Modified Diphtheria Toxin Reducing Vascular Leak Syndrome
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Solution Overview
Problem
Therapeutic proteins often induce immune responses and vascular leak syndrome (VLS) due to their immunogenic nature, limiting their efficacy and causing adverse effects in patients.
Innovation Solution
Modified diphtheria toxins with specific amino acid residue modifications in T-cell epitopes and VLS motifs are developed to reduce immunogenicity and binding to endothelial cells, thereby minimizing immune responses and VLS.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If therapeutic proteins are used to treat diseases, then disease treatment efficacy is improved, but immune responses and vascular leak syndrome occur
Solution Approach 1:
The patent modifies specific amino acid residues at defined positions in the toxin protein sequence (e.g., positions 7, 29, 97, 107, 124, 148, 290, 291, 292) to change the protein's immunogenicity parameters while preserving its biological activity. These parameter changes reduce T-cell epitope recognition and vascular endothelial binding, thereby reducing immune responses and vascular leak syndrome.
Solution Approach 2:
The patent applies local modifications to specific regions of the toxin protein that are responsible for immunogenicity and vascular leak. By targeting specific amino acid positions in the T-cell epitope regions and VLS motif regions, the invention locally alters the protein properties without affecting the overall toxin structure and function.
2Object-affected harmful factors
If amino acid modifications are made in T-cell epitopes to reduce immunogenicity, then immune responses are reduced, but toxin activity may be compromised
Solution Approach 1:
The patent carefully selects amino acid modifications that change immunogenic parameters while preserving toxin activity parameters. The modifications at specific positions are designed to reduce T-cell recognition without disrupting the toxin's ability to bind and inhibit protein synthesis in target cells.
Solution Approach 2:
The patent converts the harmful T-cell epitope regions into beneficial modified sequences that reduce immunogenicity. By strategically modifying epitope regions, the invention transforms these harmful elements into features that enhance safety while maintaining therapeutic efficacy.
3Object-affected harmful factors
If amino acid modifications are made in VLS motifs to reduce vascular leak, then VLS effects are reduced, but binding to endothelial cells may be affected
Solution Approach 1:
The patent modifies amino acid residues in VLS motif regions (such as positions 7-9, 29-31, and 290-292) to change the protein's vascular leak properties. These parameter changes reduce binding to vascular endothelial cells and subsequent VLS effects while maintaining other critical toxin functions.
Solution Approach 2:
The patent applies local modifications to specific VLS motif regions of the toxin protein. By targeting specific amino acid positions known to be involved in vascular leak, the invention locally alters the protein's interaction with endothelial cells without affecting the overall toxin structure and cytotoxic activity.
Data Source
AI summary
The present application relates to compositions of modified toxins exhibiting reduced immunogenicity and reduced binding to vascular endothelium or vascular endothelial cells, thereby reducing the incidence of Vascular Leak Syndrome. Also provided are polypeptide toxophores from a modified diphtheria toxin, where modifications are in at least one amino acid residue of at least one T-cell epitope. Another aspect relates to a polypeptide toxophore from a modified diphtheria toxin, where modifications are in at least one amino acid residue of at least one T-cell epitope and at least one amino acid residue of at least one VLS motif of an unmodified native diphtheria toxin. Another aspect relates to a fusion protein which comprises a modified diphtheria toxin and a non-diphtheria toxin fragment that is a cell binding portion. Another aspect relates to the use of a modified diphtheria toxin for the treatment of a malignant disease or a non-malignant disease.