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通过白蛋白融合延长 C1 酯酶抑制剂的循环半衰期。

Prolonging the circulatory half-life of C1 esterase inhibitor via albumin fusion.

机构信息

Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.

Canadian Blood Services, Innovation and Portfolio Management, Hamilton, Ontario, Canada.

出版信息

PLoS One. 2024 Oct 23;19(10):e0305719. doi: 10.1371/journal.pone.0305719. eCollection 2024.

DOI:10.1371/journal.pone.0305719
PMID:39441778
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11498661/
Abstract

Hereditary Angioedema (HAE) is an autosomal dominant disease characterized by episodic swelling, arising from genetic deficiency in C1-esterase inhibitor (C1INH), a regulator of several proteases including activated Plasma kallikrein (Pka). Many existing C1INH treatments exhibit short circulatory half-lives, precluding prophylactic use. Hexahistidine-tagged truncated C1INH (trC1INH lacking residues 1-97) with Mutated N-linked Glycosylation Sites N216Q/N231Q/N330Q (H6-trC1INH(MGS)), its murine serum albumin (MSA) fusion variant (H6-trC1INH(MGS)-MSA), and H6-MSA were expressed in Pichia pastoris and purified via nickel-chelate chromatography. Following intravenous injection in mice, the mean terminal half-life of H6-trC1INH(MGS)-MSA was significantly increased versus that of H6-trC1INH(MGS), by 3-fold, while remaining ~35% less than that of H6-MSA. The extended half-life was achieved with minimal, but significant, reduction in the mean second order rate constant of Pka inhibition of H6-trC1INH(MGS)-MSA by 33% relative to that of H6-trC1INH(MGS). Our results validate albumin fusion as a viable strategy for half-life extension of a natural inhibitor and suggest that H6-trC1INH(MGS)-MSA is worthy of investigation in a murine model of HAE.

摘要

遗传性血管性水肿（HAE）是一种常染色体显性疾病，其特征为突发性肿胀，由 C1-酯酶抑制剂（C1INH）的遗传缺陷引起，C1INH 是包括激活的血浆激肽释放酶（Pka）在内的几种蛋白酶的调节剂。许多现有的 C1INH 治疗方法具有较短的循环半衰期，排除了预防性使用。具有突变的 N 连接糖基化位点 N216Q/N231Q/N330Q（H6-trC1INH（MGS））的六组氨酸标记的截断 C1INH（缺乏残基 1-97 的 trC1INH），其鼠血清白蛋白（MSA）融合变体（H6-trC1INH（MGS）-MSA）和 H6-MSA 在巴斯德毕赤酵母中表达，并通过镍螯合色谱法进行纯化。在小鼠中静脉注射后，与 H6-trC1INH（MGS）相比，H6-trC1INH（MGS）-MSA 的平均终末半衰期显著增加了 3 倍，而仍比 H6-MSA 低约 35%。通过将 H6-trC1INH（MGS）-MSA 对 Pka 的抑制的平均二级速率常数降低 33%，达到了延长半衰期的效果，与 H6-trC1INH（MGS）相比，这一降低幅度虽小，但具有显著性。我们的结果验证了白蛋白融合作为延长天然抑制剂半衰期的可行策略，并表明 H6-trC1INH（MGS）-MSA 值得在 HAE 的小鼠模型中进行研究。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e899/11498661/5c46663bbb89/pone.0305719.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e899/11498661/520272489d64/pone.0305719.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e899/11498661/62236b9389dd/pone.0305719.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e899/11498661/5c46663bbb89/pone.0305719.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e899/11498661/520272489d64/pone.0305719.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e899/11498661/62236b9389dd/pone.0305719.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e899/11498661/5c46663bbb89/pone.0305719.g003.jpg

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