Newcastle disease viruses and uses thereof
Inventors
Palese, Peter • Garcia-Sastre, Adolfo • Zamarin, Dmitriy • Wolchok, Jedd D.
Assignees
Merck Sharp and Dohme LLC • Icahn School of Medicine at Mount Sinai • Memorial Sloan Kettering Cancer Center
Publication Number
US-12042534-B2
Publication Date
2024-07-23
Expiration Date
2038-05-11
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Abstract
Described herein are chimeric Newcastle disease viruses comprising a packaged genome comprising a transgene encoding interleukin-12. The chimeric Newcastle disease viruses and compositions thereof are useful in combination with an antagonist of programmed cell death protein 1 (“PD-1”) or a ligand thereof in the treatment of cancer. In particular, described herein are methods for treating cancer comprising administering the chimeric Newcastle disease viruses in combination with an antagonist of PD-1 or a ligand thereof, wherein the chimeric Newcastle disease virus comprises a packaged genome comprising a transgene encoding interleukin-12.
Core Innovation
Described herein are chimeric Newcastle disease viruses (NDV) comprising a packaged genome comprising a transgene encoding interleukin-12 (IL-12). The chimeric NDVs and compositions thereof are useful in combination with antagonists of programmed cell death protein 1 (PD-1) or its ligands in the treatment of cancer. The methods include administering chimeric NDVs encoding IL-12, alone or in combination with anti-PD-1 antibodies that block PD-1 interactions with PD-L1, PD-L2, or both.
The problem solved by the invention is the marginal success of naturally occurring NDV strains in clinical trials for advanced human cancers. There remains a need for improved NDV-based therapies for cancer treatment, particularly for advanced cancers. Additionally, while immune checkpoint inhibitors such as anti-PD-1 antibodies have shown some success, better therapeutic strategies are needed. The invention addresses these challenges by combining chimeric NDVs engineered to express IL-12 with PD-1 antagonists to enhance anti-tumor efficacy.
Claims Coverage
The patent contains eight independent claims focused on chimeric NDVs comprising a packaged genome with a transgene encoding human IL-12 and related compositions.
Chimeric Newcastle disease virus comprising a transgene encoding human IL-12
A chimeric NDV comprising a packaged genome comprising a transgene encoding a human IL-12, wherein the transgene comprises the corresponding negative sense RNA sequence of the nucleotide sequence set forth in SEQ ID NO:61 or 26.
Chimeric Newcastle disease virus encoding specific IL-12 polypeptides
The chimeric NDV comprises a packaged genome encoding a human IL-12 polypeptide comprising the amino acid sequences set forth in SEQ ID NO:43 or 42, with the transgene sequence corresponding to negative sense RNA sequences set forth in SEQ ID NO:63, 68, 53, or 66.
Chimeric Newcastle disease virus backbone and mutated F protein
The chimeric NDV comprises an NDV backbone of LaSota strain with the packaged genome encoding a mutated F protein with the amino acid mutation L289A incorporated into the virion.
Genomic organization of chimeric NDV with inserted IL-12 transgene
The packaged genome comprises transcription units for NDV NP, P, M, F, HN, and L genes, and the IL-12 transgene is inserted between the NDV P gene and M gene transcription units.
Pharmaceutical compositions comprising chimeric NDVs
Pharmaceutical compositions comprising the chimeric NDVs with packaged genomes encoding IL-12 or derivatives thereof in admixture with pharmaceutically acceptable carriers.
The claims cover chimeric Newcastle disease viruses genetically engineered to express human interleukin-12 transgenes, specific IL-12 polypeptides, incorporation of mutated F proteins enhancing fusogenicity, defined insertion sites of the transgene in the viral genome, and compositions comprising these chimeric NDVs for cancer treatment, especially in combination with PD-1 antagonists.
Stated Advantages
The chimeric NDV comprising a transgene encoding IL-12 significantly increases gene expression profiling (GEP) scores associated with tumor immune response.
Combination of the chimeric NDVs expressing IL-12 with PD-1 antagonists results in robust anti-tumor activity including abscopal effects on non-injected tumors.
The chimeric NDVs stimulate infiltration of activated effector T cells and upregulation of immune activation markers improving the therapeutic response relative to natural NDV strains.
Documented Applications
Treatment of cancer by administering chimeric NDVs encoding IL-12, alone or in combination with antagonists of PD-1 or ligands thereof (e.g., anti-PD-1 antibodies).
Use of chimeric NDVs in combination with PD-1 antagonists for cancers such as melanoma, non-small cell lung cancer, head and neck cancer, urothelial cancer, gastric and gastroesophageal adenocarcinoma, classical Hodgkin lymphoma, and other solid tumors and hematologic malignancies.
Use of chimeric NDVs encoding IL-12 for increasing response to anti-PD-1 therapy in patients refractory or relapsed to PD-1 antagonist monotherapy.
Combination therapy involving intratumoral administration of the chimeric NDVs and intravenous administration of PD-1 or PD-L1-blocking antibodies.
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