FELZARTAMAB

Felzartamab 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 including anti-PLA2R antibody-positive membranous nephropathy (MN) and IgA nephropathy (IgAN), both autoimmune renal diseases. In the future, felzartamab might potentially be evaluated as targeting therapy in additional autoimmune mediated diseases.

End of 2017, MorphoSys entered into an exclusive regional licensing agreement with I-Mab Biopharma to develop and commercialize felzartamab in Greater China, in particular in patients with multiple myeloma.

Therapeutic fields and proposed mode of action

Glomerulonephritis (GN) 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. Membranous nephropathy (MN) and IgA Nephropathy (IgAN) account for 40-45% of all GN (Cattran et al., 2017) and are 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)

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 MN is estimated at 1.2 per 100,000; about 3,000 adults newly diagnosed every year (Mc Gorgan, 2011). Around 80% of MN 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).

Anti-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 anti-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).

IgAN, also known as Berger’s disease, is the most prevalent chronic glomerular disease worldwide; it accounts for 27% of renal biopsy (Yim T, 2020, Schena 2018). The clinical and pathological manifestations are highly variable and may include asymptomatic hematuria, massive proteinuria, hypertension, interstitial fibrosis, glomerulosclerosis and a slow progression to chronic kidney disease (Hass, 1997, Rodrigues, 2017, Moriyama, 2014). Although spontaneous remission of IgAN occurs in 10–20% of patients, a minority of cases are considered ‘rapidly progressing IgAN’, defined as an increase in serum creatinine to >1.5 mg/dL; the 5-year renal survival rate in these patients is approximately 30% (Suzuki, 2014; Lv, 2013). Within 20 years of diagnosis, about 40% of patients with IgAN progress to ESRD (Schena et al. 2018). Major risk factors for progression to ESRD are persistent proteinuria, hypertension, and reduced glomerular filtration rate (Fellstroem 2017, Wyatt 2013). Worldwide IgAN incidence is estimated at 2.5 per 100,000 (McGrogan, 2011). IgA nephropathy can affect all ages but is most common in the second and third decades of life.(Wen, 2010).

IgAN is an autoimmune disease of the glomeruli, in which a combination of genetic and environmental factors cause patients to produce galactose-deficient IgA1 (Gd-IgA1; Rodrigues, 2017; Knoppova, 2016). Patients’ immune system reacts against Gd-IgA1 by producing specific autoantibodies. The binding of these IgG autoantibodies to Gd-IgA1 form immune complexes in the circulation, then accumulates in the glomerular mesengium where they induce local inflammation, mesangial proliferation, glomerulosclerosis and loss of renal function (Figure 2; Knoppova, 2016; Rodrigues, 2017).

Management of IgAN is initially focused on non-immunosuppressive strategies, so-called supportive care, to slow the rate of progression of the disease: rigorous blood pressure control, optimal inhibition of the renin angiotensin system, and lifestyle modification, including weight reduction, exercise, smoking cessation, and dietary sodium restriction (KDIGO 2020). If not well-managed, they move on to immunosuppressive treatment.

B-cells provide immunity, and have a key role in autoimmunity, by differentiating into antibody-secreting plasma cells. This differentiation is associated with a change of cell markers. Earlier B-cell stages expressed CD20 marker at their cell surface, while CD38 molecule is highly expressed on differentiated B-cells called plasmablasts and short/long lived-plasma cells. CD38-positive plasma cells are the main source of autoantibodies in autoimmune diseases as they produce quantitatively more autoantibodies than CD20-positive B cells (Bayles, 2014; Jackson, 2015, Halliley, 2016)

 Felzartamab specifically binds to the cell surface antigen CD38. Binding of felzartamab to CD38-positive plasma cells facilitates the depletion of such cells via two modes of action: i) antibody-dependent cell-mediated cytotoxicity (ADCC) in which the plasma cells are lysed by Natural killer (NK) cells, and ii) antibody-dependent cell-mediated phagocytosis (ADCP) in which the macrophages clear away the plasma cells  (Endell, 2012; Boxhammer, 2015; Raab, 2020). Since the depletion of antibody producing cells should subsequently lead to a decrease in antibody titers, treatment with felzartamab may be potentially beneficial in autoimmune diseases with a causal relationship between autoantibodies and the disease (Figure 3).

In both MN and IgAN, long-lived plasma cells drive pathogenic antibody production, contributing to functional damage to the glomeruli (Rodrigues, 2017; Ruggenenti, 2015). In IgAN, plasma cells are also the main source of the disease trigger, ie Gd-IgA1 (Rodrigues, 2017).

• In Membranous Nephropathy, a tight correlation has been described between the clinical course of the disease and PLA2R pathogenic autoantibody titer. Patients with a higher anti-PLA2R autoantibody titer have more severe disease and a longer time to disease remission (Pozdzik, 2018; van de Logt, 2019). High titers and sustained or recurrent positivity for anti-PLA2R antibody titers during therapy emerge as negative predictors for outcome (Bomback 2018; Ruggenenti, 2015). By contrast, a reduction in anti-PLA2R autoantibody levels is predictive of future likelihood of remission of proteinuria (Dahan, 2017; Ruggenenti, 2015). It precedes a reduction in proteinuria and increase in serum albumin (Beck, 2011; Ruggenenti, 2015). Patients presenting with high autoantibody titers are treated with anti-CD20 antibodies (Ruggenent, 2015; Fervenza et al., 2019). However, anti-CD20 therapeutic approaches target only activated B-cells that produce less autoantibodies, and leave C20-negative/CD38-positive long-lived plasma cells, which maintains the autoimmunity. As a result, up to 40% of patients failed to respond to anti-CD20 therapies (Bomback, 2018, Couser 2017). 

In this context, a felzartamab-induced depletion of the main source of pathogenic antibodies, ie the plasma cells, may potentially provide a viable emerging therapeutic option sparing patients of significant toxicity by conventional immunosuppressive agents and possibly improve outcomes for patients with limited benefit of an anti-CD20 directed therapy.

• In IgAN, high immunological activity is correlated with worse clinical outcomes in patients with IgAN. Serum levels of Gd-IgA1 are associated with risk of decline in renal function and serum levels of anti-Gd-IgA1 antibodies at the time of biopsy are associated with progression to dialysis and death (Berthoux, 2012; Zhao, 2012). High serum levels of Gd-IgA1, anti-Gd-IgA1 and circulating immune complexes are all associated with severity of proteinuria and/or hematuria (Suzuki, 2009; Suzuki, 2019). Current therapeutic options are limited to supportive care or broad-acting immunosuppressive therapies (KDIGO, 2020). As Gd-IgA1-containing immune complexes play a critical role in the pathogenesis of IgAN, a therapeutic intervention that targets the production of Gd-IgA1 and/or the autoantibodies specific to Gd-IgA1 could be an effective disease-specific treatment for IgAN (Knoppova, 2016).

In this context, felzartamab may have a dual action through the depletion of the plasma cells. It may remove both components of the immune complexes, the antigen Gd-IgA1 and the IgG autoantibodies to Gd-IgA1. Hence, felzartamab may potentially be an emerging disease-modifying therapeutic option for patients with IgAN.

Multiple myeloma (MM) is subtype of blood cancer that originates in plasma cells. The malignant cells accumulate in the bone marrow, where they displace and suppress healthy blood progenitor cell populations (Kyle, 2009; Rawstron, 1998). Multiple myeloma is also characterized by destructive lytic bone lesions (rounded, punched-out areas of bone), diffuse osteoporosis, bone pain, and the production of abnormal proteins, which accumulate in the urine (Dispenzieri, 2005; Kyle, 2003). Anemia is also present in most multiple myeloma patients at the time of diagnosis and during follow-up. Anemia in multiple myeloma is multifactorial and is secondary to bone marrow replacement by malignant plasma cells, chronic inflammation, relative erythropoietin deficiency, and vitamin deficiency (Baz, 2004; Bouchnita, 2016).

PROPOSED MODE OF ACTION OF FELZARTAMAB IN MULTIPLE MYELOMA
CD38 is one of the most strongly and uniformly expressed antigens on the surface of malignant plasma cells and is an established diagnostic marker for Multiple myeloma (Jeong, 2012; Flores-Montero, 2016). Binding of felzartamab to CD38 may result in in antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) mediated killing of cancer cells (Raab, 2020). 
 

Disclaimer: MorphoSys’ product candidates are investigational and are currently not approved for the treatment of any disease or condition anywhere in the world. They cannot be prescribed or purchased for therapy at present. The MorphoSys website may contain information on drug candidates and clinical trials sponsored by MorphoSys with the intention of increasing the transparency of the company’s clinical research. There is no guarantee any product will be approved in the sought-after indication. Information contained within this website is not intended to replace the advice of a healthcare professional and should not be considered as a recommendation. Patients should always seek medical advice before making any decisions on their treatment. All reasonable precautions have been taken to ensure the accuracy, security, and confidentiality of information available through the site. MorphoSys may amend the information at any time without notice.

REFERENCES

1. Bayles I, et al. Plasma Cell Formation, Secretion, and Persistence: The Short and the Long of It. Critical Reviews in Immunology. 2014;34(6):481–99.
2. Baz R, et al. Prevalence of vitamin B12 deficiency in patients with plasma cell dyscrasias: a retrospective review. Cancer. 2004; 101(4):790-795.
3. Beck LH Jr, et al. Rituximab-Induced Depletion of Anti-PLA 2 R Autoantibodies Predicts Response in Membranous Nephropathy. Journal of the American Society of Nephrology. 2011;22(8):1543–50.
4. Bomback AS, et al. Membranous Nephropathy: Approaches to Treatment. American Journal of Nephrology. 2018;47(1):30–42.
5. Bouchnita A, et al. Bone marrow infiltration by multiple myeloma causes anemia by reversible disruption of erythropoiesis. Am J Hematol. 2016;91(4):371-378.
6. Boxhammer R, et al. MOR202, a Human Anti-CD38 Monoclonal Antibody, Mediates Potent Tumoricidal Activity In Vivo and Shows Synergistic Efficacy in Combination with Different Antineoplastic Compounds. ASH annual meeting. 2015;3015
7. Canetta PA, et al. Health-related quality of life in glomerular disease. Kidney Int. 2019;95(5):1209-1224.
8. Couser WG, et al. The etiology of glomerulonephritis: roles of infection and autoimmunity. Kidney Int. 2014;86(5):905-914.
9. Couser WG. Primary Membranous Nephropathy. Clinical Journal of the American Society of Nephrology. 2017;12(6):983–97.
10. Dahan K, et al. Rituximab for Severe Membranous Nephropathy: A 6-Month Trial with Extended Follow-Up. Journal of the American Society of Nephrology. 2017;28(1):348-58.
11. Dispenzieri A, et al. Multiple myeloma: clinical features and indications for therapy. Best Pract Res Clin Haematol. 2005;18(4):553-568.
12. Endell J, et al. The Activity of MOR202, a Fully Human Anti-CD38 Antibody, Is Complemented by ADCP and Is Synergistically Enhanced by Lenalidomide in Vitro and in Vivo. Blood. 2012;120(21):4018–4018.
13. Fervenza FC, et al. Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy. New England Journal of Medicine. 2019;381(1): 36-46.
14. Flores-Montero J, et al. Immunophenotype of normal vs. myeloma plasma cells: Toward antibody panel specifications for MRD detection in multiple myeloma. Cytometry B Clin Cytom. 2016;90(1):61-72
15. Halliley JL et al. Long-Lived Plasma Cells Are Contained within the CD19−CD38hiCD138+ Subset in Human Bone Marrow. Immunity. 2015;43(1):132–145.
16. Heaf J, et al. The Epidemiology and Prognosis of Glomerulonephritis in Denmark 1985–1997. Nephrology Dialysis Transplantation. 1999;14(8):1889-1897.
17. Jackson DA and Elsawa SF. Factors Regulating Immunoglobulin Production by Normal and Disease-Associated Plasma Cells. Biomolecules. 2015;5(1):20–40.
18. Jeong TD, et al. Simplified flow cytometric immunophenotyping panel for multiple myeloma, CD56/CD19/CD138(CD38)/CD45, to differentiate neoplastic myeloma cells from reactive plasma cells. Korean J Hematol. 2012;47(4):260-266
19. KDIGO Clinical Practice Guideline on Glomerular Diseases; June 2020. Available at: https://kdigo.org/wp-content/uploads/2017/02/KDIGO-GN-GL-Public-Review-Draft_1-June-2020.pdf
20. Kyle RA, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc. 2003;78(1):21-33.
21. Kyle RA, et al. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2009;23(1):3-9.
22. Lee T, et al. Patients with Primary Membranous Nephropathy Are at High Risk of Cardiovascular Events. Kidney International. 2016;89(5):1111–1118.
23. Mirrakhimov A, et al. Primary Nephrotic Syndrome in Adults as a risk Factor for Pulmonary Embolism: An up-to-Date Review of the Literature. International Journal of Nephrology. 2014;2014:916760
24. Murphy SL, et al. Longitudinal Changes in Health-Related Quality of Life in Primary Glomerular Disease: Results From the CureGN Study. Kidney Int Rep. 2020;5(10):1679-1689.
25. National Kidney Foundation. Hemodialysis - Definition, procedure, and types. Available at https://www.kidney.org/atoz/content/hemodialysis. Accessed May 2021.
26. Nordio M, et al. Survival in patients treated by long-term dialysis compared with the general population. Am J Kidney Dis. 2012;59(6):819-828.
27. Passerini P, et al. Membranous Nephropathy (MN) Recurrence After Renal Transplantation. Front Immunol. 2019;10:1326.
28. Ponticelli C, et al. Posttransplant recurrence of primary glomerulonephritis. Clin J Am Soc Nephrol. 2010;5(12):2363-2372.
29. Pozdzik A, et al. Membranous Nephropathy and Anti-Podocytes Antibodies: Implications for the Diagnostic Workup and Disease Management. BioMed Research International. 2018:1–19.
30. Raab MS, et al. MOR202, a Novel Anti-CD38 Monoclonal Antibody, in Patients with Relapsed or Refractory Multiple Myeloma: A First-in-Human, Multicentre, Phase 1–2a Trial. The Lancet Haematology. 2020;7(5):e381–e394.
31. Rawstron AC, et al. B-lymphocyte suppression in multiple myeloma is a reversible phenomenon specific to normal B-cell progenitors and plasma cell precursors. Br J Haematol. 1998;100(1):176-183.
32. Rodrigues JC, et al. IgA Nephropathy. Clin J Am Soc Nephrol. 2017;12(4):677-686
33. Ronco P, et al. Advances in Membranous Nephropathy. Journal of Clinical Medicine. 2021;10(4): 607.
34. Ruggenenti P, et al. Anti-Phospholipase A 2 Receptor Antibody Titer Predicts Post-Rituximab Outcome of Membranous Nephropathy. Journal of the American Society of Nephrology. 2015;26(10):2545–58.
35. Sim JJ, et al. End-Stage Renal Disease and Mortality Outcomes Across Different Glomerulonephropathies in a Large Diverse US Population. Mayo Clin Proc. 2018;93(2):167-178.
36. Troyanov S, et al. Idiopathic Membranous Nephropathy: Definition and Relevance of a Partial Remission. Kidney International. 2004;66(3):1199–1205.
37. Trujillo H and Praga M. Membranous Nephropathy: An Update. Portuguese Journal of Nephrology & Hypertension. 2019;33(1): 19-27.
38. Van de Logt AE, et al. The Anti-PLA2R Antibody in Membranous Nephropathy: What We Know and What Remains a Decade after Its Discovery. Kidney International. 96(6): 1292–1302.
39. Wagoner RD, et al. Renal Vein Thrombosis in Idiopathic Membranous Glomerulopathy and Nephrotic Syndrome: Incidence and Significance. Kidney International. 1983;23(2): 368–374.
40. Wakasugi M, et al. High mortality rate of infectious diseases in dialysis patients: a comparison with the general population in Japan. Ther Apher Dial. 2012;16(3):226-231.
41. Wyatt J, et al. IgA Nephropathy. N Engl J Med. 2013;368:2402-2414
42. Wetmore JB, et al. The incidence, prevalence, and outcomes of glomerulonephritis derived from a large retrospective analysis. Kidney Int. 2016;90(4):853-860.