Administration of polynucleotide toll-like receptor 9 agonists for treating cancer
Inventors
Guiducci, Cristiana • Coffman, Robert L.
Assignees
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Publication Number
US-10369168-B2
Publication Date
2019-08-06
Expiration Date
Abstract
The present disclosure relates to methods for treating cancer by intrapulmonary administration of a polynucleotide Toll-like receptor 9 agonist. The methods of the present disclosure are suitable for treating primary cancer of the lung, as well as metastatic cancer to the lung and extra pulmonary cancers thereof. Additionally, the present disclosure provides polynucleotide Toll-like receptor 9 agonists with immune stimulatory and toxicity profiles suitable for intrapulmonary administration.
Core Innovation
The invention relates to treating cancer in a mammalian subject by administering, by injection, a pharmaceutical composition that includes an isolated polynucleotide and a pharmaceutically acceptable excipient. The isolated polynucleotide is a 2′-deoxyribopolynucleotide consisting of the sequence 5′-TCGTAACGTTCGAACGTTCGANx-3′ (SEQ ID NO:2), where x is 0, 1, or 2, and each N is A, C, or T. The polynucleotide contains phosphorothioate internucleotide linkages throughout.
The disclosed polynucleotides function as a polynucleotide Toll-like receptor 9 (TLR9) agonist containing unmethylated CG dinucleotides. The polynucleotide is described as comprising phosphorothioate internucleotide linkages and includes variants corresponding to SEQ ID NO:7, SEQ ID NO:8, and SEQ ID NO:9. The composition is optionally single-stranded or double-stranded.
The treatment aims to achieve improved intrapulmonary immune stimulation with a therapeutic window, described as inducing moderate IFN-α while reducing lung toxicity and flu-like symptoms on repeated dosing. The document also describes combination regimens in which the polynucleotide TLR9 agonist is administered together with chemotherapeutic agents or immune modulators, including immune checkpoint inhibitors and immune stimulatory agonists, with potential synergy or additivity.
Claims Coverage
The provided independent claim framework centers on an injection-based cancer treatment using a specific isolated 2′-deoxyribopolynucleotide TLR9 agonist with phosphorothioate linkages. The inventive features include a defined nucleotide sequence with controlled variability, phosphorothioate backbone linkage, and formulation with a pharmaceutically acceptable excipient.
Injected cancer treatment with a pharmaceutically acceptable composition containing an isolated 2′-deoxyribopolynucleotide
Administering to a mammalian subject by injection an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an isolated polynucleotide for treating cancer.
Defined 5′-TCGTAACGTTCGAACGTTCGANx-3′ polynucleotide sequence with controlled variability
The polynucleotide is a 2′-deoxyribopolynucleotide consisting of 5′-TCGTAACGTTCGAACGTTCGANx-3′ (SEQ ID NO:2), where x is 0, 1 or 2 and each N is A, C or T.
Phosphorothioate internucleotide linkages throughout the 2′-deoxyribopolynucleotide
All internucleotide linkages are phosphorothioate linkages.
Overall, the claim coverage centers on an injection-based cancer treatment method using a specifically defined 2′-deoxyribopolynucleotide sequence (SEQ ID NO:2 with x=0–2 variability and A/C/T positions) together with phosphorothioate internucleotide linkages, formulated with a pharmaceutically acceptable excipient.
Stated Advantages
Improved intrapulmonary immune stimulation with a therapeutic window.
Induces moderate IFN-α.
Reduced lung toxicity and reduced flu-like symptoms on repeated dosing.
Combination with a systemic immune checkpoint inhibitor can synergize or be additive, improving survival and reducing lung metastases.
Documented Applications
Treatment of cancer in a mammalian subject using injection of a pharmaceutical composition containing a TLR9 agonist 2′-deoxyribopolynucleotide with phosphorothioate internucleotide linkages.
Intrapulmonary/intranasal delivery contexts for cancer treatment, including mouse lung metastasis models, with described combination use with systemic anti-PD-1 to improve survival and reduce lung metastases.
Combination regimens with chemotherapeutic agents and immune modulators including immune checkpoint molecules (e.g., PD-1/PD-L1/CTLA-4/IDO/TDO) and immune stimulatory molecules (e.g., CD27/CD40/OX40/GITR/CD137/ICOS) for potential synergy or additivity.
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