Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow. Plasma cells are B lymphocytes (B-cells) that have been activated to produce immunoglobulins. When plasma cells become cancerous, the produce copious amounts of immunoglobulins and proliferate in the bone marrow, causing crowding-out of other essential hematopoietic cells, leading to reduced numbers of functioning white blood cells (leukopenia leading to immunosuppression), red blood cells (anemia), and megakaryocytes (thrombocytopenia).
What are BCMA and APRIL?
BCMA (B-Cell Maturation Antigen) is a receptor expressed on mature B-cells – it transduces signals important for cell survival and proliferation by activating the NFkB and MAPK pathways. BCMA is part of the TNF (Tumor Necrosis Factor) Receptor superfamily – its ligand is TNFSF13B, which is also known as APRIL (A Proliferation Inducing Ligand).
Overexpression or activation of B-cell maturation antigen (BCMA) by its ligand, a proliferation-inducing ligand (APRIL), promotes human multiple myeloma (MM) progression in vivo. BCMA downregulation strongly decreases viability and MM colony formation; conversely, BCMA overexpression augments MM cell growth and survival via induction of protein kinase B (AKT), MAPK, and nuclear factor (NF)-κB signaling cascades. Importantly, BCMA promotes in vivo growth of xenografted MM cells harboring p53 mutation in mice. BCMA-overexpressing tumors exhibit significantly increased CD31/microvessel density and vascular endothelial growth factor compared with paired control tumors. These tumors also express increased transcripts crucial for osteoclast activation, adhesion, and angiogenesis/metastasis, as well as genes mediating immune inhibition including programmed death ligand 1, transforming growth factor β, and interleukin 10. These target genes are consistently induced by paracrine APRIL binding to BCMA on MM cells.
Monoclonal Antibody to APRIL
Aduro has developed hAPRIL.01A (BION-1301), a monoclonal antibody that binds to APRIL to disrupt its binding to BCMA.
The MAb blocked CLL survival and inhibited mouse B1 hyperplasia and IgA production in vivo (Guadagnoli et al., 2011). APRIL is produced by cells in the bone marrow niche, including myeloid-derived cells, osteoclasts and plasmacytoid dendritic cells. APRIL critically triggers BCMA in vitro and in vivo to drive proliferation and survival of human MM (Tai et al., 2016). Importantly, APRIL induces resistance to lenalidomide, bortezomib and other standard-of-care drugs for multiple myeloma. Furthermore, APRIL drives expression of PD-L1, IL-10, VEGF and TGFβ forcing an immunosuppressive phenotype on BCMA+ cells. As MM and B-cell survival, resistance to treatment and the immunosuppressive phenotype can be blocked by neutralizing APRIL (Tai et al., 2016), development of an antibody blocking APRIL provides a novel avenue for the treatment of MM and possibly CLL.
The company plans to initiate a Phase 1 study of patients with multiple myeloma in 2017. Given that APRIL induces resistance to lenalidomide, bortezomib and other standard-of-care drugs and drives expression of PD-L1, IL-10, VEGF and TGFβ forcing an immunosuppressive phenotype, it is appropriate to consider use of BION-1301 in combination with standard of care therapies and PD-(L)1 checkpoint inhibitors.
In patients with rectal cancer, elevated serum levels of APRIL have been shown to portend a poor prognosis. In addition to multiple myeloma, anti-APRIL treatment may be useful in refractory CLL (chronic lymphocytic leukemia) and rectal cancer.
Other potential clinical applications for anti-APRIL antibody therapy?