A First in Class APRIL Fully Blocking Antibody Targets Novel Immune Regulation of APRIL in Multiple Myeloma: Further Therapeutic Implication

A proliferation inducing ligand (APRIL), a critical paracine factor for human multiple myeloma (MM), is mainly secreted by myeloid cells, including macrophages and osteoclasts in the bone marrow (BM) microenvironment. Recently, an antagonistic APRIL monoclonal antibody (mAb) 01A significantly reduced myeloma burden in SCID-hu mice (Blood. 2016;127:3225-3236). This data suggests that the humanized 01A named BION-1301, which also potently (IC50 + [JD2] FOXP3 high fractions; conversely, 01A blocks APRIL-induced upregulation of iTreg. Osteoclasts also upregulated iTreg generation induced by MM cells. On the contrary, 01A or C4 partially blocks such induction. Importantly, APRIL directly promotes proliferation and viability of Treg via the induction of CCND1/2, BCL2, and BCL2L1/BCL-xL, which is blocked by 01A or C4. Finally, APRIL enhances the suppressive function of Treg on the proliferation of autologous conventional T cells, which could also be overcome by 01A or C4. Collectively, our data therefore demonstrate that APRIL, via TACI but not BCMA, critically modulates regulatory T cell function; and, importantly, 01A or C4 targets these immune regulatory subsets that have been linked to MM progression via APRIL-dependent manner. Moreover, since patients with active diseases have severe bone lesions induced by hyperactive osteoclasts, inhibiting the APRIL-TACI interaction may also overcome osteoclast-inhibited T cell killing on MM cells. Anti-APRIL Ab (BION-1301) will be entering clinical trial in late 2017 to target the immunosuppressive BM microenvironment and improve patient outcome in MM. Disclosures Dulos: Aduro Biotech Europe: Employment, Equity Ownership. Van Elsas: Aduro Biotech Europe: Employment, Equity Ownership. Richardson: Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Oncopeptides AB: Membership on an entity9s Board of Directors or advisory committees. Anderson: Millenium Pharmaceuticals: Membership on an entity9s Board of Directors or advisory committees; MedImmune: Membership on an entity9s Board of Directors or advisory committees; C4 Therapeutics: Other: scientific founder; Gilead Sciences: Membership on an entity9s Board of Directors or advisory committees; Oncopep: Other: scientific founder; Bristol-Myers Squibb: Membership on an entity9s Board of Directors or advisory committees.