AAV Capsid Antibody Evasion via Antigenic Modification
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Solution Overview
Problem
Existing AAV vectors face challenges in evading neutralizing antibodies, limiting their repeated administration in gene therapy and vaccine applications due to pre-existing antibodies in the human population.
Innovation Solution
Modification of AAV capsid proteins with specific amino acid substitutions or deletions to alter antigenic sites, allowing the vectors to evade neutralizing antibodies while maintaining transduction efficiency.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If AAV vectors are used for gene therapy, then transduction efficiency is achieved, but neutralizing antibodies prevent repeated administration
Solution Approach 1:
The patent modifies the capsid proteins by changing amino acid sequences at specific positions (e.g., positions 70-80, 140-150, 210-220) to alter the antigenic properties of the virus. These parameter changes in the protein sequence enable the virus to evade neutralizing antibodies while maintaining transduction efficiency, allowing repeated administrations.
Solution Approach 2:
The capsid protein is divided into multiple antigenic sites (first antigenic site, second antigenic site, third antigenic site) that can be independently modified. By segmenting the antigenic regions and modifying each separately, the patent achieves antibody evasion while preserving the functional integrity of the capsid for efficient transduction.
2Object-affected harmful factors
If capsid proteins are modified to evade antibodies, then antibody evasion is achieved, but transduction efficiency may decrease
Solution Approach 1:
The patent applies local modifications to specific antigenic regions of the capsid protein while maintaining the overall structure and function of the capsid. By making localized changes at specific positions rather than global modifications, the patent achieves antibody evasion at the surface level while preserving the transduction functionality in the core.
Solution Approach 2:
The modified capsid proteins exhibit dynamic conformational changes that allow them to evade antibody recognition while maintaining their ability to bind to cellular receptors for transduction. The flexibility in the capsid structure enables it to adapt to different cellular environments.
Data Source
AI summary
The present disclosure provides AAV capsid proteins comprising a modification in the amino acid sequence and virus vectors comprising the modified AAV capsid protein. The disclosure also provides methods of administering the virus vectors and virus capsids of the disclosure to a cell or to a subject in vivo.