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Publication Number
US-11203629-B2
Publication Date
2021-12-21
Expiration Date
Abstract
The present invention provides improved LAMP Constructs comprising specific fragments of the LAMP lumenal domain to deliver antigens to immune cells for enhanced processing. These LAMP Constructs can be used for the treatment of disease and in particular, allergies, infectious disease, diabetes, 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.
Core Innovation
The invention relates to lysosomal-associated membrane protein (LAMP) vaccine constructs in which antigen trafficking and antigen presentation are improved by using defined structural elements from LAMP luminal domains. In particular, the construct comprises two homology domains of a luminal domain of a LAMP protein, rather than using full LAMP luminal domains, and the luminal architecture includes cysteine conserved fragments and other luminal homology domain fragments as part of the construct design.
A heterologous antigenic domain is incorporated into the LAMP construct and is positioned between the two luminal homology domains. This placement is described as producing improved trafficking to endosomal/lysosomal compartments and improved MHC class II presentation, and the construct framework is described as an LAMP-structured antigen delivery construct that can be further refined with additional LAMP structural elements.
The constructs can optionally include transmembrane domains and cytosolic tails from LAMP, and can use alternative antigenic domains such as Survivin or Herpesvirus entry mediator (HVEM). The document further describes nucleic acid encoding constructs, delivery as a vaccine, and prime-boost concepts for generating immune responses, including Th1 responses characterized by increased IFNγ and antibody titers in mice, as well as related HVEM-LAMP prime/boost outcomes and antibody generation in non-human vertebrates.
Claims Coverage
The independent claim set is grounded in a LAMP-structured antigen delivery construct with a heterologous antigenic domain inserted between two luminal homology domains, defining the inventive placement. Dependent claims further refine the construct by adding specific LAMP structural components, specifying alternative antigenic domains, applying sequence-identity constraints, and extending to polynucleotides, host cells, compositions, and prime-boost relationships.
Two luminal homology domains with intervening heterologous antigenic domain
A lysosomal associated membrane protein ("LAMP") Construct comprising two homology domains of a luminal domain of a LAMP protein, and an antigenic domain heterologous to the LAMP protein, wherein the antigenic domain is placed between the two homology domains.
LAMP transmembrane domain added to the LAMP construct
The LAMP construct of claim 1 further comprises a Transmembrane Domain of a LAMP Protein.
Heterologous antigenic domain selected as Survivin or HVEM
The LAMP construct of claim 1 is defined such that its antigenic domain is either Survivin or Herpesvirus entry mediator (HVEM).
Sequence-identity constraint for the LAMP protein homology domains
The claim defines that the LAMP Protein in the LAMP construct has at least about the specified sequence-identity levels relative to SEQ ID NO:1-113.
Encoded nucleic acid type as DNA
The polynucleotide defined in claim 11 is specified to be DNA.
Prime-boost uses the same antigen
The method of claim 19 uses the same antigen to prime and to boost.
Overall claim coverage centers on a LAMP construct architecture that uses two luminal homology domains with a heterologous antigenic domain positioned between them, with optional refinement by adding LAMP transmembrane components, selecting Survivin or HVEM as the antigenic domain, constraining the LAMP protein sequence identity, and extending to DNA encoding, and prime-boost methods that can use the same antigen.
Stated Advantages
Improved antigen trafficking to endosomal/lysosomal compartments.
Improved MHC II presentation.
Stronger Th1 IFNγ responses.
Increased antibody titers with particular fragment arrangements.
Antibody generation outcomes described for HVEM-LAMP prime/boost in non-human vertebrates.
Documented Applications
A vaccine approach using LAMP-structured antigen delivery constructs with heterologous antigenic domains positioned between two luminal homology domains.
Prime-boost vaccination concepts using LAMP constructs (including HVEM-LAMP prime/boost outcomes) in non-human vertebrates.
Immune response evaluation in mice, including Th1 IFNγ responses and antibody titers associated with specific construct fragment arrangements.
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