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TLR9 agonist MGN1703 enhances B cell differentiation and function in lymph nodes
Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review
DOI
- https://doi.org/10.1016/j.ebiom.2019.07.005
Forlagets udgivne version
- Mariane H Schleimann
- Maria-Louise Kobberø ,
- Line K Vibholm ,
- Kathrine Kjær
- Leila B Giron, Wistar Institute ,
- Kathleen Busman-Sahay, Oregon Health & Science University ,
- Chi Ngai Chan, Oregon Health & Science University ,
- Michael Nekorchuk, Oregon Health & Science University ,
- Manuel Schmidt, Mologen AG, Berlin, Germany. ,
- Burghardt Wittig, Mologen AG, Berlin, Germany; MolBio2Math - Molecular Biology & Integral Biomathics, a non-profit Foundation Institute, Berlin, Germany. ,
- Tine E Damsgaard ,
- Peter Ahlburg
- Michel B Hellfritzsch
- Kaja Zuwala
- Frederik H Rothemejer
- Rikke Olesen
- Phillipp Schommers, Institute of Virology, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany; Department of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; German Center for Infection Research, Partner Site Bonn-Cologne, 50931 Cologne, Germany. ,
- Florian Klein, Institute of Virology, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany; German Center for Infection Research, Partner Site Bonn-Cologne, 50931 Cologne, Germany. ,
- Harsh Dweep, Wistar Institute ,
- Andrew Kossenkov, Wistar Institute ,
- Jens R Nyengaard
- Jacob D Estes, Oregon Health & Science University ,
- Mohamed Abdel-Mohsen, Wistar Institute ,
- Lars Østergaard
- Martin Tolstrup
- Ole S Søgaard
- Paul W Denton
- Institut for Klinisk Medicin - Infektionssygdomme
- Institut for Klinisk Medicin
- Institut for Klinisk Medicin - Plastik- og Brystkirurgi
- Institut for Klinisk Medicin - Bedøvelse
- Institut for Klinisk Medicin - Røntgen og Skanning
- Institut for Klinisk Medicin - Center for Molekylær Morfologi, sektion for Stereologi og Mikroskopi
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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | EBioMedicine |
| Vol/bind | 45 |
| Sider (fra-til) | 328-340 |
| DOI | |
| Status | Udgivet - jul. 2019 |
Bibliografisk note
Copyright © 2019. Published by Elsevier B.V.
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