Modified AAV Capsid Proteins Evading Neutralizing Antibodies

Solution Overview

Problem

Adeno-associated virus (AAV) vectors face challenges due to pre-existing host antibodies, which prevent first-time and repeat administrations for gene therapy and vaccine applications, limiting their efficacy and expanding the eligible patient cohort.

Innovation Solution

Modified AAV capsid proteins with specific amino acid substitutions that alter antigenic sites to evade neutralizing antibodies, allowing AAV vectors to bypass immune recognition without compromising transduction efficiency.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If AAV vectors are administered to patients, then gene therapy can be delivered, but pre-existing host antibodies prevent first-time and repeat administrations

Engineering Contradiction:

Improvegene therapy deliveryVSAvoidpre-existing host antibodies

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by making specific amino acid substitutions at antigenic sites on the AAV capsid protein while leaving other regions unchanged. This targeted modification approach alters only the antibody-binding regions to evade neutralizing antibodies, while preserving the transduction function of the rest of the capsid structure.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by substituting specific amino acid residues (e.g., K293E, K293Q, K293R, K293M, K293L, K293A, K293V, K293F, K293G, K293S, K293T, K293D, K293N, K293C, K293P, K293Y, K293H, K293W) at antigenic sites to change the chemical properties and structure of these regions, thereby evading antibody recognition while maintaining viral function.

Inventive Principle:

Principle #35Parameter changes

2Adaptability or versatility

If AAV vectors are modified to evade antibodies, then repeat administrations become possible, but transduction efficiency might be compromised

Engineering Contradiction:

Improverepeat administrationsVSAvoidtransduction efficiency

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent applies local quality by making specific amino acid substitutions at antigenic sites on the AAV capsid protein while leaving other regions unchanged. This targeted modification approach alters only the antibody-binding regions to evade neutralizing antibodies, while preserving the transduction function of the rest of the capsid structure.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs feedback by selecting and optimizing specific amino acid substitutions based on their ability to evade neutralizing antibodies while maintaining transduction efficiency. The modifications are chosen and refined through testing to ensure both antibody evasion and functional preservation.

Inventive Principle:

Principle #23Feedback

Data Source

PatentUS11840555B2Methods and compositions for antibody-evading virus vectors

Publication Date: 2023.12.12 UNIV OF FLORIDA RESEARCH FOUNDATION INC

AI summary

The present invention provides AAV capsid proteins comprising a modification in the amino acid sequence and virus vectors comprising the modified AAV capsid protein. The invention also provides methods of administering the virus vectors and virus capsids of the invention to a cell or to a subject in vivo.