Alphavirus replicon vector and immunotherapy by administering same
Inventors
Akahata, Wataru • Smith, Jonathan F.
Assignees
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Publication Number
US-12134777-B2
Publication Date
2024-11-05
Expiration Date
Abstract
Provided herein is a novel immunologically-active alphavirus replicon vector which comprises a nucleic acid encoding alphavirus nonstructural proteins nsp1-4 and a cytokine protein(s)/polypeptide(s), which is useful for the treatment of a cancer and/or an inflammatory disease.
Core Innovation
The invention relates to an alphavirus replicon-based cytokine immunotherapy for cancer and inflammatory disease. It uses an alphavirus replicon vector that encodes alphavirus non-structural proteins nsp1, nsp2, nsp3 and nsp4 together with a cytokine polypeptide, so the replicon vector delivers both the alphavirus replication function and the cytokine expression component.
The disclosed compositions include an alphavirus replicon vector encapsulated in a delivery vehicle carried with a pharmaceutically acceptable carrier. The delivery vehicle is described as an alphavirus particle and/or a lipid delivery system, including lipid nanoparticles and liposomes, with examples of formulations where the replicon is delivered in alphavirus replicon particle (ARP) and lipid nanoparticles.
The cytokine is engineered to enable cytokine presentation via fusion to a transmembrane domain. The disclosed transmembrane fusion domains include hemagglutinin (HA) TM, TLR4 TM/TIR, and IgG4CH3/HA constructs with linkers (GS), and the replicon genetic elements are described for a VEEV TC-83 platform including an SG promoter, 5’ UTR, 3’ UTR, and a polyA tail.
The document further describes preclinical tumor model outcomes and immunological effects associated with the IL-12 replicon therapy. It reports enhanced anti-tumor activity with IL-12 replicon alone and combined with anti–PD-1, together with increased M1 macrophages and reduced Treg cells (FoxP3+) in tumor infiltrating cells.
Claims Coverage
The document contains two independent claims. Across these independent claims, the inventive coverage centers on an encapsulated composition format and an alphavirus replicon vector specifying nsp1–nsp4 plus a cytokine polypeptide, with the alphavirus selected from CHIKV strains 37997/OPY-1 or VEEV TC-83.
Encapsulated alphavirus replicon cytokine composition
A composition comprising a pharmaceutically acceptable carrier and an alphavirus replicon vector comprising a polynucleotide which encodes alphavirus non-structural proteins nsp1, nsp2, nsp3 and nsp4 and a polypeptide comprising a cytokine, wherein the pharmaceutically acceptable carrier is a delivery vehicle and the alphavirus replicon vector is encapsulated in the delivery vehicle.
Selected alphavirus replicon vector for cytokine payload
An alphavirus replicon vector comprising a polynucleotide which encodes alphavirus non-structural proteins nsp1, nsp2, nsp3 and nsp4 and a polypeptide comprising a cytokine, wherein the alphavirus is selected from the group consisting of CHIKV strain 37997, CHIKV strain OPY-1 and VEEV strain TC-83.
Overall, the independent claim coverage ties the cytokine payload to an alphavirus replicon encoding nsp1–nsp4 and limits either the composition to an encapsulated delivery-vehicle format or the vector itself to specific CHIKV and VEEV strains.
Stated Advantages
Enhanced anti-tumor activity with IL-12 replicon alone and combined with anti–PD-1.
Increased M1 macrophages in tumor infiltrating cells.
Reduced Treg cells (FoxP3+) in tumor infiltrating cells.
Documented Applications
Preclinical tumor model anti-tumor use of the IL-12 replicon therapy, including combination with anti–PD-1.
Immunotherapy for cancer via use of an alphavirus replicon vector administered to a subject (including treating and/or immunizing).
Immunotherapy for inflammatory disease via use of an alphavirus replicon vector administered to a subject (including treating and/or immunizing).
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