji cells.Further,PD-1 BiKE induced apoptosis of primary PD-1^(+)T lymphocytes that are highly relevant to autoimmune disease progression.The BiKE depleted 42%of primary T cells that were stimulated in vitro.Importantly,those ablated primary T cells were activated cells.Meanwhile,naive T cells were spared by the BiKE treatment,supporting the crucial selectivity of PD-1 BiKE-directed cell depletion.Lastly,PD-1 BiKE is more effective than a conventional depleting antibody in the depletion of PD-1^(+)cells.The current work supports PD-1 BiKE is a selective,potent,and safe tool to deplete PD-1^(+)cells.展开更多
基金supported by the HCI Melanoma Center Grant,the National Institutes of Health AI139535 grant,and the National Multiple Sclerosis Society GR-1807-31630 grant to Mingnan Chen(USA)supported by the HCI Melanoma Center Grant,the National Institutes of Health AI139535 grant,and the National Multiple Sclerosis Society GR-1807-31630 grant to Mingnan Chen(USA).
文摘Bispecific killer cell engagers(BiKEs)are a powerful tool to incite the killing power of natural killer(NK)cells.Here,we posited that the BiKE technology could be utilized to deplete activated immune cells expressing programmed death-1(PD-1^(+)cells),and hence treat autoimmune diseases since these cells drive the disorders.We designed and generated PD-1 BiKE that targets an activating NK cell receptor,CD16,and PD-1.PD-1 BiKE showed specific binding to PD-1^(+)cells and engaged CD16 simultaneously.PD-1 BiKE enhanced NK cell-mediated apoptosis and depletion of PD-1^(+)Raji cells,but not PD-1-Raji cells.Further,PD-1 BiKE induced apoptosis of primary PD-1^(+)T lymphocytes that are highly relevant to autoimmune disease progression.The BiKE depleted 42%of primary T cells that were stimulated in vitro.Importantly,those ablated primary T cells were activated cells.Meanwhile,naive T cells were spared by the BiKE treatment,supporting the crucial selectivity of PD-1 BiKE-directed cell depletion.Lastly,PD-1 BiKE is more effective than a conventional depleting antibody in the depletion of PD-1^(+)cells.The current work supports PD-1 BiKE is a selective,potent,and safe tool to deplete PD-1^(+)cells.
