@article{70ecd37b171e4501842c8f13657a8437,
title = "TLR9 agonist MGN1703 enhances B cell differentiation and function in lymph nodes",
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",
author = "Schleimann, {Mariane H.} and Kobber{\o}, {Maria Louise} and Vibholm, {Line K.} and Kathrine Kj{\ae}r and Giron, {Leila B.} and Kathleen Busman-Sahay and Chan, {Chi Ngai} and Michael Nekorchuk and Manuel Schmidt and Burghardt Wittig and Damsgaard, {Tine E.} and Peter Ahlburg and Hellfritzsch, {Michel B.} and Kaja Zuwala and Rothemejer, {Frederik H.} and Rikke Olesen and Phillipp Schommers and Florian Klein and Harsh Dweep and Andrew Kossenkov and Nyengaard, {Jens R.} and Estes, {Jacob D.} and Mohamed Abdel-Mohsen and Lars {\O}stergaard and Martin Tolstrup and S{\o}gaard, {Ole S.} and Denton, {Paul W.}",
note = "Funding Information: 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.We thank the participants for their generous contribution to the study as well as Lene Svinth J{\o}nke and Helena M. Andersen for laboratory assistance. Fulbright Visiting Scholar Award to MHS, Augustinus Foundation (17–3250; MHS), Julie von M{\"u}llers Foundation award to MHS, Aarhus University Research Foundation (AUFF-E-2016-FLS-8-9; PWD); Danish Council for Independent Research (DFF-6120-00017 and DFF-7025-00022; PWD), and the Novo Nordisk Foundation (NNF17OC0028462; MT). PS and FK were supported by the German Center for Infection Research (DZIF) and the European Research Council (ERC-StG639961). Mologen AG provided study drug free of charge. The funders had no role in study design, data collection, data analyses, interpretation, or writing of the report. BW reports personal fees and other from MOLOGEN AG, during the conduct of the study. BW is listed as inventor of an issued patent family, owned by MOLOGEN AG, protecting the TLR9 agonist (dSLIM{\textregistered}, MGN1703), used in the trial; INN Lefitolimod. JDE reports personal fees from Advanced Cell Diagnostics, outside the submitted work. MS is an employee of Mologen AG. MS, MT and OSS have a patent Schroff M, Schmidt M, Kapp K, Zurlo A, Tolstrup M, Offersen R, S{\o}gaard OS: MEANS FOR THE TREATMENT OF HIV Pub. No WO/2017/050806 issued to Mologen AG. Concept development: PWD, MHS, OSS, MT, L{\O}, and LV. Clinical study and collection of patient material: LV, PWD, TD, PA, and MBH. Performed data collection: MHS, M-LK, LV, KK, LBG, KB-S, CNC, MN, KZ, FHR, RO, PS, HD, and AK. Performed data analyses and interpretation of the results: MHS, M-LK, LV, KK, LBG, KB-S, CNC, MN, MS, BW, KZ, FHR, RO, PS, FK, HD, AK, JRN, JDE, MA-M, MT, OSS, and PWD. First draft of the manuscript: MHS and PWD. Critically revising the manuscript for important intellectual content: all authors. The RNA-seq data was deposited to GEO (https://www.ncbi.nlm.nih.gov/geo/) under accession number GSE130307. Funding Information: Fulbright Visiting Scholar Award to MHS, Augustinus Foundation ( 17–3250 ; MHS), Julie von M{\"u}llers Foundation award to MHS, Aarhus University Research Foundation ( AUFF-E-2016-FLS-8-9 ; PWD); Danish Council for Independent Research ( DFF-6120-00017 and DFF-7025-00022 ; PWD), and the Novo Nordisk Foundation ( NNF17OC0028462 ; MT). PS and FK were supported by the German Center for Infection Research (DZIF) and the European Research Council ( ERC-StG639961 ). Mologen AG provided study drug free of charge. The funders had no role in study design, data collection, data analyses, interpretation, or writing of the report. Publisher Copyright: {\textcopyright} 2019",
year = "2019",
month = jul,
doi = "10.1016/j.ebiom.2019.07.005",
language = "English (US)",
volume = "45",
pages = "328--340",
journal = "EBioMedicine",
issn = "2352-3964",
publisher = "Elsevier BV",
}