What are the therapeutic candidates targeting GPRC5D?

Overview of GPRC5D
Biological Role and Significance
GPRC5D is an orphan G protein‐coupled receptor (GPCR) that belongs to the class C group 5 family. Unlike many other cell‐surface proteins, its endogenous ligand is yet to be determined, which contributes to its elusive role in physiological signaling. It is predominantly expressed on certain specialized tissues such as hair follicles and in hard keratinized tissues, with relatively low expression in most normal cells. This restricted normal tissue expression pattern reduces the risk of on‐target/off‐tumor toxicity when the receptor is therapeutically targeted. In addition, as a seven‐pass transmembrane protein, GPRC5D does not shed into the serum—unlike targets such as BCMA—thus making it a more stable marker on malignant cells.

Current Understanding in Disease Context
In multiple myeloma (MM), GPRC5D is expressed on malignant plasma cells, with expression levels correlating with higher tumor burden and a poorer prognosis. Its expression is independent of BCMA, which is currently targeted in MM therapies, thereby offering an alternative therapeutic option, especially in cases of relapse after BCMA‐directed treatment. The differential expression of GPRC5D in myeloma cells compared to healthy plasma cells and other normal tissues not only underscores its significance in disease pathology but also makes it a prime candidate for targeted immunotherapy. A series of studies and reviews retrieved from structured data in the synapse database have consistently emphasized the potential of GPRC5D as an attractive target for both direct tumor cell killing and for enhancing immune system engagement against MM cells.

Therapeutic Candidates for GPRC5D
Small Molecules
A limited number of efforts have been directed toward the development of small-molecule inhibitors targeting GPRC5D. In the realm of drug discovery, small molecules have historically been a favorite modality given their ease of synthesis, potential for oral bioavailability, and relatively low manufacturing costs. However, for GPRC5D, the current development is predominantly skewed towards the biologics space. Preclinical investigations using computational modeling and screening have provided some insights into potentially druggable pockets on this seven-pass receptor, but no small-molecule candidates have yet advanced to clinical evaluation. The inherent challenges—such as targeting an orphan receptor with minimal extracellular domain exposure and the difficulty of achieving specificity in a GPCR with limited known ligands—have so far relegated small-molecule efforts to a much earlier stage relative to antibody-based interventions. Nonetheless, the continued advancement of computer-aided drug design (CADD) and structure-based virtual screening methodologies could eventually pave the way for identifying and optimizing small-molecule modulators of GPRC5D.

Biologics and Antibodies
The majority of therapeutic candidates targeting GPRC5D are in the realm of biologics, particularly monoclonal antibodies, bispecific antibodies, and cell-based therapies. Among these, several key candidates stand out:

• Talquetamab (JNJ-64407564)
Talquetamab is a first-in-class, CD3 bispecific antibody specifically designed to target GPRC5D on malignant plasma cells as well as the CD3 molecule on T-cells. This dual-targeting mechanism facilitates the redirection of T-cells to eliminate MM cells effectively. Clinical data have demonstrated promising overall response rates in relapsed or refractory MM patients; preliminary phase 1/2 studies have shown durable responses with an acceptable safety profile despite the expected immune-related adverse events such as cytokine release syndrome. Moreover, its mechanism—based on simultaneous engagement of a tumor-associated antigen and T-cell activation—positions it as a strong alternative for patients who have failed anti-BCMA therapies.

• OriCAR-017
Cell-based therapies have emerged as a cutting-edge modality for cancer treatment, and OriCAR-017 is one such state-of-the-art CAR T-cell therapy candidate targeting GPRC5D. Unlike conventional monoclonal antibodies, CAR T-cells are engineered to recognize and kill MM cells expressing GPRC5D directly. Preclinical and early-phase clinical studies have noted robust overall response rates and deep, durable responses in a small cohort of MM patients, suggesting a potential advantage in terms of long-term disease control. Techniques such as lentiviral transduction are utilized to generate these engineered T-cells, and studies have indicated that even in patients with relapsed/refractory disease, T-cell cytotoxicity remains effective.

• LBL-034
LBL-034 is a bispecific antibody candidate developed by leveraging an asymmetric design to target both GPRC5D and CD3. Preclinical investigations have shown that LBL-034 effectively engages T-cells, leading to T cell–mediated cytotoxicity of MM cells in in vitro models. This candidate is particularly notable because of its unique design that balances safety and efficacy, potentially reducing off-target effects while maintaining strong anti-tumor activity. Patent literature further corroborates the innovative approaches undertaken by different organizations to design antibodies that specifically bind GPRC5D and thus expand the therapeutic arsenal available for MM.

• Other Antibody-Based Candidates
Additional candidates include various novel anti-GPRC5D monoclonal antibodies that have been described in the patent literature. Patents detail the development of antibodies and bispecific molecules with high affinity and specificity to GPRC5D that are intended to diagnose, treat, or monitor cancer progression. These approaches include the generation of single-chain variable fragments (scFvs) and full-length antibody constructs that can be engineered with altered Fc regions to modulate effector functions. Although many of these candidates are at the preclinical stage, they represent a robust pipeline that reflects the translational potential of GPRC5D-targeted immunotherapies.

Research and Development Status
Preclinical Studies
Preclinical research on GPRC5D-targeted therapies has provided compelling evidence supporting the utility of this target in MM. Studies have employed both in vitro cell-based assays and in vivo xenograft models to evaluate candidate efficacies. For example, experiments with bispecific antibodies such as talquetamab have shown that even at low concentrations, significant T cell–mediated cytotoxicity is achieved against MM cell lines overexpressing GPRC5D. In addition, studies conducted using genetically engineered mouse models have demonstrated that targeting GPRC5D, either as monotherapy or in combination with other agents, can significantly inhibit tumor growth and improve survival outcomes. Research efforts are also evaluating pharmacodynamic markers, such as T-cell activation, cytokine secretion (e.g., interferon-γ, TNF-α, IL-2), and overall clinical benefit rates, to optimize dosing regimens and mitigate potential adverse events. In patents and detailed regulatory filings, safety data from these preclinical models have been instrumental in supporting first-in-human studies.

Moreover, preclinical models are now increasingly incorporating 3D cell culture systems and organoid models to better recapitulate the in vivo tumor microenvironment. These refined models are critical in ensuring that candidate therapies not only have potent anti-tumor activity but are also safe when subjected to the complex interactions that occur in a living organism. Continued advancements in CADD approaches further aid in structure-based optimization and the virtual screening of lead compounds, thereby supporting an integrated drug development pipeline.

Clinical Trials
Clinical development of GPRC5D-targeted agents has accelerated in recent years. Talquetamab, for instance, has progressed through phase 1 and early phase 2 clinical trials. Data from these studies have shown encouraging overall response rates, with durable responses in a significant percentage of heavily pretreated MM patients. The clinical trials are designed not only to assess antitumor efficacy but also to closely monitor the safety profile, particularly immune-mediated adverse events such as cytokine release syndrome (CRS) and neurological toxicities. Regulatory milestones have been reached with innovative trial designs to manage these side effects effectively while maximizing therapeutic benefit.

CAR T-cell therapies such as OriCAR-017 are also undergoing clinical evaluation. Early-phase trials are demonstrating promising results, with high overall response rates and deep remissions, highlighting the potential of adoptive cell therapies targeting GPRC5D to overcome resistance observed with other immunotherapies. Additionally, the patent documentation for these cell-based approaches outlines strategies for improving persistence, expansion, and safety of the engineered T-cells. Current clinical trials often utilize a 3 + 3 dose-escalation design to determine the maximal tolerated dose and to monitor long-term responses and potential toxicities. Trial endpoints include overall response rate, progression-free survival, minimal residual disease negativity, and quality-of-life assessments, which are particularly relevant in the context of MM with its high-risk patient population.

Challenges and Future Directions
Development Challenges
Despite the promising data, several challenges remain in the clinical and preclinical development of GPRC5D-targeted therapies. One significant challenge lies in managing the on-target/off-tumor toxicities. Although GPRC5D expression is largely restricted to malignant plasma cells and limited normal tissues, the receptor’s presence in hair follicles and other tissues may generate dermatologic or other adverse events that require careful management and precise dosing strategies.

Another challenge is the phenomenon of antigen escape. Since GPRC5D expression can vary among patients and even within a single tumor over time, there is a risk that malignant cells might downregulate or inactivate the target, leading to therapeutic resistance. Early evidence of acquired resistance through genetic or epigenetic mechanisms has been documented in patients treated with bispecific T-cell engagers, and this may require combination strategies or sequential immunotherapies to overcome.

Manufacturing and scalability are also pivotal challenges, especially for cell-based therapeutics like CAR T-cells. The complexity and cost of generating patient-specific cell products, along with the need for reliable expansion and persistence of these cells in vivo, remain significant hurdles. Moreover, the logistics of coordinating treatment across multiple centers and ensuring consistency in cell preparation underscore the need for robust manufacturing platforms.

Finally, the lack of well-defined biomarkers for early response and resistance mechanisms further complicates clinical decision-making. Continuous development and integration of genomic and proteomic analyses into clinical trials are required to tailor therapies to individual patient profiles.

Future Research Opportunities
Future research in GPRC5D-targeted therapy is directed toward multiple fronts. One promising approach is the combination of GPRC5D-targeted agents with other immunotherapeutic modalities—for instance, combining bispecific antibodies with checkpoint inhibitors or immunomodulatory drugs to enhance T-cell activity and overcome resistance mechanisms.

Further exploration of multi-target strategies may involve dual or triple targeting constructs that simultaneously bind GPRC5D and another antigen (such as BCMA or CD38), thus reducing the risk of antigen escape and providing a broader antitumor effect. Researchers are also investigating ways to improve the precision of cell-based therapies by integrating gene editing techniques (e.g., CRISPR/Cas9) to further enhance the efficacy and safety of CAR T-cells targeting GPRC5D.

Advanced computational modeling and machine learning approaches provide additional opportunities to design even more potent molecules. With the increasing availability of 3D structural data and high-throughput screening technologies, virtual screening can be leveraged to identify novel structural motifs that interact with the receptor. These strategies could lead to the discovery of small-molecule modulators or improved antibody frameworks that ensure higher specificity and better pharmacokinetic properties.

Moreover, future research should focus on in-depth longitudinal studies that provide insight into the dynamics of GPRC5D expression throughout disease progression and in response to therapy. Such studies are vital for establishing reliable biomarkers that could predict patient response, monitor therapeutic efficacy, and identify early mechanisms of resistance. Bioinformatics-driven analyses of patient samples, combined with multi-omic approaches, will further refine our understanding of GPRC5D biology and its implications in the tumor microenvironment.

Another important research opportunity lies in expanding clinical trials to include a broader range of MM patient subpopulations and potentially other plasma cell dyscrasias. Given that current trials predominantly enroll patients with relapsed or refractory MM, there is scope for exploring the efficacy of GPRC5D-targeted therapies in earlier lines of therapy or in combination with standard chemotherapeutic regimens.

On the manufacturing front, standardizing production methods for biologics and cell-based therapies could reduce costs and improve access. Innovations in automated manufacturing platforms and quality control systems are expected to streamline the production process, ensuring consistency in cell product quality while reducing turnaround times.

Finally, enhanced collaboration between academic researchers, clinical scientists, and industry stakeholders will be essential. Such partnerships can accelerate translational research and ensure that laboratory discoveries are rapidly tested and refined in clinical settings, thus shortening the bench-to-bedside time.

Conclusion
In summary, the therapeutic candidates targeting GPRC5D encompass a diverse set of modalities that are predominantly focused on biologics and cell-based therapies. Talquetamab, a bispecific antibody that co-targets GPRC5D and CD3, has emerged as one of the lead candidates with encouraging clinical responses in relapsed/refractory MM patients. Meanwhile, innovative cell-based therapies, such as OriCAR-017, leverage CAR T-cell technology to exhibit potent anti-myeloma activity. Additionally, novel bispecific antibody candidates like LBL-034 are being developed to refine therapeutic efficacy with manageable safety profiles. Small-molecule approaches, although less developed due to inherent challenges with orphan receptor targeting, remain an area of potential future exploration with the aid of advanced CADD and virtual screening techniques.

The current research and development landscape features robust preclinical studies that have demonstrated the promise of GPRC5D-targeted agents in both cell culture systems and animal models. Early clinical trials, particularly those evaluating talquetamab and CAR T-cell therapies, are showing promising response rates and durable remissions in heavily pretreated patients. However, challenges such as potential on-target/off-tumor toxicities, antigen escape, manufacturing complexities, and the need for reliable predictive biomarkers remain significant hurdles.

Looking forward, research opportunities include the development of combination strategies to enhance efficacy and overcome resistance, improved computational methods for lead optimization, and advanced manufacturing techniques to scale up production of biologics and cell therapies. With continued efforts in these areas, GPRC5D-targeted therapies hold the potential to not only expand the treatment arsenal for multiple myeloma but also potentially address other malignancies where plasma cell dyscrasias play a role.

The cumulative evidence from both peer-reviewed literature and robust patent documents in the synapse database supports the strategic importance of GPRC5D as a therapeutic target. As further clinical trials mature and long-term safety and efficacy data become available, it is expected that these therapeutic candidates will contribute significantly to improved patient outcomes in multiple myeloma and possibly other cancers. The promise shown by these innovative modalities underlines the need for continued investment and collaboration across multidisciplinary fields, ultimately paving the way for a new era in targeted cancer therapy.