An immunomodulatory antibody–drug conjugate targeting BDCA2 strongly suppresses plasmacytoid dendritic cell function and glucocorticoid responsive genes

医学 免疫学 浆细胞样树突状细胞 外周血单个核细胞 抗体 树突状细胞 内科学 抗原 药理学 生物 体外 生物化学
作者
Xi Li,Yu Zhang,Bing Li,Jian Li,Yang Qiu,Zhenduo Zhu,Haiqing Hua
出处
期刊:Rheumatology [Oxford University Press]
卷期号:63 (1): 242-250 被引量:3
标识
DOI:10.1093/rheumatology/kead219
摘要

Abstract Objectives Blood dendritic cell antigen 2 (BDCA2) is exclusively expressed on plasmacytoid dendritic cells (pDCs) whose uncontrolled production of type I IFN (IFN-I) is crucial in pathogenesis of 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 agonist and used it as a payload to conjugate with an anti-BDCA2 antibody to form an BDCA2 antibody–drug conjugate (BDCA2-ADC). The activation of BDCA2-ADC was evaluated in vitro. Methods Inhibitory activity of BDCA2-ADC was evaluated in peripheral blood mononuclear cells or in purified pDCs under ex vivo toll-like receptor agonistic stimulation. The global gene regulation in purified pDCs was analysed by RNA-seq. The antigen-dependent payload delivery was measured by reporter assay. Results The BDCA2-ADC molecule causes total suppression of 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. Conclusion Taken together, these data suggest dual mechanisms of BDCA2-ADC on pDCs and the potential for BDCA2-ADC to be the first ADC treatment for SLE in the world and a better treatment option than anti-BDCA2 antibody for SLE patients.
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