Modified Diphtheria Toxin T-Cell Epitope Engineering
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Solution Overview
Problem
Therapeutic proteins, such as monoclonal antibodies and granulocyte-macrophage colony stimulating factor, often induce immune responses due to their immunogenic nature, limiting their efficacy as treatments for human diseases, and existing computational methods for identifying T-cell epitopes are not effective in predicting epitopes that bind MHC class II molecules in all situations, particularly in vivo.
Innovation Solution
Modified diphtheria toxins with specific amino acid residue modifications in T-cell epitopes are developed, which exhibit reduced immunogenicity and cytotoxicity compared to unmodified toxins, and can be used as fusion proteins with non-diphtheria toxin polypeptides like antibodies or cytokines to treat diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If therapeutic proteins are used to treat diseases, then therapeutic efficacy is achieved, but immune response is induced which limits treatment effectiveness
Solution Approach 1:
The patent applies parameter changes by modifying amino acid residues at specific positions within T-cell epitopes of the therapeutic protein. This changes the chemical parameters of the protein structure to reduce its immunogenicity while preserving therapeutic function, directly resolving the contradiction between efficacy and immune response induction
Solution Approach 2:
The invention applies local quality by making targeted amino acid substitutions only at specific positions within T-cell epitopes rather than throughout the entire protein. This localized modification approach reduces immune response at critical epitope regions while maintaining the overall therapeutic protein structure and function
2Object-generated harmful factors
If amino acid substitutions are made in T-cell epitopes to reduce immunogenicity, then immune response is reduced, but cytotoxicity may be affected
Solution Approach 1:
The patent systematically changes amino acid parameters at epitope positions to reduce immunogenicity while monitoring and preserving cytotoxicity. By selecting specific amino acid substitutions that alter epitope recognition by T-cells without disrupting the protein's cytotoxic mechanism, the contradiction between reduced immunogenicity and maintained cytotoxicity is resolved
Solution Approach 2:
The invention applies local quality by restricting amino acid modifications to specific regions within T-cell epitopes that are responsible for MHC class II binding and T-cell recognition. This localized approach ensures that modifications reduce immunogenicity at epitope interfaces while preserving the cytotoxic domains of the protein that are responsible for therapeutic activity
Data Source
AI summary
The present application relates to compositions of modified toxins exhibiting cytotoxicity and/or reduced immunogenicity. 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 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. A modified diphtheria toxin or fusion protein may be administered with one or more other agents.