{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Howe JM"],"funding":["NIAID NIH HHS","National Institute of General Medical Sciences","NIGMS NIH HHS","Division of Intramural Research, National Institute of Allergy and Infectious Diseases"],"pagination":["2348-2357"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10650436"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["14(11)"],"pubmed_abstract":["Glucocorticoids (GCs) are effective in treating autoimmune and inflammatory disorders but come with significant side effects, many of which are mediated by non-immunological cells. Therefore, there is rapidly growing interest in using antibody drug conjugate (ADC) technology to deliver GCs specifically to immune cells, thereby minimizing off-target side effects. Herein, we report the study of anti-CD11a, anti-CD38, and anti-TNFα ADCs to deliver dexamethasone to monocytes. We found that anti-CD11a and anti-CD38 were rapidly internalized by monocytes, while uptake of anti-TNFα depended on pre-activation with LPS. Using these antibodies were attached to a novel linker system, ValCitGlyPro-Dex (VCGP-Dex), that efficiently released dexamethasone upon lysosomal catabolism. This linker relies on lysosomal cathepsins to cleave after the ValCit sequence, thereby releasing a GlyPro-Dex species that undergoes rapid self-immolation to form dexamethasone. The resulting monocyte-targeting ADCs bearing this linker payload effectively suppressed LPS-induced NFκB activation and cytokine release in both a monocytic cell line (THP1) and in human PBMCs. <b>Anti-TNFα_VCGP-Dex</b> and <b>anti-CD38_VCGP-Dex</b> were particularly effective, suppressing ∼60-80% of LPS-induced IL-6 release from PBMCs at 3-10 μg mL-1 concentrations. In contrast, the corresponding isotype control ADC (anti-RSV) and the corresponding naked antibodies (anti-CD38 and anti-TNFα) resulted in only modest suppression (0-30%) of LPS-induced IL-6. Taken together, these results provide further evidence of the ability of glucocorticoid-ADCs to selectively suppress immune responses, and highlight the potential of two targets (CD38 and TNFα) for the development of novel immune-suppressing ADCs."],"journal":["RSC medicinal chemistry"],"pubmed_title":["ValCitGlyPro-dexamethasone antibody conjugates selectively suppress the activation of human monocytes."],"pmcid":["PMC10650436"],"funding_grant_id":["R01GM144450","1R03AI156696","R03 AI156696","R01 GM144450"],"pubmed_authors":["Tumey LN","Watts KA","Benjamin SR","Fang S","Xu F","Howe JM"],"additional_accession":[]},"is_claimable":false,"name":"ValCitGlyPro-dexamethasone antibody conjugates selectively suppress the activation of human monocytes.","description":"Glucocorticoids (GCs) are effective in treating autoimmune and inflammatory disorders but come with significant side effects, many of which are mediated by non-immunological cells. Therefore, there is rapidly growing interest in using antibody drug conjugate (ADC) technology to deliver GCs specifically to immune cells, thereby minimizing off-target side effects. Herein, we report the study of anti-CD11a, anti-CD38, and anti-TNFα ADCs to deliver dexamethasone to monocytes. We found that anti-CD11a and anti-CD38 were rapidly internalized by monocytes, while uptake of anti-TNFα depended on pre-activation with LPS. Using these antibodies were attached to a novel linker system, ValCitGlyPro-Dex (VCGP-Dex), that efficiently released dexamethasone upon lysosomal catabolism. This linker relies on lysosomal cathepsins to cleave after the ValCit sequence, thereby releasing a GlyPro-Dex species that undergoes rapid self-immolation to form dexamethasone. The resulting monocyte-targeting ADCs bearing this linker payload effectively suppressed LPS-induced NFκB activation and cytokine release in both a monocytic cell line (THP1) and in human PBMCs. <b>Anti-TNFα_VCGP-Dex</b> and <b>anti-CD38_VCGP-Dex</b> were particularly effective, suppressing ∼60-80% of LPS-induced IL-6 release from PBMCs at 3-10 μg mL-1 concentrations. In contrast, the corresponding isotype control ADC (anti-RSV) and the corresponding naked antibodies (anti-CD38 and anti-TNFα) resulted in only modest suppression (0-30%) of LPS-induced IL-6. Taken together, these results provide further evidence of the ability of glucocorticoid-ADCs to selectively suppress immune responses, and highlight the potential of two targets (CD38 and TNFα) for the development of novel immune-suppressing ADCs.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Nov","modification":"2025-04-21T14:54:33.832Z","creation":"2025-04-21T14:54:33.832Z"},"accession":"S-EPMC10650436","cross_references":{"pubmed":["37974960"],"doi":["10.1039/d3md00336a"]}}