B-cell Maturation Antigen (BCMA) A Promising Target in Cancer Therapy

What is Multiple Myeloma?

Multiple myeloma is a cancer of plasma cells that originates in the bone marrow, where normal plasma cells are produced. The precise etiology that transform normal antibody producing plasma cells into malignant multiple myeloma (MM) is not clear. Globally there were over 138,000 new cases and 98,000 deaths from multiple myeloma in 2016 [1]. A recent report from the American Cancer Society suggests that in the USA alone there will be 32,270 new cases of MM in 2020 and the estimated number of deaths from this disease will be 12,830 [2].

Multiple myeloma usually occurs in middle-aged and older people, especially those over the age of 60. Its etiology is not fully understood, but it is related to chromosomal abnormalities, immune system disorders, and environmental factors. Clinically, multiple myeloma may manifest as symptoms such as bone pain, fatigue, anemia, and fractures. Due to the massive proliferation of plasma cells, the bone marrow will gradually be replaced, thereby affecting normal hematopoietic function.

Treatment of multiple myeloma has always been a challenging task. Traditional treatment methods include chemotherapy, radiotherapy, and hematopoietic stem cell transplantation, however, these treatments have limited effects and are prone to drug resistance. In recent years, targeted therapy has become the focus of research. BCMA (B-cell maturation antigen), as the surface antigen of multiple myeloma, has become an important target of targeted therapy. CAR-T cell therapy and drugs targeting BCMA have become a new hope for the treatment of multiple myeloma and have achieved remarkable clinical progress.

Introduction to BCMA

BCMA, also known as B cell maturation antigen, was initially discovered by several research groups [3-6]. The BCMA gene was identified to be involved in the t(4;16) (q26;p13) translocation in a malignant T-cell lymphoma, where it was fused to the interleukin-2 gene. The BCMA gene is located on chromosome band 16p13.13 and encodes a peptide consisting of 184 amino acid residues with an estimated molecular weight of 20kd.

BCMA is alternatively referred to as CD269 and belongs to the TNF receptor superfamily 17 (TNFRSF17) [7]. It interacts with ligands such as B cell-activating factor (BAFF, also known as TNFSF13B) and a proliferation-inducing ligand (APRIL, also known as TNFSF13) [8]. The expression of BCMA is predominantly observed in B lineage cells, particularly during the transition from mature B cells to plasma cell (PC) terminal differentiation, including plasmablasts. Although primarily present in normal B cells, BCMA is also found on malignant B cells and MM cells [9-10]. However, naïve and most memory B cells lack BCMA expression. BCMA-deficient mice exhibited normal B cell development and an intact humoral immune system [11]. While BCMA might not be essential for B-cell development, it significantly influences B-cell maturation and differentiation into plasma cells, particularly by upregulating during PC differentiation. This role is crucial for enhancing the survival of normal PCs, plasmablasts, and long-lived PCs in the bone marrow.

A soluble form of BCMA has been identified in the peripheral blood of MM patients [12]. The injection of soluble BCMA disrupted immune responses, influenced splenic architecture, and hindered the accumulation of peripheral B cells [13-15]. The presence of soluble BCMA might theoretically interfere with the myeloma-targeting capabilities of BCMA-specific immunotherapeutics [16].

Schematics showing BCMA protein.
Fig.1 Schematics showing BCMA protein.[17]

Rationale for targeting BCMA for treatment of MM

B cell maturation antigen (BCMA) is a surface marker exclusively expressed on plasmablasts and differentiated plasma cells (PCs), distinguishing it from memory B cells, naive B cells, CD34+ hematopoietic stem cells, and other normal tissue cells[18-20]. Gene expression profiling and immunohistochemistry studies have validated that BCMA mRNA and protein are more prominently expressed on malignant PCs compared to their normal counterparts[21-23]. Research by Carpenter et al. detected BCMA cDNA copies via qPCR in various hematologic tissues such as bone marrow, lymph nodes, spleen, and tonsils, with minimal expression found in select normal tissues like the testis, trachea, duodenum, rectum, and stomach. Immunohistochemistry showed BCMA protein expression exclusively on MM cells, lymphoid cells, or PCs from specific human organs, with no detection on other cell types in those organs. Additional flow cytometry studies confirmed BCMA expression on specific blood cells and Hodgkin lymphoma cells, further confirming its specificity[24]. Consequently, BCMA protein emerges as a highly specific marker for PCs, with low levels of BCMA RNA in normal organs attributed to the presence of PCs.

A substantial body of evidence demonstrates that BCMA transcript, protein, and serum levels are significantly higher in MM cell lines and patient MM cells compared to healthy donors. Recent studies, however, indicate that median BCMA expression on patient MM cells may not surpass that of normal bone marrow PCs in large patient cohorts. At the protein level, BCMA shedding by γ-secretase influences PCs in the bone marrow, potentially serving as a biomarker for B-cell involvement in autoimmune diseases[25]. Moreover, levels of soluble BCMA (sBCMA) are elevated in MM patients compared to healthy individuals[26-28]. These levels correlate with disease status and prognosis, offering potential insight into disease progression. Anti-BCMA antibodies detected in MM patients in remission after donor lymphocyte infusion with graft-vs-tumor response suggest a direct contribution of these antibodies to tumor elimination[29]. Interestingly, low BCMA expression is found in plasmacytoid dendritic cells (pDCs), which support MM cell survival and drug resistance. Remarkably, pDCs and PCs are the only cell types demonstrating detectable BCMA expression, albeit significantly lower in pDCs. These cumulative findings solidify BCMA as a promising MM antigen for targeted immunotherapy.

BCMA signaling pathway

BCMA (B cell maturation antigen) engages with two activating ligands: a proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF). These ligands are primarily secreted by bone marrow stromal cells, osteoclasts, and macrophages in a paracrine manner within the bone marrow environment [30-31]. APRIL exhibits a higher binding affinity to BCMA than BAFF and also binds to TACI, while BAFF has a greater selectivity for BAFF-R [32]. APRIL is particularly pertinent to plasma cells (PCs) and is linked to downstream pathophysiological activities. Notably, xenografted MM cell lines showed significantly reduced growth in APRIL−/− mice, suggesting its role in MM progression [33]. In MM patients, elevated serum levels of APRIL and BAFF, up to 5-fold that of healthy controls, are detected, with higher concentrations correlating to advanced MM stages [33]. Augmented MM-induced osteoclast-produced APRIL fosters an immunosuppressive bone marrow microenvironment, indicating that incorporating APRIL-blocking monoclonal antibodies (mAbs) into BCMA-directed immunotherapies might enhance antibody-dependent cell-mediated cytotoxicity (ADCC) against MM cells.

Following ligand binding, BCMA triggers multiple growth and survival signaling cascades within MM cells, predominantly the nuclear factor κ-light-chain enhancer of activated B cells (NF-κB) pathway. This includes rat sarcoma/mitogen-activated protein kinase (RAS/MAPK) and phosphoinositide-3-kinase–protein kinase B/Akt (PI3K-PKB/Akt) pathways. These pathways drive proliferation by influencing cell cycle checkpoints, enhance survival through upregulating anti-apoptotic proteins (e.g., Mcl-1, BCL-2, BCL-XL), and induce the production of molecules vital for cell adhesion (e.g., ICAM-I), angiogenesis (e.g., VEGF, IL-8), and immune suppression (e.g., IL-10, PD-L1, TGF-β) [34]. Intriguingly, BCMA overexpression can activate NF-κB and MAPK pathways even without APRIL or BAFF stimulation [35]. Further interplays between APRIL/BCMA signaling and other pathways are evident. For instance, APRIL interacts with CD138/syndecan-1 and heparan sulfate proteoglycans (HSPG) to support MM cell proliferation and survival [36]. Concurrent FGF-R3 and JAK2 blockade leads to BCMA downregulation [37]. Additionally, in vitro studies highlight BCMA's association with interferon regulatory factor-4 (IRF-4), a pivotal transcription factor in MM cell survival [38]. These insights emphasize BCMA's intricate role in MM oncogenesis.

BCMA signaling pathway.
Fig.2 BCMA signaling pathway.[39]

Advancements in BCMA-Targeted CAR T Cell Trials for Multiple Myeloma

BCMA-targeted chimeric antigen receptor (CAR) T cell therapy has emerged as a promising avenue in the quest to treat multiple myeloma (MM). Numerous clinical trials have been undertaken to assess the safety and efficacy of BCMA-targeted CAR T cell therapies, yielding encouraging outcomes.

Among these, idecabtagene vicleucel (ide-cel or bb2121) stands out. Developed collaboratively by Bluebird Bio and Celgene (now a part of Bristol Myers Squibb), this investigational CAR T cell therapy specifically targets BCMA. Clinical trials of ide-cel have demonstrated promising results, boasting high response rates among heavily treated MM patients. It has even earned the prestigious breakthrough therapy designation from the U.S. FDA.

Another significant contender in this domain is JNJ-4528, crafted by Janssen, a subsidiary of Johnson & Johnson. JNJ-4528 has showcased remarkable efficacy in clinical trials, revealing profound and lasting responses in MM patients. Its FDA approval has been granted under the trade name Abecma, catering to the treatment of relapsed or refractory MM.

Numerous other BCMA-targeted CAR T cell therapies are currently under scrutiny in clinical trials, aimed at broadening the therapeutic arsenal for MM patients. These trials are exhaustively assessing various aspects, encompassing safety, efficacy, optimal dosing, and long-term outcomes.

Nonetheless, despite the optimistic strides, hurdles persist. Cytokine release syndrome (CRS) and neurotoxicity emerge as potential side effects tied to CAR T cell therapy. Researchers are diligently working on refining treatment protocols and management strategies to effectively mitigate these risks. Furthermore, the ongoing endeavor to devise BCMA-targeted therapies that efficaciously combat relapse and drug-resistant MM remains a paramount focus.

BCMA Protein

Recombinant Human BCMA Protein

References:

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