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Rigshospitalet - en del af Københavns Universitetshospital
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TLR9 agonist MGN1703 enhances B cell differentiation and function in lymph nodes

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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  • Mariane H Schleimann
  • Maria-Louise Kobberø
  • Line K Vibholm
  • Kathrine Kjær
  • Leila B Giron
  • Kathleen Busman-Sahay
  • Chi Ngai Chan
  • Michael Nekorchuk
  • Manuel Schmidt
  • Burghardt Wittig
  • Tine E Damsgaard
  • Peter Ahlburg
  • Michel B Hellfritzsch
  • Kaja Zuwala
  • Frederik H Rothemejer
  • Rikke Olesen
  • Phillipp Schommers
  • Florian Klein
  • Harsh Dweep
  • Andrew Kossenkov
  • Jens R Nyengaard
  • Jacob D Estes
  • Mohamed Abdel-Mohsen
  • Lars Østergaard
  • Martin Tolstrup
  • Ole S Søgaard
  • Paul W Denton
Vis graf over relationer

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.

OriginalsprogEngelsk
TidsskriftEBioMedicine
Vol/bind45
Sider (fra-til)328-340
Antal sider13
DOI
StatusUdgivet - jul. 2019
Eksternt udgivetJa

Bibliografisk note

Copyright © 2019. Published by Elsevier B.V.

ID: 59210102