MGN1703, an immunomodulator and toll-like receptor 9 (TLR-9) agonist: From bench to bedside

Abstract

The adaptive immune system has been the main focus of immunological strategies in oncology with only more recent approaches targeting innate immunity. Endosomal toll-like receptors (TLR-7, TLR-9) activate innate immune responses by signaling damage-associated molecular patterns (DAMP) from decaying tumor cells. This has led to the development of DNA-based TLR-9 agonists, which induce antitumor activity through innate and subsequent adaptive immune responses. Early clinical trials with CpG-ODN as TLR-9 agonists were associated with unfavorable tolerability and narrow clinical efficacy, leading to failure in pivotal trials. dSLIM, the active ingredient of MGN1703, is a DNA-based, radically different molecular alternative to CpG-ODN, which results in genuine antitumor immunomodulation. Preclinical and clinical studies of MGN1703 have confirmed that this TLR-9 agonist has therapeutic potential in a variety of solid tumors, while long-term treatment with high doses was very well tolerated. A pivotal trial of first-line maintenance treatment with MGN1703 in patients with metastatic colorectal cancer is underway.

Short-Course Toll-Like Receptor 9 Agonist Treatment Impacts Innate Immunity and Plasma Viremia in Individuals With Human Immunodeficiency Virus Infection

“…As 120 mg MGN1703 per week is considered safe in cancer patients and healthy controls [18,21,22], study participants received 4 weeks of 60 mg (concentration 15 mg/mL) of MGN1703 (MOLOGEN AG, Berlin, Germany), administered subcutaneously by the study investigator as two 2-mL bilateral injections twice weekly. ART was maintained during the entire study period.…”

“…Preclinical testing and data from cancer trials demonstrates that MGN1703 activates immune functions through TLR9 stimulation. MGN1703-induced TLR9 signaling leads to increased secretion of a range of cytokines (eg, interferon [IFN] α) and activation of plasmacytoid dendritic cells (pDCs) and B cells [18]. Furthermore, MGN1703 increases activation and cytotoxicity of NK cells in vitro [19].…”

“…MGN1703 (lefitolimod), a novel Toll-like receptor 9 (TLR9) agonist, belongs to a class of drugs referred to as immune surveillance reactivators and is currently in phase 3 testing for treatment of metastatic colorectal cancer [18]. Preclinical testing and data from cancer trials demonstrates that MGN1703 activates immune functions through TLR9 stimulation.…”

A Novel Toll-Like Receptor 9 Agonist, MGN1703, Enhances HIV-1 Transcription and NK Cell-Mediated Inhibition of HIV-1-Infected Autologous CD4 + T Cells

“…MGN1703 is a novel, dumbbell-shaped, covalently closed DNA construct, synthesized from nonmodified natural DNA, that we used to agonize TLR9 (7)(8)(9), and we refer to cells activated via this TLR9-triggered pathway as "MGN1703-activated" cells here.…”

Immunotherapy in the treatment of colorectal cancer: a new kid on the block

“…MGN1703 is a DNA-based Toll-like receptor that acts as an immunomodulator with immune activation in heavily pre-treated patients with mCRC in the phase II IMPACT trial in maintenance setting [66] . Patients who had completed first line standard chemotherapy + bevacizumab were randomly allocated to lefitolimod or placebo.…”