CD206 targeted drug delivery vehicles carrying novel bisphosphonate drug payloads via a degradable linker
Inventors
Ralph, David A. • Arnold, Jeffrey Scott
Assignees
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Publication Number
US-12006339-B2
Publication Date
2024-06-11
Expiration Date
Abstract
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.
Core Innovation
The invention relates to compounds that target mannose-binding C-type lectin receptor expression using one or more mannose-binding C-type lectin receptor targeting moieties coupled to a polymeric carbohydrate backbone. The compounds also include a nitrogenous bisphosphonate compound coupled to the polymeric carbohydrate backbone via a thiol-maleimide conjugation, producing a targeted macromolecular construct.
The disclosed structures define polymeric carbohydrate backbone-supported subunits according to Formula (I), including a maleimide moiety and a bisphosphonate-associated portion modified with a hydrazone moiety. The disclosure includes subunits where hydrazone-modified bisphosphonate can be present or absent, and where linker/leash components are amine terminated.
A key functional concept in the disclosure is pH-sensitive behavior enabled by hydrazone linkers in acidic conditions, including release after receptor-mediated internalization. The compounds are described as enabling delivery to tumor associated macrophages and repolarizing TAMs from an immunosuppressive (M2-like) phenotype to a proinflammatory (M1-like) phenotype.
The disclosed approach is contrasted with prior TAM-targeted liposomal bisphosphonate constructs, and is described as providing smaller MAD-like constructs for tumor penetration and TAM localization while addressing off-target/bone localization challenges. The disclosure further includes pharmaceutical compositions and combination therapy options, together with disease treatment contexts including cancer and related inflammatory/autoimmune disorders.
Claims Coverage
The provided claim set contains three independent claims. Across these independent claims, the core coverage centers on the targeted carbohydrate–bisphosphonate thiol-maleimide conjugate, repolarization of TAMs from M2-like to M1-like phenotype by administering the conjugate, and structural constraints of a Formula (I)-defined subunit and thiol-maleimide conjugation between A and Z.
Mannose-binding C-type lectin receptor-targeted carbohydrate–bisphosphonate via thiol-maleimide conjugation
A compound comprising a polymeric carbohydrate backbone, one or more mannose-binding C-type lectin receptor targeting moieties; and a nitrogenous bisphosphonate compound coupled to the polymeric carbohydrate backbone via a thiol-maleimide conjugation.
Repolarizing TAMs from M2-like to M1-like phenotype
A method of repolarizing a tumor associated macrophage (TAM) from an immunosuppressive (M2-like) phenotype to a proinflammatory (M1-like) phenotype, comprising administering to a subject in need thereof an effective dose of a compound comprising a polymeric carbohydrate backbone, one or more mannose-binding C-type lectin receptor targeting moieties, and a nitrogenous bisphosphonate compound coupled to the polymeric carbohydrate backbone via a thiol-maleimide conjugation.
Formula (I) subunit-defined conjugate with thiol-maleimide coupling between A and Z
A method wherein the compound comprises a subunit as shown in Formula (I) with each X bound to an OH group; L1 and L2 independently amine terminated leashes; A comprising a substituted or unsubstituted maleimide moiety; Z independently comprising a bisphosphonate compound modified with a hydrazone moiety or is absent; and R independently comprising the mannose-binding C-type lectin receptor targeting moiety or H (with n greater than zero), wherein at least one A is the substituted maleimide moiety and the thiol-maleimide conjugation is between A and Z.
Taken together, the independent claims cover a mannose-binding C-type lectin receptor-targeted polymeric carbohydrate conjugate bearing a nitrogenous bisphosphonate linked through thiol-maleimide chemistry, and a TAM repolarization method using that conjugate. They additionally specify that the compound can include Formula (I) subunits with defined maleimide (A), hydrazone-modified bisphosphonate (Z) or absence of Z, and thiol-maleimide conjugation occurring between A and Z.
Stated Advantages
Improved tumor penetration and TAM localization versus prior TAM-targeted liposomal bisphosphonate constructs.
Reduction of off-target/bone localization challenges relative to prior approaches.
Provides neutral pH stability.
Enables acidified endosome pH-triggered, hydrazone-driven payload release.
Modulates macrophage phenotype, including reduced CD206/CD163/SIRPα and increased CD80/CD86/PD-1.
Repolarizes tumor associated macrophages (TAM) from an immunosuppressive (M2-like) phenotype to a proinflammatory (M1-like) phenotype.
Documented Applications
Treating cancer, autoimmune disease, or an inflammatory disorder by administering an effective amount of the compound to a subject in need thereof.
Repolarizing tumor associated macrophages (TAMs) from an immunosuppressive (M2-like) phenotype to a proinflammatory (M1-like) phenotype by administering an effective dose of the targeted carbohydrate–bisphosphonate conjugate.
Combination therapy uses with at least one other treatment selected from chemotherapy, radiation therapy, or immunotherapy.
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