Virus like particle comprising modified envelope protein E3
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Publication Number
US-9969986-B2
Publication Date
2018-05-15
Expiration Date
Abstract
A virus like particle comprising a viral structural protein which comprises modified envelope protein E3. The viral structural protein may be that derived from or alphavirus or flavivirus. Especially, the viral structural protein may be derived from Chikungunya virus or Venezuelan equine encephalitis virus.
Core Innovation
The invention relates to alphavirus virus-like particles that comprise an alphaviral structural protein including an envelope protein E3. The envelope protein E3 is modified such that it contains at least one foreign antigen inserted into its furin cleavage site, and the furin cleavage site is altered to prevent cleavage and/or is used as an insertion locus for the foreign antigen(s).
In disclosed embodiments, the modified E3 serves as a site for insertion of foreign antigens in alphavirus envelope protein structural contexts in virus-like particle assemblies. The invention further contemplates insertion of foreign antigens into E3 and optionally into E2, with described comparative outcomes for virus-like particle production efficiency.
The documented embodiments include particular virus-like particles based on alphaviruses such as CHIKV and VEEV, and compositions that include nucleic acids, vectors, and pharmaceutical or vaccine compositions. The antigen insertion embodiments are supported by described immunogenicity/protection results, including malaria-related sporozoite challenge outcomes and tumor protection outcomes associated with immune checkpoint related antigens.
Claims Coverage
The independent claim set includes 1 independent claim. The claimed coverage centers on an alphavirus virus-like particle with an E3 furin cleavage site modified by inserting at least one foreign antigen, with dependent refinements adding specific antigen selections and insertion/location constraints, and further embodiments covering nucleic acids, vectors, cell lines, and functional effects such as preventing furin cleavage.
Foreign antigen inserted into E3 furin cleavage site
An alphavirus virus-like particle comprising an alphaviral structural protein with an envelope protein E3, wherein said envelope protein E3 is modified to contain at least one foreign antigen inserted into furin cleavage site thereof.
Antigen insertion prevents furin cleavage
The virus-like particle wherein inserting at least one antigen into a furin cleavage site prevents furin from cleaving that site.
Defined residue-position insertion constraints
The virus-like particle wherein an antigen is inserted between specified residue positions of SEQ ID NO: 1, residues 321 and 326 of SEQ ID NO: 2, or residues 330 and 335 of SEQ ID NO: 3.
Selected foreign antigen set
The virus-like particle wherein the at least one antigen is selected from a defined list including Plasmodium falciparum circumsporozoite protein and immune-related proteins such as PD-1, PD-L1, CTLA-4, DISC1, IL-2, HER2, BTLA, and HVEM.
Nucleic-acid and vector embodiments
A vector containing the nucleic acid molecule of claim 10, optionally including an expression control sequence operably linked to that nucleic acid.
Protease-mediated E3 removal in a modified cell line
A cell line modified such that E3 is removed using a protease.
Overall, the claim coverage is directed to alphavirus VLPs whose alphaviral envelope protein E3 is modified by inserting at least one foreign antigen into the E3 furin cleavage site, including variants where the insertion prevents furin cleavage. Dependent refinements narrow the insertion to defined residue positions, specify antigen choices, and additionally cover nucleic acids/vectors and modified cell line embodiments involving protease-mediated E3 removal.
Stated Advantages
Antigen insertion into E3 yields more efficient VLP production than insertion into E2.
Antigen insertion into the E3 furin cleavage site prevents furin cleavage of that site.
Antigen insertion provides functional immunogenicity/protection, including malaria sporozoite challenge outcomes and tumor protection outcomes.
Documented Applications
Malaria sporozoite challenge using malaria antigens, including a Plasmodium falciparum circumsporozoite protein (CSP) antigen.
Tumor protection using immune checkpoint related antigens such as PD-L1 (PD-1 ligand) in the context of CT26 tumor protection.
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