Compositions and methods for altering macrophage phenotype
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Publication Number
US-11590236-B2
Publication Date
2023-02-28
Expiration Date
Abstract
Disclosed are methods and compositions for repolarizing a tumor associated macrophage (TAM) from M2 to M1 comprising administering to a subject in need thereof an effective dose of a compound comprising a dextran backbone and one or more CD206 targeting moieties conjugated thereto. In certain aspects, the compound further comprises a therapeutic agent selected from: paclitaxel, gemcitabine, lapatinib, and doxorubicin. In further aspect, the therapeutic agent comprises a chelator and at least one metal ion. In certain implementations, the at least one metal ion comprises at least one Cu(II) ions.
Core Innovation
The disclosed invention relates to repolarizing a tumor associated macrophage (TAM) from an immunosuppressive (M2-like) phenotype to a proinflammatory (M1-like) phenotype by administering an effective dose of a compound of Formula (I). The compound includes a therapeutic agent tethered to an amino-terminated leash and a targeting substituent R, with at least one therapeutic agent and at least one R being mannose. The targeting substituent R is mannose, fucose, n-acetylglucosamine, or H.
In Formula (I), each X is independently H, L1-A, or L2-R, and each L1 and L2 is independently an amino-terminated leash. The amino-terminated leash has the formula —(CH2)pS(CH2)q—NH—, and may include an optional attachment with amide, amidine, and/or hydrazone group. The therapeutic agent A is H or a therapeutic agent bound to the amine-terminated leash, and the therapeutic agent is selected from paclitaxel, gemcitabine, lapitinib, doxorubicin, and a bisphophonate.
The document describes functional outcomes consistent with M2-to-M1 repolarization, including CD206 downregulation and CD80/CD86 upregulation after exposure to Cu(II)-tilmanocept, and increased M1-associated markers/cytokines with reduced macrophage toxicity compared with free doxorubicin for MT1001.8. The described compositions are linked to reduced toxicity versus an equivalent non-conjugated drug and improved anti-CTLA4 efficacy in the 4T1 mouse model. The document further indicates broad utility suggested for cancer and infectious diseases including dengue fever, tuberculosis, leishmaniasis, and HIV/AIDs.
Claims Coverage
The claims coverage centers on one independent claim defining a method of repolarizing TAMs using a Formula (I) compound with a therapeutic agent tethered to an amino-terminated leash and a targeting substituent that includes at least one mannose. Dependent claims refine the therapeutic agent choice and add comparative toxicity and efficacy constraints, including combination use with additional therapies.
Formula (I) TAM repolarizing method via amino-terminated leash and targeting substituent
A method for repolarizing a tumor associated macrophage (TAM) from an immunosuppressive (M2-like) phenotype to a proinflammatory (M1-like) phenotype by administering an effective dose of a compound of Formula (I), wherein each X is independently H, L1-A, or L2-R; each L1 and L2 is independently an amino-terminated leash with optional attachment with amide, amidine, and/or hydrazone group; A is H or a therapeutic agent bound to the amine-terminated leash selected from paclitaxel, gemcitabine, lapitinib, doxorubicin, and a bisphophonate; R is mannose, fucose, n-acetylglucosamine, or H; and wherein at least one A is the therapeutic agent and at least one R is mannose.
Therapeutic agent subset selection within Formula (I)
In the method, the therapeutic agent is selected from paclitaxel, gemcitabine, lapatinib, or doxorubicin.
Reduced toxicity compared with non-conjugated therapeutic agent at equivalent dose
Administering a compound to a subject lowers toxicity compared with the same effective dose of a therapeutic agent that is not conjugated to the compound.
Bisphosphonate selection as zoledronic acid
The therapeutic agent is a bisphosphonate selected as zoledronic acid.
Combination with anti-CTLA4 immunotherapy
The method further includes at least one other treatment or therapy, where the additional treatment or therapy is anti-CTLA4 immunotherapy.
Synergistic or greater efficacy versus administration alone
Combining administration of a compound with at least one treatment/therapy yields greater efficacy and is synergistically effective compared with administering the compound or the treatment/therapy alone.
Overall, the independent claim is directed to a TAM repolarization method using Formula (I) compounds that combine a therapeutic agent tethered to an amino-terminated leash and a mannose-containing targeting substituent R. Dependent claims further narrow therapeutic agent options, add comparative reduced toxicity versus non-conjugated drug, specify zoledronic acid for the bisphosphonate option, and require synergy and enhanced efficacy in combination with anti-CTLA4 immunotherapy.
Stated Advantages
Reduced toxicity compared with the same effective dose of a therapeutic agent not conjugated to the compound.
Greater efficacy and synergistically effective outcomes when combined with at least one other treatment/therapy compared with administration of the compound or the treatment/therapy alone.
Improved anti-CTLA4 efficacy in a 4T1 mouse model.
Documented Applications
Repurpose TAMs in cancer, including improved anti-CTLA4 efficacy in a 4T1 mouse model.
Infectious disease utility is suggested for dengue fever, tuberculosis, leishmaniasis, and HIV/AIDs.
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