Compounds and compositions for treating leishmaniasis and methods of diagnosis and treating using same
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Publication Number
US-11369680-B2
Publication Date
2022-06-28
Expiration Date
Abstract
Compositions and methods of using these compositions that can include a targeting moiety and a therapeutic agent are described herein. These compositions can be used for treating inflammatory diseases, such as parasitic diseases that result in cutaneous lesions. For example, and without limitation, such an parasitic disease can be leishmaniasis.
Core Innovation
The invention relates to dextran/carbohydrate carrier constructs for treatment of leishmaniasis. The constructs comprise a dextran backbone having one or more CD206 targeting moieties and one or more therapeutic agents attached thereto, and the compound is effective for treatment of leishmaniasis disease. CD206 is associated with macrophages, including M2-type dermal macrophages in inflammatory environments.
In the disclosed constructs, CD206 targeting moieties include mannose, fucose, and N-acetylglucosamine. Linkers connect the therapeutic agents or detection label concepts to the dextran backbone, and at least one of the linkers comprises a biodegradable linker. The compound is defined as a compound of Formula (II) with defined linker substituents and attachment points, using variables including X, L1, L2, A, R, and an integer n greater than zero.
Therapeutic agents include therapeutic agents and detection label concepts, where A independently comprises a therapeutic agent or a detection label or H. The disclosed therapeutic agent classes include metal chelators and antileishmanial or other agents, including amphotericin, isoniazid, paromomycin, miltefosine, fluconazole, pentamidine, and Meglumine antimoniate, and additional examples include doxorubicin and dexamethasone. Detection concepts are tied to imaging via chelation, including DTPA chelation for imaging isotopes as described.
Reported findings include receptor-mediated binding and co-localization of labeled tilmanocept with macrophages/CD206 and internalization in infected cells, with in vivo uptake of labeled tilmanocept in dermal macrophages described as "unexpectedly superior." These observations support use of the CD206-targeted dextran constructs for leishmaniasis treatment and diagnosis in the described inflammatory context.
Claims Coverage
The independent claims are directed to methods of treating leishmaniasis by administering an effective amount of a dextran-backbone compound defined by Formula (II) and including CD206 targeting moieties (R) and attached therapeutic agents (A) or optionally detection labels, with constraints on linkers including at least one biodegradable linker. Across the independent claims, the inventive features include the Formula (II) construct, CD206 targeting moieties, attachment of therapeutic agents/detection labels, and the presence of at least one biodegradable linker, with claim 11 further specifying mannose and specific therapeutic agents.
Formula (II) dextran backbone construct with CD206 targeting moieties and attached agents
A method of treating leishmaniasis comprising administering an effective amount of a compound comprising a dextran backbone having one or more CD206 targeting moieties and one or more therapeutic agents attached thereto, wherein the compound is a compound of Formula (II) with variables defining linkers (L1, L2), therapeutic/detection attachment group (A), CD206 targeting moiety (R), and integer n greater than zero.
Biodegradable linker inclusion in the construct
Each L1 and L2 are independently linkers, and at least one L1 and at least one L2 comprises a biodegradable linker.
CD206 targeting moiety selection including mannose, fucose, or N-acetylglucosamine
At least one R is a CD206 targeting moiety selected from the group consisting of mannose, fucose, and N-acetylglucosamine.
Therapeutic agent or detection label attachment via A
Each A independently comprises a therapeutic agent or a detection label or H, and at least one A is a therapeutic agent.
Mandatory combination of biodegradable linker positions and therapeutic-attachment positions
The compound comprises at least one L1-A and at least one L2-R.
Specified targeting and specified therapeutic agents
The CD206 targeting moiety is mannose, and the therapeutic agent comprises doxorubicin or dexamethasone, within the Formula (II) construct having at least one biodegradable linker.
Together, the independent claims cover administering Formula (II) dextran constructs bearing CD206 targeting moieties (R) and attached therapeutic agents (A) (and optionally detection labels), requiring biodegradable linker(s) among L1 and L2 and requiring at least one L1-A and at least one L2-R. Claim 11 narrows this to mannose targeting with doxorubicin or dexamethasone as the therapeutic agent.
Stated Advantages
The labeled tilmanocept shows "unexpectedly superior" uptake in dermal macrophages, as described.
Documented Applications
Treatment of leishmaniasis by administering CD206-targeted dextran constructs effective for leishmaniasis disease.
Diagnosis/imaging related to detection label concepts, including DTPA chelation for imaging isotopes, as described.
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