Plasmids Coding for Truncated Chimeric p185neu Protein Variants
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Solution Overview
Problem
Current DNA vaccination methods for Her-2/neu-positive tumors face challenges in eliciting a strong immune response, particularly in overcoming immunotolerance and achieving effective protection against p185neu-positive carcinomas, as the p185neu protein is a 'self' antigen, and existing vaccines may not adequately induce both antibody and T lymphocyte-mediated responses.
Innovation Solution
Development of plasmids encoding truncated and chimeric forms of the p185neu protein, which are inserted into suitable vectors and combined with transcription control elements, to induce specific immune responses, including the use of truncated forms to target defined TAA portions and chimeric forms to enhance immunogenicity by combining human and rat sequences, thereby overcoming immunotolerance and eliciting both antibody and T lymphocyte-mediated immunity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If full-length p185neu protein is used as vaccine antigen, then complete protein structure is provided, but immunotolerance is reinforced and immune response is insufficient
Solution Approach 1:
The patent extracts specific functional domains (EC and TM domains) from the full-length p185neu protein to create truncated vaccine antigens. By removing the intracytoplasmic domain and other non-essential regions, the vaccine focuses immunogenicity on critical epitopes that drive T cell and antibody responses without reinforcing tolerance to the complete self-antigen structure.
Solution Approach 2:
The p185neu protein is segmented into distinct functional domains (EC domain, TM domain, IC domain) and only specific segments (EC and TM) are used in the vaccine. This segmentation allows the immune system to recognize and respond to specific tumor-associated epitopes while avoiding the immunosuppressive effects of the complete protein structure.
2Manufacturing precision
If truncated forms of p185neu protein are used, then defined TAA portions are targeted, but complete protein function is not provided
Solution Approach 1:
The patent extracts and retains only the essential epitope-containing domains (EC and TM) from the full-length protein, removing the intracytoplasmic domain and other non-essential regions. This extraction maintains epitope specificity for tumor recognition while eliminating functional regions that would promote immunotolerance.
Solution Approach 2:
The vaccine employs local quality by focusing immunogenicity on specific local regions (EC and TM domains) that contain critical epitopes, rather than providing uniform protein structure throughout. This localized approach ensures precise targeting of tumor-associated antigens while maintaining versatility in inducing both antibody and T cell responses.
3Reliability
If chimeric forms combining human and rat sequences are used, then immunogenicity is enhanced, but sequence complexity increases
Solution Approach 1:
The patent merges human and rat protein sequences into chimeric vaccine antigens, combining the immunogenicity of human epitopes with the tumor-reactivity of rat sequences. This merging creates vaccines that leverage the advantages of both species: human sequences provide strong immunogenicity while rat sequences maintain tumor-specific recognition, overcoming immunotolerance more effectively than either sequence alone.
Solution Approach 2:
The chimeric vaccine antigens function as composite molecular structures integrating human and rat protein sequences. This composite approach creates a unified antigen structure that simultaneously presents human epitopes for strong immune recognition and rat epitopes for tumor-specific targeting, achieving enhanced immunogenicity without excessive sequence complexity.
Data Source
AI summary
DNA plasmids containing sequences coding for different fragments of 185neu oncoprotein which are able to induce an immune response against p185neu-overexpressing tumors, and pharmaceutical compositions thereof are described.