G protein-coupled receptors (GPCRs) are a large family of proteins that play important roles in human health and disease. Roughly one third of all approved medicines work by targeting a GPCR however, historically none of these medicines have been monoclonal antibodies.
Recent advances in antibody technologies have seen a surge of GPCR directed biopharmaceuticals being developed and tested, leading to the first approvals of GPCR directed monoclonal antibodies. Here we review the background to GPCRs and the development status of GPCR targeting biopharmaceuticals.
GPCRs bind a wide variety of signalling molecules in the body including hormones, growth factors and other endogenous molecules yet they all share a common structure.
GPCRs consist of a single polypeptide chain that is folded into a globular shape and embedded in a cell’s plasma membrane. Seven segments of this molecule span the width of the membrane (thus GPCRs are sometimes called seven-transmembrane receptors).
The sequences between transmembrane domains loop inside or outside the cell and the extracellular loops form sites at which signalling molecules bind to the GPCR. The binding of a ligand to a GPCR occurs at an exposed extracellular site and can induce a conformational change in the receptor.
This change in protein conformation can change the coupling of the receptor to G proteins and other proteins in the cytoplasm that can drive intracellular signal transduction.
Image Source: Click Here © 2002-2024 Nature Publishing Group Li, J. et al. The Molecule Pages database. Nature 420, 716-717 (2002). All rights reserved.
G proteins cross the cell membrane seven times. In unstimulated cells, the state of G alpha (orange circles) is bound with GDP, G beta-gamma (purple circles), and a G-protein-coupled receptor (GPCR; light green loops). Upon receptor stimulation by a ligand the state of the receptor changes. G alpha dissociates from the receptor and G beta-gamma, and GTP is exchanged for the bound GDP, which leads to G alpha activation. G alpha then goes on to activate other molecules in the cell. Image credit: Li, J. et al. The Molecule Pages database. Nature 420, 716-717 (2002).
GPCRs regulate a range of cellular processes that are critical for cancer including cellular proliferation, chemo-resistance, self-renewal, apoptosis, stress signalling, immune evasion, invasion, angiogenesis and metastasis. GPCRs can regulate many intracellular signal transduction pathways relevant to cancer cells including EGFR/Ras (proliferation), ATF4/CHOP (cellular stress), chemokine (metastasis) and p53 (apoptosis) mediated signalling.
From analysis of cancer genomes, it is suggested that GPCR mutations are found in about 20 percent of all cancers. GPCRs have been largely overlooked in oncology drug discovery efforts as this mutation rate is less frequent compared to other oncology pathways. Currently however there is increased interest in the idea that pharmacological targeting of GPCRs could provide an opportunity to block tumorigenic signals.
Because GPCRs play such a wide variety of roles in the body, further therapeutic areas in which GPCRs are relevant to include psychiatric disorders, diabetes and obesity, cardiometabolic disorders, irritable bowel syndrome, graves’ disease, migraine, inflammation, hypertension, neuropathic pain and chronic infection.
Despite the wider success of monoclonal antibodies in the clinic, the development of GPCR targeting antibodies has so far been limited by the many technical challenges presented particularly by GPCRs. For example, the conformation of the GPCR extracellular region is highly variable and the exposed area of the GPCR extracellular epitopes is limited, preparation of homogeneous functional GPCR antigens is difficult and it is not easy to develop efficient antibody screening tools.
However, recent advances in the development of antibody isolation technologies and the understanding of GPCR structure and function has delivered the first success in overcoming these hurdles, leading to the first GCPR targeted antibodies achieving marketing approval. In oncology, talquetamab is a GPRC5D targeting bispecific antibody approved for treatment of multiple myeloma, and mogamulizumab is a CCR4 targeting antibody approved for the treatment of szeary syndrome. In addition, erenumab which targets the calcitonin G related peptide receptor has been approved for the treatment of migraine.
In addition to the three medicines already achieving marketing approval there are many GPCR targeting biopharmaceuticals in development and trials. Examples of products currently in clinical trials are given in the table below and there are dozens more in earlier stages of development. These clinical trials will validate GPCRs as therapeutic targets and deliver new treatments in the years to come.
GLP-1R is the glucagon-like peptide 1 receptor, ETA is the endothelin receptor A, GCGR is the glucagon receptor, C5AR1 is a receptor for complement C5A, FZD are frizzled receptors, CCR8 is a chemokine receptor, IND (investigational new drug) clearance allows clinical trials to begin.
Improvements in antibody technologies have seen G-protein coupled receptors become a tractable target for biopharmaceutical therapies such as monoclonal antibodies. This opens a massive opportunity for drug development in several therapeutic areas.
GPCRs are already the target of a third of all approved medicines yet these drugs currently target roughly one tenth of the GPCR family of proteins, suggesting many more therapeutic targets exist. The development of GPCR targeted biopharmaceuticals will lead to new treatments for an array of diseases and the three molecules already approved represent the tip of an iceberg.
Richard brings over 20 years of industry experience into work every day to make sure Bath ASU pursues innovation and is a business Where patients come first.
I have worked at Bath ASU for nine years now. I started as a research scientist, designing and implementing assays (measuring biochemical or immunological activity) of protein-based medicines, mostly MABs (monoclonal antibodies).
I am now Principal Scientist, which involves coordinating the efforts of the team to deliver stability studies, making sure the lab runs safely and effectively, and occasionally getting my head up to try and understand what’s coming up next.
