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Article ; Online: Mini-review: antibody therapeutics targeting G protein-coupled receptors and ion channels.

Hutchings, Catherine J

Antibody therapeutics

2020 Volume 3, Issue 4, Page(s) 257–264

Abstract: Antibodies are now well established as therapeutics with many additional advantages over small molecules and peptides relative to their selectivity, bioavailability, half-life and effector function. Major classes of membrane-associated protein targets ... ...

Abstract	Antibodies are now well established as therapeutics with many additional advantages over small molecules and peptides relative to their selectivity, bioavailability, half-life and effector function. Major classes of membrane-associated protein targets include G protein-coupled receptors (GPCRs) and ion channels that are linked to a wide range of disease indications across all therapeutic areas. This mini-review summarizes the antibody target landscape for both GPCRs and ion channels as well as current progress in the respective research and development pipelines with some example case studies highlighted from clinical studies, including those being evaluated for the treatment of symptoms in COVID-19 infection.
Language	English
Publishing date	2020-12-09
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2516-4236
ISSN (online)	2516-4236
DOI	10.1093/abt/tbaa023
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Article ; Online: A review of antibody-based therapeutics targeting G protein-coupled receptors: an update.

Hutchings, Catherine J

Expert opinion on biological therapy

2020 Volume 20, Issue 8, Page(s) 925–935

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 ... ...

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.
MeSH term(s)	Animals ; Antibodies, Monoclonal/immunology ; Antibodies, Monoclonal/therapeutic use ; Antibodies, Monoclonal, Humanized/immunology ; Antibodies, Monoclonal, Humanized/therapeutic use ; Clinical Trials as Topic ; Diabetes Mellitus, Type 1/drug therapy ; Diabetes Mellitus, Type 1/pathology ; Gastrointestinal Neoplasms/drug therapy ; Gastrointestinal Neoplasms/pathology ; HIV Antibodies/immunology ; HIV Antibodies/therapeutic use ; Humans ; Receptors, G-Protein-Coupled/chemistry ; Receptors, G-Protein-Coupled/immunology ; Receptors, G-Protein-Coupled/metabolism
Chemical Substances	Antibodies, Monoclonal ; Antibodies, Monoclonal, Humanized ; HIV Antibodies ; Receptors, G-Protein-Coupled ; erenumab (I5I8VB78VT) ; leronlimab (Y1J4NP8FF0) ; mogamulizumab (YI437801BE)
Keywords	covid19
Language	English
Publishing date	2020-04-08
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2052501-1
ISSN	1744-7682 ; 1471-2598
ISSN (online)	1744-7682
ISSN	1471-2598
DOI	10.1080/14712598.2020.1745770
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Article: A review of antibody-based therapeutics targeting G protein-coupled receptors: an update

Hutchings, Catherine J

Expert Opin Biol Ther

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: ...

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	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #42119
Database	COVID19

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Article ; Online: The Neutrophil Dynamic Mass Redistribution Assay as a Medium throughput Primary Cell Screening Assay.

Stott, Lisa A / la Rochelle, Armand Drieu / Brown, Susan / Osborne, Greg / Hutchings, Catherine J / Poulter, Simon / Bennett, Kirstie A / Barnes, Matt

The Journal of pharmacology and experimental therapeutics

2024 Volume 389, Issue 1, Page(s) 19–31

Abstract: In a typical G protein coupled receptor drug discovery campaign, an in vitro primary functional screening assay is often established in a recombinant system overexpressing the target of interest, which offers advantages with respect to overall throughput ...

Abstract	In a typical G protein coupled receptor drug discovery campaign, an in vitro primary functional screening assay is often established in a recombinant system overexpressing the target of interest, which offers advantages with respect to overall throughput and robustness of compound testing. Subsequently, compounds are then progressed into more physiologically relevant but lower throughput ex vivo primary cell assays and finally in vivo studies. Here we describe a dynamic mass redistribution (DMR) assay that has been developed in a format suitable to support medium throughput drug screening in primary human neutrophils. Neutrophils are known to express both CXC chemokine receptor (CXCR) 1 and CXCR2 that are thought to play significant roles in various inflammatory disorders and cancer. Using multiple relevant chemokine ligands and a range of selective and nonselective small and large molecule antagonists that block CXCR1 and CXCR2 responses, we demonstrate distinct pharmacological profiles in neutrophil DMR from those observed in recombinant assays but predictive of activity in neutrophil chemotaxis and CD11b upregulation, a validated target engagement marker previously used in clinical studies of CXCR2 antagonists. The primary human neutrophil DMR cell system is highly reproducible, robust, and less prone to donor variability observed in CD11b and chemotaxis assays and thus provides a unique, more physiologically relevant, and higher throughput assay to support drug discovery and translation to early clinical trials. SIGNIFICANCE STATEMENT: Neutrophil dynamic mass redistribution assays provide a higher throughput screening assay to profile compounds in primary cells earlier in the screening cascade enabling a higher level of confidence in progressing the development of compounds toward the clinic. This is particularly important for chemokine receptors where redundancy contributes to a lack of correlation between recombinant screening assays and primary cells, with the coexpression of related receptors confounding results.
MeSH term(s)	Humans ; Interleukin-8/metabolism ; Neutrophils ; Receptors, Chemokine ; Chemokines/metabolism ; Chemotaxis, Leukocyte/physiology ; Receptors, Interleukin-8B/metabolism ; Receptors, Interleukin-8A/metabolism
Chemical Substances	Interleukin-8 ; Receptors, Chemokine ; Chemokines ; Receptors, Interleukin-8B ; Receptors, Interleukin-8A
Language	English
Publishing date	2024-03-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	3106-9
ISSN	1521-0103 ; 0022-3565
ISSN (online)	1521-0103
ISSN	0022-3565
DOI	10.1124/jpet.123.001787
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Article ; Online: Discovery and design of G protein-coupled receptor targeting antibodies.

Peterson, Sean M / Hutchings, Catherine J / Hu, Cameron F / Mathur, Melina / Salameh, Janelle W / Axelrod, Fumiko / Sato, Aaron K

Expert opinion on drug discovery

2023 Volume 18, Issue 4, Page(s) 417–428

Abstract: Introduction: G protein-coupled receptors (GPCRs) are the target of one-third of all approved drugs; however, these drugs only target about one-eighth of the human repertoire of GPCRs. GPCRs regulate a diverse range of critical physiological processes ... ...

Abstract	Introduction: G protein-coupled receptors (GPCRs) are the target of one-third of all approved drugs; however, these drugs only target about one-eighth of the human repertoire of GPCRs. GPCRs regulate a diverse range of critical physiological processes including organ development, cardiovascular function, mood, cognition, multicellularity, cellular motility, immune responses and sensation of light, taste, and odor. However, many GPCRs are expressed poorly, and a significant proportion have unknown ligands and unclear signaling pathways. Areas covered: GPCRs are better suited to be targeted by monoclonal antibodies (mAbs) because of the challenges encountered in small-molecule discoveries such as druggability, selectivity, and distribution. mAbs have better drug-like properties in these respects. Herein, the authors review previously discovered functional mAbs that target GPCRs that are in the clinic and/or in development. They also review the biophysical considerations that make GPCRs so challenging to work with but also provide opportunities for biologic druggability. Expert opinion: GPCRs are proven targets of small molecules yet remain an under-represented target of biologics. We believe that antibody drugs that target GPCRs have the potential to unlock new therapeutic avenues and also uncover previously unappreciated receptor biology, particularly when harnessing next-generation biologic modalities.
MeSH term(s)	Humans ; Receptors, G-Protein-Coupled/metabolism ; Signal Transduction ; Antibodies, Monoclonal/pharmacology ; Ligands
Chemical Substances	Receptors, G-Protein-Coupled ; Antibodies, Monoclonal ; Ligands
Language	English
Publishing date	2023-03-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2259618-5
ISSN	1746-045X ; 1746-0441
ISSN (online)	1746-045X
ISSN	1746-0441
DOI	10.1080/17460441.2023.2193389
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Article ; Online: Ion channels as therapeutic antibody targets.

Hutchings, Catherine J / Colussi, Paul / Clark, Theodore G

mAbs

2018 Volume 11, Issue 2, Page(s) 265–296

Abstract: It is now well established that antibodies have numerous potential benefits when developed as therapeutics. Here, we evaluate the technical challenges of raising antibodies to membrane-spanning proteins together with enabling technologies that may ... ...

Abstract	It is now well established that antibodies have numerous potential benefits when developed as therapeutics. Here, we evaluate the technical challenges of raising antibodies to membrane-spanning proteins together with enabling technologies that may facilitate the discovery of antibody therapeutics to ion channels. Additionally, we discuss the potential targeting opportunities in the anti-ion channel antibody landscape, along with a number of case studies where functional antibodies that target ion channels have been reported. Antibodies currently in development and progressing towards the clinic are highlighted.
MeSH term(s)	Animals ; Antibodies/chemistry ; Antibodies/pharmacology ; Drug Development/methods ; Drug Discovery/methods ; Humans ; Ion Channels/antagonists & inhibitors
Chemical Substances	Antibodies ; Ion Channels
Language	English
Publishing date	2018-12-10
Publishing country	United States
Document type	Journal Article ; Review
ISSN	1942-0870
ISSN (online)	1942-0870
DOI	10.1080/19420862.2018.1548232
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Article ; Online: Opportunities for therapeutic antibodies directed at G-protein-coupled receptors.

Hutchings, Catherine J / Koglin, Markus / Olson, William C / Marshall, Fiona H

Nature reviews. Drug discovery

2017 Volume 16, Issue 9, Page(s) 661

Language	English
Publishing date	2017-09-01
Publishing country	England
Document type	Journal Article
ZDB-ID	2062954-0
ISSN	1474-1784 ; 1474-1776
ISSN (online)	1474-1784
ISSN	1474-1776
DOI	10.1038/nrd.2017.173
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Article ; Online: A South-to-South Cultural Adaptation of an Evidence-Based Parenting Program for Families in the Philippines.

Mamauag, Bernice Landoy / Alampay, Liane Peña / Lachman, Jamie M / Madrid, Bernadette J / Hutchings, Judy / Ward, Catherine L / Gardner, Frances

Family process

2021 Volume 60, Issue 4, Page(s) 1202–1216

Abstract: Rates of child maltreatment are higher in low- and middle-income countries due to risk factors such as social inequities, economic adversity, and sociocultural norms. Given the evidence showing the effectiveness of parenting interventions to prevent ... ...

Abstract	Rates of child maltreatment are higher in low- and middle-income countries due to risk factors such as social inequities, economic adversity, and sociocultural norms. Given the evidence showing the effectiveness of parenting interventions to prevent child maltreatment, this study embarked on a cultural adaptation of an evidence-based parenting program with the eventual goal of integrating it within a nationwide conditional cash transfer program for low-income Filipino parents with children aged 2-6 years. We document the systematic adaptation of the Parenting for Lifelong Health for Young Children program that was developed and tested in South Africa, for low-resource Filipino families using the heuristic framework for the cultural adaptation of interventions. We underscore the merits of conducting a multistage top-down and bottom-up process that uses a participatory approach among cultural insiders and outsiders to develop a parenting intervention that reflects the contextual realities and cultural values of end users. The adapted program, Masayang Pamilya Para sa Batang Pilipino, is the product of a delicate and deliberate effort to balance Filipino childrearing goals and values with the scientific evidence on components of parenting interventions known to promote positive parenting and prevent child maltreatment.
MeSH term(s)	Child ; Child Abuse/prevention & control ; Child, Preschool ; Humans ; Parenting ; Parents ; Philippines ; Poverty
Language	English
Publishing date	2021-01-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	212740-4
ISSN	1545-5300 ; 0014-7370
ISSN (online)	1545-5300
ISSN	0014-7370
DOI	10.1111/famp.12625
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Article ; Online: Opportunities for therapeutic antibodies directed at G-protein-coupled receptors.

Hutchings, Catherine J / Koglin, Markus / Olson, William C / Marshall, Fiona H

Nature reviews. Drug discovery

2017 Volume 16, Issue 9, Page(s) 787–810

Abstract: G-protein-coupled receptors (GPCRs) are activated by a diverse range of ligands, from large proteins and proteases to small peptides, metabolites, neurotransmitters and ions. They are expressed on all cells in the body and have key roles in physiology ... ...

Abstract	G-protein-coupled receptors (GPCRs) are activated by a diverse range of ligands, from large proteins and proteases to small peptides, metabolites, neurotransmitters and ions. They are expressed on all cells in the body and have key roles in physiology and homeostasis. As such, GPCRs are one of the most important target classes for therapeutic drug discovery. The development of drugs targeting GPCRs has therapeutic value across a wide range of diseases, including cancer, immune and inflammatory disorders as well as neurological and metabolic diseases. The progress made by targeting GPCRs with antibody-based therapeutics, as well as technical hurdles to overcome, are presented and discussed in this Review. Antibody therapeutics targeting C-C chemokine receptor type 4 (CCR4), CCR5 and calcitonin gene-related peptide (CGRP) are used as illustrative clinical case studies.
MeSH term(s)	Animals ; Antibodies, Monoclonal/pharmacology ; Antibodies, Monoclonal/therapeutic use ; Drug Discovery/methods ; Humans ; Molecular Targeted Therapy/methods ; Receptors, G-Protein-Coupled/antagonists & inhibitors ; Receptors, G-Protein-Coupled/physiology
Chemical Substances	Antibodies, Monoclonal ; Receptors, G-Protein-Coupled
Language	English
Publishing date	2017-07-14
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2062954-0
ISSN	1474-1784 ; 1474-1776
ISSN (online)	1474-1784
ISSN	1474-1776
DOI	10.1038/nrd.2017.91
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Article ; Online: Nanoalloy magnetic and optical properties, applications and structures: general discussion.

Aikens, Christine M / Alloyeau, Damien / Amendola, Vincenzo / Amiens, Catherine / Andreazza, Pascal / Bakker, Joost M / Baletto, Francesca / Barcikowski, Stephan / Barrabés, Noelia / Bowker, Michael / Chen, Fuyi / Daniel, Isaac T / Ernst, Wolfgang E / Ferrando, Riccardo / Ferrari, Piero / Fortunelli, Alessandro / Grandjean, Didier / Guesmi, Hazar / Hutchings, Graham J /

Janssens, Ewald / Jones, Robert M / Jose Yacaman, Miguel / Kuttner, Christian / Lopez, Maria J / Marceau, Éric / Mariscal, Marcelo M / McGrady, John / Mottet, Christine / Nelayah, Jaysen / Owen, Cameron J / Polak, Micha / Quinson, Jonathan / Roncaglia, Cesare / Schäfer, Rolf / Svensson, Rasmus / Treguer-Delapierre, Mona / Zhang, Yufei

Faraday discussions

2023 Volume 242, Page(s) 389–417

Language	English
Publishing date	2023-01-31
Publishing country	England
Document type	Congress
ISSN	1364-5498
ISSN (online)	1364-5498
DOI	10.1039/d2fd90087d
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