Multimeric HIV Binding Molecules for Viral Reservoir Clearance

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Solution Overview

Problem

Current treatments for HIV infection, including chronic HIV, are inadequate as they only halt viral replication without clearing the virus, and there is a need for more potent and accessible therapies that can target dormant HIV reservoirs.

Innovation Solution

Development of multimeric binding molecules with specificity for HIV antigens, such as gp120/gp41, which are more potent in preventing, controlling, or treating HIV infection by binding to multiple epitopes on the HIV spike protein, including the immunodominant region, MPER, CD4 binding site, V1/V2 loop, V3 loop, and associated carbohydrates, and can neutralize diverse HIV variants.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current HIV treatments (HAART) are used, then viral replication is halted, but the virus is not cleared and reservoirs persist

Engineering Contradiction:

Improvetreatment efficacyVSAvoidviral clearance

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The treatment approach is segmented into two phases: first, HAART is used to halt viral replication and reduce viral load; second, multimeric binding molecules are introduced to specifically target and clear dormant reservoirs. This segmentation allows each treatment modality to address its specific function optimally without interference.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

Multimeric binding molecules serve as intermediary agents that bridge the gap between detecting HIV presence and achieving viral clearance. These molecules bind to multiple epitopes on HIV proteins (gp120, gp41) and facilitate immune-mediated clearance of reservoirs while maintaining compatibility with ongoing HAART therapy.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Measurement precision

If monoclonal antibodies targeting single epitopes are used, then binding specificity is achieved, but cross-reactivity with diverse HIV variants is limited

Engineering Contradiction:

Improvebinding specificityVSAvoidcross-reactivity

Core Design Contradiction:

Measurement precisionVSAdaptability or versatility

Solution Approach 1:

The multimeric binding molecules are designed with multiple binding units, each capable of recognizing different epitopes on HIV proteins. This multi-functionality enables a single molecular construct to target multiple HIV variants and clades simultaneously, achieving both specificity for individual epitopes and broad cross-reactivity across diverse HIV strains.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Solution Approach 2:

The binding molecules are composite structures combining multiple antibody binding units (e.g., IgM pentamers with five binding units, or engineered multimers) that work synergistically. Each binding unit contributes specificity for its target epitope while the composite structure provides overall versatility against diverse HIV variants through combinatorial recognition.

Inventive Principle:

Principle #40Composite materials

3Reliability

If high-dose therapies are used to achieve potent neutralization, then viral clearance is improved, but accessibility and cost barriers increase

Engineering Contradiction:

Improveneutralization potencyVSAvoidaccessibility

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The therapeutic approach utilizes parameter changes in the molecular structure of the binding molecules, specifically employing IgM class antibodies with five binding units per molecule. This structural parameter change enables higher avidity and potency at lower dosages compared to conventional monoclonal antibodies, as the multimeric structure provides cumulative binding strength without requiring proportionally higher doses.

Inventive Principle:

Principle #35Parameter changes

4Productivity

If therapies targeting only actively replicating virus are used, then viral replication is controlled, but dormant reservoirs are not affected

Engineering Contradiction:

Improveviral replication controlVSAvoidreservoir targeting

Core Design Contradiction:

ProductivityVSAdaptability or versatility

Solution Approach 1:

The treatment strategy dynamically adapts to different HIV states: during active infection, HAART controls replication; upon introduction of multimeric binding molecules, the system transitions to targeting dormant reservoirs. The binding molecules are designed with high affinity for multiple epitopes that remain accessible on both actively replicating virus and dormant reservoirs, enabling the system to address both states effectively.

Inventive Principle:

Principle #15Dynamics

Data Source

PatentUS10570191B2Multi-valent human immunodeficiency virus antigen binding molecules and uses thereof

Publication Date: 2020.02.25 IGM BIOSCIENCES INC

AI summary

This disclosure provides a multimeric human immunodeficiency virus (HIV) protein binding molecule, e.g., an dimeric IgA or a pentameric or hexameric IgM binding molecule, comprising at least two bivalent binding units, or variants or fragments thereof, each comprising at least two antibody heavy chain constant regions or fragments thereof, wherein each heavy chain constant region or fragment thereof is associated with an HIV antigen binding domain. Also provided are compositions comprising the multimeric binding molecules, polynucleotides encoding the multimeric binding molecules, and methods to make and use the multimeric binding molecules.