De-immunized Polypeptides for Targeted MHC Class I Epitope Delivery
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Solution Overview
Problem
Current polypeptide-based therapeutics face challenges in delivering T-cell epitopes to the MHC class I presentation pathway while minimizing immunogenicity and avoiding undesirable immune responses, as they often induce immune responses that reduce therapeutic efficacy and cause adverse reactions.
Innovation Solution
Development of T-cell epitope delivering polypeptides, such as CD8+ T-cell hyper-immunized and de-immunized polypeptides, which are designed to reduce antigenicity and immunogenicity by incorporating heterologous T-cell epitopes and toxin-derived effector functions, allowing for targeted delivery and presentation to the MHC class I system without inducing B-cell or CD4+ T-cell responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current polypeptide-based therapeutics are administered to deliver T-cell epitopes, then the therapeutic molecules can potentially reach the MHC class I presentation pathway, but they induce undesirable immune responses that reduce therapeutic efficacy and cause adverse reactions
Solution Approach 1:
The patent extracts and removes B-cell epitopes and CD4+ T-cell epitopes from the polypeptide structure, retaining only the CD8+ T-cell epitopes necessary for therapeutic action. This selective removal eliminates the harmful immunogenic responses while preserving the desired CD8+ T-cell activation function.
Solution Approach 2:
The patent applies local quality by creating heterogeneous epitope distribution within the polypeptide structure. Different regions of the polypeptide are engineered to have specific epitope characteristics: some regions contain CD8+ T-cell epitopes for therapeutic action, while other regions are designed to be immunologically inert or contain tolerogenic epitopes, thereby localizing immunogenicity to only where necessary.
2Reliability
If polypeptides are designed to reduce antigenicity and immunogenicity by incorporating heterologous T-cell epitopes, then CD8+ T-cell immunogenicity is enhanced, but the polypeptide structure becomes more complex
Solution Approach 1:
The patent segments the polypeptide structure into distinct functional domains: cell-binding domains, cell-internalization domains, and epitope-containing domains. Each segment is independently optimized for its specific function, allowing systematic design and assembly of complex polypeptides with controlled immunogenicity profiles.
Solution Approach 2:
The patent creates composite polypeptide structures by combining multiple functional elements: heterologous CD8+ T-cell epitopes, cell-targeting moieties, and internalization signals. These composite structures integrate different biological functions into a single molecule, achieving enhanced CD8+ T-cell immunogenicity while maintaining structural organization.
3Reliability
If exogenous peptides are administered to cells, then the peptides can potentially be processed and presented, but they are degraded by extracellular enzymatic activities and lysosomal proteolysis before reaching the MHC class I pathway
Solution Approach 1:
The patent incorporates cell-internalization domains and protease-resistant linkers that protect the epitope cargo during extracellular circulation. These preliminary protective measures prevent enzymatic degradation before the polypeptide reaches its intracellular target, ensuring intact delivery of the T-cell epitope to the MHC class I presentation pathway.
Data Source
AI summary
The present invention is directed to T-cell epitope delivering polypeptides which deliver one or more CD8+ T-cell epitopes to the MHC class I presentation pathway of a cell, including toxin-derived polypeptides which comprise embedded T-cell epitopes and are de-immunized. The present invention provides cell-targeted, CD8+ T-cell epitope delivering molecules for the targeted delivery of cytotoxicity to certain cells, e.g., infected or malignant cells, for the targeted killing of specific cell types, and the treatment of a variety of diseases, disorders, and conditions, including cancers, immune disorders, and microbial infections. The present invention also provides methods of generating polypeptides capable of delivering one or more heterologous T-cell epitopes to the MHC class I presentation pathway, including polypeptides which are 1) B-cell and/or CD4+ T-cell de-immunized, 2) comprise embedded T-cell epitopes, and/or 3) comprises toxin effectors which retain toxin functions.