Engineered Gag and Nef Antigen Complexes for Dendritic Cell Targeting
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Solution Overview
Problem
The complexity of C-type lectin-like receptors (LLRs) in immune cells, including redundancy and unidentified natural ligands, hinders understanding of their detailed functions, and existing methods for targeting dendritic cells with antigens are limited in efficacy and specificity.
Innovation Solution
Development of engineered proteins with interstructural domain linkers and antibody-antigen complexes, specifically binding to dendritic cell surface receptors, to enhance antigen presentation and immune response, using flexible linkers like SEQ ID NO:4 and SEQ ID NO:6 to improve protein expression and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If C-type lectin-like receptors (LLRs) are used for antigen capture and uptake in dendritic cells, then antigen presentation capability is improved, but the complexity and redundancy of multiple LLRs hinders understanding of their detailed functions and reduces targeting specificity
Solution Approach 1:
The patent uses engineered proteins with specific interstructural domain linkers (SEQ ID NO:4 and SEQ ID NO:6) as intermediaries to bridge the antigen and dendritic cell surface receptors. These standardized linkers simplify the complex interactions between multiple LLRs and antigens by providing a uniform interface, thereby improving antigen presentation capability while reducing the functional complexity of targeting multiple different LLRs.
Solution Approach 2:
The patent creates universal engineered proteins containing conserved LLR-binding motifs that can bind to multiple different C-type lectin-like receptors simultaneously. This multi-functional approach allows a single engineered protein to engage various LLRs (such as DEC-205, Langerin, and mannose receptor) without requiring separate targeting strategies for each receptor, thus improving reliability while managing complexity.
2Reliability
If existing methods for targeting dendritic cells with antigens are used, then antigen delivery is achieved, but the efficacy and specificity of immune response activation is limited
Solution Approach 1:
The patent modifies the structural parameters of antigen-protein constructs by incorporating specific interstructural domain linkers (SEQ ID NO:4 and SEQ ID NO:6) that optimize the spatial arrangement and flexibility of antigen presentation. These parameter changes enhance the binding affinity to dendritic cell receptors and improve the efficiency of antigen internalization and processing, thereby increasing both the reliability and productivity of immune response activation.
Solution Approach 2:
The engineered proteins are pre-configured with optimized linkers and conserved LLR-binding motifs before administration, ensuring proper folding, stability, and receptor recognition. This preliminary structural optimization occurs in vitro, allowing the proteins to immediately engage dendritic cell receptors with high efficacy upon injection, without requiring additional in vivo maturation or processing steps.
3Duration of action of moving object
If antigens are targeted to dendritic cells, then T cell responses are activated, but proteolytic degradation of antigens reduces the stability and duration of immune activation
Solution Approach 1:
The engineered proteins act as protective intermediaries that shield the antigen from proteolytic enzymes. The specific interstructural domain linkers (SEQ ID NO:4 and SEQ ID NO:6) create a stable structural framework that protects the antigen epitopes from degradation while still allowing receptor binding and antigen processing in controlled environments. This intermediary structure extends the half-life and stability of the antigen during circulation and cellular uptake.
Data Source
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AI summary
The present invention includes compositions and methods for making and using a vaccine that includes a DC-specific antibody or fragment thereof to which an engineered Gag antigen is attached to form an antibody-antigen complex, wherein the Gag antigen is less susceptible to proteolytic degradation by eliminating one or more proteolytic sites or a DC-specific antibody or fragment thereof to which an engineered Nef antigen is attached to form an antibody-antigen complex, wherein the Nef antigen comprises one or more codon usage optimization that increase antibody-antigen complex secretion, or both, wherein the vaccine is able to elicit an HIV-specific T cell immune response to Gag p17, Gag p24, Nef and/or Cyclin D1.