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Published on: July 26, 2017

A single, oral dose of the TLR7 agonist JNJ-64794964 induces transcriptomic and phenotypic changes in peripheral

Wim Pierson¹, Marianne Tuefferd¹, Florence Herschke¹

¹Janssen Pharmaceutica NV, Beerse, Belgium.

Antiviral Therapy

|May 18, 2023

Insights

The investigational drug JNJ-4964, a toll-like receptor-7 (TLR7) agonist, activates natural killer (NK) and B cells in healthy volunteers. These immune changes, linked to interferon-alpha, may serve as biomarkers for chronic hepatitis B treatment.

Area of Science:

Immunology
Pharmacology
Virology

Background:

Chronic hepatitis B (CHB) presents a significant global health burden with limited therapeutic options.
Achieving a cure for CHB remains a major challenge in clinical practice.
JNJ-64794964 (JNJ-4964) is an orally administered toll-like receptor-7 (TLR7) agonist under investigation for CHB treatment.

Purpose of the Study:

To assess the transcriptomic and immune cell alterations induced by JNJ-4964 in healthy individuals.
To explore the correlation between JNJ-4964 exposure, cytokine induction, and immune cell modulation.

Main Methods:

A first-in-human Phase 1 clinical trial was conducted.
Peripheral blood samples were collected at multiple time points post-administration.
Transcriptomic analysis and flow cytometry were used to evaluate immune cell frequency and phenotype.
Correlations with JNJ-4964 exposure (Cmax) and cytokine levels (CXCL10, IFN-α) were analyzed.

Main Results:

JNJ-4964 administration upregulated 59 genes, primarily interferon-stimulated genes.
Increased frequencies of activated natural killer (NK) cells (expressing CD69, CD134, CD137, CD253) and B cells (expressing CD86) were observed.
Immune changes correlated with JNJ-4964 exposure and interferon-alpha (IFN-α) induction, occurring at acceptable levels for adverse events.

Conclusions:

JNJ-4964 modulates transcriptional profiles and activates immune cells, notably NK and B cells.
These observed immune responses may serve as potential biomarkers for evaluating TLR7 agonist efficacy in CHB patients.
The findings provide insights into the immunomodulatory effects of JNJ-4964 relevant to CHB therapy.

Read full analysis

Abstract

Background:

Chronic hepatitis B (CHB) is responsible for major disease burden worldwide. However, the number of available therapies is limited; cure remains an elusive goal. JNJ-64794964 (JNJ-4964) is an oral toll-like receptor-7 (TLR7) agonist being evaluated for the treatment of CHB. Here, we investigated the capacity of JNJ-4964 to induce transcriptomic and immune cell changes in peripheral blood in healthy volunteers.

Methods:

Peripheral blood was collected in the JNJ-4964 first-in-human phase 1 trial at multiple time points to assess transcriptomics and changes in frequency and phenotype of peripheral-blood mononuclear cells. Correlation of changes to JNJ-4964 exposure (C_max) and changes in cytokine levels (C-X-C motif chemokine ligand 10 [CXCL10] and interferon alpha [IFN-α]) were evaluated.

Results:

Fifty-nine genes, mainly interferon-stimulated genes, were up-regulated between 6 hours and 5 days after JNJ-4964 administration. JNJ-4964 increased frequencies of CD69, CD134, CD137, and/or CD253-expressing natural killer (NK) cells, indicative of NK cell activation. These changes correlated with C_max, increase of CXCL10, and induction of IFN-α and were observed at IFN-α levels that are associated with no/acceptable flu-like adverse events. JNJ-4964 administration resulted in increased frequencies of CD86-expressing B cells, indicative of B-cell activation. These changes were predominantly observed at high IFN-α levels, which are associated with flu-like adverse events.

Conclusions:

JNJ-4964 administration led to changes in transcriptional profiles and immune cell activation phenotype, particularly for NK cells and B cells. Together, these changes could represent a set of biomarkers for the characterization of the immune response in CHB patients receiving TLR7 agonists.

Keywords:

Chronic hepatitis B JNJ-4964 TLR7 agonist immune cells transcriptomics

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