Development of ganglioside specific IgGs for the treatment of Guillian-Barré Syndrome

PROJECT SUMMARY Campylobacter jejuni is the leading cause of bacterial foodborne diarrheal disease in the USA. The majority of C. jejuni isolates express surface glycans mimicking human gangliosides that play a key role in triggering Guillain-Barré Syndrome (GBS) through formation of anti-ganglioside antibodies (Abs) that fix complement onto human neurons and Schwann cells. Due to the commonality of C. jejuni infection worldwide, GBS has now become the leading cause of paralysis since the near-eradication of polio. Patient treatment involves use of intravenous immunoglobulin G (IVIg) intended to compete with these auto-antibodies, but up to one-third of patients do not respond to this treatment. We hypothesize that specific IgGs exist in the B cell repertoire of Guillain-Barré Syndrome (GBS) patients that can be exploited for GBS therapeutic development. We will screen B cells derived from former GBS patients for anti-ganglioside IgG expression using human Ab isolation to identify IgG sequences linked with pathogenesis. These Abs will be tested in competition ELISAs and C. jejuni serum bactericidal assays. The most effective Abs will be verified on human pluripotent stem cell (hPSC)-derived Schwann cells and assessed on hPSC-derived myelinated peripheral neurons measuring electrical activity and myelin complex disruption. Candidate IgGs will be transformed into therapeutic blocking Abs by Fc modification and tested against the original Abs in our combined assays. The most effective blocking Abs will then be tested on two IVIg-responder and two IVIg-non-responder patient induced pluripotent stem cell (iPSC)-derived neurons in comparison to pooled immunoglobulins typically used for IVIg treatment. This study will identify therapeutic blocking antibodies for the development of a targeted GBS treatment.