See also: Drug targetting under “Pharmacology”
Introduction:
Lupus Nepthritis also known as “membranous glomerulonephritis” refers to an inflammation of the kidney caused by the chronic autoimmune disease SLE. Those afflicted with lupus nephritis may or may not have renal symptoms, but the disease can manifest itself through weight gain, high blood pressure, darker foamy urine or swelling around the eyes, legs, ankles or fingers. In some cases, the only renal manifestation of the disease is painless hematuria or proteinuria, but in some cases patients develop lupus nephritis, leading to acute or end stage renal failure.
Pathology
Complement is known to be involved in eitology and progression of renal inflammation and lupus nephritis. Complement cascade proteins and their proteolytically generated fragments (i.e., fragments of C3 and C4) are deposited on the glomerulocapillary, mesangial and tubulointerstitial cells during may types of renal injury. Renal biopsies are routinely stained for deposits of C3 activation fragments (C3b/iC3b/C3d) and glomerualr C3 deposits are found in most forms of glomerulonephritis (Sargsyan, Kidney International (2012) 81, 152-159
Diagnosis
Biopsy: The most commonly used system for classifying the different histologic patters of lupus nephritis is based upon the appearance of glomeruli by light microscopy. Percutaneous renal biopsy is the gold standard for diagnosis of lupus nephritis and for monitoring the course of disease.
Noninvasive detection of C3 fragments in the kidneys:
Complement activation is central to the pathogenesis of many inflammatory and autoimmune diseases. It is also a robust marker of tissue inflammation since activation of the complement system leads to the rapid covalent linkage of multiple c3b, iC3b, and C3d molecules to cell surfaces. Immunostaining for tissue C3 fragments is routinely performed on kidney biopsy samples when patients are suspected of having an autoimmune disease and when the presence of flomerular C3 deposits indicates active glomerulonephritis. (Serkova, Radiology, 255(2), 2010).
targeted CR2-Fc-SPIO fusion proteins: Thurman (US 13/148028; see also Sargsyan, Kidney International (2012) 81, 152-159) disclose conjugating superparagmentic iron oxide (SPIO) particles and ultrasmall SPIO particles conjugated with complement receptor type 2 (CR2)-Fc which can be used as negative contrast agents for MRA for the detection of intra-renal C3b/iC3b/C3d deposits in the kidneys of mouse models for lupus nepthritis. Interestingly, CR2-targeted SPIO reduced T2 relaxation times occured in the inner medulla of the mice kidneys, in spit of the fact that this is little C3b/iC3b/C3d at this location. The authors explain this result that during intra-renal trafficking of CR2 targeted SPIO, the CR2 interaction may trap them within the diseased kidney.
Treatment
Steroids: Patients with active proliferative nephritis are usually treated with steroids in combination with cytotoxic agents or mycophenolate mofetil.
B-cell Activator Factor/B-lymphocyte stimulator (BLyS) Inhibitors:
–Benlysta (belimumab -Glaxo Smith): is an anti-BLyS monocloanl antibody for systemic lupus erythematosus and lupus nephritis. Overactive B cell responses are seen in autoimmune diseases such as systemic lupus erythematosus. Belimumab binds to BAFF and prevents it from binding to B cells. Without BAFF, B cells commit suicide and no longer contribute to the autoimmune damage of systemic lupus erythematosus.
CD19 and CD20 Targeted T cell engager:
–CMG1A46: is a dual CD19 and CD20 targeted T cell engager for lupus and related auto-immune conditions. GSK plc (LSE/NYSE: GSK) and Chimagen Biosciences (Chimagen), a privately held biotechnology company, signed an agreement for GSK to acquire CMG1A46, a clinical-stage dual CD19 and CD20-targeted T cell-engager (TCE), from Chimagen for $300 million upfront. GSK plans to develop and commercialise CMG1A46 with a focus on B cell-driven autoimmune diseases, such as systemic lupus erythematosus (SLE) and lupus nephritis (LN), with potential to expand into related autoimmune diseases.