Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial

Cree, Bruce A.C.; Bennett, Jeffrey L.; Kim, Ho Jin; Weinshenker, Brian G.; Pittock, Sean J.; Wingerchuk, Dean M.; Fujihara, Kazuo; Paul, Friedemann; Cutter, Gary; Marignier, Romain; Green, Ari J.; Aktaş, Orhan; Hartung, Hans‐Peter; Lublin, Fred; Drappa, Jörn; Barron, Gerard; Madani, Soraya; Ratchford, John N.; She, Dewei; Cimbora, Daniel; Katz, Eliezer; investigators, N-MOmentum study

doi:10.1016/s0140-6736(19)31817-3

Cited by 505 publications

(568 citation statements)

References 26 publications

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“…Inebilizumab demonstrated a favorable safety and tolerability profile, with an adverse event rate similar to placebo. 47 Leronlimab (CytoDyn Inc.) Leronlimab (PRO140) is a humanized IgG4 antibody directed against CC chemokine receptor 5 (CCR5), which is involved in many pathophysiological processes, such as HIV-1 entry into CD4 + T cells, promotion of tumor invasion and metastases, pathogenesis of nonalcoholic steatohepatitis (NASH) and development of acute graft-versus-host disease (GvHD). Leronlimab was granted FDA's Fast Track designation, which allows CytoDyn Inc. to submit individual sections of the BLA for review, i.e., a 'rolling' review.…”

Section: Inebilizumab (Viela Bio)mentioning

confidence: 99%

Antibodies to watch in 2020

Kaplon

Muralidharan²,

Schneider

et al. 2019

mAbs

405

296

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This 2020 installment of the annual 'Antibodies to Watch' series documents the antibody therapeutics approved in 2019 and in regulatory review in the United States or European Union, as well as those in late-stage clinical studies, as of November 2019*. At this time, a total of 5 novel antibody therapeutics (romosozumab, risankizumab, polatuzumab vedotin, brolucizumab, and crizanlizumab) had been granted a first approval in either the US or EU, and marketing applications for 13 novel antibody therapeutics (eptinezumab, teprotumumab, enfortumab vedotin, isatuximab, [fam-]trastuzumab deruxtecan, inebilizumab, leronlimab, sacituzumab govitecan, satralizumab, narsoplimab, tafasitamab, REGNEB3 and naxituximab) were undergoing review in these regions, which represent the major markets for antibody therapeutics. Also as of November 2019, 79 novel antibodies were undergoing evaluation in late-stage clinical studies. Of the 79 antibodies, 39 were undergoing evaluation in late-stage studies for non-cancer indications, with 2 of these (ublituximab, pamrevlumab) also in late-stage studies for cancer indications. Companies developing 7 (tanezumab, aducanumab, evinacumab, etrolizumab, sutimlimab, anifrolumab, and teplizumab) of the 39 drugs have indicated that they may submit a marketing application in either the US or EU in 2020. Of the 79 antibodies in late-stage studies, 40 were undergoing evaluation as treatments for cancer, and potentially 9 of these (belantamab mafodotin, oportuzumab monatox, margetuximab, dostarlimab, spartalizumab, 131I-omburtamab, loncastuximab tesirine, balstilimab, and zalifrelimab) may enter regulatory review in late 2019 or in 2020. Overall, the biopharmaceutical industry's clinical pipeline of antibody therapeutics is robust, and should provide a continuous supply of innovative products for patients in the future. *Note on key updates through December 18, 2019: 1) the US Food and Drug Administration granted accelerated approval to enfortumab vedotin-ejfv (Padcev) on December 18, 2019, bringing the total number of novel antibody therapeutics granted a first approval in either the US or EU during 2019 to 6; 2) the European Commission approved romosozumab on December 9, 2019; 3) the European Medicines Agency issued a positive opinion for brolucizumab; 4) Sesen Bio initiated a rolling biologics license application (BLA) on December 6, 2019; 5) GlaxoSmithKline submitted a BLA for belantamab mafodotin; and 6) the status of the Phase 3 study (NCT04128696) of GSK3359609, a humanized IgG4 anti-ICOS antibody, in patients with head and neck squamous cell carcinoma was updated to recruiting from not yet recruiting. ARTICLE HISTORY

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Section: Inebilizumab (Viela Bio)mentioning

confidence: 99%

Antibodies to watch in 2020

Kaplon

Muralidharan²,

Schneider

et al. 2019

mAbs

405

296

View full text Add to dashboard Cite

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“…CD19-specific inebilizumab targets a broader range of B cell subsets. The use of inebilizumab has been demonstrated to successfully treat NMO [52]. Precise targeting of MuSK autoantibody-expressing B cells with CAAR-T cells [53] gains further justification by the additional mechanistic details provided in the current study.…”

Section: Immunomodulating Therapy In Musk Mgmentioning

confidence: 83%

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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“…These studies could test the hypothesis that the depletion of common B cell subsets may predict efficacy across diseases. Applying STAIR analysis to the simultaneous investigation of other therapies such as anti-CD19 therapy (inebilizumab)-recently shown to be efficacious for the treatment of NMO-could allow for the optimal selection of B cell depleting agents for preventing disease relapse (65). While RTX is a reliable treatment modality for MuSK MG, data for AChR MG has been mixed and patient relapses are common (8).…”

Section: Discussionmentioning

confidence: 99%

Single-cell repertoire tracing identifies rituximab refractory B cells during myasthenia gravis relapses

Jiang

Fichtner

Hoehn

et al. 2019

Preprint

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One Sentence Summary: Disease relevant B cells during post-rituximab (RTX) relapse emerge from the unsuccessful depletion of pre-existing B cell clones; single-cell transcriptomic phenotyping combined with lineage tracing using paired B cell receptor repertoires identified both persistent antibody-secreting cell as well as memory B cell subsets.Abstract: Rituximab, an anti-CD20 B cell-depleting therapy, is indicated to treat a growing number of autoimmune disorders. However, disease relapses can occur when the B cell compartment is re-established after treatment. To explore the mechanism of relapse, we studied patients with muscle-specific kinase (MuSK) myasthenia gravis (MG), a paradigm for B cellmediated autoimmune diseases in which pathology is directly associated with autoantibody production. Whether the failed depletion of specific clones leads to the persistence of autoantibody producing B cell subsets has yet to be elucidated. Here we show that rituximab (RTX) therapy is not fully effective at eliminating disease-associated B cells and provide a mechanistic understanding of relapse. We carried out single-cell transcriptional and B cell receptor (BCR) profiling on longitudinal B cell samples from the peripheral blood of MuSK MG patients who relapsed after rituximab therapy. Computational analysis of these data identified individual B cells that were refractory to rituximab depletion by linking them to clones that were present prior to therapy and continued to persist after therapy. These persistent B cell clones were present at high frequency, and included both antibody-secreting cells and memory B cells. They were disproportionately isotype switched with elevated somatic hypermutation frequencies and a gene expression signature associated with antigen-experience and B cell clonal expansion. We further identified both antibody-secreting cells and memory B cells with specificity for MuSK autoantigen that were clonally expanded during relapse and persistent. Our results provide evidence that post-rituximab relapse in MuSK MG is associated with the failed depletion of autoantigen-specific B cell subsets. This work provides insight into the durability of human B cells during treatment with therapeutic CD20-specific monoclonal antibodies. The transcriptional signatures associated with B cell resistance may represent new therapeutic avenues for treatment and biomarkers of depletion efficacy.

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Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial

Cited by 505 publications

References 26 publications

Antibodies to watch in 2020

Antibodies to watch in 2020

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

Single-cell repertoire tracing identifies rituximab refractory B cells during myasthenia gravis relapses

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