Ocrelizumab (OCR) is a humanized anti-CD20 monoclonal antibody approved for both Relapsing and Primary Progressive forms of Multiple Sclerosis (MS) treatment. OCR is postulated to act via rapid B cell depletion; however, by analogy with other anti-CD20 agents, additional effects can be envisaged, such as on Protein Kinase C (PKC). Hence, this work aims to explore novel potential mechanisms of action of OCR in peripheral blood mononuclear cells from MS patients before and after 12 months of OCR treatment. We first assessed, up-stream, PKCβII and subsequently explored two down-stream pathways: hypoxia-inducible factor 1 alpha (HIF-1α)/vascular endothelial growth factor (VEGF), and human antigen R (HuR)/manganese-dependent superoxide dismutase (MnSOD) and heat shock proteins 70 (HSP70). At baseline, higher levels of PKCβII, HIF-1α, and VEGF were found in MS patients compared to healthy controls (HC); interestingly, the overexpression of this inflammatory cascade was counteracted by OCR treatment. Conversely, at baseline, the content of HuR, MnSOD, and HSP70 was significantly lower in MS patients compared to HC, while OCR administration induced the up-regulation of these neuroprotective pathways. These results enable us to disclose the dual positive action of OCR: anti-inflammatory and neuroprotective. Therefore, in addition to B cell depletion, the effect of OCR on these molecular cascades can contribute to counteracting disease progression.

中文翻译：

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揭示 Ocrelizumab 在多发性硬化症中的新型保护机制：PKC Beta 的作用及其下游靶标


Ocrelizumab (OCR) 是一种人源化抗 CD20 单克隆抗体，被批准用于复发性和原发性进展型多发性硬化症 (MS) 的治疗。假设 OCR 通过快速消耗 B 细胞发挥作用；然而，通过与其他抗 CD20 药物类比，可以设想额外的作用，例如对蛋白激酶 C (PKC) 的作用。因此，这项工作旨在探索 OCR 在 OCR 治疗前后 12 个月的 MS 患者外周血单核细胞中的新的潜在作用机制。我们首先评估了上游 PKCβII，随后探索了两条下游途径：缺氧诱导因子 1 α (HIF-1α)/血管内皮生长因子 (VEGF) 和人类抗原 R (HuR)/锰依赖性超氧化物歧化酶 (MnSOD) 和热休克蛋白 70 (HSP70)。基线时，与健康对照 (HC) 相比，MS 患者的 PKCβII、HIF-1α 和 VEGF 水平较高；有趣的是，这种炎症级联反应的过度表达被 OCR 治疗所抵消。相反，在基线时，与 HC 患者相比，MS 患者的 HuR、MnSOD 和 HSP70 含量显着降低，而 OCR 给药则诱导这些神经保护途径的上调。这些结果使我们能够揭示 OCR 的双重积极作用：抗炎和神经保护。因此，除了 B 细胞耗竭之外，OCR 对这些分子级联的影响也有助于阻止疾病进展。