GPRC5D is a protein found on the surface of cells, belonging to a large family called G protein-coupled receptors (GPCRs). These receptors act like cellular antennae, receiving signals from outside the cell and relaying them inward. This internal signal relay is fundamental for a wide array of cellular activities, maintaining normal function.
Understanding GPRC5D
GPRC5D is classified as an orphan G protein-coupled receptor, meaning its natural activating molecule, or ligand, has not yet been definitively identified. Despite this, it is known to be a member of the Class C GPCR family, which typically feature a distinctive large extracellular domain. However, GPRC5D, along with a few other related receptors, forms a unique subgroup within Class C, characterized by shorter extracellular domains.
In healthy human tissues, GPRC5D exhibits a remarkably restricted and low expression pattern. It is primarily found in hard keratinized tissues, such as hair follicles, the epithelial cells of eccrine sweat glands, and the filiform papillae of the tongue. Beyond these specialized tissues, its protein expression is observed in interstitial plasma cells, which are a type of immune cell. While its precise normal physiological function is still under investigation, studies suggest a role in hard keratin expression and potentially in the development of hair and nails.
GPRC5D and Disease
The pathological role of GPRC5D becomes particularly evident in certain diseases, most notably multiple myeloma (MM), a type of blood cancer. In individuals with MM, GPRC5D is significantly overexpressed on the surface of cancer cells compared to healthy cells. Elevated GPRC5D mRNA expression in MM patients has been linked to a higher plasma cell burden and aggressive disease, suggesting its involvement in disease progression.
The presence of GPRC5D on malignant cells makes it a promising marker for monitoring tumor load in MM patients. The overexpression of GPRC5D in the bone marrow of MM patients has also been associated with a less favorable prognosis. Furthermore, GPRC5D expression on MM cells is independent of other known myeloma targets like BCMA, which can be lost during treatment, thereby offering an alternative target for therapeutic intervention.
Therapeutic Targeting of GPRC5D
The selective and high expression of GPRC5D on multiple myeloma cells, with limited expression in most healthy tissues, makes it an attractive target for therapeutic interventions. Researchers are actively developing innovative strategies that specifically target GPRC5D to eliminate cancer cells.
One prominent therapeutic approach is GPRC5D-directed CAR T-cell therapy. In this method, a patient’s own T cells are genetically engineered in a laboratory to express a chimeric antigen receptor (CAR) that specifically recognizes and binds to GPRC5D on the surface of myeloma cells. Once infused back into the patient, these modified CAR T cells locate and attach to the GPRC5D-expressing cancer cells, leading to T-cell activation and the subsequent destruction of the malignant cells. Early clinical trials of GPRC5D-targeted CAR T cells have demonstrated promising efficacy, even in patients who have previously undergone other treatments.
Another innovative strategy involves the use of bispecific antibodies that target GPRC5D. These specially engineered antibodies have two binding sites: one that attaches to GPRC5D on the myeloma cell and another that binds to CD3, a protein found on the surface of T cells. By simultaneously binding to both the cancer cell and the T cell, these bispecific antibodies effectively bring the patient’s own immune T cells into close proximity with the GPRC5D-expressing myeloma cells. This proximity triggers T-cell activation and directs the immune system to attack and eliminate the cancer cells. Talquetamab and forimtamig are examples of GPRC5D-targeting bispecific antibodies that have shown considerable promise in clinical trials for multiple myeloma, with talquetamab having already received accelerated approval.