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Antagonists of complement system for use in methods of treating paraproteinemia neuropathy

A complement system, neurological technology, applied in neurological diseases, blood diseases, immunoglobulins, etc., can solve problems such as the complexity of the complement cascade

Pending Publication Date: 2022-04-01
ARGENX BVBA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This is most likely due to the complexity of the complement cascade

Method used

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  • Antagonists of complement system for use in methods of treating paraproteinemia neuropathy
  • Antagonists of complement system for use in methods of treating paraproteinemia neuropathy
  • Antagonists of complement system for use in methods of treating paraproteinemia neuropathy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0216] Example 1 Complement Inhibition Using Live Schwann Cells in an In Vitro Model of Multifocal Motor Neuropathy (MMN)

[0217] Schwann cells are myelin-secreting glial cells that spirally wrap around axons in the peripheral nervous system to form myelin sheaths. These cells attach to axons via the protein GM1. Its most important function is the myelination of axons to improve neuronal jump conduction, but it also contributes to neuronal survival and signaling. Dysfunction of these cells leads to demyelination, which leads to reduced signal transduction. Thus, Schwann cells are associated with several demyelinating disorders such as MMN. There exists a human Schwann cell line - sNF02.2 - and it was derived from lung metastases in patients diagnosed with malignant peripheral nerve sheath tumors. These cells were established from multiple passages of primary tumor material in culture until they formed a homogeneous Schwann-like population that displayed clonal morphology...

Embodiment 2

[0260] Example 2 Complement Inhibition in an In Vitro Model of Multifocal Motor Neuropathy (MMN) Using Fixed Schwann Cells system

[0261] A. method

[0262] 2.1 Protocol for culturing and fixing Schwann cells on coverslips

[0263] Incubate Schwann cells in DMEM medium containing 100 U / mL penicillin, 100 μg / mL streptomycin and supplemented with 10% FCS at 37 °C and 5% CO 2 under cultivation. Twice weekly, cells were passaged or used for experiments when >80% confluency was reached. Discard the medium and wash the cells with 10 ml PBS. To dissociate cells, add 3 mL (T75) or 5 mL (T175) of Accutase cell detachment solution and incubate cells at 37°C for 5 min, or until cells are completely detached. Then, medium was added (7 mL to T75, 10 mL to T175) and cells were transferred to 15 mL tubes, followed by centrifugation (125 x g, 10 min). The pellet was resuspended in 5 ml of medium and counted using trypan blue to differentiate live from dead cells. Next, cells we...

Embodiment 3

[0297] Example 3 Using induced pluripotent stem cells (induced pluripotent stem cells, iPSCs) in multifocal Complement Inhibition in an In Vitro Model of Motor Neuropathy (MMN)

[0298] A. method

[0299] 3.1 Protocol for Spinal Motor Neuron Differentiation from iPSCs

[0300] Motor neuron-like cells (MN) from induced pluripotent stem cells (iPSCs) were prepared as described in the literature (Harschnitz Oet al. J Clin Immunol. 2014, Jul; 34 Suppl 1: S112-9), and with Dr L van Prepared in collaboration with der Pol and colleagues (Department of Neurology, UMCU, The Netherlands). Briefly, human fibroblasts were obtained from skin biopsies of healthy individuals according to an institutional review board-approved protocol. These cells were cultured in mouse embryonic fibroblast (MEF) medium containing DMEM GlutaMAX supplemented with 10% fetal bovine serum and 1% penicillin / streptomycin at 37°C in 5% CO 2 under cultivation. Cells were reprogrammed within the first 5 p...

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Abstract

The present invention relates to methods of treating paraproteinemia neuropathy in a subject by administering to the subject an antagonist of the complement system. The antagonist inhibits the complement system upstream of complement factor C5. More particularly, the antagonist may be an antibody or antigen-binding fragment thereof that blocks or inhibits the complement system by inhibiting the C2b domain of complement factor C2. The paraproteinemia neuropathy that can be treated includes in particular multifocal motor neuropathy (MMN), chronic inflammatory demyelinating polyneuropathy (CIDP), and Gillan-Bar Syndrome (GBS).

Description

technical field [0001] The present invention relates to methods of treating paraproteinaemic neuropathies using antagonists of the complement system. The antagonist blocks or inhibits the complement system upstream of complement factor C5. Paraproteinaemic neuropathies that may be treated include, inter alia, multifocal motor neuropathy (MMN), chronic inflammatory demyelinating polyneuropathy (CIDP) and Guillain-Barre Syndrome (Guillain-Barré syndrome, GBS). Background technique [0002] The complement system is an important aspect of the innate immune system that enhances (replenishes) the ability of antibodies and phagocytes to clear microbial invaders and damaged cells from the organism. Complement thus forms an important line of defense against infection. [0003] Responses to infection must be rapid and comprehensive enough to prevent risks to the host, but selective enough not to damage healthy cells. Complement normally achieves this delicate balance by employing ...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61K39/395A61P7/00A61P25/00
CPCA61K39/3955A61P25/02C07K16/18C07K2317/76C07K2317/32C07K16/3084A61K39/395A61K2039/505
Inventor 克里斯托弗·布朗什托凯文·巴丁埃里克·哈克卡伦·西伦斯英格·万德瓦勒卢多·万德尔波尔彼得·博罗什
Owner ARGENX BVBA
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