F-Actin-Binding Immunoconjugates for APC Cross-Presentation
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Solution Overview
Problem
Current immunotherapy approaches struggle to effectively target and elicit an immune response against tumour-associated antigens (TAAs) and tumour-specific antigens (TSAs) due to their low immunogenicity, and existing vaccines face challenges in delivering antigens to antigen-presenting cells (APCs) for efficient cross-presentation.
Innovation Solution
Conjugating antigens to an F-actin-binding moiety, such as LifeAct, to enhance retention at the site of cell death, allowing for uptake by APCs and subsequent immune response activation through the DNGR-1 pathway, using nucleic acids like mRNA to encode the conjugate for expression in cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional vaccines are used to deliver antigens, then the immune response can be elicited, but the cross-presentation efficiency by APCs is insufficient and the immune response is weak
Solution Approach 1:
The patent introduces an F-actin binding moiety as an intermediary component that bridges the antigen and the APC uptake mechanism. This moiety specifically interacts with F-actin on necrotic cells, facilitating efficient antigen capture by APCs through the DNGR-1 pathway, thereby resolving the contradiction between cross-presentation efficiency and immune response strength
Solution Approach 2:
The patent changes the physical-chemical parameters of the antigen delivery system by conjugating the antigen to an F-actin binding moiety. This modification alters the antigen's interaction properties, enabling it to bind to F-actin and be efficiently internalized by APCs, thus improving both cross-presentation efficiency and subsequent immune response
2Duration of action of stationary object
If antigens are delivered to APCs for cross-presentation, then immune response can be activated, but the retention of antigens at the site of cell death is insufficient
Solution Approach 1:
The F-actin binding moiety serves as a mediator that anchors the antigen to F-actin structures at the site of cell death. This intermediary interaction ensures prolonged antigen retention and facilitates efficient uptake by APCs through the DNGR-1 pathway, simultaneously improving both retention duration and uptake efficiency
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The approach improves the cross-presentation of antigens by APCs, particularly cDC1 cells, leading to enhanced CD8+ T-cell responses and immune activation against tumour cells or infectious agents, thereby increasing the effectiveness of cancer and infectious disease vaccines.
Implementation Method 1
conjugating an antigen to a moiety that binds to a cytoskeleton component, specifically, F-actin
Implementation Method 2
Upon binding to F-actin via its C-type lectin domain (CTLD), DNGR-1 triggers SYK signalling, which causes rupture of ligand-containing phagosomes
Data Source
AI summary
The present invention provides immunoconjugates comprising an antigen and an F-actin-binding moiety. These immunoconjugates promote the presentation of antigens. The invention also provides vaccines that comprise or encode conjugates tint allow antigens to be presented to the immune system. Related medical uses and methods of eliciting an immune response are also provided.