Selective In Vivo Removal of Anti-Glycan Autoantibodies with a Glycopolymer - A Promising New Drug Candidate for Anti-MAG Neuropathy

Session: 
PS2 Poster session 2 Even numbers
Code: 
P78
Location (hall): 
Foyer
Start/end time: 
Tuesday, July 2, 2019 - 15:45 to 17:15
Pascal
Hänggi

Pascal Hänggi1, Butrint Aliu2, Emilie Seydoux1, Alex Brodovitch3, Joseph Boucraut3, Emilien Delmont3, Beat Ernst2, Ruben Herrendorff1

1Polyneuron Pharmaceuticals AG, Basel, Switzerland, 2University of Basel, Basel, Switzerland, 3Hôpitaux de Marseille, Centre Hospitalier Universitaire, Marseille, France

Anti-myelin-associated glycoprotein (MAG) neuropathy is a disabling autoimmune peripheral neuropathy caused by monoclonal IgM autoantibodies that recognize the glycan epitope HNK-1 (human natural killer-1). The glycoepitope consists of the sulphated trisaccharide SO4-3GlcAβ1-3Galβ1-4GlcNAc and is highly expressed on adhesion molecules, such as MAG, present in myelinated nerve fibers. The binding of the anti-MAG IgM autoantibodies to the HNK-1 glycoepitope causes demyelination and axonal damage, so that the patients suffer from severe symptoms including sensorimotor deficits, ataxia, pain and tremors. 

Currently, only off-label treatments with limited efficacy are available. We hypothesized that significant clinical improvements could be achieved by selective removal of the pathogenic anti-MAG antibodies with a biodegradable, poly-L-lysine based polymer (PPSGG) presenting multiple copies of HNK 1 glycoepitope mimetic on the peptide backbone. 

We assessed the difference in the inhibitory activity of an HNK-1 glycoepitope mimetic and its multivalent presentation on the polymer. The multivalent presentation improved the inhibitory activity towards patients sera, i.e. inhibition of antibody-binding to MAG, by a factor of up to 230,000 per epitope compared to the monomer, resulting in a low nanomolar inhibitory potency (mean IC₅₀ = 3.6 ± 0.4 nM). The pharmacodynamic properties of the glycopolymer were analysed in vitro with patients’ sera using both a MAG-ELISA and an immunofluorescence assay with sciatic nerves from non-human primates, and in vivo using an immunological mouse model. Furthermore, ADME parameters and safety pharmacology of PPSGG were assessed in different species.

PPSGG efficiently inhibited MAG-binding of patients’ antibodies at nanomolar epitope concentrations and antibody-binding to sciatic nerves was strongly inhibited by 62.5 μg/mL and completely inhibited by 125 μg/mL PPSGG. In vivo, single intravenous injections of 10 mg/kg led to significant reductions in anti-MAG IgM titers for up to five days, and weekly treatments resulted in a decreased anti-MAG IgM antibody rebound. A tissue distribution study showed fast uptake and metabolism of both PPSGG and the PPSGG:anti-MAG IgM complex in the mononuclear phagocyte system, which is consistent with the short in vivo plasma half-life of PPSGG in mice of ca. 17 min (t₁/₂ = 16.9 ± 5.5 min). No signs of aggregate formation were detected either in vitro or in vivo. Neither could immunogenicity be induced in the different treated animal species nor could human B cells or dendritic cells be activated ex vivo by the glycopolymer. More importantly, the dose-range finding studies in two animal species showed no safety concerns for PPSGG. 

In conclusion, PPSGG efficiently neutralized and removed pathogenic anti-MAG IgM in vitro and in vivo, and had a favorable safety profile. Taken together, the obtained data shows that PPSGG is a very promising drug candidate for clinical trials in anti-MAG neuropathy.

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