Virus-inspired compositions and methods of redirecting preexisting immune responses using the same for treatment of cancer
Inventors
WANG, Joshua Weiyuan • Matsui, Ken • STORM, Philip Alan • PETERS, Kristin Marie
Assignees
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Publication Number
US-11858964-B2
Publication Date
2024-01-02
Expiration Date
Abstract
Disclosed are virus-inspired compositions and preparation methods thereof, where the compositions comprise mutant papillomavirus L1 proteins that spontaneously form capsid backbones and that are conjugated to a peptide comprising an epitope to form immune redirector capsids (IRCs). The epitopes on the peptides are designed to be recognized by a subject's immune system based on the subject's preexisting immune memory developed from the subject's past exposure to the epitope through infection or vaccination. The mutant papillomavirus L1 proteins possess three mutations including an amino-terminal truncation, a carboxy-terminal truncation, and a truncation at helix four. These mutations in the L1 protein yield capsomeres that are form non-canonical T=1 geometry capsid backbones. Disclosed are uses and methods of using the compositions in treating and/or preventing cancers in subjects in need thereof.
Core Innovation
The invention provides a composition comprising a plurality of mutated Papillomaviridae L1 virus proteins, where each virus protein comprises a mutated amino acid sequence of a Papillomaviridae L1 protein. The mutated Papillomaviridae L1 proteins spontaneously assemble into an icosahedron or dodecahedron capsid having a triangulation number T equal to 1, with deletions in an amino-terminus, a helix four region, and, in some embodiments, a carboxy-terminus.
The capsid further comprises one or more peptides attached to the plurality of virus proteins, where the peptides comprise one or more epitopes from one or more pathogens other than a Papillomaviridae antigenic peptide. The assembled T=1 capsid binds to proteoglycan expressed on tumor cells, including heparin sulfate proteoglycan (HSPG) and other proteoglycan such as perlecan, versican, glypican-3, small leucine-rich proteoglycans (SLRP), and/or biglycan.
The capsid backbone tumor preference is associated with capsid charge, shape, shielding, and targeting, and the document describes binding to proteoglycan, peptide cleavage, and released peptides loading onto tumor-cell MHC-I to form an epitope-coating complex. Recognition by preexisting memory CD8+ T cells triggers tumor destruction and includes epitope spreading and second-wave immunity.
Claims Coverage
The independent claims identify five inventive features: a mutated Papillomaviridae L1 T=1 capsid composition, attached non-Papillomaviridae pathogen epitope peptides, tumor-cell proteoglycan binding, a defined mutant L1 sequence and encoding, and a method of treating cancer by administration.
T=1 capsid formed by mutated Papillomaviridae L1 with specified deletions
A composition comprising a plurality of virus proteins wherein each virus protein comprises a mutated amino acid sequence of a Papillomaviridae L1 protein with deletions from an amino-terminus, a helix four region, and a carboxy-terminus, and wherein the plurality spontaneously assemble to form an icosahedron or dodecahedron capsid having triangulation number T equal to 1.
Pathogen-epitope peptides attached to the mutated L1 proteins
One or more peptides each comprising one or more epitopes from one or more pathogens other than a Papillomaviridae antigenic peptide, where the one or more peptides are attached to the plurality of virus proteins.
Capsid binding to tumor-cell expressed proteoglycan
The capsid having triangulation number T equal to 1 that binds to proteoglycan expressed on tumor cells.
Defined mutated L1 sequence and encoding
A composition wherein an amino acid sequence of each mutant Papillomaviridae L1 protein is SEQ ID NO:134 and is encoded by nucleic acid sequence SEQ ID NO:135 or 136, with the one or more peptides attached to the plurality of virus proteins and the plurality spontaneously assembling to form the T=1 capsid that binds to proteoglycan expressed on tumor cells.
Cancer treatment by administering the T=1 proteoglycan-binding epitope-bearing composition
A method of treating, reducing the occurrence of, inhibiting the progression and/or metastasis of a cancer in a subject in need thereof by administering a pharmaceutically effective amount of a composition comprising a plurality of mutated Papillomaviridae L1 virus proteins with attached peptides comprising pathogen epitopes other than a Papillomaviridae antigenic peptide, wherein the plurality spontaneously assemble to form a T=1 capsid that binds to proteoglycan expressed on tumor cells.
Overall, the independent claims are directed to an epitope-bearing, T=1 spontaneously assembling capsid formed from mutated Papillomaviridae L1 proteins with specified deletions, including binding to proteoglycan on tumor cells. Coverage is reinforced by a variant composition using a specifically defined mutant L1 amino-acid sequence and by a therapeutic method for treating cancer via administering the proteoglycan-binding epitope-bearing composition.
Stated Advantages
Treating, reducing the occurrence of, inhibiting the progression and/or metastasis of cancer by administering a pharmaceutically effective amount of the disclosed composition.
Documented Applications
Treating, reducing the occurrence of, inhibiting the progression and/or metastasis of cancer in a subject in need thereof by administering a pharmaceutically effective amount of the disclosed composition.
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