Uncleaved Prefusion Optimized gp140 Trimeric Complex for HIV Immunogen Design

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Solution Overview

Problem

Developing HIV envelope (Env) immunogens that can elicit broad and effective antibody responses against a wide array of HIV-1 isolates remains a significant challenge in HIV vaccine development, as existing vaccine candidates have not successfully generated broadly neutralizing antibodies (bNAbs) in clinical trials.

Innovation Solution

The development of trimeric complexes comprising an uncleaved prefusion optimized gp140 env trimer, which includes three monomeric polypeptides each comprising an uncleaved prefusion optimized gp140 env, designed to induce an immune response capable of generating neutralizing antibodies against HIV.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If existing HIV vaccine candidates are used to elicit cross-reactive antibodies against Env, then vaccine trials are conducted with multiple platforms and regimens, but broadly neutralizing antibodies are not generated

Engineering Contradiction:

Improvecross-reactive antibody responseVSAvoidbroadly neutralizing antibody generation

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The gp140 envelope protein is divided into three monomeric polypeptides that assemble into a trimeric complex, preserving the native trimeric structure of the HIV envelope while enabling improved immunogenicity. This segmentation approach maintains the functional integrity of the antigen while facilitating better antibody response.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The gp140 protein is engineered in an uncleaved prefusion optimized conformation, changing its structural parameters to stabilize the prefusion state. This parameter change ensures the antigen presents the correct conformational epitopes necessary for eliciting broadly neutralizing antibodies, addressing the failure of previous vaccine candidates.

Inventive Principle:

Principle #35Parameter changes

2Adaptability or versatility

If diverse HIV variants are exposed to over years to promote bNAb development, then bNAbs may be generated in a small subset of individuals, but the process takes multiple years and is not fully understood

Engineering Contradiction:

ImprovebNAb developmentVSAvoidtime for bNAb generation

Core Design Contradiction:

Adaptability or versatilityVSLoss of time

Solution Approach 1:

The vaccine candidate pre-organizes the gp140 protein into a stable trimeric complex with optimized prefusion conformation before administration. This preliminary structuring action eliminates the need for years of natural infection to guide antibody maturation, as the correct conformational epitopes are immediately available to drive bNAb development.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The trimeric gp140 complex serves as an intermediary structure that bridges the gap between vaccine administration and bNAb generation. By providing a stable, pre-organized antigen structure, it mediates the immune response to produce broadly neutralizing antibodies without requiring prolonged exposure to diverse variants.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Reliability

If gp140 is engineered as uncleaved prefusion optimized trimer, then neutralizing antibodies effective against broad HIV isolates can be induced, but the molecular complexity of the antigen structure increases

Engineering Contradiction:

Improveneutralizing antibody effectivenessVSAvoidantigen structure complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

Three monomeric polypeptides of gp140 are combined to form a trimeric complex, merging individual units into a functional assembly that mimics the native HIV envelope structure. This merging approach achieves the desired neutralizing antibody response while organizing the molecular complexity into a defined, reproducible structure.

Inventive Principle:

Principle #5Merging (Combining)

Data Source

PatentUS20250073328A1Compositions and methods for treating or preventing HIV infection

Publication Date: 2025.03.06 MOLSOFT LLC

AI summary

Disclosed are trimeric complexes comprising an uncleaved prefusion optimized gp140 env trimer. Disclosed are compositions comprising a trimeric complex, wherein the trimeric complex comprises an uncleaved prefusion optimized gp140 env trimer. Disclosed are methods of inducing an immune response against HIV in a subject comprising administering one or more of the disclosed compositions to a subject in need thereof. Disclosed are methods of generating neutralizing antibodies (nAbs) to HIV in a subject comprising administering one or more of the disclosed compositions to a subject in need thereof. Disclosed are method of treating a subject infected with HIV comprising administering one or more of the disclosed compositions to a subject in need thereof. Disclosed are methods of inducing an immune response against HIV in a subject comprise administering a composition or vaccine comprising a trimeric complex, wherein the trimeric complex comprises an uncleaved prefusion optimized gp140 env trimer, as disclosed herein, in combination with administering a composition or vaccine comprising a nucleic acid construct, wherein the nucleic acid construct comprises a nucleic acid sequence that encodes for a polypeptide comprising an HIV-1 derived V1V2 domain and a trimer-forming scaffold.