Methods for treating liver cancers using an orally administered dioxolane nucleotide in combination with an anti-PD1 or anti-PDL1 monoclonal antibody
Inventors
Assignees
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Publication Number
US-12303521-B2
Publication Date
2025-05-20
Expiration Date
Abstract
Use of a compound of the formula I:or a pharmaceutically acceptable salt thereof, in the therapy of a liver cancer in a mammal, characterized by the concurrent or sequential treatment of the mammal with a monoclonal antibody which blocks the binding of PD-L1 and/or PD-L2 to PD-1.
Core Innovation
The patent discloses a combination method for treating liver cancer in a mammal in need thereof. The method administers a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, together with a therapeutically effective amount of a monoclonal antibody that blocks the binding of PD-L1 and/or PD-L2 to PD-1. The compound and the monoclonal antibody are administered concurrently or sequentially as a therapeutically effective combination for liver cancer.
The patent further specifies cyclically administering the compound of formula I and the PD-L1/PD-L2 blocking monoclonal antibody for treating a mammal afflicted with a primary or secondary liver tumour. It distinguishes administration routes by stating that the compound is administered orally, while the antibody is administered parenterally. The treated indications explicitly include primary liver tumours and secondary liver tumours, including hepatocellular carcinoma and liver metastases.
The patent states a rationale that MIV-818 and related dioxolane nucleotide compounds can stimulate the immune system to enhance efficacy and/or tolerability of PD-1/PD-L1 blockade. It further describes potential abscopal effects for extra-hepatic lesions as part of the combination's intended immune-related impact. Mechanistic and model support described in the patent includes an immune microenvironment BioMAP model and PBMC-based evidence showing increased immune activation markers and enhanced cytokine and secreted protein changes, as well as PBMC-mediated tumor cell killing for the combination versus monotherapy.
Claims Coverage
The independent claims cover combination treatment of liver cancer using a compound of formula I, including pharmaceutically acceptable salts, together with a PD-1 axis blocking monoclonal antibody. Across the independent claims, the inventive framework includes concurrent or sequential combination administration, cyclic dosing, and route differentiation with oral compound and parenteral antibody, while additional dependent claim coverage specifies antibody subclass and target details and an optional stereochemical purity constraint.
Concurrent or sequential co-administration for PD-L1/PD-L2 blockade
A method of treatment of liver cancer in a mammal in need thereof comprising administration of a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, with concurrent or sequential treatment with a therapeutically effective amount of a monoclonal antibody which blocks the binding of PD-L1 and/or PD-L2 to PD-1.
Cyclic co-administration with oral compound and parenteral antibody
A method for treating a mammal afflicted with a primary or secondary liver tumour comprising cyclically administering a therapeutically effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a monoclonal antibody which blocks the binding of PD-L1 or PD-L2 to PD1, wherein the compound is administered orally and the antibody is administered parenterally.
Human liver cancer treatment using human PD-1 binding monoclonal antibody
A method of treating liver cancer in a human in need thereof comprising administrating a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of an anti-PD-1, anti-PD-L1, and/or anti-PD-L2 monoclonal antibody comprising means for binding human PD-1.
Cyclic treatment in humans with oral compound and parenteral PD-1 axis antibody
A method for treating liver cancer in a human afflicted with a primary or secondary liver tumour comprising cyclically administering to the human a therapeutically effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of an anti-PD-1, anti-PD-L1, and/or anti-PD-L2 monoclonal antibody comprising means for binding human PD-1, wherein the compound is administered orally and the antibody is administered parenterally.
Collectively, the independent claims define a liver cancer treatment regimen that pairs a compound of formula I with a monoclonal antibody targeting the PD-1 axis by blocking PD-L1 and/or PD-L2 binding to PD-1, with concurrent or sequential administration, cyclic administration, and route differentiation. Additional disclosed refinements in dependent claims include specific antibody subclasses such as IgG4 or IgG1 and the option to specify the liver cancer indication as HCC.
Stated Advantages
Enhances efficacy of PD-1/PD-L1 blockade.
Potentially improves tolerability of PD-1/PD-L1 blockade.
May produce abscopal effects for extra-hepatic lesions.
Shows increased immune activation markers and enhanced cytokine and secreted protein changes with the combination versus monotherapy.
Provides PBMC-mediated tumor cell killing enhanced with the combination versus monotherapy.
Documented Applications
Treatment of primary or secondary liver tumours, including hepatocellular carcinoma and liver metastases, in a mammal or in a human using a compound of formula I, including MIV-818 and dioxolane nucleotide forms, combined with a PD-L1/PD-L2 blocking monoclonal antibody.
Immune microenvironment and PBMC-based experimental or model contexts described in the patent support immune activation and enhanced anti-tumor activity for MIV-818 plus pembrolizumab versus monotherapy.
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