G-protein-coupled receptors (GPCRs) are activated by a diverse range of ligands ranging from large proteins and proteases to small peptides, metabolites, neurotransmitters and ions. They are expressed on all cells in the body and play key parts 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 immune and inflammatory disorders, cancer and 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.
Advances in our understanding of GPCR biology in oncology, notably immuno-oncology, have made remarkable gains in recent years and facilitated further opportunities for strategic targeting either as stand-alone or combination therapies.
Many technical hurdles are still present but are not insurmountable given developments in stabilizing receptors using mutagenesis or additives as well as methods to overexpress receptors. These advances, combined with powerful high-throughput screening systems and an in-depth understanding of GPCR structure, biology and clinical relevance are enabling the knowledge necessary to overcome technical bottlenecks in GPCR antibody drug discovery and development.
It is also noticeable that the application of next-generation protein therapeutics, such as bispecifics and antibody–drug conjugates, to GPCR targets is gaining momentum.
Antibody therapeutics targeting C-C chemokine receptor type 4 (CCR4), CCR5 and calcitonin gene-related peptide (CGRP) are used as illustrative clinical case studies.
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.
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The authors thank B. Tehan (Heptares Therapeutics) for his assistance in compiling figure 1.
C.J.H. is a shareholder and owns stock options of Heptares Therapeutics and Sosei Group, and has provided consultancy services to Heptares Therapeutics, TetraGenetics, Crescendo Biologics, Abcam, Tusk Therapeutics and xCella Biosciences. M.K. and F.H.M. are employees, shareholders and hold stock options of Heptares Therapeutics and Sosei Group. W.C.O. is an employee, a shareholder and holds stock options of Regeneron Pharmaceuticals.
- Antibody-dependent cellular cytotoxicity
(ADCC). A mechanism of cell death that forms part of the humoral immune response, is mediated by the crystallizable fragment (Fc) region of an antibody and is isotype-dependent. In ADCC, an effector cell of the immune system (such as a natural killer cell, macrophage, neutrophil or eosinophil) actively lyses a target cell whose membrane surface antigens have been bound by specific antibodies. The Fc receptor on the immune cell binds to the Fc portion of the antibody.
- Complement-dependent cytotoxicity
(CDC). A mechanism of cell death that is mediated by the crystallizable fragment (Fc) region of an antibody. This is a function of the complement system and is initiated by C1q binding. CDC kills pathogens by damaging their membranes and is one of the mechanisms by which antibodies can have an antitumour effect.
- Antibody-dependent cellular phagocytosis
(ADCP). This is a key effector function that is mediated by the crystallizable fragment (Fc) region. It is increasingly becoming important in antibody development and relies on macrophages to attack and assimilate tumour cells following antibody binding.
- Antibody–drug conjugates
(ADCs). These are composed of an antibody that is linked to a toxic payload or drug and form an important modality for the treatment of cancer.
These are compounds that are formed by the joining of smaller, usually repeating, amphiphilic polymers linked by covalent bonds. They are used to make membrane proteins water-soluble by trapping them with polymers rather than detergents.
Genetically identical, or sufficiently identical, and immunologically compatible as to allow for transplantation. In this context, it refers to the use of syngenic cells of the animal to overexpress the target and then transfer the transfected cells back into the animal as a broader species-related approach rather than an individual approach.
- Hybridoma technology
This technology is a means of immortalizing an antibody-producing B cell by fusing it with a cell that is derived from a myeloma cell line to generate large amounts of antibody. However, hybridoma cell lines can be notoriously unstable.
- Single-domain antibody
A single-domain antibody is the smallest antibody-derived binding structure based on the separate variable domains of an IgG molecule and is monomeric in nature.
A biparatopic antibody is a type of bispecific antibody that is bivalent and directed against two different non-overlapping epitopes on the same target antigen molecule.
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Hutchings, C., Koglin, M., Olson, W. et al. Opportunities for therapeutic antibodies directed at G-protein-coupled receptors. Nat Rev Drug Discov 16, 787–810 (2017). https://doi.org/10.1038/nrd.2017.91
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