Modified HER2 Immunogenic Composition to Overcome Self-Tolerance
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Solution Overview
Problem
Existing cancer vaccines targeting unmodified tumor-associated antigens (TAAs) face challenges in balancing self-tolerance and tumor immunity, limiting their effectiveness in stimulating immune activity against tumor-associated self-antigens like HER2.
Innovation Solution
Development of immunogenic compositions that include proteins with specific amino acid sequences, such as HER2, designed to stimulate immune activity while maintaining the native structure and overcoming self-tolerance, using recombinant expression constructs and adjuvants to enhance immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If unmodified tumor-associated self-antigens are used in cancer vaccines, then the native structure is maintained, but self-tolerance prevents effective immune stimulation
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid substitutions (e.g., L324P, L324D, L324E, L324H, L324R, L324Q, L324K, L324N, L324S, L324T, L324V, L324Y, L324F, L324M, L324W, L324A, L324G, L324I, L324C) at position 324 of the HER2 protein sequence. These substitutions modify the antigen's properties to overcome self-tolerance while maintaining the overall native structure and immunogenicity of the HER2 protein, thereby enabling effective immune stimulation against tumor-associated self-antigens.
2Reliability
If amino acid substitutions are introduced to overcome self-tolerance, then immune recognition is enhanced, but the native structure may be altered
Solution Approach 1:
The patent applies local quality by introducing amino acid substitutions at a specific local position (position 324) of the HER2 protein while maintaining the overall native structure. This localized modification approach allows the antigen to overcome self-tolerance and enhance immune recognition at the substitution site without disrupting the global three-dimensional structure and functional domains of the HER2 protein, thus resolving the contradiction between immune recognition and structural stability.
3Reliability
If modified HER2 variants are used to stimulate immunity, then self-tolerance is overcome, but manufacturing complexity increases
Solution Approach 1:
The patent applies parameter changes by implementing a systematic approach to amino acid substitution at position 324 of HER2, creating a defined series of variants with specific substitutions. This systematic modification strategy, while increasing complexity, provides a structured framework for manufacturing and characterization, allowing for controlled production of modified HER2 variants that effectively stimulate tumor immunity while maintaining manageable composition complexity through standardized substitution patterns.
Data Source
AI summary
Only limited success has been previously achieved from cancer vaccines targeting unmodified tumor-associated self-antigens and new compositions and methods are needed. Immunogenic compositions and methods of use thereof are provided according to the present disclosure which include a protein effective to stimulate immune activity against a tumor-associated self-antigen, or a variant thereof which is a tumor-associated self-antigen.