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Publication Number
US-11773153-B2
Publication Date
2023-10-03
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 improved human LAMP-1 constructs for targeting an antigenic domain to the endosomal/lysosomal compartment for MHC class II presentation. The described constructs include two homology domains of a luminal domain of human LAMP-1, where an antigenic domain heterologous to human LAMP-1 is placed between the two homology domains. This design is positioned as an improvement over prior approaches using complete LAMP lumenal constructs.
The core construct architecture uses specific fragments and variants of the LAMP lumenal domain, including configurations based on a single homology domain or two homology domains and cysteine conserved fragments. The antigenic domain heterologous to human LAMP-1 is inserted between these homology domains, including hinge-insertion configurations described in the document. The constructs are presented in multivalent vaccine formats and are associated with nucleic acid delivery and host cell expression concepts.
The document links the LAMP-1 fragment-based designs to enhanced antigen presentation and downstream immune outcomes, including Th1-biased immune responses characterized by IFN-gamma and associated cytokine patterns. Example results described include robust IFN-gamma-producing Th1 responses and increased IgG titers for antigens such as survivin and HVEM-LAMP. The fragment placement is described as providing unexpected advantages for immune bias and antibody generation.
Claims Coverage
The claim set focuses on a human LAMP-1 construct architecture comprising two homology domains and a heterologous antigenic domain placed between them. Dependent features further define sequence identity, linker sequence options, transmembrane-domain residue range, mRNA format, and priming and boosting.
Two homology domains flanking a heterologous antigenic domain
A human LAMP-1 construct comprising two homology domains of a luminal domain of human LAMP-1 protein, and an antigenic domain heterologous to the human LAMP-1 protein, wherein the antigenic domain is placed between the two homology domains.
Homology domain 1 with a defined sequence-identity threshold
Human LAMP-1 Homology Domain 1 contains an amino acid sequence that is at least about 95% identical to residues 29-194 of SEQ ID NO: 1.
Linker comprising GPGPG or PMGLP
The human LAMP-1 construct includes a linker comprising an amino acid sequence of GPGPG or PMGLP.
Transmembrane domain defined by residue range
The transmembrane domain comprises residues 383 to 405 of SEQ ID NO: 1.
Polynucleotide as an mRNA molecule
The polynucleotide described in claim 14 is an mRNA molecule.
Priming plus boosting treatment regimen structure
The method of claim 21 further includes a priming step and at least one boosting step.
The claims center on a human LAMP-1 fragment construct with two luminal-domain homology domains and a heterologous antigenic domain between them, with dependent refinements for sequence identity, linker options, transmembrane-domain residues, mRNA format, and priming plus boosting.
Stated Advantages
Enhanced Th1-biased immune responses for MHC class II presentation, including IFN-gamma production.
Increased IgG titers associated with the described LAMP-1 construct designs.
Unexpected advantages associated with fragment and hinge-insertion configurations for immune bias and antibody generation.
Documented Applications
Vaccine formats using the improved LAMP constructs and associated nucleic acid delivery concepts.
Antigen targeting for MHC class II presentation to generate Th1-biased immune responses.
Use in non-human vertebrates to generate antibodies, including antibodies associated with antigens such as survivin and HVEM-LAMP.
Treatment regimens using priming and at least one boosting step in connection with the constructs described.
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