Telratolimod (MEDI 9197) is an effective agonist for toll-like receptor 7 (TLR-7) and toll-like receptor 8 (TLR-8) [1]. TLR is a type of protein that recognizes pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), and is involved in the regulation of the innate immune system [2]. Telratolimod has anti-tumor activity [3].
In vitro, Telratolimod (3μM) stimulated human peripheral blood mononuclear cells (PBMCs) in the culture medium for 24 hours, promoting the production of high levels of Th1-type cytokines, namely IFNγ and IL-12 p70. Telratolimod can inhibit the release of IL-5 by PBMCs stimulated by phytohemagglutinin, thereby causing the deviation of the polyclonal immune response from the Th2 phenotype [3].
In vivo, administration of radiolabeled Telratolimod (0.1, 0.3, and 1mg/kg; single SC injection) in rats showed that Telratolimod induced very low levels of systemic serum TNF-α. Radiolabeled Telratolimod could be detected in plasma and whole blood for at least 14 days and remained at the injection site for at least 28 days. In the mouse melanoma model, a single IT administration of Telratolimod (20μg) could increase the percentage of tumor-infiltrating lymphocytes (TIL), enhance T cell activation, and lead to a qualitative transformation from single-cell factor production to double-cell factor production (IFN-γ and tumor necrosis factor α, TNF-α) [3].
References:
[1] Zhao BG, Vasilakos JP, Tross D, Smirnov D, Klinman DM. Combination therapy targeting toll like receptors 7, 8 and 9 eliminates large established tumors. J Immunother Cancer. 2014 May 13;2:12.
[2] Federico S, Pozzetti L, Papa A, et al. Modulation of the innate immune response by targeting toll-like receptors: a perspective on their agonists and antagonists[J]. Journal of Medicinal Chemistry, 2020, 63(22): 13466-13513.
[3] Mullins S R, Vasilakos J P, Deschler K, et al. Intratumoral immunotherapy with TLR7/8 agonist MEDI9197 modulates the tumor microenvironment leading to enhanced activity when combined with other immunotherapies[J]. Journal for immunotherapy of cancer, 2019, 7: 1-18.
Telratolimod (MEDI 9197)是一种有效的toll-like receptor 7（TLR-7）和toll-like receptor 8（TLR-8）的激动剂 [1]。TLR是一类识别病原体相关分子模式（PAMPs）和损伤相关分子模式（DAMPs）的蛋白质，参与先天免疫系统的调节 [2]。Telratolimod具有抗肿瘤活性[3]。
在体外, Telratolimod（3μM）在培养基中刺激人类外周血单个核细胞（human PBMCs）24h，促使其产生了高水平的Th1类细胞因子，即IFNγ和IL-12 p70。Telratolimod能抑制由植物血凝素刺激的PBMCs释放IL-5，从而导致多克隆免疫反应偏离Th2型表型[3]。
在体内，在大鼠中施用放射性标记的Telratolimod（0.1、0.3和1mg/kg；单次皮下注射）显示，Telratolimod诱导非常低水平的全身血清TNFα水平。放射性标记的Telratolimod在血浆和全血中可检测到至少14天，保留在注射部位至少28天。在B16-F10 AP 3小鼠黑素瘤模型中，Telratolimod单次IT给药（20μg）可增加肿瘤浸润淋巴细胞（TIL）的百分比，增强T细胞的活化，并导致从单细胞因子产生到双细胞因子产生（IFN-γ和肿瘤坏死因子α，TNF-α）的定性转变[3]。