Single-Chain Multivalent Polypeptide for Tumor Apoptosis
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Solution Overview
Problem
Current therapies targeting MHC-peptide complexes for cancer treatment face challenges due to lack of specificity, requiring external cross-linking and causing side effects by affecting both normal and abnormal cells, and are difficult to produce and stabilize.
Innovation Solution
Development of single-chain multivalent polypeptides comprising multiple domains that specifically bind to MHC-peptide complexes, allowing for cross-linking and induction of apoptosis in tumor cells without affecting normal cells, using recombinant DNA assembly and optimized linker sequences for stability and flexibility.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If polypeptide complexes are assembled via post-translational covalent or non-covalent linker chemistry, then the ability to cross-link MHC-peptide complexes and induce apoptosis is achieved, but the manufacturing complexity and production difficulty increase significantly
Solution Approach 1:
The patent merges multiple separate polypeptide components into a single-chain polypeptide structure. The single-chain polypeptide comprises multiple domains (e.g., VH domains) that can cross-link MHC-peptide complexes, eliminating the need for post-translational assembly of separate polypeptides via covalent or non-covalent linkers. This simplifies production while maintaining the apoptosis induction capability.
Solution Approach 2:
The single-chain polypeptide is segmented into multiple functional domains (e.g., multiple VH domains) connected by linker sequences. Each domain can independently bind to MHC-peptide complexes, and the segmented structure allows for simplified recombinant production compared to assembling multiple separate polypeptides.
2Reliability
If multivalent polypeptide complexes are produced through post-translational assembly, then cross-linking functionality is achieved, but the stability of the complex in vivo becomes problematic
Solution Approach 1:
The patent combines multiple binding domains into a single polypeptide chain with stable covalent peptide bonds between domains. This integrated structure is more stable in vivo compared to complexes assembled through post-translational non-covalent interactions, while maintaining the cross-linking functionality through the multiple domains.
3Measurement precision
If antibodies are used to target tumor antigens, then selective binding to tumor cells is achieved, but normal cells are also affected causing side effects
Solution Approach 1:
The single-chain polypeptide is designed to target specific MHC-peptide complexes that are locally present on tumor cells. By targeting the peptide component presented by MHC molecules, the polypeptide achieves local specificity to tumor antigens while sparing normal cells that do not present the same tumor-specific peptides, thereby reducing side effects.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The solution effectively induces apoptosis in tumor cells while sparing normal cells, offering improved specificity and manufacturing ease, with demonstrated efficacy in preclinical models.
Implementation Method 1
specifically binding molecules that induce apoptosis in tumor cells... single-chain multivalent, preferably tetravalent or bigger, specifically hexavalent repeats of human antibody variable (heavy) fragments... specifically bind MHC-peptide complexes
Data Source
AI summary
The disclosure relates to a polypeptide comprising at least four domains specifically binding to a certain MHC peptide complex, the domains separated by linker amino acid sequences, thereby providing each domain with the capability to bind a separate MHC peptide complex, to a nucleic acid encoding for such a polypeptide, to a vector comprising such a nucleic acid, to a host cell for expression of such a polypeptide, to a pharmaceutical composition comprising such a polypeptide, and to a kit of parts comprising at least two polypeptides according to the disclosure.