Modified AAV Capsid Proteins Evading Neutralizing Antibodies
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Solution Overview
Problem
Adeno-associated virus (AAV) vectors face challenges due to pre-existing host antibodies, which prevent repeated administration in gene therapy and vaccines, limiting their efficacy and applicability due to high antibody prevalence in the human population.
Innovation Solution
Modified AAV capsid proteins with specific amino acid substitutions are introduced to evade neutralizing antibodies, allowing AAV vectors to maintain transduction efficiency while evading antibody recognition.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If AAV vectors are administered to patients, then gene therapy can be delivered, but pre-existing host antibodies prevent repeated administration
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of the AAV capsid protein. Specifically, it introduces mutations in antigenic regions (such as the HI loop and other surface-exposed residues) to alter the immunogenic properties of the vector while maintaining its transduction function. This allows the vector to evade pre-existing neutralizing antibodies and enables repeat administrations.
Solution Approach 2:
The patent applies local quality by making targeted modifications only in specific antigenic regions of the capsid protein rather than throughout the entire structure. By focusing mutations on surface-exposed epitopes that are recognized by neutralizing antibodies (while preserving regions critical for cell entry and transduction), the vector maintains its therapeutic function while gaining antibody evasion capability.
2Adaptability or versatility
If AAV capsid proteins are modified to evade antibodies, then repeat administrations become possible, but transduction efficiency may decrease
Solution Approach 1:
The patent carefully selects amino acid substitutions that change the immunogenic parameters of the capsid without disrupting the structural or functional parameters required for transduction. By choosing specific residues in antigenic loops that are not critical for receptor binding or capsid assembly, the vector achieves antibody evasion while maintaining reliable transduction efficiency.
Solution Approach 2:
The patent applies local quality by restricting modifications to specific antigenic regions (such as the HI loop and other surface epitopes) that are separate from the functional regions required for cell entry and gene delivery. This localized modification strategy ensures that transduction efficiency is preserved while antibody evasion is achieved.
Data Source
AI summary
The present disclosure provides recombinant AAV capsid proteins comprising a modification in the amino acid sequence and virus vectors comprising the recombinant AAV capsid proteins. The disclosure also provides methods of administering the virus vectors and vims capsids of the disclosure to a cell or to a subject in vivo.