APRIL Pathway

Plasma cells play a key role in the immune system by producing antibodies important for protection against infection. Antibodies constitute a class of proteins called immunoglobulins (abbreviated Ig); there are five classes of immunoglobulins: IgG, IgM, IgD, IgE, and IgA.

Serious disorders, including certain blood cancers and autoimmune diseases, affect plasma cells and antibody production. Aduro is currently developing a treatment for IgA nephropathy (also known as IgAN or Berger’s disease), an inflammatory kidney disease caused by an auto-immune response to IgA.

APRIL stands for A Proliferation-Inducing Ligand – a protein involved in regulating plasma cells and normal levels of immunoglobulin production. Specifically, APRIL binds to BCMA and TACI receptors on the surface of plasma cells to stimulate production of IgA.

BION-1301: Targeting the APRIL Pathway to Treat IgA Nephropathy

IgA nephropathy is a chronic autoimmune kidney disease. In patients with IgA nephropathy, plasma cells secrete abnormal, galactose-deficient IgA (Gd-IgA1). A critical step in the pathology of IgA nephropathy is the generation of auto-antibodies to Gd-IgA1, leading to the formation of immune complexes which deposit in the kidney causing inflammation and organ damage. As the disease advances, patients with IgA nephropathy may require dialysis or kidney transplantation. There is no available treatment to reduce production of Gd-IgA1 associated with IgA nephropathy.

BION-1301, a first-in-class humanized IgG4 monoclonal antibody that fully blocks APRIL binding to both the BCMA and TACI receptors, is being evaluated in IgA nephropathy. APRIL stimulates plasma cells through the BCMA and TACI receptors to produce high levels of IgA, and is known to promote the disease process in cancers and autoimmune diseases involving plasma cells. Studies have shown high levels of APRIL correlate with poor prognosis in patients with IgA nephropathy.

BION-1301 binds and neutralizes APRIL. Blockade of APRIL by BION-1301 has been shown to significantly lower IgA and IgM and to a lesser extent IgG in preclinical studies. In patients with IgA nephropathy, BION-1301 has the potential to neutralize APRIL, inhibit secretion of Gd-IgA1, and thereby reduce immune complex formation and kidney deposition.

Aduro has initiated a Phase 1 clinical trial of BION-1301 in healthy volunteers and patients with IgA nephropathy. Additional clinical trials are planned to further evaluate the safety and efficacy of BION-1301 in patients with IgA nephropathy.

Separately, Aduro recently completed the dose escalation portion of a Phase 1/2 clinical trial evaluating safety and tolerability of BION-1301 in patients with relapsed or refractory multiple myeloma whose disease had progressed after at least three prior systemic therapies. In the trial, BION-1301 was well tolerated across a wide dose range; no dose limiting toxicities were observed at any dose level examined. While 95% APRIL target engagement was achieved at peak exposure levels, and levels of free APRIL decreased in a dose-dependent manner, no objective responses were observed.

Anti-CD27 Antibody: Targeting CD27

Aduro’s anti-CD27 antibody is being advanced by Merck under a development and commercialization collaboration agreement. CD27 has been recognized as having a critical role in activating a productive anti-cancer (CD8 T cell) immune response and has demonstrated the potential to be combined with checkpoint inhibitors in preclinical studies. Aduro’s anti-CD27 antibody is distinct because it targets a functional epitope on CD27 which demonstrated potent activation of the CD27 co-stimulatory pathway in preclinical studies.