Human IL-27 Alpha Mutein Autonomous Secretion
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Solution Overview
Problem
The human Interleukin 27 alpha-subunit (IL-27α) requires the presence of its beta-subunit EBI3 for secretion, whereas the mouse IL-27α can be secreted independently, creating a discrepancy that hampers the development of accurate mouse models mimicking the human immune system and limits the understanding of IL-27's immunomodulatory functions.
Innovation Solution
A secretion-competent mutein of the human Interleukin 27 alpha-subunit is created by mutating specific amino acid residues, allowing it to be secreted autonomously, and a secretion-incompetent mutein of the mouse IL-27α is engineered to depend on EBI3 for secretion, mimicking the human system.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the human IL-27 alpha-subunit is expressed in isolation, then it cannot be secreted autonomously and requires EBI3 for secretion, but this creates a discrepancy from mouse models where IL-27α can be secreted independently
Solution Approach 1:
The patent applies parameter changes by mutating specific amino acid residues in the human IL-27 alpha-subunit (such as C107L, C158L, C162L mutations) to alter its secretion properties. These mutations change the physical-chemical parameters of the protein, enabling it to be secreted autonomously without requiring EBI3, thus creating a humanized mouse model that accurately reflects human immune system behavior.
2Reliability
If the human IL-27 alpha-subunit requires EBI3 for secretion, then secretion control is maintained, but this limits the understanding of IL-27's independent immunomodulatory functions
Solution Approach 1:
The patent segments the IL-27 system by creating muteins of the alpha-subunit that can be secreted independently of the beta-subunit EBI3. This segmentation allows researchers to study the alpha-subunit's immunomodulatory functions in isolation, providing insights into IL-27's independent actions that would be obscured in the native heterodimeric form where secretion requires EBI3.
3Ease of operation
If mouse IL-27α is used in humanized models, then it can be secreted independently, but this does not accurately mimic the human secretion dependency on EBI3
Solution Approach 1:
The patent creates a copy of the human IL-27 alpha-subunit with modified secretion properties by introducing specific mutations (such as C107L, C158L, C162L). This mutated human alpha-subunit is then expressed in mouse models, copying the human system's amino acid sequence while altering the secretion behavior to enable autonomous secretion, thus creating an accurate humanized mouse model that combines human sequence fidelity with mouse secretion capability.
Data Source
AI summary
The present invention refers to a secretion-competent mutein of the α-subunit of human Interleukin 27 and to a human heterodimeric Interleukin 27. The present invention further refers to a nucleic acid molecule comprising a nucleotide sequence encoding a secretion-competent mutein of the α-subunit of human Interleukin 27 or the human heterodimeric Interleukin 27, to a host cell containing a nucleic acid molecule comprising a nucleotide sequence encoding a secretion-competent mutein of the α-subunit of human Interleukin 27 or of the human heterodimeric Interleukin 27. The invention also refers to an immune modulator comprising a secretion-competent mutein of the α-subunit of human Interleukin 27 or of the human heterodimeric Interleukin 27, to the respective use thereof as well as to a method of producing said secretion-competent muteins and to a secretion-incompetent mutein of the α-subunit of mouse Interleukin 27 and a secretion-competent mutein of the β-subunit of mouse Interleukin 27.