IgA nephropathy (IgAN) is the most frequent glomerulonephritis in the world. Recently we have provided evidence for the autoimmune character of IgAN: nephritogenic immune complexes are formed in which IgA1 molecules with altered O-linked glycans in the unique hinge region (HR) of the heavy (H) chains serve as antigens that are recognized by naturally occurring, glycan-specific antibodies. We have also demonstrated that the pathogenic potential of IC formed is strongly dependent on the molecular mass: we demonstrated in vitro and in vivo that only large IC with molecular mass ~700-1000 kDa display nephritogenicity. In this application we propose to explore a novel, highly unconventional and emerging approach exploiting the potential of camelid single domain antibodies containing only the variable region of H chain (VHH fragments) as inhibitors of the formation of nephritogenic IC. VHH fragments of camelid antibodies contain the antigen- binding site contributed only by complementarity-determining regions of the H, but NOT light chains, display a high affinity for antigens, contain ~100 amino acids (~16 kDa), do not activate the complement cascade, are extremely stable, highly water-soluble, and not antigenic when injected in diverse species, including humans. Most importantly for our proposal, VHH are monovalent and consequently non-cross-linking, so that IC formed would be of low-molecular mass, and therefore, not nephritogenic. Furthermore, we have developed in vitro and in vivo assays which can be used for testing of the IC nephrotoxicity. Importantly, results emerging from our studies may be applicable and extended in the ultimate interference with the formation of pathogenic IC in other human IC diseases and VHH fragment may be also used as excellent diagnostic tools due their exquisite specificity and stability.
IgA nephropathy (IgAN) is the most common form of glomerulonephritis in the world, with 20-40% patients progressing to the end-stage renal failure. Our studies will provide proof of the concept that monovalent single- chain anti-glycan antibodies can block formation of nephritogenic high-molecular-weight immune complexes and thus lessen or prevent the glomerular injury in patients with IgAN. Such an approach may ultimately provide the first disease-specific treatment of IgAN and reduce health-care expenditures in the United States.
|Mestecky, Jiri; Novak, Jan; Moldoveanu, Zina et al. (2016) IgA nephropathy enigma. Clin Immunol 172:72-77|
|Novak, Jan; Rizk, Dana; Takahashi, Kazuo et al. (2015) New Insights into the Pathogenesis of IgA Nephropathy. Kidney Dis (Basel) 1:8-18|