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Publication Number
US-12116396-B2
Publication Date
2024-10-15
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 provides a polynucleotide encoding a lysosomal associated membrane protein (LAMP) construct that is configured for antigen presentation. The LAMP construct comprises two homology domains of a luminal domain of a LAMP protein and an antigenic domain heterologous to the LAMP protein, with the antigenic domain placed between the two homology domains, and the construct further comprises a transmembrane domain of a LAMP protein.
In described embodiments, the invention focuses on using fragments or variants of the luminal domain in the form of luminal homology domains rather than a complete luminal domain. The luminal homology domains can correspond to specific homology-domain segments, including human LAMP-1 homology-domain segments, and the design optionally includes additional LAMP regions such as a cytoplasmic tail.
The disclosed LAMP construct is intended to target antigen delivery to endosomal/lysosomal compartments to enhance MHC class II presentation and to bias immune responses toward a Th1 immune response. The document further indicates improved antigen-specific Th1 IFNγ responses, enhanced CD4 effector memory, stronger total IgG/IgG2a responses, and improved antibody epitope binding compared with prior complete LAMP constructs.
Claims Coverage
The document provides two independent claims covering a polynucleotide encoding a LAMP construct with two luminal homology domains flanking a heterologous antigenic domain, together with a LAMP transmembrane domain, with one independent claim additionally limited to homology domains derived from human LAMP-1. In total, four main inventive features span the independent claim scope.
Two luminal homology domains with antigen between them
A LAMP construct comprises two homology domains of a luminal domain of a LAMP protein, an antigenic domain heterologous to the LAMP protein, and a transmembrane domain of a LAMP protein, with the antigenic domain placed between the two homology domains.
LAMP transmembrane domain for the construct
A LAMP construct includes a transmembrane domain of a LAMP protein together with two luminal homology domains and a heterologous antigenic domain positioned between the homology domains.
Human LAMP-1 homology domains flanking a heterologous antigenic domain
A LAMP construct comprises two homology domains of a luminal domain of human LAMP-1 protein, an antigenic domain heterologous to the human LAMP-1 protein, and a transmembrane domain of a LAMP protein, with the antigenic domain placed between the two homology domains.
Disease treatment administration of the polynucleotide
A method for treating a disease or disorder by administering the polynucleotide of claim 1 to a subject in a sufficient amount to reduce or treat the disease or disorder.
Overall, the claim set centers on a LAMP construct architecture in which a heterologous antigenic domain is positioned between two luminal homology domains of a LAMP luminal domain, together with a LAMP transmembrane domain, and it includes embodiments limited to human LAMP-1 homology domains.
Stated Advantages
Enhances MHC class II presentation.
Enhances Th1 immune responses.
Increases antigen-specific Th1 IFNγ responses.
Enhances CD4 effector memory.
Provides stronger total IgG/IgG2a responses.
Improves antibody epitope binding.
Shows better performance of fragment constructs compared with prior complete LAMP constructs.
Documented Applications
Delivery formats are described for antigen delivery and immune response induction, including DNA, viral vectors (adenovirus, AAV, retrovirus, poxviruses), self-replicating RNA virus vectors, lipid-based formulations, and cell-based delivery.
Treating a disease or disorder by administering the polynucleotide to a subject in a sufficient amount to reduce or treat the disease or disorder.
Use of the polynucleotide in isolated antigen-presenting cells, including dendritic cells.
Antibody generation in non-human vertebrates is described.
Vaccination/prime-boost protocols are described in connection with the immune responses elicited by the constructs.
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