A proliferation-inducing ligand (APRIL) is produced by multiple accessory and myeloid cells in the bone marrow niche. Through binding to its receptors B-cell maturation antigen (BCMA) and transmembrane activator and CAML interactor (TACI), APRIL plays an important role in the development and maintenance of cells derived from the B cell lineage. Both APRIL and its receptors have been identified as promotors of multiple myeloma (MM), a disease that is characterized by malignant proliferation of plasma cells in the bone marrow. We have shown that BION-1301, a first-in-class APRIL-targeting humanized antibody, blocks APRIL-induced effects on MM cell survival and the tumor microenvironment (TME).
Despite recent approval of new therapies for MM, this type of cancer remains incurable as patients relapse and eventually become refractory to the current therapeutic regimens. We hypothesize that the presence of high levels of APRIL in the bone marrow of patients with MM establishes a protected environment favoring tumor cell survival and proliferation. The effects of APRIL were studied on tumor cell lines alone or in co-culture with osteoclasts, which are thought to produce APRIL in the bone marrow niche. We further hypothesize that engaging APRIL with BION-1301 sensitizes MM cells for other MM-targeting therapeutic agents.
First, stimulation of MM cells with APRIL led to rapid phosphorylation of proteins in the NFκB pathway, that was completely blocked by the BION-1301 parental antibody hAPRIL.01A. In addition, by validating expression of known NFκB target genes, APRIL appears to protect MM cells from drug-induced toxicity by upregulation of anti-apoptotic genes (e.g. MCL-1), since APRIL enhanced survival of MM cells that were treated with anti-MM drugs, such as dexamethasone. Importantly, addition of hAPRIL.01A blocked this pro-survival effect, highlighting the potential of BION-1301 to enhance MM sensitivity towards MM-targeting agents.
We confirmed the immune suppressive potential of APRIL by showing that APRIL upregulates known immunosuppressive proteins such as IL-10 and PD-L1, indicating that BION-1301 could increase sensitivity to therapies such as daratumumab that depend on the immune system.
Finally, in vitro APRIL increased secretion of the chemokines MIP-1α and MIP-1β by MM cell lines, which are known to stimulate osteoclast differentiation and activation. This suggests a positive feedback loop in which APRIL, produced mainly by osteoclasts in the bone marrow, induces chemokine production by MM cells, and these chemokines in turn stimulate osteoclasts. Importantly, when hAPRIL.01A is added to block APRIL, chemokine production drops, indicating that in addition to sensitizing MM tumor cells for drug treatment, BION-1301 also suppresses osteoclast activity.
Altogether, we demonstrate in vitro that APRIL induces anti-apoptotic signaling, triggers expression of an immune suppressive phenotype, and could potentially modulate the tumor microenvironment through the production of key chemokines. Blocking APRIL with BION-1301 may dampen these effects, illustrating the potential of BION-1301, as a therapeutic agent for MM, particularly in combination therapies. BION-1301 is currently in a phase 1 clinical trial for MM.
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Asterisk with author names denotes non-ASH members.