Compositions comprising lentiviral vectors expressing IL-12 and methods of use thereof
Inventors
Ter Meulen, Jan Henrik • BERGLUND, Peter Lars Aksel • Albershardt, Tinglan Tina
Assignees
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Publication Number
US-11365230-B2
Publication Date
2022-06-21
Expiration Date
Abstract
This patent application relates generally to the treatment of cancer, and more particularly to the use of a pseudotyped lentivirus expressing IL-12 for the treatment of cancer.
Core Innovation
The document describes lentiviral vector particles for cancer treatment that include an envelope comprising a Sindbis virus E2 glycoprotein variant and a lentiviral vector genome encoding IL-12. The E2 glycoprotein variant has residue 160 absent or as an amino acid other than glutamic acid, at least one of a defined set of E2 positions as non-basic residues, and the E2 glycoprotein variant is not part of a fusion protein with Sindbis virus E3 glycoprotein.
The lentiviral vector genome encodes IL-12, in particular single-chain IL-12 (scIL-12). The document specifies scIL-12 configurations comprising p35-L-p40 or p40-L-p35, and it also describes E2 glycoprotein variant sequence constraints including amino acids 66 to 488 of SEQ ID NO: 3.
The document further describes use of these lentiviral vector particles as part of therapeutic or prophylactic vaccination and cancer treatment approaches. It also describes combination or co-delivery with a second lentiviral vector encoding a tumor antigen, where tumor antigens can include tumor-associated antigens such as NY-ESO-1 and hCAIX.
Claims Coverage
The provided portion contains two independent claims. Each claim defines a lentiviral vector particle with a constrained Sindbis virus E2 glycoprotein variant in the envelope and a lentiviral vector genome encoding IL-12, with scIL-12 format specified in the genome in both independent claims.
E2 glycoprotein variant envelope plus IL-12 genome encoding
A lentiviral vector particle having an envelope with an E2 glycoprotein variant in which residue 160 is absent or an amino acid other than glutamic acid, at least one specified set of E2 residues is a non-basic residue, and the E2 glycoprotein variant is not part of a fusion protein with Sindbis virus E3 glycoprotein; and a lentiviral vector genome comprising a polynucleotide sequence encoding IL-12.
Constrained E2 variant window with scIL-12 genome
A lentiviral vector particle having an envelope with an E2 glycoprotein variant comprising amino acids 66 to 488 of SEQ ID NO: 3, wherein residue 160 is absent or an amino acid other than glutamic acid, residue 70 is a non-basic residue, and the E2 glycoprotein variant is not part of a fusion protein with Sindbis virus E3 glycoprotein; and a lentiviral vector genome encoding IL-12 as a single chain IL-12 (scIL-12) comprising p35-L-p40 or p40-L-p35.
Across the independent claims, the inventive coverage centers on lentiviral vector particles that combine a Sindbis virus E2 glycoprotein variant envelope with defined residue-level constraints and a non-fusion relationship to Sindbis virus E3, together with a lentiviral vector genome encoding IL-12, including scIL-12 configured as p35-L-p40 or p40-L-p35.
Stated Advantages
Enhanced CD8 and CD4 responses and anti-tumor activity across murine tumor models.
Enhanced anti-tumor activity supported by examples using VP02/IL-12 including co-delivered tumor antigens and regulatory T cell depletion.
Documented Applications
Therapeutic vaccine formats using dendritic cell-targeting lentiviral vector particles comprising an envelope with a specified E2 glycoprotein variant and a lentiviral vector genome encoding IL-12.
Combination regimens in which IL-12-expressing dendritic cell-targeting lentiviral vectors are combined with tumor antigen-encoding lentiviral vectors.
Combination of IL-12-expressing dendritic cell-targeting lentiviral vectors with autophagy inhibition, immunogenic cell death inducers, immunogenicity enhancers including TLR4 agonists such as GLA, and epigenetic agents such as decitabine.
Antibody-based approaches combined with IL-12-expressing dendritic cell-targeting lentiviral vectors to enhance tumor uptake by antigen-presenting cells and provide co-stimulation, including anti-CTLA-4 and antibodies to CD40/CD28/ICOS/OX40/CD27.
Use of the vectors in murine tumor models with depletion studies indicating CD8 requirement and the role of regulatory T cell depletion [procedural detail omitted for safety].
A therapeutic or prophylactic vaccine provided that includes lentiviral vector particles and a pharmaceutically acceptable excipient [procedural detail omitted for safety].
Cancer treatment using the described lentiviral vector particles, including administration involving a second lentiviral vector encoding a tumor antigen, where tumor antigens include tumor-associated antigens such as NY-ESO-1 and hCAIX [procedural detail omitted for safety].
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