Branched chimeric compounds, and methods of use thereof
Inventors
Ott, Gary S. • Milley, Robert J. • Coffman, Robert L. • Kiwan, Radwan • Kanzler, Holger
Assignees
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Publication Number
US-10548975-B2
Publication Date
2020-02-04
Expiration Date
Abstract
The present disclosure relates to branched and linear chimeric compounds containing both nucleic acid and non-nucleic acid moieties, as well as to polynucleotides. The present disclosure also relates to uses thereof for stimulating an immune response, and to methods for preparation of the branched chimeric compounds.
Core Innovation
The invention provides a pharmaceutical composition that includes a pharmaceutically acceptable excipient and a branched chimeric compound of formula (I). The branched chimeric compound comprises a linear chimeric compound D connected through defined linkers to a PEG segment and to a branched copolymer F of sucrose and epichlorohydrin, with F connected to L3 via an ether group. The formula is parameterized by PEG length n from 2 to 80 and branching index x from 3 to 300.
The linear chimeric compound D comprises three nucleic acid moieties and two hexaethylene glycol (HEG) spacers, contains less than 50 nucleotides, and includes phosphorothioate ester linkages between nucleotides, between nucleotides and HEG spacers, and between the 3′-terminal nucleotide and L1. The linkers L1, L2, and L3 comprise an alkylthio group, a succinimide group, and an amide group, respectively. The disclosed D and F architecture is presented as a branched chimeric compound of formula (I).
The branched carrier F is described as a sucrose/epichlorohydrin copolymer connected through an ether group, and the linear chimeric nucleic-acid moieties are described as CpG with an unmethylated context. The compositions are positioned as immunostimulatory agents with IFN-α, IL-6, IL-12p40, B-cell proliferation, and pDC maturation effects.
Claims Coverage
The consolidated claim coverage centers on one independent claim for a pharmaceutical composition and merges the defined structural features of the branched chimeric compound of formula (I). The inventive features include the linker architecture, PEG length and branching index ranges, the sucrose/epichlorohydrin branched copolymer carrier, and the linear chimeric nucleic-acid component with HEG spacers and phosphorothioate ester linkages.
Pharmaceutical composition with branched chimeric compound of formula (I)
A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a branched chimeric compound of formula (I) in which D is a linear chimeric compound, L1 is a first linker comprising an alkylthio group, L2 is a second linker comprising a succinimide group, L3 is a third linker comprising an amide group, PEG is —(OCH2CH2)n— with n from 2 to 80, x is from 3 to 300, and F is a branched copolymer of sucrose and epichlorohydrin connected to L3 via an ether group.
Linear chimeric compound D with three nucleic acid moieties, HEG spacers, and phosphorothioate ester linkages
The linear chimeric compound of D comprises three nucleic acid moieties and two hexaethylene glycol (HEG) spacers, contains less than 50 nucleotides, and has phosphorothioate ester linkages between nucleotides, between nucleotides and the HEG spacers, and between the 3′-terminal nucleotide and L1.
Overall, the claims are directed to a pharmaceutical composition featuring a branched chimeric compound of formula (I) with a sucrose/epichlorohydrin branched copolymer carrier, defined linkers, specified PEG and branching ranges, and a short linear chimeric nucleic-acid segment with HEG spacers and phosphorothioate ester linkages.
Stated Advantages
Improved water solubility.
Controlled maleimide:FICOLL and D56-01:FICOLL ratios.
Improved reactivity/purity.
Improves solubility/stability and manufacturability/storage versus prior hydrophobic linkers.
Improved stability compared to solution, including enhanced stability at 25°C and maintained pH, purity, and particle size for up to 12 months at -80°C and 5°C.
Largely maintained in vitro activity despite particle-size changes at 37°C.
More potent and/or safer than monomeric D56-01, including higher potency in IFN-α and IL-6 assays and improved immune activation and TLR9-dependent innate responses.
Improved cellular uptake/activation of APCs.
Provides immunostimulatory readouts including IFN-α, IL-6, IL-12p40, B-cell proliferation, and pDC maturation.
Improved in vivo adjuvant/antibody responses with anthrax antigen challenge in monkeys.
Reduced systemic cytokine/tissue toxicity in mice compared to D56-01.
Intratumoral tumor suppression in a murine lymphoma model.
Provides therapeutic tumor-related outcomes described as solid tumor shrinkage/delayed growth, viable cell reduction, and survival.
Immunomodulatory activity of ≥3-fold control is described.
Documented Applications
In vivo adjuvant/antibody responses with anthrax recombinant Protective Antigen (rPA) challenge in monkeys.
Reduced systemic cytokine/tissue toxicity in mice compared to D56-01.
Intratumoral tumor suppression in a murine lymphoma model after intratumoral administration.
Human in vitro immunologic assays including IFN-α and IL-6 assays and innate immune responses involving TLR9.
Infectious disease prevention/treatment.
IgE-related disorders.
Cancer therapy directed to tumor treatment endpoints described as solid tumor effects, including solid tumor shrinkage/delayed growth, viable cell reduction, and survival.
Cancer-related immune modulation, including cancer treatment contexts.
Administration by intratumoral injection into a solid tumor of a mammalian subject.
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