Abstract 2645: Development of a first in class APRIL fully blocking antibody BION-1301 for the treatment of multiple myeloma
Authors: Dulos John , Driessen Lilian , Snippert Marc , Guadagnoli Marco , Bertens Astrid , Hulsik David Lutje , Tzu Tai Yu , Anderson Kenneth , Medema Jan Paul , Cameron Kate , Eenennaam Hans , Elsas Andrea 
Published: July 2017

Abstract
APRIL, or tumor necrosis factor super family member 13 (TNFSF13), is a ligand for the receptors B-cell maturation antigen (BCMA) and transmembrane activator calcium modulator and cyclophilin ligand (CAML) interactor (TACI). APRIL serum levels are enhanced in patients diagnosed with multiple myeloma (MM), chronic lymphocytic leukemia (CLL) and colorectal carcinoma and are correlated with poor prognosis.
As a paracrine factor produced by osteoclasts, macrophages and other cells in the bone marrow niche, APRIL binds to BCMA to drive proliferation and survival of human Multiple Myeloma (MM) cells and induces resistance to several standard of care agents. Using a mouse anti-human APRIL blocking antibody 01A1 originally discovered using Aduro’s B-Select platform, we demonstrated that osteoclast-induced MM cell in vitro proliferation and survival is dependent on APRIL. In these co-cultures, cytolytic activity of lenalidomide and bortezomib is significantly enhanced by 01A in a dose-dependent fashion2. Importantly, APRIL drives and 01A inhibits expression of an immunosuppressive gene set including the immune checkpoint programmed death ligand-1 (PD-L1), interleukin-10, vascular endothelial growth factor, and transforming growth factor beta.
The human APRIL antagonist antibody 01A was humanized and designated BION-1301. The antibody binds an epitope overlapping the BCMA and TACI binding sites potently and fully blocks BCMA and TACI binding (IC50 &lt;1 nM). Biophysical and functional experiments indicated that BION-1301 recapitulated all characteristics of 01A. In vivo, BION-1301 was shown to suppress T cell-independent B cell responses to NP-Ficoll. Furthermore, APRIL blockade demonstrated single agent anti-multiple myeloma activity in a humanized SCID model2 confirming its activity in vivo, and potentially indicating that BION-1301 is active targeting multiple myeloma cells in a tumor-protective bone marrow microenvironment.
To our knowledge, BION-1301 is a first-in-class humanized APRIL antagonist demonstrated in to inhibit multiple myeloma survival, drug resistance and an immune suppressive phenotype preclinical. These data suggest a rationale to develop BION-1301 as a single agent, and in combination with lenalidomide, bortezomib, or possibly checkpoint inhibitors such as anti-PD-1. BION-1301 is expected to enter Phase 1 in 2017.
1) Guadagnoli at al. Blood. 2011 Jun 23;117(25):6856-65
2) Yu-Tzu et al. Blood. 2016 Jun 23;127(25):3225-36
Citation Format: John Dulos, Lilian Driessen, Marc Snippert, Marco Guadagnoli, Astrid Bertens, David Lutje Hulsik, Tai Yu Tzu, Kenneth Anderson, Jan Paul Medema, Kate Cameron, Hans Eenennaam, Andrea Elsas. Development of a first in class APRIL fully blocking antibody BION-1301 for the treatment of multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2645. doi:10.1158/1538-7445.AM2017-2645