Frequent injections of anti-CD124 monoclonal antibody (αCD124) over long periods of time are used to treat chronic rhinosinusitis with nasal polyps (CRSwNP). Needle-free, intranasal administration (i.n.) of αCD124 is expected to provide advantages of localized delivery, improved efficacy, and enhanced medication adherence. However, delivery barriers such as the mucus and epithelium in the nasal tissue impede penetration of αCD124. Herein, two novel protamine nanoconstructs: allyl glycidyl ether conjugated protamine (Nano-P) and polyamidoamine-linked protamine (Dendri-P) were synthesized and showed enhanced αCD124 penetration through multiple epithelial layers compared to protamine in mice. αCD124 was mixed with Nano-P or Dendri-P and then intranasally delivered for the treatment of severe CRSwNP in mice. Micro-CT and pathological changes in nasal turbinates showed that these two nano-formulations achieved ∼50 % and ∼40 % reductions in nasal polypoid lesions and eosinophil count, respectively. Both nano-formulations provided enhanced efficacy in suppressing nasal and systemic Immunoglobulin E (IgE) and nasal type 2 inflammatory biomarkers, such as interleukin 13 (IL-13) and IL-25. These effects were superior to those in the protamine formulation group and subcutaneous (s.c.) αCD124 given at a 12.5-fold higher dose. Intranasal delivery of protamine, Nano-P, or Dendri-P did not induce any measurable toxicities in mice.

中文翻译：

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鼻内递送低剂量抗 CD124 抗体可增强慢性鼻窦炎伴鼻息肉的治疗

长期频繁注射抗 CD124 单克隆抗体 (αCD124) 用于治疗伴有鼻息肉的慢性鼻窦炎 (CRSwNP)。 αCD124 的无针鼻内给药有望提供局部递送、提高疗效和增强药物依从性的优点。然而，鼻组织中的粘液和上皮等递送屏障阻碍了 αCD124 的渗透。在此，合成了两种新型鱼精蛋白纳米结构：烯丙基缩水甘油醚缀合的鱼精蛋白（Nano-P）和聚酰胺胺连接的鱼精蛋白（Dendri-P），与小鼠中的鱼精蛋白相比，它们显示出增强的αCD124对多个上皮层的渗透。 αCD124 与 Nano-P 或 Dendri-P 混合，然后鼻内给药，用于治疗小鼠的严重 CRSwNP。鼻甲骨的显微 CT 和病理变化表明，这两种纳米制剂分别使鼻息肉样病变和嗜酸性粒细胞计数减少约 50% 和约 40%。两种纳米制剂在抑制鼻腔和全身免疫球蛋白 E (IgE) 以及鼻腔 2 型炎症生物标志物（例如白细胞介素 13 (IL-13) 和 IL-25）方面均具有增强功效。这些效果优于鱼精蛋白制剂组和皮下 (sc) αCD124 给予 12.5 倍高剂量的效果。鼻内递送鱼精蛋白、Nano-P 或 Dendri-P 不会在小鼠中引起任何可测量的毒性。