Navidea Biopharmaceuticals, Inc.

Jeffrey Scott Arnold

David A Ralph

Provided are methods of attaching a mannose-binding C-type lectin receptor targeting moiety to a polymeric carbohydrate backbone using an amide linkage. The amide linkage may be found between a leash, such as an amine terminated leash, and the mannose-binding C-type lectin receptor targeting moieties. The compounds and compositions disclosed utilizing the amide linkage provide for highly stable compounds with a significant reduction in loss of mannose-binding C-type lectin receptor targeting moieties from the polymeric carbohydrate backbone.

Amide linkages of sugar moieties to amine terminated leashes attached to carbohydrate polymers

Provided are novel compounds containing a polymeric carbohydrate backbone, one or more mannose-binding C-type lectin receptor targeting moieties, and a nitrogenous bisphosphonate compound coupled to the backbone via a thiol-maleimide conjugation, in addition to pharmaceutical compositions, methods of synthesizing, and methods of use. The thiol-maleimide conjugation of a bisphosphonate to a polymeric carbohydrate backbone provides for methods of using the compounds and compositions thereof for releasing the therapeutic payload when internalized into a mannose-binding C-type lectin receptor-expressing cell, such as tumor associated macrophages (TAMs) for the treatment of various diseases, including, cancer, autoimmune diseases, and inflammatory disorders.

CD206 targeted drug delivery vehicles carrying novel bisphosphonate drug payloads via a degradable linker

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.

Altering net charge on mannosylated dextrans to maximize target tissue uptake and off target competitive blocking

Disclosed herein is method for conjugating a metal chelating agent to a functionalized dextran by reacting a chelator with an aminated dextran backbone, where the chelator comprises a one, and only one, derivatized carboxylic acid group to form a chelator-dextran complex. In certain aspects, the dextran-chelator complex is substantially free of intra- or intermolecular crosslinking. In certain aspects, the functionalized dextran is an amine dextran, an alkynyl dextran, or a thiol dextran. In exemplary implementations, the functionalized dextran is an amine dextran. In further embodiments, one and only one carboxylic acid group on the chelating agent is derivatized as a N-hydroxysuccinimide (NHS) ester.

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Andover, MA, United States of America

Jeffrey Scott Arnold