Altering net charge on mannosylated dextrans to maximize target tissue uptake and off target competitive blocking
Inventors
Ralph, David A. • Arnold, Jeffrey Scott
Assignees
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Publication Number
US-12178829-B2
Publication Date
2024-12-31
Expiration Date
Abstract
Provided are compounds, compositions, methods, and kits for increasing target specificity of a mannosylated carbohydrate polymeric therapeutic or diagnostic compound to reduce or eliminate localization of the mannosylated carbohydrate polymeric therapeutic or diagnostic compound to off-target sites. Mannosylated carbohydrate polymers are synthesized to be modified to be either polyanionic (i.e., net negatively charged) or electrostatically neutral, and using these polyanionic or neutral mannosylated carbohydrate polymers as competitors for polycationic (i.e., net positively charged) mannosylated carbohydrate polymers carrying small molecule drug payloads or imaging moieties to CD206 expressing cells in target tissues, such as tumors or other sites of inflammation.
Core Innovation
The invention relates to mannosylated carbohydrate polymeric therapeutic or diagnostic compounds comprising a dextran backbone and one or more CD206 targeting moieties, together with one or more therapeutic agents attached thereto or one or more diagnostic moieties attached thereto. The CD206 targeting is provided by mannose-binding C-type lectin receptor targeting moieties, including mannose, fucose, GalNAc/GlcNAc, galactose, and glucuronic acid. The mannosylated dextran constructs are described as polycationic and positively charged.
To increase target specificity, the invention further provides a blocking compound comprising a carbohydrate backbone with one or more mannose-binding C-type lectin receptor targeting moieties and one or more negatively charged or neutral moieties attached thereto. The negatively charged or neutral moieties include acidic groups, mannose moieties, galactose, or fucose, and the blocking compound is described as polyanionic and negatively charged or neutral. The blocking compound and the mannosylated carbohydrate polymeric therapeutic or diagnostic compound are combined so that the mannosylated compound remains polycationic while blocking controls binding and localization toward CD206.
The mannosylated carbohydrate polymeric therapeutic or diagnostic compound is defined by Formula (I), and the blocking compound is defined by Formula (II), including variable selections for the targeting moieties, moiety positions, and an integer n. The constructs include leash/linker concepts with amino-terminated leashes and terminal polyamine/guanidine/quaternary ammonium groups to produce the described polycationic character. Biodegradable linker options are described, including a hydrazone linker, and therapeutic agents and diagnostic moieties include examples such as doxorubicin and chelating agents.
Claims Coverage
The document includes two independent claims, one directed to a composition and one directed to a method of increasing target specificity. Each independent claim centers on combining a carbohydrate blocking compound that is polyanionic or neutral and a polycationic mannosylated carbohydrate polymeric therapeutic or diagnostic compound with CD206 targeting moieties.
Polyanionic or neutral carbohydrate blocking compound with mannose-binding targeting moieties
A blocking compound comprising a carbohydrate backbone, one or more mannose-binding C-type lectin receptor targeting moieties attached thereto, and one or more negatively charged or neutral moieties attached thereto, wherein the negatively charged or neutral moieties comprise an acidic group, a mannose moiety, galactose, or fucose, and wherein the blocking compound is polyanionic and thereby negatively charged, or neutral.
Polycationic mannosylated carbohydrate polymeric therapeutic or diagnostic compound with dextran backbone
A mannosylated carbohydrate polymeric therapeutic or diagnostic compound comprising a dextran backbone and one or more CD206 targeting moieties and one or more therapeutic agents attached thereto, wherein the mannosylated carbohydrate polymeric therapeutic or diagnostic compound is polycationic and thereby positively charged.
Increasing target specificity by co-administering a blocking compound
Administering a blocking compound comprising a carbohydrate backbone, one or more mannose-binding C-type lectin receptor targeting moieties attached thereto, and one or more negatively charged or neutral moieties attached thereto, wherein the negatively charged or neutral moieties comprise an acidic group, a mannose moiety, galactose, or fucose, and wherein the blocking compound is polyanionic and thereby negatively charged, or neutral.
Increasing target specificity by administering a CD206-targeted mannosylated carbohydrate polymeric therapeutic or diagnostic compound
Administering an effective amount of the mannosylated carbohydrate polymeric therapeutic or diagnostic compound comprising a carbohydrate polymer backbone and one or more CD206 targeting moieties and one or more therapeutic or diagnostic agents attached thereto, wherein the mannosylated carbohydrate polymeric therapeutic or diagnostic compound is polycationic and thereby positively charged.
Across the two independent claims, the core coverage requires pairing a polyanionic or neutral carbohydrate blocking compound carrying mannose-binding C-type lectin receptor targeting moieties with a polycationic mannosylated carbohydrate polymeric therapeutic or diagnostic compound that includes CD206 targeting moieties and, for the composition claim, a dextran backbone and therapeutic agents.
Stated Advantages
Increase target specificity of a mannosylated carbohydrate polymeric therapeutic or diagnostic compound.
Decreased binding to CD206 cells in the liver, kidney, and/or spleen compared with the same dose given without a blocking compound.
Effective dose of the mannosylated carbohydrate polymeric therapeutic or diagnostic compound is lower than the effective dose of the same compound without administering the blocking compound.
Reducing or eliminating localization of the mannosylated carbohydrate polymeric therapeutic or diagnostic compound to off-target sites in the liver, kidney, and/or the spleen.
Documented Applications
Used in a subject to increase target specificity of a mannosylated carbohydrate polymeric therapeutic or diagnostic compound by administering a blocking compound and an effective amount of the mannosylated compound.
Therapeutic or diagnostic use targeting CD206 via mannosylated carbohydrate polymeric compounds and mannose-binding C-type lectin receptor targeting moieties, with the goal of reducing off-target localization and/or decreased binding to CD206 cells in liver, kidney, and/or spleen.
Therapeutic and/or diagnostic use of mannosylated carbohydrate polymeric compounds that target CD206, including payloads such as diagnostic imaging moieties and therapeutic agents.
Imaging context referencing tilmanocept, including DTPA-chelated imaging and radionuclides such as Tc99m in example descriptions.
Use in reducing off-target localization and binding to CD206 cells in liver, kidney, and spleen, as described for tumors and inflammation contexts involving CD206-expressing cells.
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