Ozoralizumab (as known as ATN-103) is a humanized monoclonal antibody designed for the treatment of inflammatory diseases and is developed by the Belgium pharmaceutical company Ablynx. In addition, it is a trivalent, bispecific nanobody that potently neutralizes TNF and binds to human serum albumin to increase its in vivo half-life. It is consisting of two anti-tumor necrosis factor-α (TNF-α) nanobodies (TR2) and one albumin-binding nanobody (ARI) with a MW~45 kDa which was successfully developed preclinically. In a phase I study, ATN-103 showed good tolerability and subsequently was licensed to Pfizer who have completed the recruitment of two phase II studies in 48 patients in Japan and the USA with subcutaneous administration of ozaralizumab every 4 weeks for 16 weeks in patients with rheumatoid arthritis. In addition, open label extension of a phase II study in 260 patients with rheumatoid arthritis is ongoing to ensure long term safety of the novel albumin binding nanobody. 2 singe ascending dose (SAD)/ multiple ascending dose (MAD) studies in 313 patients (world-wide and Japan) with active RA on stable MTX background evaluated ozoralizumab's clinical activity and safety during 12 weeks of treatment. The 80mg Q4W dosing regimen significantly improved disease activity measures compared with placebo. The novel anti-TNFα inhibitor ATN-103 enabled highly effective and well-tolerated individualized treatment. Specific molecular features of Nanobodies (small size, low immunogenicity potential, manufacturability) contributed to the desired treatment outcome with the majority of patients showing marked improvement in their disease activity and, moreover, once induced remission could be maintained at doses less than 80mg monthly.
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease of unknown etiology that is characterized by polyarticular pain and swelling. RA should be diagnosed and treated early in order to limit joint damage, associated complications, and progressive disability. The worldwide prevalence of RA is estimated to be around 1%, with considerable variation depending on the population studied. Current treatments for RA include anti-tumor necrosis factor (TNF) alpha drugs, which have proven able to control disease progression and reduce the rate of disability. Tumor necrosis factor (TNF, tumor necrosis factor alpha or TNF-α) is a cell signaling protein (cytokine) involved in systemic inflammation and is one of the cytokines that make up the acute phase reaction. It is produced chiefly by activated macrophages, although it can be produced by many other cell types. The primary role of TNF is in the regulation of immune cells. TNF, being an endogenous pyrogen, is able to induce fever, apoptotic cell death, cachexia, inflammation and to inhibit tumorigenesis and viral replication and respond to sepsis via IL1 & IL6 producing cells. In addition, human serum albumin (HSA) is the most abundant plasma protein in human blood. It is synthesized in the liver hepatocytes and released into the vascular space daily. Circulation in the blood proceeds for an extended period of ~19 days. Albumin contains multiple hydrophobic binding pockets and naturally serves as a transporter of a variety of different ligands such as fatty acids and steroids as well as different drugs. Furthermore, the surface of albumin is negatively charged making it highly water-soluble. Ozoralizumab is a small trivalent, bispecific nanobody which has two peptides, one to interact with TNF-α, and the other, albumin. The drug can inhibit TNFα while prolonging its own half-life. Simultaneously, its specific molecular features (small size, low immunogenicity potential, manufacturability) contributed to the desired treatment outcome.
Fig 1. Mechanism of Action of Ozoralizumab