Oral Selective TLR8 Agonist Selgantolimod Induces Multiple Immune Cell Responses in Humans

Abstract

TLR8 agonists have the potential for use as immunomodulatory components in therapeutic modalities for viral infections such as chronic HBV (CHB) and HIV. In this study, using peripheral blood samples from a phase 1a clinical trial, we examined the acute effects of a single oral administration of a selective TLR8 agonist on immune cell phenotypes. Administration of the TLR8 agonist selgantolimod (SLGN) in healthy individuals resulted in alteration in frequencies of peripheral blood monocytes, pDCs, mDCs and MAIT cells. Frequencies of mDCs and lymphoid cells significantly reduced after 8 h of SLGN administration, whereas pDC frequencies significantly increased, with changes possibly reflecting migration of different cell types between peripheral and tissue compartments in response to the agonist. Myeloid cell activation was evident by an upregulated expression of co-stimulatory molecules CD40 and CD86 accompanied by the production of IL-6 and IL-18 from these cells. Concomitantly, there was induction of the early activation marker CD69 on innate and adaptive lymphoid cells, including MAIT and NK cell subsets. Further, these activated lymphoid cells had enhanced expression of the effector molecules granzyme B and perforin. Microarray analysis of isolated lymphocytes and monocytes from baseline and post-SLGN treatment revealed changes in expression of genes involved in cellular response to cytokine stimulus, innate immune response, myeloid cell differentiation and antigen receptor-mediated signaling pathway. In a preliminary analysis of samples from CHB patients treated with selgantolimod, activation of innate and adaptive lymphocytes was evident. In conclusion, this first in-human study shows that selgantolimod administration in humans results in activation of multiple immune cell responses with antiviral potential.

Targeting toll-like receptor 7/8 for immunotherapy: recent advances and prospectives

“…Myeloid cell activation was evident by the upregulated expression of co-stimulatory molecules CD40 and CD86, accompanied by the production of IL-6 and IL-18 from these cells. Concomitantly, there was induction of the early activation marker CD69 on innate and adaptive lymphoid cells and enhanced expression of the effector molecules granzyme B and perforin [175]. Furthermore, the phase Ia study also showed that the single doses of up to 5 mg GS-9688 were safe and induced dose-dependent pharmacodynamics responses [176].…”

Oligonucleotide-Based Therapies for Chronic HBV Infection: A Primer on Biochemistry, Mechanisms and Antiviral Effects

“…These immunostimulatory activities have been attributed to TLR8 based on studies in mice but mice do not accurately model TLR reactivity in humans (Table 1) and this finding is at odds with the well understood biochemical properties of oligonucleotides: TLR8 reacts to unmodified ssRNA and TLR reactivity to TLR7/8 is well shielded by 2 MOE modification in bepirovirsen. Moreover, the oral TLR8 antagonist selgantolimod (GS-9688) did not elicit any HBsAg responses in human infection [149] despite clear immunostimulatory effects [149,150].…”

Advances in discovery of novel investigational agents for functional cure of chronic hepatitis B: A comprehensive review of phases II and III therapeutic agents

“…Selgantolimod (GS-9688): Selgantolimod is a selective TLR-8 agonist with antiviral activity against chronic HBV infection. It leads to the production of proinflammatory cytokines, chemokines, and interferons that initiate an innate and adaptive immune response against HBV[ 66 ].…”