Newcastle disease viruses and uses thereof
Inventors
Palese, Peter • Garcia-Sastre, Adolfo • Zamarin, Dmitriy • Wolchok, Jedd D.
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Assignees
Merck Sharp and Dohme LLC • Memorial Sloan Kettering Cancer Center
Member
Icahn School of Medicine at Mount SinaiThe Icahn School of Medicine at Mount Sinai, located in New York City, is an international leader in biomedical education, research, and patient care. As the academic partner of the Mount Sinai Health System, the school is renowned for its innovative education, groundbreaking research, and commitment to health equity. With over 7,000 faculty, 1,200 students, and 2,500 residents and fellows, the institution fosters a culture of bold thinking, multidisciplinary teamwork, and a willingness to challenge conventional wisdom. Its mission is to radically advance the art and science of medical care through collaborative learning, scholarly inquiry, and a deep respect for diversity, preparing the next generation of healthcare leaders to revolutionize medicine and biomedical science.
The Icahn School of Medicine at Mount Sinai, located in New York City, is an international leader in biomedical education, research, and patient care. As the academic partner of the Mount Sinai Health System, the school is renowned for its innovative education, groundbreaking research, and commitment to health equity. With over 7,000 faculty, 1,200 students, and 2,500 residents and fellows, the institution fosters a culture of bold thinking, multidisciplinary teamwork, and a willingness to challenge conventional wisdom. Its mission is to radically advance the art and science of medical care through collaborative learning, scholarly inquiry, and a deep respect for diversity, preparing the next generation of healthcare leaders to revolutionize medicine and biomedical science.
Publication Number
US-12042534-B2
Publication Date
2024-07-23
Expiration Date
2038-05-11
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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