G-protein coupled receptors (GPCRs) are important transmembrane proteins superfamily, accounting for 4% of the human genome. The structure of a GPCR typically consists of an extracellular N-terminus linked to seven α-helical transmembrane domains (TMDs) with an intracellular C-terminus. Within the TMD, several motifs are highly conserved with GPCR subfamilies, but the homology between these subfamilies is very limited.
GPCRs play key roles in tissue and cellular physiology, as well as homeostasis. They are implicated in various diseases, including cancer, immune-mediated inflammatory diseases, cardiovascular diseases, infectious diseases, neurological diseases, and metabolic diseases. Approximately 800 GPCRs are known, about 370 of which reveal drug targeting capabilities.
Currently, small-molecule drugs are developed to target only a limited proportion of GPCRs. Thus, receptors may be better targeted by antibody-based therapeutics rather than small molecules when given the size of the ligand-binding pocket. The mechanisms of action afforded by antibody-based therapeutics include antagonism (or blocking), agonism (or activating), receptor modulation, as well as other functional effects specifically mediated by the Fc region (such as complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cell-mediated phagocytosis (ADCP)).
In the field of drug development that targets GPCRs, antibodies have revealed unique advantages over small molecule drugs:
Drug discovery targeting GPCRs remains challenging. However, there are a number of startups that use innovative technology platforms to develop small molecules and therapeutic antibodies targeting challenging or previously undruggable GPCRs.
At Protheragen, we help out-license and find co-development opportunities for GPCR-targeted therapeutics in the early stages of development. If you are interested in any of these projects, please contact us for further discussion. We look forward to our collaboration.
|GPCR-targeted Project 001||Thyroid stimulating hormone receptor (TSHR)||Monoclonal antibody||Preclinical||Graves’ disease|
|GPCR-targeted Project 002||Sphingosine 1-phosphate receptor 1 (S1PR1)||Monoclonal antibody||Discovery||Autoimmune diseases; Inflammation|
|GPCR-targeted Project 003||R-spondin 3 (RSPO3)||Monoclonal antibody||Preclinical||Cancers|
|GPCR-targeted Project 004||Parathyroid hormone 1 receptor (PTH1R)||Monoclonal antibody||Preclinical||Hypercalcemia; Hyperparathyroidism|
|GPCR-targeted Project 005||Prokineticin receptor 1 (PKR1)||Monoclonal antibody||Preclinical||Inflammation|
|GPCR-targeted Project 006||Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5)||Monoclonal antibody||Preclinical||Colorectal cancer; Solid tumors|
|GPCR-targeted Project 007||Leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4); Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5)||Bispecific antibody||Preclinical||Solid tumors|
|GPCR-targeted Project 008||Gastrin releasing peptide receptor (GRPR)||Small molecule||Preclinical||Solid tumors|
|GPCR-targeted Project 009||G protein-coupled receptor 5D (GPRC5D); CD3||Monoclonal antibody||Preclinical||Multiple myeloma|
|GPCR-targeted Project 010||G-protein coupled receptor 20 (GPR20)||Antibody-drug conjugate||Discovery||Gastrointestinal stromal tumor|
|GPCR-targeted Project 011||G-protein coupled receptor G2A (GRP132)||Monoclonal antibody||Discovery||Pancreatic cancer|
|GPCR-targeted Project 012||Glucagon-like peptide-1 receptor (GLP-1R)||Monoclonal antibody||Preclinical||Hypoglycemia; Type 2 diabetes mellitus|
|GPCR-targeted Project 014||Glucagon receptor (GCGR)||Monoclonal antibody||Preclinical||Diabetes; Hyperglycemia|
|GPCR-targeted Project 015||Frizzled 8 (FZD8)||Monoclonal antibody||Discovery||Solid tumors|
|GPCR-targeted Project 016||Frizzled 7 (FZD7)||Monoclonal antibody||Preclinical||Cancers|
|GPCR-targeted Project 017||Frizzled 5 (FZD5)||Monoclonal antibody||Discovery||Ovarian cancer|
|GPCR-targeted Project 018||Frizzled 4 (FZD4)||Monoclonal antibody||Preclinical||Familial exudative vitreoretinopathy; Cancers|
|GPCR-targeted Project 019||Frizzled homologue 10 (FZD10)||Monoclonal antibody||Preclinical||Cancers|
|GPCR-targeted Project 020||Follicle-stimulating hormone receptor (FSHR)||Monoclonal antibody||Discovery||Infertility|
Protheragen is actively seeking partners to develop these GPCR-targeted therapeutics further. Potential collaboration can be a strategic alliance, licensing, or marketing agreement.