TLR9 is an important receptor existing in immune system cells (including dendritic cells, macrophages, and other antigen-presenting cells). TLR9 recognizes cellular DNA fragments containing unmethylated cytidine-phosphate-guanosine (CpG DNA) which only exists in bacterial and viral DNA. And then, TLR9 was activated for alarming the immune system to clean bacteria or viruses. TLR9 activation leads to pro-inflammatory responses, resulting in cytokines production such as IL-6, TNF, and IL-12. The activation of TLR9 is beneficial to self-defense against foreign organisms. Therefore, TLR9 activators have become effective agents to treat cancer and immunodeficiency-related diseases (like immunodeficiency caused by HIV).
Lefitolimod (MGN 1703) is a DNA-based TLR9 agonist.
It is also an immune surveillance reactivator. In addition, Lefitolimod consists of only natural DNA and avoids toxicities or clinical side effects which most likely arise from the phosphorothioate modifications.
This agonist targets TLR9-positive plasmacytoid dendritic cells and triggers their secretion of IFN-α to activate the effector cells of innate immunity subsequently leading to an elevated systemic level of IP-10 (a chemotactic and angiostatic protein). Epistolized (1 μM, 48 h) stimulated cytokine secretion (such as IFN-α, IFN-γ, IL-12, IL-6, and IL-2) and activated immune cells by increased expression of CD80, CD40, human leukocyte antigen (HLA)-DR and ICAM-1.
Besides, Lefitolimod (2.5 and 60 μg/day, i.p., daily for 7 days) raises IL-12p40 levels in mice sera but without toxicity (did not detect any increase of liver, spleen, or lymph node weight compared with PBS injection). It is also proved that Lefitolimod can induce HIV-specific immune responses and reverses latency in HIV patients.
In conclusion, Lefitolimod is a potent TLR9 agonist and an immune surveillance reactivator. It has the potential to research cancer and HIV-1.
1. Jin Y, et al. Expert Rev Anticancer Ther. 2021 Aug;21(8):841-851.
2. Schmidt M, et al. Nucleic Acid Ther. 2015 Jun;25(3):130-40.