Epitope-Modified Interferon Gamma Bypasses Autoantibody Neutralization
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Solution Overview
Problem
Anti-IFNr autoantibodies, associated with disseminated mycobacterial infections, particularly in Southeast Asia, neutralize interferon gamma (IFNr) activity, leading to severe infections, and the mechanism of their production remains unclear, with existing technologies failing to effectively bypass their neutralizing effects.
Innovation Solution
Characterization of the major epitope recognized by anti-IFNr autoantibodies and generation of an epitope-erased recombinant IFNr protein (EE-IFNr) with a modified C-terminal region, which has a lower affinity for these antibodies and can activate the IFNr signaling pathway even in their presence, and the use of a homologous peptide sequence to replace the critical epitope in human IFNr, creating a recombinant protein that induces receptor activation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If anti-IFNr autoantibodies are present in patients, then IFNr signaling is neutralized leading to severe disseminated mycobacterial infections, but the autoantibodies themselves cannot be eliminated and continue to block IFNr activity
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of IFNr at the epitope region (residues 121-127) to create variants with altered binding affinity to autoantibodies while preserving receptor activation capability. This changes the chemical parameters of the IFNr molecule to escape neutralization.
Solution Approach 2:
The patent applies local quality by making specific localized changes only at the autoantibody-binding epitope region (residues 121-127) while leaving the rest of the IFNr molecule unchanged. This allows the protein to maintain its overall structure and receptor-binding capability while gaining resistance to autoantibody neutralization at the specific problematic location.
2Object-affected harmful factors
If the C-terminal region of IFNr (residues 121-127) is modified to reduce autoantibody binding, then neutralization is bypassed, but the modification must not compromise IFNr receptor activation
Solution Approach 1:
The patent changes the amino acid parameters at residues 121-127 to reduce autoantibody binding affinity while monitoring and preserving the biological activity parameters related to receptor activation through in vitro and in vivo assays.
Solution Approach 2:
The patent applies localized modifications specifically at the C-terminal epitope region (residues 121-127) that is responsible for autoantibody binding, while maintaining the quality and functionality of the rest of the IFNr molecule for receptor activation.
3Adaptability or versatility
If homologous peptide sequences from Aspergillus Noc2 are used to replace the human IFNr epitope, then molecular mimicry is broken and autoantibody recognition is reduced, but the replacement must maintain IFNr biological function
Solution Approach 1:
The patent changes the amino acid sequence parameters of the epitope region by introducing homologous sequences from Aspergillus Noc2 that share structural similarities but have different primary sequences, thereby reducing autoantibody recognition while attempting to preserve functional properties.
Solution Approach 2:
The patent uses copying by taking the structural and functional properties of the Aspergillus Noc2 protein and creating a human IFNr variant that mimics these properties at the epitope region, allowing escape from autoantibody recognition that was raised against the original human sequence.
Data Source
AI summary
The present invention discloses a fragment of peptide which can be utilized in patients suffering from a disseminated mycobacterial infection. The fragment of peptide contains a sequence of amino acids with seven residues as formula (I) shown below, wherein X.sub.1 is Leucine (Leu); X.sub.2 is Proline (Pro); X.sub.3 is Glutamate (Glu); X.sub.4 is serine (Ser); X.sub.5 is Serine (Ser); X.sub.6 is Leucine (Leu) and X.sub.7 is Arginine (Arg): X.sub.1-X.sub.2-X.sub.3-X.sub.4-X.sub.5-X.sub.6-X.sub.7 (I).