A Novel Bispecific Anti-GPRC5D × CD3 Antibody: A New Treatment Paradigm in Multiple Myeloma

In a recent preclinical study published in Nature, researchers constructed a novel humanized bispecific anti-G-protein-coupled receptor class 5 member D (GPRC5D) and CD3 monoclonal antibody, BsAb5003, and evaluated its efficacy against multiple myeloma.¹ The researchers found the antibody to induce specific cytotoxicity of multiple myeloma cells with GPRC5D on their surfaces and enhance T cell activation and subsequent cytokine release. The results suggest the monoclonal antibody to be a highly effective treatment approach for most patients with multiple myeloma.¹

“The discovery solidifies the effectiveness of the GPRC5D and CD3 antibody, aligning with expectations,” said Attaya Suvannasankha, MD, a physician-scientist at the Indiana University Melvin and Bren Simon Comprehensive Cancer Center and an associate professor of clinical medicine at the Division of Hematology and Oncology, Indiana University School of Medicine, commenting on the findings of the study in an interview with Pharmacy Times. “Utilizing superior technology, this advanced agent demonstrated the anticipated robust activity in myeloma models, including animal xenografts.”

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Multiple myeloma is a complex hematologic malignancy with a high tendency to relapse and develop drug resistance. Despite tremendous advancements in therapeutic approaches, the majority of patients still relapse and remain incurable. Hence, new therapeutic approaches with different mechanisms of action, particularly targeting novel biomarkers, are needed to improve the survival of patients with multiple myeloma.

In recent years, novel immunotherapeutic approaches such as bispecific antibodies targeting different cell surface antigens overexpressed by multiple myeloma cells have been the most promising developments in the treatment of multiple myeloma.² Bispecific antibodies are monoclonal antibodies with 2 binding sites, one targeting CD3 on the surface of T cells and the other targeting tumor-specific target antigen. Binding to both sites brings the T cell close to tumor cells, which leads to the formation of an immune synapse. This, in turn, results in the activation of T cells and cytokine release that induce cytotoxicity.³ Evidence suggests that bispecific antibodies targeting GPRC5D have shown potent efficacy in heavily pretreated patients with refractory/relapsed multiple myeloma.⁴

GPRC5D, an orphan receptor protein with an unknown ligand, is predominantly expressed in malignant plasma cells of patients with multiple myeloma, even those with heavily treated and high-risk diseases.¹

“GPRC5D is an orphan G-protein coupled receptor with an unknown ligand. Its role in normal tissue and multiple myeloma is still unclear,” said Suvannasankha in the interview. “GPRC5D is highly expressed in multiple myeloma cells. Increased GPRC5D expression is associated with genetic aberrations and high-risk disease, reflecting poor prognosis and shorter survival in patients with myeloma.”

Approximately 90% of patients with multiple myeloma exhibit GPRC5D expression in multiple myeloma cells, with limited expression in cells that produce hard keratin, such as cortical cells of the hair shaft and in a central region of the filiform papillae of the tongue.⁵ Successful T-cell–redirection therapy depends on eliminating malignant cells expressing a target with minimal to no expression in other tissues.⁶ For this reason, this selective expression of GPRC5D makes it an ideal target for effective cell-mediated therapies.

In August 2023, talquetamab (Talvey; Janssen Biotech, Inc), a T cell-redirecting bispecific antibody targeting GPRC5D, was granted accelerated approval in the United States for treating adult patients with relapsed/refractory multiple myeloma.⁷ However, several challenges still remain to overcome that may include antigen escape and associated toxicities such as cytokine release syndrome (CRS).

“The use of antibodies that bind both T cells and surface antigens on tumor cells has transformed myeloma care, with GPRC5D emerging as a promising target due to its unique expression in normal plasma cells and its consistent overexpression in myeloma cells, especially during relapse,” Suvannasankha said in the interview with Pharmacy Times. “Talquetamab, an approved GPRC5D bispecific antibody for relapsed/refractory myeloma, has shown a remarkable response rate of approximately 60% in patients who have previously failed other therapies.”

However, Suvannasankha noted that challenges persist, including immune-mediated adverse effects and resistance due to surface antigen down regulation.

“Advances in antibody technology offer solutions to these issues. While targeting the antibody to the antigen is crucial, the design of the hinge and constant domains of the heavy chain is equally important, as they regulate antibody circulation and mediate effector functions,” Suvannasankha said. “By leveraging improved antibody scaffold design, it is possible to enhance tumor binding while minimizing off-target immune activation.”

In the current study, researchers constructed a novel humanized bispecific monoclonal antibody BsAb5003 that binds to CD3 and GPRC5D on T cells and plasma cells, respectively. Bone marrow specimens were collected from 49 patients with multiple myeloma at Nagoya City University in Japan. The researchers then evaluated the preclinical activity of the antibody in multiple myeloma cell lines and in samples from patients with multiple myeloma with high to low GPRC5D expression.¹

“BsAb5003 utilizes modified technology to reduce T cell affinity and enhance GPRC5D binding. It effectively targets GPRC5D-positive multiple myeloma cells, inducing cytotoxicity and T-cell activation,” Suvannasankha said. “Its efficacy correlates with GPRC5D expression levels, particularly in patient samples, and shows potent tumor growth inhibition in animal models through T-cell recruitment. BsAb5003 holds potential as a standalone therapy or in combination with immunomodulatory drugs for multiple myeloma treatment.”

Additionally, Suvannasankha explained that the mechanism of action for this agent is similar to the approved Talquetamab. However, the technology used to develop this agent introduces notable differences.

“For instance, low CD3 affinity may reduce the risk of CRS, and high-affinity anti-GPRC5D domain shows strong affinity to the low-expressed target antigen,” Suvannasankha said. “Moreover, the azymetric and effect platforms to enhance the biophysical properties of bispecific antibodies may prevent nonspecific cytokine production unrelated to cancer-killing.”

FCM analysis was conducted to confirm the binding affinity of the antibody to GPRC5D. The researchers investigated the in vivo efficacy of the antibody in a xenograft mouse model and found that BsAb5003 induced target cell cytotoxicity, T-cell activation, and cytokine release in a dose-dependent manner in GPRC5D-positive cells.1 Also, the findings indicated a link between the efficacy of the antibody and GPRC5D expression level and showed that GPRC5D-specific multiple myeloma cell cytotoxicity and T-cell activation were observed in a dose-dependent manner in cell lines with different GPRC5D expression levels.¹

“The effectiveness of tumor killing by the antibody requires strong binding to the target antigen, as demonstrated here,” Suvannasankha said. “This binding is closely linked to the level of T-cell activation. Essentially, higher antigen levels lead to increased binding, greater T cell activation, and enhanced tumor killing.”

Researchers further investigated the efficacy of BsAb5003 in combination with other primary therapies for multiple myeloma, such as immunomodulatory drugs (IMiDs) or proteasome inhibitors (PIs). They found when combined with PIs at low concentrations and IMiDs like lenalidomide (Revlimid;Celgene) and pomalidomide (Imnovid; Bristol Myers Squibb), the antibody-induced significantly higher tumor cell cytotoxicity, suggesting the therapeutic potential of combination treatment.¹

These findings suggest that BsAb5003 could be a powerful treatment for many patients with multiple myeloma, either as monotherapy or combination therapy with other drugs like IMiDs and PIs.1Regarding the next steps, Suvannasankha explained that further clinical trials are needed, especially involving patients who progress on talquetamab, which is the FDA-approved GPRC5D therapy. This clinical research, according to Suvannasankha, will be crucial for assessing the efficacy and safety of BsAb5003, either alone or in combination with IMiDs.

“Although the agent demonstrates some promising characteristics, it has yet to be directly compared to talquetamab in vitro or in vivo in this publication. Therefore, the full comparative effectiveness remains unknown,” Suvannasankha said. “Since this study is confined to preclinical testing in myeloma models, the translation of its efficacy to clinical settings and its comparative safety and efficacy against talquetamab necessitates clinical testing.”

REFERENCES

1. Tomita U, Ishimoto Y, Ri M, et al. A novel T cell-redirecting anti-GPRC5D × CD3 bispecific antibody with potent antitumor activity in multiple myeloma preclinical models. Scientific Reports. 2024;14(1). doi:10.1038/s41598-024-55143-0
2. Lakshman A, Kumar SK. Chimeric antigen receptor T-cells, bispecific antibodies, and antibody-drug conjugates for multiple myeloma: An update. Am J Hematol. 2022;97(1):99-118. doi:10.1002/ajh.26379
3. Sedykh SE, Prinz VV, Buneva VN, Nevinsky GA. Bispecific antibodies: design, therapy, perspectives. Drug Des Devel Ther. 2018;12:195-208. Published 2018 Jan 22. doi:10.2147/DDDT.S151282
4. Lee H, Neri P, Bahlis NJ. BCMA- or GPRC5D-targeting bispecific antibodies in multiple myeloma: efficacy, safety, and resistance mechanisms. Blood. 2024;143(13):1211-1217. doi:10.1182/blood.2023022499
5. Inoue S, Nambu T, Shimomura T. The RAIG family member, GPRC5D, is associated with hard-keratinized structures. J Invest Dermatol. 2004;122(3):565-573. doi:10.1046/j.0022-202X.2004.12628.x
6. Pillarisetti K, Edavettal S, Mendonça M, et al. A T-cell-redirecting bispecific G-protein-coupled receptor class 5 member D x CD3 antibody to treat multiple myeloma. Blood. 2020;135(15):1232-1243. doi:10.1182/blood.2019003342
7. Keam SJ. Talquetamab: First Approval. Drugs. 2023;83(15):1439-1445. doi:10.1007/s40265-023-01945-x