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

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 receivedMGN1703 for 24weeks concurrentwith antiretroviral therapy. Seven participants completed the sub-study including lymph node resection at baseline and after 24weeks 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 MGN 1703 modulates human lymph node B cells in vivo. These findingswarrant further considerations in the development of TLR9 agonists as immunotherapy against cancers and infectious diseases. (C) 2019 The Authors. Published by Elsevier B.V.