MuSK myasthenia gravis monoclonal antibodies

Huijbers, Maartje G.; Vergoossen, Dana L.E.; Fillié-Grijpma, Yvonne E.; Es, Inge E. van; Koning, Marvyn T.; Slot, Linda M.; Veelken, Hendrik; Plomp, Jaap J.; Maarel, Silvère M. van der; Verschuuren, Jan J.

doi:10.1212/nxi.0000000000000547

Cited by 76 publications

(112 citation statements)

References 33 publications

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“…Neither IgG1 nor IgG3 participate in Fab-arm exchange. However, the collective findings regarding the pathogenic capacity of MuSK autoantibodies demonstrate that they require both high affinity, as described here, and monovalent binding [14] for robust pathogenic capacity. Thus, the roles of IgG1 and IgG3 MuSK autoantibodies are not clear.…”

Section: Relevance To Disease Mechanismsmentioning

confidence: 66%

“…The MuSK specific mAbs that we generated were derived from two IgG4-expressing B cells and one IgG3 expressing B cell [15,16]. MuSK specific mAbs have also been derived from IgG1expressing B cells [14]. Neither IgG1 nor IgG3 participate in Fab-arm exchange.…”

Section: Relevance To Disease Mechanismsmentioning

confidence: 99%

“…MuSK mAbs do demonstrate pathogenic capacity using in vitro AChR clustering assays, but they are not as effective as their monovalent counterparts. In addition, the divalent antibodies stimulate rather than inhibit MuSK phosphorylation, whereas their monovalent counterparts, like IgG4 antibodies in sera from MuSK MG patients, inhibit MuSK phosphorylation [14,16,44]. The difference between the divalent and monovalent antibodies is likely due to the dual activity of the divalent antibodies, as the divalent antibodies can dimerize MuSK, known to stimulate transphosphorylation [45], and at the same time inhibit binding of Lrp4 to MuSK.…”

Section: Relevance To Disease Mechanismsmentioning

confidence: 99%

“…Autoantibodies with pathogenic capacity, isolated from patients with neuromyelitis optica (NMO), pemphigus vulgaris (PV) or AChR MG are characterized by the hallmarks of this process including the accumulation of somatic hypermutation [11][12][13]. Recently, cloned autoantibodies that target MuSK were isolated from patients with MG [14][15][16]. These autoantibodies include the hallmarks of affinity maturation, including a high frequency of somatic hypermutation.…”

Section: Introductionmentioning

confidence: 99%

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Self-antigen driven affinity maturation is required for pathogenic monovalent IgG4 autoantibody development

Fichtner

Vieni

et al. 2020

Preprint

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Pathogenic IgG4 autoantibodies in autoimmune myasthenia gravis (MG) are functionally monovalent as a result of Fab-arm exchange. The origin and development of these unique autoantibodies are not well understood. We examined MG patient-derived monoclonal autoantibodies (mAbs), their corresponding germline-encoded unmutated common ancestors (UCA) and monovalent antigen-binding fragments (Fabs) to investigate how antigen-driven affinity maturation contributes to both binding and immunopathology. Mature mAbs, their UCA counterparts and mature monovalent Fabs bound to the autoantigen and retained their pathogenic capacity. However, monovalent UCA Fabs still bound the autoantigen but lost their pathogenic capacity. The mature Fabs were characterized by very high affinity (sub-nanomolar) driven by a rapid on-rate and slow off-rate. However, the UCA affinity was approximately 100fold less than that of the mature Fabs, which was driven by a rapid off-rate. Crystal structures of two Fabs shed light on how mutations acquired during affinity maturation may contribute to increased MuSK binding affinity. These collective findings indicate that the autoantigen initiates the autoimmune response in MuSK MG and drives autoimmunity through the accumulation of somatic hypermutation such that monovalent IgG4 Fab-arm exchanged MG autoantibodies reach a high affinity threshold required for pathogenic capacity.

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Section: Relevance To Disease Mechanismsmentioning

confidence: 66%

Section: Relevance To Disease Mechanismsmentioning

confidence: 99%

Section: Relevance To Disease Mechanismsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Self-antigen driven affinity maturation is required for pathogenic monovalent IgG4 autoantibody development

Fichtner

Vieni

et al. 2020

Preprint

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“…These MuSK autoantibodies are present in 5-10% of the patients (80,84) and are typically of the IgG4 subclass which are associated with anti-inflammatory responses. To a lesser extent, IgG1 anti-MuSK antibodies may be found alongside the IgG4 variants (85). To our knowledge, Koers et al were the first to investigate the frequency and distribution of variable domain glycans in MG patients (46).…”

Section: Myasthenia Gravismentioning

confidence: 93%

A Comparison of Immunoglobulin Variable Region N-Linked Glycosylation in Healthy Donors, Autoimmune Disease and Lymphoma

et al. 2020

Self Cite

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N-linked glycans play an important role in immunity. Although the role of N-linked glycans in the Fragment crystallizable (Fc) region of immunoglobulins has been thoroughly described, the function of N-linked glycans present in Ig-variable domains is only just being appreciated. Most of the N-linked glycans harbored by immunoglobulin variable domain are of the complex biantennary type and are found as a result of the presence of N-linked glycosylation that most often have been introduced by somatic hypermutation. Furthermore, these glycans are ubiquitously present on autoantibodies observed in some autoimmune diseases as well as certain B-cell lymphomas. For example, variable domain glycans are abundantly found by anti-citrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA) as well as by the B-cell receptors of follicular lymphoma (FL). In FL, variable domain glycans are postulated to convey a selective advantage through interaction with lectins and/or microbiota, whereas the contribution of variable domain glycans on autoantibodies is not known. To aid the understanding how these seemingly comparable phenomena contribute to a variety of deranged B-responses in such different diseases this study summarizes the characteristics of ACPA and other auto-antibodies with FL and healthy donor immunoglobulins, to identify the commonalities and differences between variable domain glycans in autoimmune and malignant settings. Our finding indicate intriguing differences in variable domain glycan distribution, frequency and glycan composition in different conditions. These findings underline that variable domain glycosylation is a heterogeneous process that may lead to a number of pathogenic outcomes. Based on the current body of knowledge, we postulate three disease groups with distinct variable domain glycosylation patterns, which might correspond with distinct underlying pathogenic processes.

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Sheathless CE‐MS as a tool for monitoring exchange efficiency and stability of bispecific antibodies

et al. 2020

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Bispecific monoclonal antibodies (BsAbs) are receiving great attention due to their extensive benefits as biopharmaceuticals and their involvement in IgG4 mediated autoimmune diseases. While the production of BsAbs is getting more accessible, their analytical characterization remains challenging. We explored the potential of sheathless CE-MS for monitoring exchange efficiency and stability of in-house produced bispecific antibodies. Two IgG4 bispecific antibodies with different molecular characteristics were prepared using controlled Fragment antigen binding (Fab)-arm exchange. Separation of BsAbs from their parent monospecific antibodies was achieved using a polyethyleniimine (PEI)-coated capillary and acidic background electrolytes permitting reliable assessment of the exchange efficiency. This was especially valuable for a Fab-glycosylated BsAb where the high glycan heterogeneity resulted in an overlap of masses with the monospecific parent antibody, hindering their discrimination by MS only. The method showed also good capabilities to monitor the stability of the generated BsAbs under different storage conditions. The levels of degradation products were different for the studied antibodies indicating pronounced differences in stability. Overall, the proposed method represents a useful analytical tool for exchange efficiency and stability studies of bispecific antibodies.

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MuSK myasthenia gravis monoclonal antibodies

Cited by 76 publications

References 33 publications

Self-antigen driven affinity maturation is required for pathogenic monovalent IgG4 autoantibody development

Self-antigen driven affinity maturation is required for pathogenic monovalent IgG4 autoantibody development

A Comparison of Immunoglobulin Variable Region N-Linked Glycosylation in Healthy Donors, Autoimmune Disease and Lymphoma

Sheathless CE‐MS as a tool for monitoring exchange efficiency and stability of bispecific antibodies

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