Serum B-cell maturation antigen (BCMA) reduces binding of anti-BCMA antibody to multiple myeloma cells

Chen, Haiming; Li, Mingjie; Xu, Ning; Ng, Nicole; Sanchez, Eric; Soof, Camilia; Patil, Saurabh; Udd, Kyle; Bujarski, Sean; Cao, Jasmin; Hekmati, Tara; Ghermezi, Matthew; Zhou, Mizi; Wang, Emily Y.; Tanenbaum, Edward J; Zahab, Brian; Schlossberg, Remy; Yashar, Moryel A; Wang, Cathy S.; Tang, George; Spektor, Tanya M.; Berenson, James R.

doi:10.1016/j.leukres.2019.04.008

Cited by 49 publications

(34 citation statements)

References 15 publications

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“…sBCMA levels have been widely demonstrated to decrease during treatment in response to new MM therapies, including BCMA-targeted therapies [7,27,36]. Although these reductions in sBCMA levels may lessen concerns with sBCMA interfering with BCMA-targeted therapies by competing with membrane-bound BCMA [38], there may also be a corresponding decline in membranebound BCMA that would alter the ability of BCMAdirected therapies to target MM. Indeed, a trial assessing BCMA CAR T-cell therapy observed that the majority of patients showed a decline in BCMA intensity post infusion, though membrane BCMA expression increased back toward baseline in the majority of these patients [37].…”

Section: Discussion and Future Perspectivesmentioning

confidence: 99%

“…The efficacy and durability of anti-BCMA therapies may be particularly dependent on sBCMA levels. It has been demonstrated that sBCMA can bind to and interfere with anti-BCMA antibodies [38]. In this case, drugs that inhibit γsecretase could enhance the efficacy of BCMA-targeted therapy by reducing shedding of BCMA from the cell surface and subsequent interference of BCMA-targeted therapies by sBCMA [20,21,38].…”

Section: Bcma As a Tool For Prognosis And Treatment Responsementioning

confidence: 99%

“…It has been demonstrated that sBCMA can bind to and interfere with anti-BCMA antibodies [38]. In this case, drugs that inhibit γsecretase could enhance the efficacy of BCMA-targeted therapy by reducing shedding of BCMA from the cell surface and subsequent interference of BCMA-targeted therapies by sBCMA [20,21,38]. An additional approach could be to use anti-BCMA monoclonal antibodies (mAbs) with higher specificity for membrane-bound BCMA than sBCMA [39].…”

Section: Bcma As a Tool For Prognosis And Treatment Responsementioning

confidence: 99%

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B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

et al. 2020

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Despite considerable advances in the treatment of multiple myeloma (MM) in the last decade, a substantial proportion of patients do not respond to current therapies or have a short duration of response. Furthermore, these treatments can have notable morbidity and are not uniformly tolerated in all patients. As there is no cure for MM, patients eventually become resistant to therapies, leading to development of relapsed/refractory MM. Therefore, an unmet need exists for MM treatments with novel mechanisms of action that can provide durable responses, evade resistance to prior therapies, and/or are better tolerated. B-cell maturation antigen (BCMA) is preferentially expressed by mature B lymphocytes, and its overexpression and activation are associated with MM in preclinical models and humans, supporting its potential utility as a therapeutic target for MM. Moreover, the use of BCMA as a biomarker for MM is supported by its prognostic value, correlation with clinical status, and its ability to be used in traditionally difficult-to-monitor patient populations. Here, we review three common treatment modalities used to target BCMA in the treatment of MM: bispecific antibody constructs, antibody-drug conjugates, and chimeric antigen receptor (CAR)-modified T-cell therapy. We provide an overview of preliminary clinical data from trials using these therapies, including the BiTE® (bispecific T-cell engager) immuno-oncology therapy AMG 420, the antibody-drug conjugate GSK2857916, and several CAR T-cell therapeutic agents including bb2121, NIH CAR-BCMA, and LCAR-B38M. Notable antimyeloma activity and high minimal residual disease negativity rates have been observed with several of these treatments. These clinical data outline the potential for BCMA-targeted therapies to improve the treatment landscape for MM. Importantly, clinical results to date suggest that these therapies may hold promise for deep and durable responses and support further investigation in earlier lines of treatment, including newly diagnosed MM.

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Section: Discussion and Future Perspectivesmentioning

confidence: 99%

Section: Bcma As a Tool For Prognosis And Treatment Responsementioning

confidence: 99%

Section: Bcma As a Tool For Prognosis And Treatment Responsementioning

confidence: 99%

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B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

et al. 2020

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“…Membrane BCMA can be cleaved by γ-secretase and released to the plasma as soluble BCMA (sBCMA). sBCMA can bind to APRIL and BAFF, which may interfere with the activation of BCMA signaling pathways BCMA and sequestering circulating ligands or anti-BCMA antibodies, thereby inhibiting efficient binding to MM cells [65,66]. It has been recently reported that a γ-secretase inhibitor (GSI, LY3039478/JSMD194) decreased sBCMA concentration, while increased cellsurface BCMA expression concurrently in MM cell lines, patient tumor cells, in murine models.…”

Section: Soluble Bcma (Sbcma)mentioning

confidence: 99%

BCMA-targeted immunotherapy for multiple myeloma

2020

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B cell maturation antigen (BCMA) is a novel treatment target for multiple myeloma (MM) due to its highly selective expression in malignant plasma cells (PCs). Multiple BCMA-targeted therapeutics, including antibody-drug conjugates (ADC), chimeric antigen receptor (CAR)-T cells, and bispecific T cell engagers (BiTE), have achieved remarkable clinical response in patients with relapsed and refractory MM. Belantamab mafodotin-blmf (GSK2857916), a BCMA-targeted ADC, has just been approved for highly refractory MM. In this article, we summarized the molecular and physiological properties of BCMA as well as BCMA-targeted immunotherapeutic agents in different stages of clinical development.

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“…The restricted expression of BCMA and its role in the pathogenesis of MM have made BCMA an attractive target for immunotherapies, especially CAR T-cells ( 21 ). Nevertheless, the role of the sBCMA remains to be elucidated, since it could interfere with BCMA-targeted immunotherapies ( 43 ). Several clinical trials with diverse BCMA-CAR T-cell constructs in patients with RRMM are ongoing, and the currently available data are encouraging.…”

Section: Car Targets In Clinical Trialsmentioning

confidence: 99%

CAR T-Cells in Multiple Myeloma: State of the Art and Future Directions

et al. 2020

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Despite recent therapeutic advances, the prognosis of multiple myeloma (MM) patients remains poor. Thus, new strategies to improve outcomes are imperative. Chimeric antigen receptor (CAR) T-cell therapy has changed the treatment landscape of B-cell malignancies, providing a potentially curative option for patients who are refractory to standard treatment. Long-term remissions achieved in patients with acute lymphoblastic leukemia and Non-Hodgkin Lymphoma encouraged its further development in MM. B-cell maturation antigen (BCMA)-targeted CAR T-cells have established outstanding results in heavily pre-treated patients. However, several other antigens such as SLAMF7 and CD44v6 are currently under investigation with promising results. Idecabtagene vicleucel is expected to be approved soon for clinical use. Unfortunately, relapses after CAR T-cell infusion have been reported. Hence, understanding the underlying mechanisms of resistance is essential to promote prevention strategies and to enhance CAR T-cell efficacy. In this review we provide an update of the most recent clinical and pre-clinical data and we elucidate both, the potential and the challenges of CAR T-cell therapy in the future.

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Serum B-cell maturation antigen (BCMA) reduces binding of anti-BCMA antibody to multiple myeloma cells

Cited by 49 publications

References 15 publications

B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

BCMA-targeted immunotherapy for multiple myeloma

CAR T-Cells in Multiple Myeloma: State of the Art and Future Directions

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