Viral vector constructs for delivery of nucleic acids encoding cytokines and uses thereof for treating cancer
Inventors
Furmanski, Brian • Gupta, Nachiketa • SCHNEPP, Bruce • Stone, Michele
Assignees
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Publication Number
US-12071633-B2
Publication Date
2024-08-27
Expiration Date
Abstract
The present disclosure provides the gene therapy compositions comprising vectors (e.g., viral vectors) suitable for delivery of nucleic acids encoding immunomodulatory proteins or functional fragments thereof, and methods of using the same. Certain aspects of the disclosure are directed to an adeno-viral vector (AAV) delivery of nucleic acids encoding two or more immunomodulatory proteins or functional fragments thereof to a tumor.
Core Innovation
The patent describes an IL-12 expression system implemented as eukaryotic expression cassette elements configured in a polynucleotide and packaged in an adeno-associated virus (AAV) vector having two inverted terminal repeat (ITR) sequences. The polynucleotide includes a promoter, a first nucleic acid encoding a first Interleukin-12 (IL-12) subunit or functional fragment thereof, a second nucleic acid encoding a second IL-12 subunit or functional fragment thereof, a translation modification sequence, and a poly(A) sequence. The first nucleic acid comprises SEQ ID NO: 77 and the second nucleic acid comprises SEQ ID NO: 8.
The translation modification sequence includes a furin cleavage sequence followed by a 2A self-processing peptide (F2A) sequence, and the patent also describes promoter configurations including a CAG promoter comprising a CMV enhancer, a CBA promoter, and a CAG intron sequence. The cassette further includes a growth hormone pA sequence in the described CAG/F2A format.
The patent further addresses combination therapy by providing a second composition comprising a checkpoint inhibitor. The checkpoint inhibitor is used together with the AAV vector expressing IL-12, and checkpoint inhibitor targets include PD-1, including an anti-PD-1 antibody, as well as PD-L1 and CTLA-4 in the broader therapeutic framework described in the document context.
Claims Coverage
The independent claims cover four inventive features. Across the claims, the core inventive coverage centers on specified promoter and processing elements, SEQ ID NO: 77 and SEQ ID NO: 8 nucleic acids, IL-12 subunit expression configuration, AAV packaging, and checkpoint inhibitor combination.
Combination therapy with AAV IL-12 cassette and checkpoint inhibitor
A first composition comprising an adeno-associated virus (AAV) vector comprising a polynucleotide comprising a promoter, a first nucleic acid encoding a first Interleukin-12 (IL-12) subunit or functional fragment thereof, a translation modification sequence, a second nucleic acid encoding a second IL-12 subunit or functional fragment thereof, a poly(A) (pA) sequence, and two inverted terminal repeat (ITR) sequences; and a second composition comprising a checkpoint inhibitor; wherein the first nucleic acid comprises SEQ ID NO: 77 and the second nucleic acid comprises SEQ ID NO: 8.
AAV-packaged polynucleotide composition encoding IL-12 subunits
A composition comprising a polynucleotide comprising a promoter, a first nucleic acid encoding a first Interleukin-12 (IL-12) subunit or functional fragment thereof, a translation modification sequence, a second nucleic acid encoding a second Interleukin-12 (IL-12) subunit or functional fragment thereof, and two inverted terminal repeat (ITR) sequences, and an AAV vector, wherein the polynucleotide is packaged in the AAV vector, and wherein the first nucleic acid comprises SEQ ID NO: 77 and the second nucleic acid comprises SEQ ID NO: 8.
Intratumoral AAV composition with CAG promoter and F2A-linked IL-12 p35/p40
A composition comprising a polynucleotide comprising a CAG promoter operably linked to a first nucleic acid encoding an IL-12 p35 subunit or a functional fragment thereof, a furin cleavage sequence followed by a 2A self-processing peptide (F2A) sequence, a second nucleic acid encoding an IL-12 p40 subunit or a functional fragment thereof, a growth hormone pA sequence, and two inverted terminal repeat (ITR) sequences; and an AAV vector comprising an AAV capsid suitable for intratumoral delivery; wherein the polynucleotide is packaged in the AAV vector, wherein the CAG promoter comprises a CMV enhancer, a CBA promoter, and a CAG intron sequence, and wherein the first nucleic acid comprises SEQ ID NO: 77 and the second nucleic acid comprises SEQ ID NO: 8.
Polynucleotide defined by SEQ ID NO: 77 and/or SEQ ID NO: 8
A polynucleotide comprising SEQ ID NO: 77 or SEQ ID NO: 8, or a combination thereof.
The claims define IL-12 gene therapy constructs centered on specified IL-12 subunit nucleic acids (SEQ ID NO: 77 and SEQ ID NO: 8) and configured expression cassette elements, with one claim combining the AAV IL-12 composition with a checkpoint inhibitor. A separate claim specifies a CAG promoter architecture and a furin cleavage plus F2A translation modification configuration for an intratumoral AAV composition, while another claim provides direct polynucleotide coverage via SEQ ID selection.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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