LAMP Constructs for MHC Class II Antigen Presentation
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Solution Overview
Problem
Conventional DNA vaccines face challenges in immunogenicity due to low access of epitopes to the major histocompatibility (MHC) class II presentation pathway, and the efficacy of LAMP Constructs is dependent on specific antigen sequences, making it difficult to predict which sequences will generate an immune response, and the production of these constructs is costly and impractical.
Innovation Solution
Development of improved LAMP Constructs using specific fragments and variants of LAMP domains that effectively direct cancer antigens to the lysosomal/endosomal compartment for processing and presentation to MHC class II molecules, including the use of a single homology domain of the LAMP protein and a transmembrane domain, to elicit strong T-cell and antibody responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional DNA vaccines are used, then safety is maintained, but immunogenicity is low due to poor access of epitopes to MHC class II presentation pathway
Solution Approach 1:
The patent introduces LAMP domain constructs as intermediary molecules that mediate between the antigen and the MHC class II presentation pathway. The LAMP domain acts as a carrier that directs antigens to the lysosomal/endosomal compartment, facilitating their presentation to MHC class II molecules and thereby enhancing immunogenicity while maintaining the safety of DNA vaccine platforms
Solution Approach 2:
The patent modifies the structural parameters of the vaccine construct by incorporating specific LAMP domain sequences (such as the hinge region with cysteine residues) that change the trafficking parameters of the antigen, directing it to specific cellular compartments (lysosomal/endosomal) where MHC class II presentation occurs, thereby optimizing the immunogenicity parameter
2Reliability
If complete LAMP Constructs are used to target antigens to lysosomal pathway, then MHC II presentation is improved, but manufacturing cost increases and predictability decreases
Solution Approach 1:
The patent extracts only the essential functional domains of LAMP (such as the hinge region, transmembrane domain, or cytoplasmic tail) rather than using the complete LAMP construct. This extraction maintains the antigen-targeting function to the lysosomal pathway while reducing the size and complexity of the construct, thereby lowering manufacturing costs and improving practicality
Solution Approach 2:
The patent segments the LAMP protein into functional domains (signal sequence, lumenal domain, hinge region, transmembrane domain, cytoplasmic tail) and selectively combines these segments with antigens. This segmentation allows optimization of each domain's contribution to antigen targeting while simplifying the overall construct for manufacturing
3Reliability
If full lumenal domain of LAMP is used for antigen trafficking, then lysosomal targeting is achieved, but antigen sequence dependency increases making prediction difficult
Solution Approach 1:
The patent applies local quality by identifying specific regions within the LAMP structure (such as the hinge region with conserved cysteine residues or the transmembrane domain) that are particularly important for lysosomal targeting function. By focusing on these specific local regions rather than the entire lumenal domain, the patent reduces antigen sequence dependency while maintaining trafficking efficiency
Data Source
AI summary
The present invention provides improved LAMP Constructs comprising specific fragments of the LAMP lumenal domain to deliver cancer antigens to immune cells for enhanced processing. These LAMP Constructs can be used for the treatment of disease and in particular hyperproliferative disorders and/or cancer. The improved LAMP Constructs allow for presentation of properly configured three dimensional epitopes for production of an immune response when administered to a subject. The improved LAMP Constructs can be multivalent molecules, and/or can be provided as part of a multivalent vaccine containing two or more LAMP Constructs. The improved LAMP Constructs as described herein can also be used to generate antibodies when administered to a non-human vertebrate.