Multiple myeloma (MM) is a malignant plasma cell tumor that primarily affects the elderly and is the second most common hematologic malignancy globally. It was reported that the prevalence and mortality rate of MM has more than doubled in the past 30 years. The continuing burden of worldwide multiple myeloma incidence is expected to rise as the world's population ages.

Rapid advancement in multiple myeloma therapy has occurred in the last 20 years. Immunomodulators (IMiDs) and proteasome inhibitors (PIs) have significantly improved therapeutic efficacy and patient survival, while innovative drugs such as antibody drugs and their derivatives, small molecule drugs, and chimeric antigen receptor T cell immunotherapy (CAR-T) also show promising results. Multiple pharmaceutical companies reported the latest clinical breakthroughs of medications targeting MM therapy at the 2022 American Society of Hematology meeting last year, including the development of prominent MM therapeutic targets such as BCMA, GPRC5D, and CD138.

BCMA

B-cell maturation antigen (BCMA), a type III transmembrane glycoprotein encoded by the TNFRSF17 gene on the short arm of chromosome 16 (16p13.13), plays a critical role in tumor cell survival, proliferation, metastasis, and drug resistance. Studies have demonstrated that BCMA is highly expressed in malignant proliferating B lymphocytes (e.g., myeloma cells, leukemia cells), but not in naive B cells, CD34+ hematopoietic stem cells, or other normal cells, making it a promising target for the treatment of multiple myeloma.

CAR-T therapy targeting BCMA^[1]

Antibody-drug conjugates (ADC): after binding to BCMA on the surface of multiple myeloma (MM) cells, ADC is first internalized and the junction is hydrolyzed within the lysosome or endosome, releasing a payload that leads to MM cell death; CAR-T cells: the extracellular domain of BCMA scFv on CAR-T cells binds to BCMA on the surface of MM cells, which activates CAR-T cells to release cytotoxic cytokines and cause MM cell death; bispecific T cell engager (BiTE): a double BiTE containing BCMA and CD3-scFv binds both CD3 and BCMA, promoting T cell/MM cell cross-linking followed by CD4+/CD8+ T cell activation and secretion of cytotoxic cytokines, leading to MM cell death.

Research Progress

Large pharmaceutical companies, including J&J, Pfizer, and Regeneron have identified BCMA as an attractive target in the MM field. Janssen's CD3-BCMA bispecific monoclonal antibody, teclistamab, recently gained accelerated approval from the FDA for treating relapsed or refractory multiple myeloma. Various clinical data sets on teclistamab were presented at the 2022 ASH conference, including an analysis of the launch trial MajesTEC-1, which investigated the safety/efficacy of teclistamab in patients with relapsed/refractory multiple myeloma (RRMM) who had previously received 3 lines of therapy, patients given the recommended phase 2 dose (RP2D) of teclistamab in phase 1/2 demonstrated better tolerance and efficacy^[2]. Although the efficacy of CD38 and BCMA-targeted therapies for MM is well established, the quest for next-generation medicines for patients with relapsed or refractory MM is critical. 

GPRC5

G protein–coupled receptor, class C, group 5, member D (GPRC5D) is a receptor whose ligand and signaling mechanisms have not been determined. It has low expression in normal tissues, is limited to hair follicles, and is specifically expressed in multiple myeloma cells, making it a suitable target for MM treatment.

GPRC5D gene expression profile^[3]

Research Progress

Currently, GPRC5D-targeting ADCs (such as LM-305 from LanovaMedicines) and double antibodies are the mainstays of clinical therapeutic development. According to NextPharma, there are 12 registered GPRC5D drugs worldwide, including J&J's GPRC5D x CD3 bispecific antibody talquetamab, which is currently in clinical phase III and recently submitted a BLA application to the FDA for Talquetamab for the treatment of relapsed or refractory MM, with success rates of up to 73%. 

CD138

CD138, also known as syndecan-1, is an extracellular matrix (ECM) transmembrane protein receptor that promotes cell adhesion by interaction with acetyl heparin-binding molecules and is involved in cell proliferation, migration, and cytoskeleton organization. Overexpression of CD138 is observed in MM cells which correlates with disease progression and prognosis, making it an ideal biomarker for MM diagnosis and a therapeutic target.

CD138 functional model under normal and malignant conditions^[4]

Research Progress

Phase Ib/IIa clinical trial of single and multiple dose escalation, the anti-CD38 antibody-drug conjugate, Indatuximab, demonstrated a reasonable safety profile. At the same time, single agent Indatuximab showed good anti-MM activity, with approximately 77% of patients in stable condition, but performed poorly in terms of overall remission rates. No further clinical trials of Indatuximab have been announced.

GemPharmatech’s humanized models and cell lines

Using gene editing technology, GemPharmatech has developed multiple mouse models targeting BCMA, GPRC5D, and CD138, and substituted these cell lines with human counterparts so that they can be utilized for MM drug screening and therapeutic efficacy evaluation.

                 BCMA expression in BALB/c-hBCMA mice                    Human mRNA expression in BALB/c-hGPRC5D mice

The human-derived BCMA protein can be detected in the serum and lymph nodes of BALB/c-hBCMA mice. The figure on the right demonstrates that the sequencing results of the human-derived gene of BALB/c-hGPRC5D mice are consistent with the human-derived GPRC5D sequence. 

References:

1. Bo Yu, Tianbo Jiang, et al. BCMA-targeted immunotherapy for multiple myeloma.J Hematol Oncol. 2020 Sep 17;13(1):125.

2. Diana Cortes-Selva, Tineke Casneuf, et al. Teclistamab, a B-Cell Maturation Antigen (BCMA) x CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM): Correlative Analyses from MajesTEC‑1.Z 64th ASH Annual Meeting and Expostion, Washington, USA. 2022. No.97.

3. Eric L Smith, Kim Harrington,et al. GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells.J Sci Transl Med. 2019 Mar 27;11(485).

4. Mohamed R Akl, Poonam Nagpal, et al. Molecular and clinical profiles of syndecan-1 in solid and hematological cancer for prognosis and precision medicine.J Oncotarget. 2015 Oct 6;6(30):28693-715.