Targeting B-cell maturation antigen in multiple myeloma

Abstract

Novel effective immunotherapies are needed for patients with multiple myeloma (MM), since disease recurrence remains a major obstacle. B-cell maturation antigen (BCMA), a cell surface protein universally expressed on malignant plasma cells , has emerged as a very selective antigen to be targeted in novel treatments for MM. We here first review BCMA-related biology, and then highlight the recent clinical development of a novel afucosylated anti-BCMA monoclonal antibody conjugated with monomethyl auristatin F via noncleavable linker (GSK2857916). Chimeric antigen receptor-expressing T cells targeting BCMA may also induce specific and durable anti-MM responses by patients' own effector cells. Clinical trials testing these two approaches (NCT02064387, NCT02215967) are currently ongoing in relapsed and refractory MM patients.

Keywords: ADC; B-cell maturation antigen; BCMA; BM; CAR-T; CAR-expressing T cells; Fc-engineered therapeutic antibody; MM; antibody drug conjugate; bone marrow; chimeric antigen receptor; microenvironment; multiple myeloma; targeted immunotherapy.

Conflict of interest statement

Financial & competing interests disclosure Y-T Tai is a consultant for Onyx. KC Anderson serves on advisory boards to Onyx, Celgene, Gilead, Bristol-Myers Squibb and Sanofi-Aventis and is a scientific founder of Acetylon and Oncopep. Funding: NIH grants RO1050947, PO1-CA078378 and DF/HCC SPORE in Multiple Myeloma P50CA100707; KC Anderson is an American Cancer Society Clinical Research Professor. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Figures

Figure 1.. B-cell maturation antigen-induced signaling in the pathophysiology of MM B-cell maturation antigen belongs to the TNFR superfamily and is closely related to BAFF receptor and calcium modulator and cyclophilin ligand interactor (TACI).

Specifically, downregulation of BAFF-R on plasma cell (PC) is coincident with the upregulation of BCMA, which can bind BAFF and a proliferation-inducing ligand (APRIL) at low (μM) and high (nM) affinity, respectively. Both ligands are synthesized as membrane-bound proteins that can be released as soluble cytokines by furin protease cleavage and form soluble trimers. APRIL, a more specific growth and survival factor for PC, binds to sulfated side chains of HSPG (such as syndecan-1/CD138) at a site distinct from its binding site to bind to TACI and BCMA. Constitutively activated APRIL/BCMA signaling cascade leads to increased numbers of hyperactive malignant PC, and therefore represents a very promising target for novel immunotherapies in MM. BAFF-R: BAFF receptor; BCMA: B-cell maturation antigen; HSPG: Heparan sulfate proteoglycan; MM: Multiple myeloma; TNFSF: TNFR superfamily.

Figure 2.. Mechanisms of action of monoclonal antibody-based targeted therapies against multiple myeloma.

Therapeutic IgG monoclonal antibodies (mAbs) are designed to mediate ADCC or CDC, and can also directly inhibit growth or trigger apoptotic signaling pathways. Examples listed are mAbs tested in recent clinical trials in MM. The majority of MM target receptors/cell surface proteins on MM cells or extracellular factors (i.e., DKK1, activin A) in the BM microenvironment. Antibody drug conjugates are designed to directly kill MM cells to increase effectiveness of naked mAb. These include mAbs targeting CD56, CD138, CD74 and BCMA (the focus of this paper). In preclinical studies, only BCMA antibody drug conjugates can both interfere with ligand binding and elicit ADCC to lyse MM cells as well as directly induce apoptosis due to potent drug conjugates released inside the tumor cells following Ab–antigen binding. †Ab–drug conjugate. Ab: Antibody; ADCC: Antibody-dependent cellular cytotoxicity; CDC: Complement-mediated cytotoxicity; MM: Multiple myeloma; NK: Natural killer.

Figure 3.. Development of a novel anti-B-cell maturation antigen antibody–drug conjugate GSK2857916.

BCMA: B-cell maturation antigen; mAb: Monoclonal antibody; MMAE: Monomethyl aurastatin E; MMAF: Monomethyl aurastatin F.

Figure 4.. GSK2857916 induces direct and indirect killing of multiple myeloma cells in the bone marrow microenvironment.

GSK2857916 specifically binds to BCMA on the MM cell membrane, and MMAF is then released inside MM cells by lysosome to induce G2-M growth arrest, followed by caspase 3/7-dependent apoptosis. It inhibits binding of APRIL and/or BAFF to BCMA, thereby blocking NF-κB signaling cascades critical for MM cell growth and survival. It has been Fc-engineered to enhance its binding to effector cells (i.e., NK cells, monocytes, macrophages), leading to significantly increased antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). ADCC and ADCP is induced via binding of FcγRs on NK cells and macrophages (myeloid effector cells) by tumor cell-bound GSK2857916. These three key anti-MM activities of GSK2857916 are further enhanced by lenalidomide or pomalidomide, triggering both direct and indirect killing of MM cells. Dexamethasone (Dex)/predonisolone, melphalan (Mel), or bortezomib (BTZ) also augment direct toxicity induced by GSK2857916. BCMA: B-cell maturation antigen; MM: Multiple myeloma.