Formulated and/or co-formulated liposome compositions containing toll-like receptor (“TLR”) agonist prodrugs useful in the treatment of cancer and methods thereof
Inventors
Stover, David • Bharali, Dhruba • Hay, Bruce A • Safaie, Tahmineh
Assignees
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Publication Number
US-11679141-B2
Publication Date
2023-06-20
Expiration Date
Abstract
Formulated and/or co-formulated liposomes comprising TLR prodrugs and/or TLR Lipid Moieties and methods of making the liposomes are disclosed herein. The TLR prodrug compositions comprise a drug moiety, a lipid moiety, and linkage unit that inhibit Toll-Like Receptor (e.g., TLR1/2, TLR4, and/or TLR7). The TLR prodrugs can be formulated and/or co-formulated into a liposome to provide a method of treating cancer, immunological disorders, and other disease by utilizing a targeted drug delivery vehicle.
Core Innovation
The invention relates to Toll-like receptor (TLR) prodrug compositions comprising a lipid-based prodrug, with TR3 provided as the TLR prodrug having a specified chemical structure. The prodrugs include a drug moiety, a lipid moiety, and a biologically cleavable linkage unit, and the disclosure emphasizes embedding lipid prodrugs into lipid-based delivery systems, including liposomes and solid-lipid nanoparticle (SLNP) formats.
The compositions and formulations address solubility limitations for lipid-based prodrugs by lipid conjugation and carrier-based delivery to improve solubility and pharmacokinetics, including half-life. The delivery system is configured to provide targeted delivery and enhanced exposure by presenting the TLR prodrug in a carrier form and to release an active TLR inhibitor after cleavage of the biologically cleavable linkage unit that separates the lipid moiety from the drug moiety.
The description further identifies exemplary TLR inhibitor prodrugs including TR3, TR5, TR6, and TR6/TR3 variants, and exemplifies lipid components suitable for nanocarrier construction, including cholesterol, CHEMS, stearic acid, DPPG, DMPG, Lyso PC, and Soy Lyso PC. In representative embodiments, liposome advantages are described, including biocompatibility, tunable size and charge, and the ability to load multiple lipids and multiple drug molecules.
Claims Coverage
The independent claim coverage centers on a TR3 Toll-like receptor prodrug composition. The claim set further defines a nanocarrier that releases an active TLR inhibitor after cleavage of a linker unit separating lipid and drug moieties, and adds co-formulated immune-stimulation and immunomodulatory components, with the nanocarrier narrowed to liposomes and a solid-lipid nanoparticle embodiment indicated as an alternative.
Tr3 toll-like receptor prodrug composition
A Toll-like receptor (TLR) prodrug composition comprising TR3 as the TLR prodrug having a specified structure.
Nanocarrier with cleavage-released active TLR inhibitor
A nanocarrier comprising the TLR prodrug, wherein an active TLR inhibitor is released after cleavage of a linker unit that separates a lipid moiety from a drug moiety.
Nanocarrier with α-GalCer iNKT activator
The nanocarrier is co-formulated with an iNKT activator defined as Alpha-galactosylceramide (α-GalCer).
Nanocarrier co-formulated with immune modulating agent
The nanocarrier is co-formulated with an immune modulating agent selected from TLR agonists or prodrugs thereof, immunogenic cell death inducing chemotherapeutics, IDO antagonists, STING agonists, CTLA-4 inhibitors, and PD-1/PD-L1 inhibitors or prodrugs thereof.
Nanocarrier co-formulated with ICD-inducing chemotherapeutic
The nanocarrier is co-formulated with an immunogenic cell death (ICD)-inducing chemotherapeutic selected from Doxorubicin, Mitoxantrone, Oxaliplatin, Cyclophosphamide, Bortezomib, Carfilzomib, or Paclitaxel.
Liposome nanocarrier format
The nanocarrier comprises a liposome.
Across the claim coverage, the core inventive focus is a TR3 TLR prodrug composition delivered in a nanocarrier that releases an active TLR inhibitor after cleavage between lipid and drug moieties. Additional claim scope includes co-formulation with α-GalCer and selected immune modulating agents and ICD-inducing chemotherapeutics, with the nanocarrier format defined as a liposome and an SLNP embodiment indicated.
Stated Advantages
Improved solubility of lipid prodrugs through lipid conjugation and liposomal delivery.
Improved pharmacokinetics, including half-life, due to lipid conjugation and liposomal delivery.
Biocompatibility of the liposome delivery system.
Tunable size and charge of the liposome delivery system.
Ability to load multiple lipids and multiple drug molecules.
Targeted delivery and enhanced exposure via carrier-based delivery.
Documented Applications
Combination-therapy and therapeutic use with co-encapsulated or combined immune modulators.
Cancer indications.
Infections (viral, bacterial, fungal, or parasite).
Cancer therapy.
Immunological disorder therapy.
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