Small molecule agonists of toll-like receptors 7 and 8: a patent review 2014 – 2020

ABSTRACT

Introduction

Toll-like receptors 7 and 8 (TLR7 and TLR8) are endosomal immune receptors that initiate an innate immune response and can facilitate activation of the adaptive immune system. Both preclinical and clinical studies have shown the downstream inflammatory response from TLR7 and TLR8 agonism results in preliminary efficacy for the treatment of cancer, viral infections, and for use as a vaccine adjuvant.

Areas covered

This patent review covers recent developments in small molecule TLR7 and TLR8 agonists published between January 2014 – February 2020. We summarize relevant chemical scaffolds, observed structure-activity relationships, and where available, preliminary animal models, and clinical data.

Expert opinion

In the last 6 years, there has been significant progress in the optimization of novel TLR7 and TLR8 small molecule agonists. These novel compounds are currently being evaluated in the clinic for multiple antiviral and oncology indications. Clinical data from these trials will provide a clearer outlook on 1) the TLR7/8 engagement necessary to obtain the desired immune response, 2) safety margin improvement using directed delivery, and 3) potential synergistic effects with checkpoint inhibitor combination therapies.

KEYWORDS:

• Hepatitis B
• immuno-oncology
• innate immune activation
• toll-like receptor 7
• toll-like receptor 8

Article highlights

• TLRs help activate the body’s immune defenses through recognition of various pathogenic and damage-associated molecular fragments.

• TLRs are implicated in several immune-related or inflammatory diseases. The ability to modulate TLR activity is a potential avenue for treatment.

• TLR agonist development is fraught with inflammation-associated side effects, as is the case with imiquimod, an approved TLR7 agonist.

• Numerous groups have recently reported TLR7 and TLR8 agonists that are potent and demonstrate efficacy in preclinical disease models. Their use in antibody-drug conjugates and in combination therapies is an area of active interest to improve efficacy and safety.

• Several Phase I and II clinical trials using new TLR7 and TLR8 agonists for antiviral and oncology indications are ongoing.

Declaration of interest

ME Kieffer, WM Seganish, AM Patel and SA Hollingsworth are employees of Merck and Co. Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by Merck and Co. Inc.