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-11833170-B2
Publication Date
2023-12-05
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 compositions that include a blocking compound comprising a compound of Formula (II) and a mannosylated carbohydrate polymeric therapeutic or diagnostic compound comprising a compound of Formula (I). Both the blocking compound and the mannosylated carbohydrate polymeric therapeutic or diagnostic compound include mannose-binding C-type lectin receptor targeting moieties (R), with defined leash structures and charge features.
The blocking compound is polyanionic and thereby negatively charged, or neutral, while the mannosylated carbohydrate polymeric therapeutic or diagnostic compound is polycationic and thereby positively charged. The blocking compound includes at least one Y comprising a carboxylate, sulfate, sulfonate, sulfinate, phosphate, phosphonate, phosphinate, or mannose moiety, and the therapeutic or diagnostic compound includes terminal amine groups comprising a linear or branched polyamine, guanidine, or quaternary ammonium moiety.
The invention addresses off-target localization to liver, kidney, and spleen while maintaining or increasing uptake in target inflammatory tissues. The targeting moiety is selected from mannose, galactose, fucose, N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), and glucuronic acid, and the description attributes differential localization to competitive binding at CD206 and other C-type lectin receptors in combination with net electrostatic charge.
Claims Coverage
The document provides one independent claim directed to a composition including both a Formula (II) blocking compound and a Formula (I) mannosylated carbohydrate polymeric therapeutic or diagnostic compound, with shared mannose-binding C-type lectin receptor targeting moieties and distinct charge features.
Combined Formula (II) blocking compound and Formula (I) mannosylated polymer therapeutic or diagnostic composition
A composition that comprises a blocking compound comprising a compound of Formula (II) and a mannosylated carbohydrate polymeric therapeutic or diagnostic compound comprising a compound of Formula (I), with at least one R on each component comprising a mannose-binding C-type lectin receptor targeting moiety.
Polyanionic or neutral blocking compound via Formula (II)
The blocking compound is polyanionic and thereby negatively charged, or neutral, wherein at least one Y comprises a carboxylate, sulfate, sulfonate, sulfinate, phosphate, phosphonate, phosphinate, or mannose moiety, and at least one R comprises the mannose-binding C-type lectin receptor targeting moiety.
Polycationic mannosylated carbohydrate polymeric therapeutic or diagnostic compound via Formula (I)
The mannosylated carbohydrate polymeric therapeutic or diagnostic compound is polycationic and thereby positively charged, wherein at least one R comprises the mannose-binding C-type lectin receptor targeting moiety and W is a terminal amine group comprising a linear or branched polyamine, guanidine, or quaternary ammonium moiety.
Shared targeting moiety R comprising mannose-binding C-type lectin receptor targeting moiety
At least one R of the blocking compound and at least one R of the mannosylated carbohydrate polymeric therapeutic or diagnostic compound independently comprises a mannose-binding C-type lectin receptor targeting moiety selected from mannose, galactose, fucose, N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), and glucuronic acid.
The independent claim coverage centers on combining a polyanionic or neutral Formula (II) mannose-binding blocking compound with a polycationic Formula (I) mannosylated carbohydrate polymeric therapeutic or diagnostic compound, both sharing mannose-binding C-type lectin receptor targeting moieties and distinct charge features.
Stated Advantages
Reduces off-target localization to liver (Kupffer cells), kidney (mesangial cells), and spleen while maintaining or increasing uptake in target inflammatory tissues such as tumors (TAMs), dendritic cells, and MDSCs.
Documented Applications
Targeting CD206-expressing cells and other C-type lectin receptor-associated uptake in inflammatory tissues, including tumors (TAMs), dendritic cells, and MDSCs, while blocking off-target localization to liver, kidney, and spleen.
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