Formulated and/or co-formulated liposome compositions containing TFGB antagonist 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-11801304-B2
Publication Date
2023-10-31
Expiration Date
Abstract
Formulated and/or co-formulated liposomes (LNP) and solid-lipid nanoparticles (SLNP) comprising TB Prodrugs and methods of making the LNPs and SLNPs are disclosed herein. The TB prodrug compositions comprise a drug moiety, a lipid moiety, and linkage unit that inhibit ALK5. The TB Prodrugs can be formulated and/or co-formulated into a liposome or solid-lipid nanoparticle 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 a nanocarrier comprising a TB prodrug, where the nanocarrier releases an active ALK5 inhibitor after cleavage of a LU. The TB prodrug includes a drug moiety, a lipid moiety, and a biologically cleavable linker, and the prodrug embodiments are described as lipid-drug conjugates.
The LU is described as a cleavable linkage unit, including hydromethylcarbamate and hydrolase-cleavable ester or amide linkages, and the disclosure defines TB prodrug embodiments including TB4, including TB4 stearic acid. The chemistry is illustrated in which cleavage and esterase hydrolysis relate to release.
The invention further includes nanocarrier formats such as liposomes, LNP, SLNP, and solid-lipid nanoparticle variants, with example characterization for LNP-TB4, LNP-TB4-ID3, SLNP-TB4, and SLNP-TB4-ID3. The disclosure also describes helper lipids, co-formulation with immunomodulating agents or PD-1/PD-L1 antagonists, and combination configurations such as SLNP-TB4 with LNP-MTO.
Claims Coverage
The claim coverage centers on one independent claim directed to a nanocarrier with a TB prodrug that releases an active ALK5 inhibitor after cleavage of a LU, with dependent claims refining the LU identity, the TB prodrug embodiment, the nanocarrier format, and co-formulation options.
Nanocarrier with LU-cleavable TB prodrug for ALK5 inhibitor release
A nanocarrier comprising a TB prodrug whereby the nanocarrier releases an active ALK5 inhibitor after cleavage of a LU.
Hydromethylcarbamate linker as the LU
The nanocarrier wherein the LU is a hydromethylcarbamate linker.
TB4 as the TB prodrug
The nanocarrier comprising a TB prodrug comprising TB4.
Specified chemical structure of TB4 prodrug
The nanocarrier comprising a TB4 prodrug having the specified chemical structure shown in the figures/images.
Liposome nanocarrier format
The nanocarrier comprising a liposome.
Co-formulation with a PD-1/PD-L1 antagonist
The nanocarrier is co-formulated with a PD-1/PD-L1 antagonist, or a lipid-prodrug of it, selected from AUNP12, CA-170, or BMS-986189.
Overall, the claims focus on LU-cleavage mediated release of an active ALK5 inhibitor from a TB prodrug, with specific refinement to a hydromethylcarbamate LU and TB4 prodrug embodiments, and further implementation via liposome and SLNP-type nanocarriers plus co-formulation with named PD-1/PD-L1 antagonists.
Stated Advantages
Not explicitly described in patent.
Documented Applications
In vivo tumor growth inhibition in B16F10 melanoma, including configurations such as combination SLNP-TB4 with LNP-MTO and additional combinations as described in the examples.
In vitro TGF-β pathway inhibition using HEK-Blue TGF-β/SEAP readout, including TGF-β/Smad signaling assessment as described in the examples.
Clinical trial approaches for formulated or co-formulated liposomes containing TB prodrugs, including adjunctive therapy versus monotherapy and inclusion based on TGFβ expression.
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