Bicistronic LAMP Vaccine Constructs for Directed MHC II Antigen Presentation
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Solution Overview
Problem
Existing vaccines face challenges in eliciting strong immune responses due to low immunogenicity and stochastic access of epitopes to the major histocompatibility (MHC) class II presentation pathway, limiting their effectiveness in treating conditions like allergies, infectious diseases, diabetes, and cancer.
Innovation Solution
Development of bicistronic LAMP constructs that express both a LAMP protein and an immune response-enhancing gene (IREG), directing antigens to the lysosomal/endosomal compartment for enhanced processing and presentation to MHC class II molecules, thereby stimulating helper T cells and generating antibodies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional vaccines are used, then safety is maintained, but immunogenicity is low
Solution Approach 1:
The patent combines the LAMP protein (which provides lysosomal targeting and antigen presentation) with immune response-enhancing genes (such as IL-12, IL-21, IL-15, CD40L, CD80, OX40, Flt3L) in a single bicistronic construct. This merging allows the vaccine to simultaneously achieve safe delivery (through the well-characterized LAMP backbone) and enhanced immunogenicity (through the co-expressed immune-enhancing cytokines and ligands), directly resolving the contradiction between safety and immunogenicity.
Solution Approach 2:
The LAMP construct serves multiple functions: it acts as a lysosomal targeting vehicle, an antigen presentation platform, and a delivery vehicle for immune response-enhancing genes. The bicistronic design allows a single construct to perform both antigen presentation and immune enhancement, making the system multi-functional and enabling it to overcome the limitations of conventional single-function vaccines.
2Ease of manufacture
If epitopes are presented without targeting technology, then the process is simple, but access to MHC class II presentation pathway is stochastic and limited
Solution Approach 1:
The LAMP protein acts as an intermediary that facilitates the interaction between antigens and the MHC class II presentation pathway. By incorporating LAMP's lysosomal targeting domains, the construct ensures that antigens are efficiently delivered to the lysosomal/endosomal compartment where they are processed and presented to MHC class II molecules, transforming a stochastic process into a directed and enhanced pathway.
Solution Approach 2:
The patent changes the cellular and molecular parameters of antigen presentation by co-expressing immune response-enhancing genes that modify the local immune environment. Cytokines like IL-12 and IL-21, along with co-stimulatory ligands like CD40L and CD80, alter the parameters of antigen processing and presentation, enhancing the efficiency and strength of MHC class II pathway access.
3Adaptability or versatility
If bicistronic LAMP constructs with secreted antigens are used, then expression of multiple proteins is achieved, but immune response enhancement is insufficient compared to using immune response enhancing genes
Solution Approach 1:
The patent applies local quality by selecting and optimizing specific immune response-enhancing genes (IL-12, IL-21, IL-15, CD40L, CD80, OX40, Flt3L) that have proven efficacy in enhancing immune responses. Rather than using any secreted antigen, the construct locally optimizes the immune enhancement function by incorporating these specifically chosen genes that directly target and enhance relevant immune pathways, achieving superior immune response enhancement.
Data Source
AI summary
The present disclosure provides nucleic acid molecules (e.g., a plasmid or vector) comprising a nucleic acid sequence encoding a bicistronic or multicistronic LAMP Construct comprising specific fragments of the LAMP luminal domain and an antigenic domain heterologous to the LAMP protein to provide at least one antigen for priming an immune response, wherein the antigen expressed by the Construct is optionally processed and presented to MHC class II molecules, and also a nucleic acid sequence encoding an immune response enhancing polypeptide that is optionally secreted from a host cell. The nucleic acid molecules can be used, for example, for the treatment of disease and in particular, allergies, infectious disease, diabetes, hyperproliferative disorders and/or cancer.