Emily Danielson

Introduction. Myasthenia Gravis (MG) is an autoimmune disease characterized by dysfunction of the neuromuscular junction.¹ The basic abnormality in MG is a reduction in the acetylcholine receptors at neuromuscular junctions due to the effects of autoantibodies.¹ The strongest evidence for complement dependent cytotoxicity in MG comes from the finding of antibody, C3 and membrane attack complex depositions at neuromuscular junctions in patients.² The existing standard of care in the management of the disease includes broad spectrum immunosuppressive treatment with medications such as corticosteroids and methotrexate, which are only palliative and do little to correct the underlying problem.³ Methods. GL-2045 was created as a recombinant human immunoglobulin G1 based Fc multimer designed to recapitulate the anti-inflammatory activities of intravenous immunoglobulin (IVIG) on the innate and adaptive immune responses. The ability of GL-2045, HAGG, and IVIG to protect Ab-opsonized cells (SUDHL4, Ramos, and SRBC) from CDC was evaluated.² GL-2045, HAGG, and IVIG were incubated with NHS for 10 to 15 minutes at 37 C. Cells were stained with Annexin and analyzed by flow cytometry and the percentage of dead/apoptotic cells represented the level of cytotoxicity. Supernatants were collected and analyzed for C3a, C4a, and C5a.² Results. GL-2045 afforded all 3 cell types the greatest protection against CDC.² Both G207 and G211 avidly bound plate coated C1q with a potency that was 3-log orders greater than IVIG in an ELISA based assay.⁴ Like the parent drug GL-2045, these drugs served as a C1q sink and were able to act through both C1q dependent and C1q independent mechanisms. They also increased iC3b generation.⁴ The therapeutic efficacy of the hexamer was examined in mice with collagen induced arthritis. It was found to reduce clinical signs of disease more rapidly than intravenous immunoglobulin and there were lower numbers of infiltrating CD45 leukocytes in their knee joints. Overall, it was found to suppress inflammatory arthritis in mice at a 10-fold lower dose than intravenous immunoglobulin.⁵ Conclusions. These multimers provide a viable drug candidate for the treatment of diverse complement-mediated diseases like Myasthenia Gravis due to their capacity to sequester C1q, augment factor H activity, and ability to generate complement split products like iC3b.

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2.  Zhou H, Olsen H, So E, et al. A fully recombinant human IgG1 Fc multimer (GL-2045) inhibits complement-mediated cytotoxicity and induces iC3b. Blood Adv. 2017;1(8):504-515. doi:10.1182/bloodadvances.2016001917
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