In vivo antiviral efficacy of LCTG-002, a pooled, purified human milk secretory IgA product, against SARS-CoV-2 in a murine model of COVID-19.
In vivo antiviral efficacy of LCTG-002, a pooled, purified human milk secretory IgA product, against SARS-CoV-2 in a murine model of COVID-19.
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DOI：
10.1080/21645515.2024.2303226
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发表时间：
2024-12-31
影响因子：
4.8
通讯作者：
中科院分区：
文献类型：
--
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免疫球蛋白 A (IgA) 是人类粘膜中最丰富的抗体 (Ab)，其中分泌型 (sIgA) 占主导地位且具有独特的稳定性。重组生产 sIgA 具有挑战性，但它天然存在于母乳中，可以被视为这种生物制剂的全球资源，证明其作为粘膜治疗剂的开发是合理的。目前，SARS-CoV-2 被用作粘膜病原体模型，并且开发了从未感染 SARS-CoV-2 或已从感染中恢复的供体中有效提取母乳 sIgA 的方法，从而在乳汁中引发高滴度抗 SARS-CoV-2 Spike sIgA（汇集以制备 LCTG-002）。质谱分析确定相对丰度为 1% 或更高的蛋白质均与 sIgA 相关。蛋白质印迹证明所有批次主要由 sIgA 组成。与对照 IgA 相比，LCTG-002 表现出显着更高的 Spike 结合（平均终点分别为 0.87 与 5.87）。与对照相比，LCTG-002 能够阻断 Spike 受体结合结构域 - 血管紧张素转换酶 2 (ACE2) 相互作用，其效力显着增强（LCTG-002 平均 IC50 为 154ug/mL，对照未达到 50% 抑制），并且对 Spike 假型病毒感染表现出显着的中和活性（LCTG-002 平均 IC50 为 49.8ug/mL，对照未达到 50% 抑制）。对照为114.5ug/mL)。测试了 LCTG-002 在接种 SARS-CoV-2 的 K18+hACE2 转基因小鼠中降低病毒肺负荷的能力。当以 0.25mg/天或 1mg/天给药时，与对照相比，LCTG-002 显着降低了 SARS-CoV-2 滴度，最大 TCID50 降低了 4.9 个对数。这项创新研究表明 LCTG-002 纯度高且体内有效，支持进一步开发乳源性多克隆 sIgA 疗法。
Immunoglobulin A (IgA) is the most abundant antibody (Ab) in human mucosae, with secretory form (sIgA) being dominant and uniquely stable. sIgA is challenging to produce recombinantly but is naturally found in human milk, which could be considered a global resource for this biologic, justifying its development as a mucosal therapeutic. Presently, SARS-CoV-2 was utilized as a model mucosal pathogen, and methods were developed to efficiently extract human milk sIgA from donors who were naïve to SARS-CoV-2 or had recovered from infection that elicited high-titer anti-SARS-CoV-2 Spike sIgA in their milk (pooled to make LCTG-002). Mass spectrometry determined that proteins with a relative abundance of 1% or greater were all associated with sIgA. Western blot demonstrated that all batches consisted predominantly of sIgA. Compared to control IgA, LCTG-002 demonstrated significantly higher Spike binding (mean endpoint of 0.87 versus 5.87). LCTG-002 was capable of blocking the Spike receptor-binding domain – angiotensin-converting enzyme 2 (ACE2) interaction with significantly greater potency compared to control (mean LCTG-002 IC50 154ug/mL versus 50% inhibition not achieved for control), and exhibited significant neutralization activity against Spike-pseudotyped virus infection (mean LCTG-002 IC50 49.8ug/mL versus 114.5ug/mL for control). LCTG-002 was tested for its capacity to reduce viral lung burden in K18+hACE2 transgenic mice inoculated with SARS-CoV-2. LCTG-002 significantly reduced SARS-CoV-2 titers compared to control when administered at 0.25 mg/day or 1 mg/day, with a maximum TCID50 reduction of 4.9 logs. This innovative study demonstrates that LCTG-002 is highly pure and efficacious in vivo, supporting further development of milk-derived, polyclonal sIgA therapeutics.
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