Felzartamab (MOR202) is a therapeutic human monoclonal antibody derived from MorphoSys’ HuCAL antibody library and directed against CD38. Felzartamab is an investigational drug that has not yet been approved by any regulatory authorities. The safety and efficacy of Felzartamab are currently evaluated in patients with glomerulonephritis, precisely anti-PLA2R antibody-positive membranous nephropathy, an autoimmune renal disease. In the future, Felzartamab might potentially be evaluated as targeting therapy in additional autoimmune mediated diseases.
Therapeutic fields and proposed mode of action
Glomerulonephritis is a group of renal disorders that cause damage to the glomeruli, the filtration units of the kidney, hindering their ability to carry out their essential functions. It is a common cause of end stage renal disease (Sim et al. 2019). Patients living with end stage renal disease are burdened by the need for lifelong dialysis and/or transplantation. Dialysis is typically required three times weekly for 4 hours per session (National Kidney Foundation, 2020); it carries an increased risk of infection (Wakasugi, 2012), and is associated with 44% mortality at 5 years (Nordio, 2012). Moreover, autoimmunity is unequivocally regarded as the predominant pathogenic process underlying most forms of Glomerulonephritis (Couser, 2014). The ongoing presence of autoantibodies can precipitate recurrence of disease after transplantation, increasing the risk of graft failure (Passerini, 2019; Ponticelli, 2010). Although some patients do not progress to end stage renal disease, they are at an increased risk for life-threatening thrombotic events including deep venous thrombosis, renal vein thrombosis, and pulmonary embolism (Mirrakhimov, 2014).
The manifestations of glomerular diseases are also associated with significantly impaired Quality of life including physical and mental health, fatigue, sleep impairment and anxiety (Canetta, 2019; Murphy, 2020).
Membranous Nephropathy (MN) is a leading cause of nephrotic syndrome in adults worldwide (Couser, 2017). Nephrotic syndrome refers mainly to the presence of heavy proteinuria (loss of protein greater than 3.5 g/day), low serum albumin and marked edema (Couser 2017; Trujillo, 2019). The natural course of MN is variable and unpredictable. Although 30-40% of patients may experience spontaneous remission, 30% of patients experience persistent proteinuria with long-term preservation of renal function, and another 30%–50% progress to renal failure within 10-15 years (Trujillo, 2019; Heaf, 1999, Troyanov, 2004). Even if patients with nephrotic syndrome do not progress to renal failure, they have an increased risk of life-threatening thromboembolic and cardiovascular events, and are subject to infections (Wagoner, 1983; Heaf, 1999; Lee, 2016).
In the United States, the incidence of Membranous Nephropathy is estimated at 1.2 per 100,000; about 3,000 adults newly diagnosed every year (Mc Gorgan, 2011). Around 80% of Membranous Nephropathy cases are primary and mediated by autoantibodies, while 20% are secondary to other diseases. The age of onset is typically 50-60 years old (Couser, 2017).
Phospholipase A2 receptor (PLA2R) antibody positive MN makes up to 85% of all primary Membranous Nephropathy (Trujillo, 2019, Pozdizk, 2018, Couser 2017). PLA2R is a membrane glycoprotein expressed on epithelial cells in glomeruli. In PLA2R antibody-positive MN, patients’ immune system reacts against PLA2R by producing specific autoantibodies. The immune complexes formed by the binding of these autoantibodies to PLA2R induces inflammation, which leads to thickening of the glomerular membrane and cause nephrotic syndrome in 80% of the patients with MN (Couser 2017; Trujillo, 2019; Pozdizk, 2018) (figure 1).
Currently, there is no approved standard treatment for Membranous Nephropathy. The KDIGO guidelines – a global nonprofit organization developing and implementing evidence-based clinical practice guidelines in kidney disease - recommend using criteria such as anti-PLA2R antibody titer and proteinuria to stratify patients by risk and determine course of treatment. The current treatment regimen mainly comprises various non-immunosuppressive drugs (eg ACE inhibitors or Angiotensin receptor blockers, statins, and diuretics), conventional immunosuppressive drugs (e.g. cyclophosphamide combined with steroids, calcineurin inhibitors, mycophenolat-Mofetil) and off-label use of B-cell depleting agents (e.g. anti-CD20 antibodies) (KDIGO 2020; Ronco, 2021).