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

Hutchings, C. J.

doi:10.1080/14712598.2020.1745770

Cited by 39 publications

(32 citation statements)

References 81 publications

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“…71 mAbs represent a promising alternative in GPCR drug discovery. 72,73 Over small molecules, mAbs possess obvious advantages of improved specificity, affinity, and other pharmacological properties. Thus they are being developed against cancers, inflammation, and metabolic disorders.…”

Section: Medicinal Chemistry Of Gpcr Agent Typementioning

confidence: 99%

G protein-coupled receptors: structure- and function-based drug discovery

Yang

Zhou

Labroska

et al. 2021

Sig Transduct Target Ther

365

280

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As one of the most successful therapeutic target families, G protein-coupled receptors (GPCRs) have experienced a transformation from random ligand screening to knowledge-driven drug design. We are eye-witnessing tremendous progresses made recently in the understanding of their structure–function relationships that facilitated drug development at an unprecedented pace. This article intends to provide a comprehensive overview of this important field to a broader readership that shares some common interests in drug discovery.

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Section: Medicinal Chemistry Of Gpcr Agent Typementioning

confidence: 99%

G protein-coupled receptors: structure- and function-based drug discovery

Yang

Zhou

Labroska

et al. 2021

Sig Transduct Target Ther

365

280

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“…The two approved GPCR antibody drugs, mogamulizumab and erenumab, both target the relatively large and stable N-terminal extracellular domain, but may not truly represent the full opportunity for anti-GPCR antibodies. 37,38 To address this challenge and increase the probability of identifying functional antibodies targeting GPCRs, we designed a synthetic human GPCR-focused antibody library. Modeled on natural GPCR receptor-ligand interactions, the library design takes into consideration all different types and orthologs of GPCR-binding motifs and incorporates over 150,000 of them into the antibody heavy chain CDR3.…”

Section: Discussionmentioning

confidence: 99%

Functional GLP-1R antibodies identified from a synthetic GPCR-focused library demonstrate potent blood glucose control

Liu

Garg

Hasdemir

et al. 2021

mAbs

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G protein-coupled receptors (GPCRs) are a group of seven-transmembrane receptor proteins that have proven to be successful drug targets. Antibodies are becoming an increasingly promising modality to target these receptors due to their unique properties, such as exquisite specificity, long half-life, and fewer side effects, and their improved pharmacokinetic and pharmacodynamic profiles compared to peptides and small molecules, which results from their more favorable biodistribution. To date, there are only two US Food and Drug Administration-approved GPCR antibody drugs, namely erenumab and mogamulizumab, and this highlights the challenges encountered in identifying functional antibodies against GPCRs. Utilizing Twist's precision DNA writing technologies, we have created a GPCR-focused phage display library with 1 × 10 10 diversity. Specifically, we mined endogenous GPCR binding ligand and peptide sequences and incorporated these binding motifs into the heavy chain complementarity-determining region 3 in a synthetic antibody library. Glucagon-like peptide-1 receptor (GLP-1 R) is a class B GPCR that acts as the receptor for the incretin GLP-1, which is released to regulate insulin levels in response to food intake. GLP-1 R agonists have been widely used to increase insulin secretion to lower blood glucose levels for the treatment of type 1 and type 2 diabetes, whereas GLP-1 R antagonists have applications in the treatment of severe hypoglycemia associated with bariatric surgery and hyperinsulinomic hypoglycemia. Here we present the discovery and creation of both antagonistic and agonistic GLP-1 R antibodies by panning this GPCR-focused phage display library on a GLP-1 R-overexpressing Chinese hamster ovary cell line and demonstrate their in vitro and in vivo functional activity.

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“…There are currently only two monoclonal antibodies against GPCRs, mogamulizumab and erenumab which target CCR4 and CGRP type 1 receptor respectively, approved by the Food and Drugs Administration (FDA) [27], [40], [41]. Around sixteen CCR6-CCL20 inhibitors have been investigated but to the date no therapeutic agents targeting CCR6 have progressed into clinical evaluation [5].…”

Section: Discussionmentioning

confidence: 99%

“…Antibodies against GPCRs offer an alternative to conventional small molecule drugs, that are often unsuccessful, and could provide valuable new treatment options [6]. Nevertheless, to date, there is no therapeutic antibody against hCCR6 approved [7] and develop an antagonizing monoclonal antibody (mAb) should be a potential alternative to conventional small molecule drugs and an effective strategy for the treatment of certain in ammatory and autoimmune diseases.…”

Section: Introductionmentioning

confidence: 99%

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Amino Terminal Recognition by a CCR6 Chemokine Receptor Antibody Blocks CCL20 Signaling and IL-17 Expression via β-arrestin

Gómez-Melero¹,

Garcı́a-Maceira²,

García-Maceira³

et al. 2021

Preprint

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Background: CCR6 chemokine receptor is an important target in inflammatory diseases. Th17 cells express CCR6 and a number of inflammatory cytokines, including IL-17 and IL-22, which are involved in the propagation of inflammatory immune responses. CCR6 antagonist would be a potential treatment for inflammatory diseases such as psoriasis or rheumatoid arthritis. The aim of this study is to develop an antagonistic monoclonal antibody (mAb) against human CCR6 receptor (hCCR6).Results: We generate monoclonal antibodies against hCCR6 immunizing Balb/c mice with hCCR6 overexpressing cells. The antibodies were tested by flow cytometry for specific binding to hCCR6, cloned by limiting dilution and resulted in the isolation and purification monoclonal antibody 1C6. By ELISA and flow cytometry, was determined that the antibody obtained binds to hCCR6 N-terminal domain. The ability of 1C6 to neutralize hCCR6 signaling was tested and we determined that 1C6 antibody were able to block response in β-arrestin recruitment assay with IC50 10.23 nM, but did not inhibit calcium mobilization. In addition, we found in a chemotaxis assay that 1C6 reduces the migration of hCCR6 cells to their ligand CCL20. Finally, we determined by RT-qPCR that the expression of IL-17A in Th17 cells treated with 1C6 was inhibited.Conclusions: In the present study, we applied whole cell immunization for successfully obtain an antibody that is capable to neutralize hCCR6 signaling and to reduce hCCR6 cells migration and IL-17 expression. These results provide an efficient approach to obtain therapeutic potential antibodies in the treatment of CCR6-mediated inflammatory diseases.

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

Cited by 39 publications

References 81 publications

G protein-coupled receptors: structure- and function-based drug discovery

G protein-coupled receptors: structure- and function-based drug discovery

Functional GLP-1R antibodies identified from a synthetic GPCR-focused library demonstrate potent blood glucose control

Amino Terminal Recognition by a CCR6 Chemokine Receptor Antibody Blocks CCL20 Signaling and IL-17 Expression via β-arrestin

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