Engineering a less immunogenic bacterial protease for treatment of IgA Nephropathy

In this talk, Dr Mike Zimmer introduces one of Moderna’s fledgling projects for their rare disease group, engineering a less immunogenic bacterial protease for treatment of IgA Nephropathy.

IgA Nephropathy (Berger’s disease) is a rare autoimmune disease for which is currently poorly understood. It is characterised by deposition of IgA-containing immune complexes in the glomerulae of the kidneys and can lead to renal failure. Many gut bacteria secrete IgA proteases as part of host defence. It has been previously shown that these IgA proteases can be used in vitro to degrade with IgA1 complexes which cause IgA nephropathy. Further, IgA1 protease treatment can reverse mesangial deposits in transgenic mice expressing human IgA1 and soluble IgA Fc receptor I (sCD89) proteins.

Moderna have developed modified bacterial IgA proteases which are amenable to expression in eukaryotic cells, and are active in in vivo mouse models. They are now working to tolerise or de-immunise IgAP via two approaches – Liver-mediated immune tolerance and targeted mutagenesis.

Using ProImmune’s ProPresent® Antigen Presentation Assay and our ProMap® naïve T cell proliferation assay, Moderna were able to identify peptides from IgAP which are presented to the immune system by APCs, and then determine which of these cause a helper T cell immune response. They were able to identify 30 peptides which were presented on antigen presenting cells, none of which produced a helper T cell response. Having narrowed down potential epitopes to these 30 peptides, Dr Zimmer’s team were able to conduct in silico mutagenic scanning of potentially immunogenic peptides, revealing possible sites for de-immunisation. Ultimately, the team identified the amino acids which contributed to the potential immunogenicity of the peptides identified by ProImmune. They have since successfully mutated many of these amino acids by targeted mutagenesis.

Their planned next step is to re-express their protein with the introduced mutation in their mouse model and determine whether the mutations allow for repeat dosing. They also plan to compare the immunogenicity of the original and mutated proteins in ProImmune’s ProScern® assay, which will measure the extent to which these proteins induce CD4+ T cell proliferation. They expect that they will ultimately develop a product which can degrade human IgA nephrotic deposits through periodic dosing.