Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Front Immunol. 2024 Sep 16;15:1371156. doi: 10.3389/fimmu.2024.1371156. eCollection 2024.
Effective treatment and immunoprophylaxis of viral respiratory infections with neutralizing monoclonal antibodies (mAbs) require maintaining inhibitory concentrations of mAbs at the airway surface. While engineered mAbs with increased affinity to the neonatal Fc receptor (FcRn) are increasingly employed, little is known how increased affinity of Fc to FcRn influences basal-to-apical transepithelial transport (transcytosis) of mAbs across the airway epithelium. To investigate this, we utilized a model of well-differentiated human airway epithelium (WD-HAE) that exhibited robust FcRn expression, and measured the transepithelial transport of a mAb against SARS-CoV-2 Spike protein (CR3022) with either wildtype IgG-Fc or Fc modified with YTE or LS mutations known to increase affinity for FcRn. Despite the marked differences in the affinity of these CR3022 variants for FcRn, we did not find substantial differences in basal-to-apical transport reflective of systemic dosing, or apical-to-basal transport reflective of inhaled dosing, compared to the transport of wildtype IgG-Fc. These results suggest increasing FcRn affinity may only have limited influence over transcytosis rates of systemically dosed mAbs across the human airway epithelium over short time scales. Over longer time scales, the elevated circulating levels of mAbs with greater FcRn affinity, due to more effective FcRn-mediated recycling, may better resupply mAb into the respiratory tract, leading to more effective extended immunoprophylaxis.
针对病毒呼吸道感染，采用中和单克隆抗体（mAb）进行有效治疗和免疫预防，需要使 mAb 在气道表面维持抑制浓度。虽然越来越多地使用对新生儿 Fc 受体（FcRn）亲和力增加的工程化 mAb，但对于增加 Fc 与 FcRn 的亲和力如何影响 mAb 穿过气道上皮的基底-顶端跨上皮转运（转胞吞作用）知之甚少。为了研究这一点，我们利用了分化良好的人气道上皮（WD-HAE）模型，该模型表现出强大的 FcRn 表达，并测量了针对 SARS-CoV-2 刺突蛋白（CR3022）的 mAb 的跨上皮转运，该 mAb 的 Fc 具有野生型 IgG-Fc 或 YTE 或 LS 突变修饰，已知这些突变可增加与 FcRn 的亲和力。尽管这些 CR3022 变体与 FcRn 的亲和力存在显著差异，但与野生型 IgG-Fc 的转运相比，我们没有发现反映全身给药的基础-顶端转运或反映吸入给药的顶端-基底转运有实质性差异。这些结果表明，增加 FcRn 亲和力可能仅对全身给药的 mAb 穿过人气道上皮的转胞吞作用速率在短时间尺度上具有有限的影响。在更长的时间尺度上，由于更有效的 FcRn 介导的再循环，具有更高 FcRn 亲和力的 mAb 循环水平升高，可能会更好地将 mAb 重新供应到呼吸道中，从而实现更有效的扩展免疫预防。
