Adenovirus armed with bispecific T cell activator
Inventors
Champion, Brian • BROMLEY, Alice Claire Noel
Assignees
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Publication Number
US-11840702-B2
Publication Date
2023-12-12
Expiration Date
Abstract
An adenovirus comprising a sequence of formula (I) 5′ITR-B1-BA-B2-BX-BB-BY-B3-3′ITR wherein BY comprises a transgene cassette containing four transgenes, said genes encoding a FAP-Bispecific T cell activator, CXL10, CXL9, and IFN. The disclosure also extends to a pharmaceutical composition comprising the virus, and use of the virus or formulation in treatment.
Core Innovation
The invention relates to an adenovirus comprising a sequence of formula (I) with defined adenoviral genome architecture. The formula (I) specifies E1A/E1B, an E2B-L1-L2-L3-E2A-L4 region, E3, a region comprising a restriction site and/or one or more transgenes, L5, and E4, together with 5′ ITR and 3′ ITR and, in some descriptions, defined adenoviral regions B1, BA, B2, X, BB, BY, and B3.
A central component is a transgene cassette comprising four transgenes encoding a FAP-bispecific T cell activator, CXCL10, CXCL9, and IFNα. The FAP-bispecific T cell activator corresponds to an anti-CD3/anti-FAP configuration, and the transgenes are provided as shown in SEQ ID NO: 95 or as a polynucleotide encoding the same amino acid sequence.
The disclosure supports cancer treatment using pharmaceutical compositions comprising the adenovirus. The described concept includes piggybacked targeted delivery to cancer/stroma, local secretion of a short half-life engager, and a two-pronged mechanism combining oncolysis and T-cell activation while reducing off-target effects.
Claims Coverage
The provided material includes one independent claim focused on a defined adenovirus with a four-transgene cassette. The claim coverage centers on the formula (I) genome architecture and the inserted cassette encoding a FAP-bispecific T cell activator, CXCL10, CXCL9, and IFNα, with dependent claims adding further sequence references, replication competence, capsid components, and therapeutic use.
Adenovirus defined by formula (I) genome architecture
An adenovirus comprising a sequence of formula (I) in which the genetic elements comprise E1A/E1B, E2B-L1-L2-L3-E2A-L4, E3, a region comprising a restriction site and/or one or more transgenes, L5, and E4.
Four-transgene cassette encoding FAP-bispecific T cell activator, CXCL10, CXCL9, and IFNα
The adenovirus of formula (I) includes a transgene cassette comprising four transgenes encoding a FAP-bispecific T cell activator, CXCL10, CXCL9, and IFNα as shown in SEQ ID NO: 95 or a polynucleotide encoding the same amino acid sequence.
Transgene cassette fixed to SEQ ID NO: 95
The adenovirus wherein the transgene cassette comprises a polynucleotide sequence shown in SEQ ID NO: 95.
Inclusion of SEQ ID NO: 84
The adenovirus defined as including SEQ ID NO: 84.
Replication competent adenovirus
The adenovirus that is replication competent.
Hexon and fibre derived from Ad11
The adenovirus that includes a hexon and a fibre derived from Ad11.
Treatment of epithelial-origin cancer by administering the adenovirus
A method of treating a patient with epithelial-origin cancer by administering the adenovirus or a related pharmaceutical composition.
Overall, the claims focus on an adenovirus defined by formula (I) carrying a transgene cassette with four transgenes encoding a FAP-bispecific T cell activator, CXCL10, CXCL9, and IFNα (SEQ ID NO: 95 or a polynucleotide encoding the same amino acid sequence), with further narrowing by sequence references, replication competence, defined capsid components, and use for treating epithelial-origin cancers.
Stated Advantages
FAP-bispecific T cell activator-expressing recombinant adenoviruses induce T-cell activation and tumor-target lysis.
The kinetics of tumor lysis are influenced by promoter choice.
Endogenous tumor-associated lymphocytes are activated and autologous FAP+ cells are depleted in malignant ascites/pleural effusion exudate fluids and patient material.
Modulation of TGFβ and partial PD-1/PD-L1 checkpoint effects are described.
TAM polarization toward a more activated phenotype is described.
Measurable transgene secretion and T-cell marker upregulation are described for additional EnAd variants.
Piggybacked targeted delivery to cancer/stroma.
Local secretion of a short half-life engager.
Two-pronged oncolysis and T-cell activation.
Reduced off-target effects.
Documented Applications
Malignant ascites and pleural effusion exudate fluids.
Patient material.
Ex vivo prostate tumor slice cultures.
Treatment of epithelial-origin cancers.
Treating a patient with epithelial-origin cancer by administering the adenovirus or a pharmaceutical composition including the adenovirus.
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