Distribution of exogenous complement factor H in mice in vivo

Abstract

Factor H is an important regulator of complement activation in plasma and on cell surfaces in both humans and mice. If FH function is compromised, inappropriate complement activation on self-surfaces can have disastrous effects as seen in the kidney diseases atypical haemolytic uremic syndrome (aHUS) and C3 glomerulopathy. As FH constructs have been proposed to be used in treatment for these diseases, we studied the distribution of exogenous FH fragments in mice. Full-length mFH, mFH1-5 and mFH18-20 fragments were radiolabelled, and their distribution was examined in WT, FH and FH C3 mice in vivo. Whole body scintigraphy revealed accumulation of radioactivity in the abdominal part of the mice, but also to the thyroid gland and urinary bladder. At organ level in WT mice, some full-length FH accumulated in internal organs, but most of it remained in the circulation. Both of the mFH fragments accumulated in the kidneys and were excreted in urine. For mFH1-5, urinary secretion is the likely cause for the accumulation. Concentration of mFH18-20 to kidneys was slower, and at tissue level, mFH18-20 was localized at the proximal tubuli in WT and FH C3 mice. No C3-independent binding to glomeruli was detected. In conclusion, these results show that glomerular glycosaminoglycans and sialic acids alone do not collect FH in kidneys. Deposition of C3 fragments is also needed, which implies that in aHUS, the problem is in simultaneous recognition of C3 fragments and glycosaminoglycans or sialic acids by FH, not just the inability of FH to recognize glomerular endothelium as such.

Homodimeric Minimal Factor H: In Vivo Tracking and Extended Dosing Studies in Factor H Deficient Mice

“…These results were broadly in keeping with studies by Koshinen et al. ( 75 ) who looked at the distribution of iodinated full length mFH or mFH1-5 or mFH18-20, although their studies were over a shorter time frame and did not involve mini-FH constructs and showed full-length FH distribution was dependent on C3 fragment deposition. Thus, our data may help to explain the lower half-life of the mini-FH drugs in CFH -/- mice compared to native serum-purified full-length mFH.…”

Moss-produced human complement factor H with modified glycans has an extended half-life and improved biological activity

“…The anticipated predominant targeting of CPV-101 to the liver probably reflects clearance by mannose-receptor C-type 1, which is strongly expressed on liver sinoidal endothelial cells and is known to accept GlcNAc-tipped glycans as ligands (65). The excretion data for all three variants were in overall good agreement with the previously published results for sd-FH (66).…”

Proof of concept of a new plasma complement Factor H from waste plasma fraction

“…Previous works have reported the tagging and imaging of FH analogues, using I-125 labelling ( 32 ) Tc-99m ( 33 ) or optical tags ( 34 ), however, these studies presents limitations in terms of imaging performance (i.e. planar scintigraphy or autoradiography), scope (i.e.…”