Classical Complement Pathway Inhibition in a “Human-On-A-Chip” Model of Autoimmune Demyelinating Neuropathies,Advanced Therapeutics

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Classical Complement Pathway Inhibition in a “Human-On-A-Chip” Model of Autoimmune Demyelinating Neuropathies
Advanced Therapeutics ( IF 3.7 ) Pub Date : 2022-04-05 , DOI: 10.1002/adtp.202200030
John W Rumsey ₁ , Case Lorance ₁ , Max Jackson ₁ , Trevor Sasserath ₁ , Christopher W McAleer ₁ , Christopher J Long ₁ , Arindom Goswami ₂ , Melissa A Russo ₃ , Shruti M Raja ₃ , Karissa L Gable ₃ , Doug Emmett ₃ , Lisa D Hobson-Webb ₃ , Manisha Chopra ₄ , James F Howard ₄ , Jeffrey T Guptill ₃ , Michael J Storek ₅ , Miguel Alonso-Alonso ₆ , Nazem Atassi ₆ , Sandip Panicker ₇ , Graham Parry ₇ , Timothy Hammond ₈ , James J Hickman _{1,

2}

Affiliation

Chronic autoimmune demyelinating neuropathies are a group of rare neuromuscular disorders with complex, poorly characterized etiology. Here the authors describe a phenotypic, human-on-a-chip (HoaC) electrical conduction model of two rare autoimmune demyelinating neuropathies, chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN), and explore the efficacy of TNT005, a monoclonal antibody inhibitor of the classical complement pathway. Patient sera is shown to contain anti-GM1 IgM and IgG antibodies capable of binding to human primary Schwann cells and induced pluripotent stem cell-derived motoneurons (MNs). Patient autoantibody binding is sufficient to activate the classical complement pathway, resulting in detection of C3b and C5b-9. A HoaC model, using a microelectrode array with directed axonal outgrowth over the electrodes treated with patient sera, exhibits reductions in MN action potential frequency and conduction velocity. TNT005 rescued the serum-induced complement deposition and functional deficits while treatment with an isotype control antibody has no rescue effect. These data indicate that complement activation by CIDP and MMN patient serum is sufficient to mimic neurophysiological features of each disease and that complement inhibition with TNT005 is sufficient to rescue these pathological effects and provide efficacy data included in an investigational new drug application, demonstrating the model's translational potential.

中文翻译：

自身免疫性脱髓鞘性神经病“人体芯片”模型中的经典补体通路抑制

慢性自身免疫性脱髓鞘性神经病是一组罕见的神经肌肉疾病，病因复杂，特征不明。在这里，作者描述了两种罕见的自身免疫性脱髓鞘性神经病、慢性炎症性脱髓鞘性多发性神经病 (CIDP) 和多灶性运动神经病 (MMN) 的表型、人芯片 (HoaC) 电传导模型，并探讨了 TNT005 的功效，TNT005 是一种经典补体途径的单克隆抗体抑制剂。患者血清显示含有抗 GM1 IgM 和 IgG 抗体，能够结合人原代雪旺细胞和诱导多能干细胞衍生的运动神经元 (MN)。患者自身抗体结合足以激活经典补体途径，从而检测到 C3b 和 C5b-9。一个HoaC模型，在用患者血清处理的电极上使用具有定向轴突生长的微电极阵列，表现出 MN 动作电位频率和传导速度的降低。TNT005 挽救了血清诱导的补体沉积和功能缺陷，而同种型对照抗体治疗没有挽救作用。这些数据表明，CIDP 和 MMN 患者血清的补体激活足以模拟每种疾病的神经生理学特征，而 TNT005 的补体抑制足以挽救这些病理效应，并提供新药研究申请中包含的疗效数据，证明该模型的转化潜在的。TNT005 挽救了血清诱导的补体沉积和功能缺陷，而同种型对照抗体治疗没有挽救作用。这些数据表明，CIDP 和 MMN 患者血清的补体激活足以模拟每种疾病的神经生理学特征，而 TNT005 的补体抑制足以挽救这些病理效应，并提供新药研究申请中包含的疗效数据，证明该模型的转化潜在的。TNT005 挽救了血清诱导的补体沉积和功能缺陷，而同种型对照抗体治疗没有挽救作用。这些数据表明，CIDP 和 MMN 患者血清的补体激活足以模拟每种疾病的神经生理学特征，而 TNT005 的补体抑制足以挽救这些病理效应，并提供新药研究申请中包含的疗效数据，证明该模型的转化潜在的。

更新日期：2022-04-05

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