An immunomodulatory antibody-drug conjugate (ADC) targeting BDCA2 strongly suppresses pDC function and glucocorticoid responsive genes.

Blood dendritic cell antigen 2 (BDCA2) is exclusively expressed on plasmacytoid dendritic cells (pDCs) whose uncontrolled production of type I interferon (IFN-I) is crucial in pathogenesis of systemic lupus erythematosus (SLE) and other autoimmune diseases. Although anti-BDCA2 antibody therapy reduced disease activity in SLE patients, its clinical efficacy needs further improvement. We developed a novel glucocorticoid receptor (GR) agonist and used it as a payload to conjugate with an anti-BDCA2 antibody to form BDCA2-ADC. The activation of BDCA2-ADC was evaluated in vitro.Inhibitory activity of BDCA2-ADC was evaluated in PBMC or in purified pDC under ex vivo TLR agonistic stimulation. The global gene regulation in purified pDC was analysis by RNA-seq. The antigen dependent payload delivery was measured by report assay.The BDCA2-ADC molecule causes total suppression of IFN alpha (IFNα) production and broader inhibition of inflammatory cytokine production compared with the parental antibody in human pDCs. Global gene expression analysis confirmed that the payload and antibody acted synergistically to regulate both type I IFN signature genes and glucocorticoid responsive genes in pDCs.Taken together, these data suggest dual mechanisms of BDCA2-ADC on pDCs and the potential of BDCA2-ADC being the first ADC treatment for SLE in the world and a better treatment option than anti-BDCA2 antibody for SLE patients.© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Citation

Xi Li, Yu Zhang, Bing Li, Jian Li, Yang Qiu, Zhongyuan Zhu, Haiqing Hua. An immunomodulatory antibody-drug conjugate (ADC) targeting BDCA2 strongly suppresses pDC function and glucocorticoid responsive genes. Rheumatology (Oxford, England). 2023 May 15

PMID: 37184875

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