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

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

doi:10.1016/j.ebiom.2019.07.005

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

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 KossenkovJens R Nyengaard, Jacob D Estes, Mohamed Abdel-Mohsen, Lars Østergaard, Martin Tolstrup, Ole S Søgaard, Paul W Denton

27 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	EBioMedicine
Vol/bind	45
Sider (fra-til)	328-340
Antal sider	13
DOI	https://doi.org/10.1016/j.ebiom.2019.07.005
Status	Udgivet - jul. 2019
Udgivet eksternt	Ja

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10.1016/j.ebiom.2019.07.005

Citationsformater

Schleimann, M. H., Kobberø, M.-L., Vibholm, L. K., Kjær, K., Giron, L. B., Busman-Sahay, K., Chan, C. N., Nekorchuk, M., Schmidt, M., Wittig, B., Damsgaard, T. E., Ahlburg, P., Hellfritzsch, M. B., Zuwala, K., Rothemejer, F. H., Olesen, R., Schommers, P., Klein, F., Dweep, H., ... Denton, P. W. (2019). TLR9 agonist MGN1703 enhances B cell differentiation and function in lymph nodes. EBioMedicine, 45, 328-340. https://doi.org/10.1016/j.ebiom.2019.07.005

Schleimann, MH, Kobberø, M-L, Vibholm, LK, Kjær, K, Giron, LB, Busman-Sahay, K, Chan, CN, Nekorchuk, M, Schmidt, M, Wittig, B, Damsgaard, TE, Ahlburg, P, Hellfritzsch, MB, Zuwala, K, Rothemejer, FH, Olesen, R, Schommers, P, Klein, F, Dweep, H, Kossenkov, A, Nyengaard, JR, Estes, JD, Abdel-Mohsen, M, Østergaard, L, Tolstrup, M, Søgaard, OS & Denton, PW 2019, 'TLR9 agonist MGN1703 enhances B cell differentiation and function in lymph nodes', EBioMedicine, bind 45, s. 328-340. https://doi.org/10.1016/j.ebiom.2019.07.005

@article{19aec9615bc04acf9d68dc5b5d1f0b47,

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 = "Adult, B-Lymphocytes/drug effects, Cell Differentiation/drug effects, DNA/administration & dosage, Dendritic Cells/drug effects, Dose-Response Relationship, Drug, Female, Gene Expression Regulation/drug effects, Glycosylation/drug effects, HIV Infections/drug therapy, HIV-1/drug effects, Humans, Interferon-alpha/genetics, Lymph Nodes, Lymphocyte Activation/drug effects, Male, Middle Aged, Toll-Like Receptor 9/agonists",

author = "Schleimann, {Mariane H} and Maria-Louise Kobber{\o} 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 = "Copyright {\textcopyright} 2019. Published by Elsevier B.V.",

year = "2019",

month = jul,

doi = "10.1016/j.ebiom.2019.07.005",

language = "English",

volume = "45",

pages = "328--340",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier BV",

}

TY - JOUR

T1 - TLR9 agonist MGN1703 enhances B cell differentiation and function in lymph nodes

AU - Schleimann, Mariane H

AU - Kobberø, Maria-Louise

AU - Vibholm, Line K

AU - Kjær, Kathrine

AU - Giron, Leila B

AU - Busman-Sahay, Kathleen

AU - Chan, Chi Ngai

AU - Nekorchuk, Michael

AU - Schmidt, Manuel

AU - Wittig, Burghardt

AU - Damsgaard, Tine E

AU - Ahlburg, Peter

AU - Hellfritzsch, Michel B

AU - Zuwala, Kaja

AU - Rothemejer, Frederik H

AU - Olesen, Rikke

AU - Schommers, Phillipp

AU - Klein, Florian

AU - Dweep, Harsh

AU - Kossenkov, Andrew

AU - Nyengaard, Jens R

AU - Estes, Jacob D

AU - Abdel-Mohsen, Mohamed

AU - Østergaard, Lars

AU - Tolstrup, Martin

AU - Søgaard, Ole S

AU - Denton, Paul W

PY - 2019/7

Y1 - 2019/7

N2 - 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.

AB - 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.

KW - Adult

KW - B-Lymphocytes/drug effects

KW - Cell Differentiation/drug effects

KW - DNA/administration & dosage

KW - Dendritic Cells/drug effects

KW - Dose-Response Relationship, Drug

KW - Female

KW - Gene Expression Regulation/drug effects

KW - Glycosylation/drug effects

KW - HIV Infections/drug therapy

KW - HIV-1/drug effects

KW - Humans

KW - Interferon-alpha/genetics

KW - Lymph Nodes

KW - Lymphocyte Activation/drug effects

KW - Male

KW - Middle Aged

KW - Toll-Like Receptor 9/agonists

U2 - 10.1016/j.ebiom.2019.07.005

DO - 10.1016/j.ebiom.2019.07.005

M3 - Journal article

C2 - 31300344

SN - 2352-3964

VL - 45

SP - 328

EP - 340

JO - EBioMedicine

JF - EBioMedicine

ER -

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

Abstract

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