Unravelling the effect of a potentiating anti-Factor H antibody on atypical hemolytic uremic syndrome associated factor H variants

Abstract

The complement system plays an important role in our innate immune system. Complement activation results in clearance of pathogens, immune complex and apoptotic cells. The host is protected from complement-mediated damage by several complement regulators. Factor H (FH) is the most important fluid-phase regulator of the alternative pathway of the complement system. Heterozygous mutations in FH are associated with complement-related diseases such as atypical hemolytic uremic syndrome (aHUS) and age-related macular degeneration.We recently described an agonistic anti-FH monoclonal antibody that can potentiate the regulatory function of FH. This antibody could serve as a potential new drug for aHUS patients and alternative to C5 blockade by Eculizumab. However, it is unclear whether this antibody can potentiate FH mutant variants in addition to wild type FH. Here, the functionality and potential of the agonistic antibody in the context of pathogenic aHUS-related FH mutant proteins was investigated. The binding affinity of recombinant WT FH, and the FH variants, W1183L, V1197A, R1210C, and G1194D to C3b was increased upon addition of the potentiating antibody and similarly, the decay accelerating activity of all mutants is increased. The potentiating anti-FH antibody is able to restore the surface regulatory function of most of the tested FH mutants to WT FH levels. In conclusion, our potentiating anti-FH is broadly active and able to enhance both WT FH function as well as most aHUS-associated FH variants tested in this study.

Therapeutic Lessons to be Learned From the Role of Complement Regulators as Double-Edged Sword in Health and Disease

“…This antibody can restore FH activity in aHUS patient sera (217). In addition, we recently showed that this potentiating antibody not only potentiates wild type FH, but also four common aHUS mutated FHs in vitro (218).…”

“…As has been described above, there is a clear need for this in specific groups of PNH patients, that suffer from extravascular hemolysis under eculizumab treatment. Potentially, treatments based on complement regulatory proteins that target C3, could be a solution there, as for example FH-CR2, miniFH and anti-FH07 (197,218). Next, the successful in vivo tests of FH-IgG chimeric proteins in bacterial infections, indicate that there might lie success in similar approaches using C4BP, C1-INH or Vn, which all are used by bacteria in complement evasion mechanisms (19).…”

Halting targeted and collateral damage to red blood cells by the complement system

“… Omeros Factor H Anti-FH.07 Potentiating monoclonal antibody n.s. aHUS Preclinical Sanquin [ 129 , 130 ] AMY201 (Mini FH) Recombinant protein n.s. Age-related macular degeneration; PNH Preclinical Amyndas [ 131 , 132 ] FH, FHmoss Recombinant n.s.…”

Differential Phase Contrast Scanning Transmission Electron Microscopy at Atomic Resolution

“…By elaborating special detector geometries, we can image local electromagnetic fields inside materials through differential phase contrast (DPC) imaging techniques [1,2]. We have been continuously developing very fast area detectors that are capable of atomic-resolution STEM imaging.…”