Immunoglobulin A1 (IgA1) desposition in human tissues and organs is a characteristic of many human diseaes including IgA nephropathy, dermatitis herpetiformis (DH), and Henoch-Schoenlein purpura, and it is responsible for a variety of clinical manifestations such as renal fialure, skin blistering, rash, arthritis, gastroinstestinal bleeding and abdominal pain (HS) (WO 2004/096157).
Specific Types of Diseases
Henoch-Schonlein purpura (HSP): is another IgA1 mediated post infectious vasculities, most often in children ages 2-11, with kidney damage very similar to IgAN (see below).
IgA nephropathy (IgAN, Berger’s disease): is characterized by the deposition of IgA1 in the mesangium of the renal glomerulus and is the most common glomerulonephritis worldwide. In Japan, it constitutes 30% or more of primary renal diseases, and is the most common renal disease. Moreover, 15-30% of the patients with IgA nephropathy achieve renal failure. The IgA depositis arise spontaneously, usually in the second or third decade of life and are thought to be immune complexes. IgA nephropaty is a disease with a poor long term prognosis and it is estimated that about 25% of patients with terminal renal failure who are in need of dialysis treatment have IgA nephropathy as the original disease.
IgA nephropathy is a chronic glomerulonephritis which is characterized in that an IgA immune complex considered to be originated form blood deposits in the glomerulus of the kidney. It has been reported that bout 50% of the patients with IgA nephropathy have a high blood IgA level. It is considered that excessive IgA is produced due to abnormality in the immune system, resulting in IgA immune complex in blood deposits on the glomerulus.
IgA nephrapathy is caused by aberrant glycosylation of IgA molecules, which are subsequently recognized by antiglycan autoantibodeis. Glomerular immune complex deposits can lead to complement activation, which casues podocyte damage either direclty or indirectly with activaiton of mesangial cells and stimulation of cytokines and other downstream immune meditors. (Lambris, “The renaissance of complement therapeutics” (2018))
IgM nephropathy (IgMN): causes nephrotic syndrome and is characterized by IgM mesangial deposits. It is sepculated that these deposits are derived from icrulating IgM aggregates or immune complexes, similar to IgAN.
–Mechanisms of Action
The mechanism of polymeric IgA1 deposition in the kidney mesangium is poorly understood in IgAN. It has been suggested that increased sialic acid content and anionic charge of the pIgA1 molecules may be operational in the IgA1 deposition in human mesangial cells. (Leung, Kindey International, 59, 2001, pp. 277-285)
–Diagnosis
Diagnosis is typically by renal biopsy, which removed a sample of the kidney tissue for pathological examination. A renal pathologist does immunofluorescent staining of kidney tissues which requires sequential applicaiton of anti-human IgA antibody.
Qui (US 13/439473) discloses a method for diagnosing an IgA or Igm kidney disease by administering to the person a compound which specifically binds IgA or IgM and detecting the compound in the kindey of the mammal. The compound can include a peptide such as the human Fc alphaR1 or streptococcal IgA binding peptide, modified Z domain protein.
Obara (US 8,2426,142 B2) discloses an IgA nephropathy testing method comprising a complex detection step of detecting a complex of human uromodulin and human IgA in a sample derived form urine collected from a subject.
Ishiwata (US 2003/0207828) discloses a novel DNA whose expression level fluctuates in leukocytes of IgA nephropathy patients as well as isoalting the protein encoded by the DNA. Based on this, an antibody recognizing the protein is disclosed and methods for detecting the protein and DNA.
–Treatment
Treatment options for patients that present with abnormal IgA1 deposition include administration of corticosteroids that have immunosuppressive and anti-inflammatory properties, dietary fish oil supplements that reduce renal inflammation, and angiotensin converting enzyme inhibitors that reduce the risk of progressive renal disease and renal fialure (Plaut, WO2004/096157).
To address the problem of IgA1 desposit removal, exogenous proteolytic enzymes have been tested in IgA1 deposition animal models. The proteases, chymopapain and subtilisin act by proteolytic cleavage of IgA1 depositis in the kidney but are not specific for IgA1 and will digest a variety of other proteins (Plaut, WO 2004/096157).
Plaut (US 2005/0136062 A1) disclose the use of bacterial IgA1 proteases to treat IgA1 which specifically cleave IgA1 molecules deposition in tissue and organs. In one embodiment, a pharmaceutical composition for the treatment of IgA1 deposition is provided that comprises an IgA1 protease complexed with an antibody, such as an anti-IgA1 protease antibody.