Nonhuman glycans can regulate anti-factor VIII antibody formation in mice
Nonhuman glycans can regulate anti-factor VIII antibody formation in mice
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DOI：
10.1182/blood.2020009210
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发表时间：
2022-03-03
期刊：
影响因子：
20.3
通讯作者：
Stowell, Sean R.
中科院分区：
文献类型：
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作者：
Arthur, Connie M.;Zerra, Patricia E.;Stowell, Sean R.
重组因子VIII（FVIII）产品代表了血友病A患者的挽救生命干预措施。然而，患者可能会产生针对FVIII的抗体，从而阻止其功能并直接增加发病率和死亡率。抗FVIII抗体的形成取决于所用重组产品的类型，既往研究表明，第二代幼仓鼠肾（BHK）衍生的FVIII产品比第三代中国仓鼠卵巢（CHO）衍生的FVIII产品显示出更高的免疫原性。然而，造成这些差异的潜在机制仍不完全清楚。我们的研究结果表明，BHK细胞表达的非人源碳水化合物α 1 - 3半乳糖（α Gal）水平高于CHO细胞，这表明α Gal掺入FVIII可能导致抗α Gal抗体识别，这可能对抗FVIII抗体的产生产生积极影响。与此一致，BHK衍生的FVIII表现出增加的α Gal水平，这对应于与抗α Gal抗体的反应性增加。将BHK衍生而非CHO衍生的FVIII输注到自发产生抗α Gal抗体的α Gal敲除小鼠中，导致显著更高的抗FVIII抗体形成，表明BHK衍生的FVIII上α Gal水平的增加可影响免疫原性。这些结果表明，重组FVIII产物与非人碳水化合物的翻译后修饰可能会影响抗FVIII抗体的产生。
Recombinant factor VIII (FVIII) products represent a life-saving intervention for patients with hemophilia A. However, patients can develop antibodies against FVIII that prevent its function and directly increase morbidity and mortality. The development of anti-FVIII antibodies varies depending on the type of recombinant product used, with previous studies suggesting that second-generation baby hamster kidney (BHK)-derived FVIII products display greater immunogenicity than do third-generation Chinese hamster ovary (CHO)-derived FVIII products. However, the underlying mechanisms responsible for these differences remain incompletely understood. Our results demonstrate that BHK cells express higher levels of the nonhuman carbohydrate alpha 1-3 galactose (alpha Gal) than do CHO cells, suggesting that alpha Gal incorporation onto FVIII may result in anti-alpha Gal antibody recognition that could positively influence the development of anti-FVIII antibodies. Consistent with this, BHK-derived FVIII exhibits increased levels of alpha Gal, which corresponds to increased reactivity with anti-alpha Gal antibodies. Infusion of BHK-derived, but not CHO-derived, FVIII into alpha Gal-knockout mice, which spontaneously generate anti-alpha Gal antibodies, results in significantly higher anti-FVIII antibody formation, suggesting that the increased levels of alpha Gal on BHK-derived FVIII can influence immunogenicity. These results suggest that posttranslational modifications of recombinant FVIII products with nonhuman carbohydrates may influence the development of anti-FVIII antibodies.