10E8-Scaffold HIV-1 Immunogen Design for Broad Neutralization

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Solution Overview

Problem

Developing a vaccine that elicits broad and potent neutralizing antibodies against HIV-1 is challenging due to the virus's ability to evade antibody-mediated neutralization and its extreme sequence variability, making it difficult to generate antibodies that are effective across diverse HIV strains.

Innovation Solution

Designing 10E8-scaffold vaccines that activate 10E8-like B cells and induce cross-reactive binding and neutralizing antibodies by engineering epitope-scaffolds with improved affinity for both mature and germline 10E8, using computational methods like flexible backbone remodeling and resurfacing to stabilize the HIV epitope conformation and enhance immune presentation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If traditional HIV vaccines are used, then some immune response is generated, but the antibodies lack broad neutralizing activity against diverse HIV strains

Engineering Contradiction:

Improvebroad neutralizing activityVSAvoidconsistency of immune response

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent modifies the scaffold protein parameters (amino acid sequence, structural conformation, epitope presentation) to optimize binding affinity for germline 10E8 B cells. This includes engineering the scaffold to display the 10E8 epitope in a conformation that mimics the native HIV gp41 MPER region, thereby eliciting broad neutralizing antibodies with consistent activity across diverse HIV strains

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The scaffold protein serves as an intermediary structure that bridges the gap between the simplified peptide epitope and the complex native HIV gp41 target. The scaffold presents the 10E8 epitope in a stable, immunogenic conformation that germline 10E8 B cells can recognize, while the induced antibodies subsequently neutralize diverse HIV strains by binding to the native gp41 MPER region

Inventive Principle:

Principle #24Intermediary (Mediator)

2Adaptability or versatility

If high concentrations of antibodies are required for neutralization, then broad coverage is achieved, but the amount of antibody needed increases

Engineering Contradiction:

Improvebreadth of neutralizationVSAvoidantibody concentration

Core Design Contradiction:

Adaptability or versatilityVSQuantity of substance

Solution Approach 1:

The engineered scaffold proteins elicit antibodies with enhanced binding affinity and neutralizing potency. By optimizing the epitope presentation on the scaffold and selecting for high-affinity 10E8-like antibodies through iterative immunization and selection processes, the resulting antibodies achieve effective neutralization at lower concentrations while maintaining broad strain coverage

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentEP2892555B1Immunogens of HIV-1 broadly neutralizing antibodies, methods of generation and uses thereof

Publication Date: 2020.03.25 INTERNATIONAL AIDS VACCINE INITIATIVE INC

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AI summary

The present application relates to immunogens of broadly neutralizing monoclonal antibodies specific for HIV-1, such as broad and potent neutralizing monoclonal antibodies specific for HIV-1 and their gernation and methods of use. Broad neutralization suggests that the antibodies can neutralize HIV-1 isolates from different individuals, Immunogens or vaccines which may elicit such antibody associated responses are useful in pharmaceutical compositions for the prevention and treatment of HIV, and for the diagnosis and monitoring of HIV infection.