Fusion protein of single-chain variable domain fragments for treatment of myasthenia gravis

Li, Fangfang; Meng, Fanping; Jin, Quanxin; Sun, Chao; Li, Yingxin; Li, Honghua; Jin, Songzhu

doi:10.4103/1673-5374.131611

Cited by 6 publications

(5 citation statements)

References 34 publications

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“…In our study we used a monoclonal antibody to induce disease in our model, while in patients the AChR autoantibodies are polyclonal 49 . The competition between the therapeutic IgG4Δhinge-637 antibody and poly-clonal patient IgG is variable, based on experiments with the scFv-637 9 and Fab-637 7 . Such an in vitro competition assay could be used to identify patients that might benefit from IgG4Δhinge blocker antibodies prior to therapy.…”

Section: Discussionmentioning

confidence: 99%

“…In passive transfer MG (PTMG) experiments using rats and mice, blocking antibody fragments directed against the MIR have been shown to prevent muscle weakness 10 , 12 . In vitro , a single chain-Fv antibody fragment of IgG1–637 blocked binding of MG patient autoantibodies by 31.4% (range 2–77.4%) 9 . Similarly, varying degrees of competition of MG patients’ antibodies were observed with Fab-637 (ranging between <10% and 100%) 7 .…”

Section: Introductionmentioning

confidence: 98%

“…In contrast to the overall AChR antibody titer, the MIR antibody titer is strongly correlated to severity of muscle weakness in MG patients 6 . The pathogenicity and restricted epitope-specificity of AChR-specific autoantibodies makes the MIR an attractive target for blocker therapy with non-pathogenic antibodies 9 – 11 . Although autoantibodies can bind to various conformational epitopes within the MIR (e.g.…”

Section: Introductionmentioning

confidence: 99%

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Hinge-deleted IgG4 blocker therapy for acetylcholine receptor myasthenia gravis in rhesus monkeys

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Kranen-Mastenbroek

et al. 2017

Sci Rep

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Autoantibodies against ion channels are the cause of numerous neurologic autoimmune disorders. Frequently, such pathogenic autoantibodies have a restricted epitope-specificity. In such cases, competing antibody formats devoid of pathogenic effector functions (blocker antibodies) have the potential to treat disease by displacing autoantibodies from their target. Here, we have used a model of the neuromuscular autoimmune disease myasthenia gravis in rhesus monkeys (Macaca mulatta) to test the therapeutic potential of a new blocker antibody: MG was induced by passive transfer of pathogenic acetylcholine receptor-specific monoclonal antibody IgG1-637. The effect of the blocker antibody (IgG4Δhinge-637, the hinge-deleted IgG4 version of IgG1-637) was assessed using decrement measurements and single-fiber electromyography. Three daily doses of 1.7 mg/kg IgG1-637 (cumulative dose 5 mg/kg) induced impairment of neuromuscular transmission, as demonstrated by significantly increased jitter, synaptic transmission failures (blockings) and a decrease in the amplitude of the compound muscle action potentials during repeated stimulations (decrement), without showing overt symptoms of muscle weakness. Treatment with three daily doses of 10 mg/kg IgG4Δhinge-637 significantly reduced the IgG1-637-induced increase in jitter, blockings and decrement. Together, these results represent proof-of principle data for therapy of acetylcholine receptor-myasthenia gravis with a monovalent antibody format that blocks binding of pathogenic autoantibodies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Hinge-deleted IgG4 blocker therapy for acetylcholine receptor myasthenia gravis in rhesus monkeys

Losen

Labrijn

Kranen-Mastenbroek

et al. 2017

Sci Rep

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“…CBCT scans depicted gluteal arterial anatomy. However, vessels typically travel together [ 22 ] and, in normovolemic patients, the diameter of the femoral vein and artery are similar [ 23 ]. Level 5 evidence advises intraoperative ultrasound for subcutaneous fat injection to reduce embolism risk [ 7 , 19 , 24 ], as it lacks large veins.…”

Section: Discussionmentioning

confidence: 99%

Danger Zones of the Gluteal Anatomy: Improving the Safety Profile of the Gluteal Fat Grafting

Seabra Robalo Gomes Jorge,

Feng,

Santos Stahl

et al. 2024

Aesth Plast Surg

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Introduction Knowledge of the vascular anatomy is critical to performing safe gluteal surgery. To date, only the course of the main blood vessels within the muscles has been outlined. These findings are based on MRI and CTA images that do not conform to a topographically standardized and normalized probability distribution. Objectives The aim of this study was to develop a three-dimensional mapping of the gluteal zones of high vascular density in relation to anatomical landmarks. Materials and Methods This single-center retrospective cohort analysis comprised all consecutive patients who underwent cone-beam computed tomography (CBCT) scans between January 2016 and October 2021. The location of blood vessels in the gluteal region was allometrically normalized in relation to anatomical landmarks. Moreover, the caliber and area of the blood vessels were assessed. Results CBCT scans of 32 patients with an average age of 64 ± 12 years (range 34–87 years) were included. Fifty-three percent were female. The median [IQR] caliber of the intramuscular gluteal vessels was 1.47 [1.15–1.88] mm, significantly greater than that of the subcutaneous vessels 1.09 [0.72–1.44] mm (p < 0.001). Vascular density was higher intramuscularly, as 4.5% of the area of the muscle was occupied by blood vessels, as opposed to 0.3% in the adipose tissue. Conclusion The analysis of the CBCT scans showed a higher vascular density and larger vessels intramuscularly. We, therefore, recommend the injection of autologous fat merely to the subcutaneous plane. Level of Evidence II This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

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“…In another study, the preparation of a scFv and HSA conjugate was discussed as a potential immunosuppressive therapy of myasthenia gravis. The mean inhibition rate of binding to the acetylcholine receptor was 31.4% for 3 days [ 154 ]. Another study investigated the different binding of HSA to FcRn across different species.…”

Section: Potential Strategies To Overcome Challenges In Antibody-bmentioning

confidence: 99%

Overview of Antibody Drug Delivery

2018

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Monoclonal antibodies (mAbs) are one of the most important classes of therapeutic proteins, which are used to treat a wide number of diseases (e.g., oncology, inflammation and autoimmune diseases). Monoclonal antibody technologies are continuing to evolve to develop medicines with increasingly improved safety profiles, with the identification of new drug targets being one key barrier for new antibody development. There are many opportunities for developing antibody formulations for better patient compliance, cost savings and lifecycle management, e.g., subcutaneous formulations. However, mAb-based medicines also have limitations that impact their clinical use; the most prominent challenges are their short pharmacokinetic properties and stability issues during manufacturing, transport and storage that can lead to aggregation and protein denaturation. The development of long acting protein formulations must maintain protein stability and be able to deliver a large enough dose over a prolonged period. Many strategies are being pursued to improve the formulation and dosage forms of antibodies to improve efficacy and to increase the range of applications for the clinical use of mAbs.

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Fusion protein of single-chain variable domain fragments for treatment of myasthenia gravis

Cited by 6 publications

References 34 publications

Hinge-deleted IgG4 blocker therapy for acetylcholine receptor myasthenia gravis in rhesus monkeys

Hinge-deleted IgG4 blocker therapy for acetylcholine receptor myasthenia gravis in rhesus monkeys

Danger Zones of the Gluteal Anatomy: Improving the Safety Profile of the Gluteal Fat Grafting

Overview of Antibody Drug Delivery

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