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

Authors

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 OmahaFollow

Author ORCID Identifier

Paul W. Denton

Document Type

Article

Publication Date

7-2019

Publication Title

EBioMedicine

Volume

45

First Page

328

Last Page

340

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.

Comments

https://doi.org/10.1016/j.ebiom.2019.07.005

Recommended Citation

Schleimann, Mariane H.; Kobberø, Maria-Louise; Vibholm, Line K.; Kjær, Katherine; Giron, Leila B.; Busman-Sahay, Kathleen; Chan, Chi Ngai; Nekorchuk, Michael; Schmidt, Manuel; Wittig, Burghardt; Damsgaard, Tine E.; Ahlburg, Peter; Hellfritzsch, Michel B.; Zuwala, Kaja; Rothemejer, Frederik H.; Olesen, Rikke; Schommers, Phillipp; Klein, Florian; Dweep, Harsh; Kossenkov, Andrew; Nyengaard, Jens R.; Estes, Jacob D.; Abdel-Mohsen, Mohamed; Østergaard, Lars; Søgaard, Ole S.; and Denton, Paul W., "TLR9 agonist MGN1703 enhances B cell differentiation and function in lymph nodes" (2019). Biology Faculty Publications. 129.
https://digitalcommons.unomaha.edu/biofacpub/129

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.