Abstract
A PRoliferation Inducing Ligand (APRIL, TNFSF13), is a ligand for the receptors BCMA and TACI. APRIL serum levels are enhanced in patients diagnosed with Multiple Myeloma (MM), Chronic Lymphocytic Leukemia (CLL), and Colorectal Carcinoma correlated with poor prognosis. Our anti-APRIL antibody blocked CLL survival and inhibited mouse B1 hyperplasia 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 vivoto drive proliferation and survival of human MM cells (Tai et al., 2016). Importantly, APRIL induces resistance to lenalidomide, bortezomib and other standard-of-care drugs. Furthermore, APRIL drives expression of PD-L1, IL-10, VEGF and TGFβ forcing an immunosuppressive phenotype on BCMA+ cells. As MM 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.A novel mouse anti-human APRIL antibody hAPRIL.01A (Guadagnoli et al., 2011) initially discovered using Aduro’s B-Select platform, was humanized and further engineered enhancing its stability (designated as BION-1301). The antibody binds to recombinant human APRIL with a KDof 0.4 ± 0.15 nM determined by BioLayer Interferometry and an EC50 of 0.29 ± 0.05 nM by ELISA. The epitope of BION-1301 was mapped to the BCMA and TACI binding site explaining its fully blocking capacity. Blocking potency (IC50) was 1.61 ± 0.78 nM (BCMA) and 1.29 ± 0.89 nM (TACI) respectively, corroborated by potent and complete blockade of APRIL-induced cytotoxicity of BCMA-Fas and TACI-Fas Jurkat transfectants. In vitro, BION-1301 suppressed APRIL-induced B-cell IgA and IgG class switching in a dose-dependent fashion. In vivo, BION-1301 was shown to suppress human APRIL induced T cell-independent B cell responses to NP-Ficoll. Biophysical and functional experiments indicated that BION-1301 recapitulated all characteristics of the mouse parental antibody hAPRIL.01A. To support the clinical development of BION-1301, quantitative assays were developed using several mouse-anti-human APRIL antibodies and shown to detect free and complexed APRIL in human blood samples. Results obtained with assays demonstrate that APRIL can be quantified reproducibly in human sera and overcome the drawbacks of previous assays, such as requirement of polyclonal sera, Ig adsorption, interference by human serum and reduced sensitivity.In conclusion, we have generated and functionally characterized a novel humanized APRIL neutralizing antibody, designated BION-1301. The mechanism-of-action and anti-tumor activity described for the parental antibody hAPRIL.01A in vitro and in vivo strongly support the development of BION-1301 as a single agent or in combination with lenalidomide, bortezomib, and suggest a rationale for combination with checkpoint inhibitors. BION-1301 is expected to enter clinical development in 2017.
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