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The C-terminal end of engineered albumin variants and fusion proteins after exposure to carboxypeptidase A

ABSTRACT: Albumin has a long plasma half-life due to engagement of the neonatal Fc receptor (FcRn), which prevents intracellular degradation. However, its C-terminal end can be cleaved by carboxypeptidase A, and removal of the last leucine residue (L585) weakens receptor binding, reducing its half-life from 20 days to 3.5 days in humans. This biology is important to consider when designing human albumin-fused biologics. Here, we explore engineering strategies to secure favorable FcRn binding and pharmacokinetic properties, and we use LC-MS/MS to analyze the amino acid sequence of the C-terminal end of engineered albumin variants and albumin fusion proteins, following incubation with or without carboxypeptidase A.

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ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

SUBMITTER: Ingrid Maria Erika Ekman Stensland

LAB HEAD: Tuula A. Nyman

PROVIDER: PXD063561 | Pride | 2025-05-19

REPOSITORIES: Pride

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Project description:Miao2010 - Innate and adaptive immune responses to primary Influenza A Virus infection This model is described in the article: Quantifying the early immune response and adaptive immune response kinetics in mice infected with influenza A virus. Miao H, Hollenbaugh JA, Zand MS, Holden-Wiltse J, Mosmann TR, Perelson AS, Wu H, Topham DJ. J. Virol. 2010 Jul; 84(13): 6687-6698 Abstract: Seasonal and pandemic influenza A virus (IAV) continues to be a public health threat. However, we lack a detailed and quantitative understanding of the immune response kinetics to IAV infection and which biological parameters most strongly influence infection outcomes. To address these issues, we use modeling approaches combined with experimental data to quantitatively investigate the innate and adaptive immune responses to primary IAV infection. Mathematical models were developed to describe the dynamic interactions between target (epithelial) cells, influenza virus, cytotoxic T lymphocytes (CTLs), and virus-specific IgG and IgM. IAV and immune kinetic parameters were estimated by fitting models to a large data set obtained from primary H3N2 IAV infection of 340 mice. Prior to a detectable virus-specific immune response (before day 5), the estimated half-life of infected epithelial cells is approximately 1.2 days, and the half-life of free infectious IAV is approximately 4 h. During the adaptive immune response (after day 5), the average half-life of infected epithelial cells is approximately 0.5 days, and the average half-life of free infectious virus is approximately 1.8 min. During the adaptive phase, model fitting confirms that CD8(+) CTLs are crucial for limiting infected cells, while virus-specific IgM regulates free IAV levels. This may imply that CD4 T cells and class-switched IgG antibodies are more relevant for generating IAV-specific memory and preventing future infection via a more rapid secondary immune response. Also, simulation studies were performed to understand the relative contributions of biological parameters to IAV clearance. This study provides a basis to better understand and predict influenza virus immunity. This model is hosted on BioModels Database and identified by: BIOMD0000000546. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

			Action	DRS
	LC-MS_files_exp1.zip	Other
	LC-MS_files_exp2.zip	Other
	mqpar_exp1.xml	Xml
	mqpar_exp2.xml	Xml
	txt_exp1.zip	Other

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The C-terminal end of engineered albumin variants and fusion proteins after exposure to carboxypeptidase A

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