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TLR9 agonist MGN1703 enhances B cell differentiation and function in lymph nodes
EBioMedicine
  • Mariane H. Schleimann, Aarhus University
  • Maria-Louise Kobberø, Aarhus University
  • Line K. Vibholm, Aarhus University
  • Katherine Kjær, Aarhus University
  • Leila B. Giron, The Wistar Institute
  • Kathleen Busman-Sahay, Oregon Health and Science University
  • Chi Ngai Chan, Oregon Health and Science University
  • Michael Nekorchuk, Oregon Health and Science University
  • Manuel Schmidt, Mologen AG
  • Burghardt Wittig, Mologen AG
  • Tine E. Damsgaard, Aarhus University
  • Peter Ahlburg, Aarhus University Hospital
  • Michel B. Hellfritzsch, Aarhus University
  • Kaja Zuwala, Aarhus University Hospital
  • Frederik H. Rothemejer, Aarhus University
  • Rikke Olesen, Aarhus University
  • Phillipp Schommers, University of Cologne
  • Florian Klein, University of Cologne
  • Harsh Dweep, The Wistar Institute
  • Andrew Kossenkov, The Wistar Institute
  • Jens R. Nyengaard, Aarhus University
  • Jacob D. Estes, Oregon Health and Science University
  • Mohamed Abdel-Mohsen, The Wistar Institute
  • Lars Østergaard, Aarhus University Hospital
  • Ole S. Søgaard, Aarhus University
  • Paul W. Denton, University of Nebraska at Omaha
Author ORCID Identifier

Paul W. Denton

Document Type
Article
Publication Date
7-1-2019
Disciplines
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.

Creative Commons License
Creative Commons Attribution-Noncommercial-No Derivative Works 4.0
Citation Information
Mariane H. Schleimann, Maria-Louise Kobberø, Line K. Vibholm, Katherine Kjær, et al.. "TLR9 agonist MGN1703 enhances B cell differentiation and function in lymph nodes" EBioMedicine Vol. 45 (2019) p. 328 - 340
Available at: http://works.bepress.com/paul-denton/9/