A review of antibody-based therapeutics targeting G protein-coupled receptors: an update

ABSTRACT

Introduction

G protein-coupled receptors (GPCRs) play key roles in many biological functions and are linked to many diseases across all therapeutic areas. As such, GPCRs represent a significant opportunity for antibody-based therapeutics.

Areas covered

The structure of the major GPCR families is summarized in the context of choice of antigen source employed in the drug discovery process and receptor biology considerations which may impact on targeting strategies. An overview of the therapeutic GPCR-antibody target landscape and the diversity of current therapeutic programs is provided along with summary case studies for marketed antibody drugs or those in advanced clinical studies. Antibodies in early clinical studies and the emergence of next-generation modalities are also highlighted.

Expert opinion

The GPCR-antibody pipeline has progressed significantly with a number of technical developments enabling the successful resolution of some of the challenges previously encountered and this has contributed to the growing interest in antibody-based therapeutics addressing this target class.

KEYWORDS:

• Erenumab
• G protein-coupled receptor
• GPCR
• leronlimab
• mogamulizumab
• monoclonal antibody
• mAb

Article highlights

• GPCRs are implicated in many diseases and present valuable opportunities for targeting with mAbs and other antibody-based therapeutics

• Significant progress has been made in the generation of functional GPCR-targeting mAbs for therapeutic applications over the past decade where two-thirds of the GPCR-antibody pipeline are directed to Family A GPCRs (half of which are chemokine receptors)

• There are now two mAbs approved in the US and EU (mogamulizumab and erenumab) with a third mAb (leronlimab) that is anticipated to attain FDA approval in 2020

• Many GPCR-targeting antibodies are now in early clinical studies in addition to the emergence of next-generation modalities, such as alternative scaffolds, bispecific antibodies, antibody-drug conjugates (ADCs), and chimeric antigen receptor T-cell therapy (CAR-T), as successful targeting strategies

This box summarizes the key points contained in the article.

Declaration of interest

CJ Hutchings has provided or is currently providing consulting services as an independent consultant to Abilita Bio, DJS Antibodies, Kyowa Kirin Pharmaceutical Research, Heptares Therapeutics, Twist Biopharma, and xCella Biosciences; and is a shareholder of Heptares Therapeutics. The author has 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 apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded.