TLR9 agonist MGN1703 enhances B cell differentiation and function in lymph nodes

EBioMedicine. 2019 Jul;45:328-340. doi: 10.1016/j.ebiom.2019.07.005. Epub 2019 Jul 9.

Abstract

Background: TLR9 agonists are being developed as immunotherapy against malignancies and infections. TLR9 is primarily expressed in B cells and plasmacytoid dendritic cells (pDCs). TLR9 signalling may be critically important for B cell activity in lymph nodes but little is known about the in vivo impact of TLR9 agonism on human lymph node B cells. As a pre-defined sub-study within our clinical trial investigating TLR9 agonist MGN1703 (lefitolimod) treatment in the context of developing HIV cure strategies (NCT02443935), we assessed TLR9 agonist-mediated effects in lymph nodes.

Methods: Participants received MGN1703 for 24 weeks concurrent with antiretroviral therapy. Seven participants completed the sub-study including lymph node resection at baseline and after 24 weeks of treatment. A variety of tissue-based immunologic and virologic parameters were assessed.

Findings: MGN1703 dosing increased B cell differentiation; activated pDCs, NK cells, and T cells; and induced a robust interferon response in lymph nodes. Expression of Activation-Induced cytidine Deaminase, an essential regulator of B cell diversification and somatic hypermutation, was highly elevated. During MGN1703 treatment IgG production increased and antibody glycosylation patterns were changed.

Interpretation: Our data present novel evidence that the TLR9 agonist MGN1703 modulates human lymph node B cells in vivo. These findings warrant further considerations in the development of TLR9 agonists as immunotherapy against cancers and infectious diseases. FUND: This work was supported by Aarhus University Research Foundation, the Danish Council for Independent Research and the NovoNordisk Foundation. Mologen AG provided study drug free of charge.

Keywords: Antibody glycosylation; B cell differentiation; B cell follicle; HIV cure; TLR9 agonist.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II

MeSH terms

  • Adult
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / metabolism
  • Cell Differentiation / drug effects*
  • DNA / administration & dosage*
  • Dendritic Cells / drug effects
  • Dose-Response Relationship, Drug
  • Female
  • Gene Expression Regulation / drug effects
  • Glycosylation / drug effects
  • HIV Infections / drug therapy*
  • HIV Infections / genetics
  • HIV Infections / virology
  • HIV-1 / drug effects
  • Humans
  • Interferon-alpha / genetics
  • Lymph Nodes
  • Lymphocyte Activation / drug effects
  • Male
  • Middle Aged
  • Toll-Like Receptor 9 / agonists
  • Toll-Like Receptor 9 / genetics*

Substances

  • Interferon-alpha
  • MGN1703
  • TLR9 protein, human
  • Toll-Like Receptor 9
  • DNA