Compositions and methods for therapeutic delivery
Inventors
Sato, Makoto • Cunha, Alexander T. • Roh, Cecilia • Johnson, Jr., Robert G.
Assignees
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Publication Number
US-12502437-B2
Publication Date
2025-12-23
Expiration Date
Abstract
Described herein are compositions and methods for therapeutic delivery using an engineered viral vector. The engineered viral vector provided herein can improve therapeutic delivery, increase targeting efficiency, and decrease off-targeting or adverse effects.
Core Innovation
The invention relates to an engineered viral vector that comprises a modified envelope protein derived from Sindbis virus and includes an E3 domain and an E2 domain. The modified envelope protein comprises a protease cleavage site located at the border between the E3 and E2 domains, at least one modification site in SEQ ID NO: 1, and at least one targeting moiety inserted at the modification site.
The engineered viral vector further comprises an engineered murine leukemia viral (MLV) vector. The targeting moiety is part of the modified Sindbis envelope protein, and the modification site(s) in SEQ ID NO: 1 serve as insertion locations for the targeting moiety.
The modified envelope protein increases transduction efficiency and specificity of the engineered viral vector to a target cell relative to a viral vector without the modified envelope protein. The overall approach is presented as enabling targeted transduction to target cells using the engineered MLV vector pseudotyped with the modified Sindbis envelope.
Claims Coverage
The independent claims center on an engineered MLV vector with a recombinant Sindbis envelope protein comprising E3 and E2 domains, a protease cleavage site at the E3-E2 border, and at least one targeting moiety inserted at at least one modification site in SEQ ID NO: 1. The claim set also addresses increased transduction efficiency and specificity to a target cell, with dependent claims further specifying receptor ligand targets, scFv format, furin cleavage site, envelope domain location constraints relative to SEQ ID NO: 1, and optional payload or therapeutic-agent classes.
Modified Sindbis e3/e2 envelope with seq id no: 1 targeting insertion sites
An engineered viral vector comprising a modified envelope protein derived from Sindbis virus comprising an E3 domain and an E2 domain, where the modified envelope protein comprises at least one modification site in SEQ ID NO: 1 and at least one targeting moiety inserted at the modification site(s).
E3/E2 border protease cleavage site
The modified envelope protein comprises a protease cleavage site located at the border between the E3 and E2 domains.
Engineered murine leukemia viral vector
The engineered viral vector comprises an engineered murine leukemia viral (MLV) vector.
Increased transduction efficiency and specificity
The modified envelope protein increases transduction efficiency and specificity of the engineered viral vector to a target cell relative to a viral vector without the modified envelope protein.
Targeted receptor ligand specificity
The targeting moiety is a ligand for one or more of the receptors GPR78, EGFR, PD-1, nectin-4, or CD47.
Furin cleavage-site specification
The protease cleavage site is a furin cleavage site located at the border between the E3 and E2 domains.
Single-chain variable fragment targeting moiety
The targeting moiety is a single-chain variable fragment (scFv).
Therapeutic agent enzyme or protein factor payload options
The therapeutic agent includes one or more of thymidine kinase, cytosine deaminase, IL-2, nitroreductase (NR), carboxylesterase, beta-glucoronidase, cytochrome p450, beta-galactosidase, diphtheria toxin A-chain (DT-1), carboxypeptidase G2 (CPG2), purine nucleoside phosphorylase (PNP), and deoxycytidine kinase (dCK).
The claims are directed to engineered MLV vectors incorporating a recombinant Sindbis envelope modified at SEQ ID NO: 1 to insert targeting moieties, with a protease cleavage site positioned at the E3-E2 border to improve transduction efficiency and specificity to a target cell. Dependent claims further specify receptor ligand targets, targeting-moiety format, cleavage-site subtype, and optional therapeutic-agent or payload classes.
Stated Advantages
Increases transduction efficiency of the engineered viral vector relative to a viral vector without the modified envelope protein.
Increases specificity of the engineered viral vector to a target cell relative to a viral vector without the modified envelope protein.
Documented Applications
Target cell targeting/transduction applications using Sindbis (SB)-enveloped engineered MLV vectors and comparisons to wild-type SB.
In vivo GFP transduction advantage compared with an amphotropic RVE control vector.
EGFR targeting applications using EGFR ligand and examples including EGFRvIII targeting.
PD-L1 targeting applications using anti-PD-L1 VH-VH.
Combination targeting applications using two targeting moieties/vectors.
Vaccine-style payload applications, including immunogenicity-related configurations incorporating SARS-CoV-2 spike NTD.
Cell-kill assay style payload applications via HSV1-TK and ganciclovir (GCV) cell kill assay.
Payload/therapeutic-agent applications including GM-CSF and multiple enzyme/protein-factor options for therapeutic agents.
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