HIV Env Immunogens Enhancing Germline bNAb Binding

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Solution Overview

Problem

Current HIV vaccine strategies fail to induce broadly neutralizing antibodies (bNAbs) effectively, particularly due to poor recognition of germline-reverted bNAbs by recombinant Env immunogens, especially at the CD4-binding site and trimer-apex epitopes, limiting their ability to activate naive B cells.

Innovation Solution

Development of recombinant or synthetic HIV Env polypeptides incorporating specific residues such as K275, D276, and R278, along with deletions in certain amino acid sequences, to enhance binding affinity for germline bNAbs and improve activation of B cells, thereby increasing the immunogenicity of HIV envelope glycoproteins.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Ease of manufacture

If recombinant Env immunogens are used, then vaccine production is feasible, but binding affinity for germline bNAbs is poor

Engineering Contradiction:

Improvevaccine production feasibilityVSAvoidbinding affinity for germline bNAbs

Core Design Contradiction:

Ease of manufactureVSReliability

Solution Approach 1:

The patent applies parameter changes by modifying specific amino acid residues in the Env polypeptide sequence. Mutations at positions 275, 276, and 278 (K275, D276, R278) were introduced to enhance binding affinity for germline bNAbs while maintaining the overall structure and manufacturability of the recombinant immunogen

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent applies local quality by making targeted modifications at specific epitope regions (CD4bs and trimer-apex) rather than altering the entire Env structure. This allows improved binding affinity at critical binding sites while preserving the overall immunogen architecture needed for production

Inventive Principle:

Principle #3Local quality

2Reliability

If Env immunogens are designed to bind germline bNAbs, then activation of naive B cells is limited, but broad neutralization is achieved

Engineering Contradiction:

Improvebroad neutralization capabilityVSAvoidactivation of naive B cells

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent applies preliminary action by pre-optimizing the Env immunogen structure to present epitopes in a configuration that facilitates initial binding by germline bNab precursors. The engineered residues K275, D276, and R278 are positioned to create high-affinity binding sites that guide the initial immune response toward broad neutralization capability

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent applies dynamics by designing an immunogen that can adapt to different stages of antibody maturation. The modified Env structure maintains flexibility to bind both germline precursors and mature bNAbs, allowing the immunogen to evolve with the immune response from initial activation to broad neutralization

Inventive Principle:

Principle #15Dynamics

Data Source

PatentUS11344618B2HIV envelope glycoprotein immunogens

Publication Date: 2022.05.31 STICHTING AMSTERDAM UMC

AI summary

The invention relates to an isolated, recombinant or synthetic polypeptide comprising an Env polypeptide of an HIV virus, the Env polypeptide comprising at least the amino acid residues K275, D276 and R278, wherein said numbering is according to the HxB2 reference sequence having the amino acid sequence of SEQ ID NO: 1.