Methods and compositions for treating conditions associated with an abnormal inflammatory response
Inventors
Glick, Gary D. • Franchi, Luigi
Assignees
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Publication Number
US-10912746-B2
Publication Date
2021-02-09
Expiration Date
Abstract
This disclosure features chemical entities (e.g., a compound exhibiting activity as a mitochondrial uncoupling agent or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof, e.g., a compound, such as niclosamide or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof, e.g., a compound, such as a niclosamide analog, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof) that are useful, e.g., for treating one or more symptoms of a pathology characterized by an abnormal inflammatory response (e.g., inflammatory bowel diseases) in a subject (e.g., a human). This disclosure also features compositions as well as other methods of using and making the same.
Core Innovation
The invention provides niclosamide and niclosamide analogs as mitochondrial uncoupling agents or chemical entities, including niclosamide-related chemical definitions, salt and hydrate forms, and cocrystals. The disclosed scope includes niclosamide structure and properties, ethanolamine salt, piperazine salt, niclosamide monohydrate, and potential cocrystal coformers formed via non-covalent interactions, including hydrogen-bond interactions.
The disclosure provides a treatment method for iatrogenic autoimmune colitis in a subject in need thereof, where the iatrogenic autoimmune colitis is induced by an immune checkpoint inhibitor targeting CTLA-4. The method comprises administering an effective amount of niclosamide, linking the niclosamide-analogue chemical scope to therapeutic use in CTLA-4-targeted immune checkpoint inhibitor-induced colitis.
The provided claim set further refines the method by specifying immune checkpoint inhibitor variants, including antibodies and particularly CTLA-4-targeting antibodies, and by defining administration formats such as oral and multiple rectal delivery formats. Additional refinement includes a compartment differential concept comparing niclosamide levels in the GI tract with levels of a mitochondrial uncoupling agent in a plasma compartment.
Claims Coverage
The independent claim covers treating iatrogenic autoimmune colitis induced by a CTLA-4-targeting immune checkpoint inhibitor by administering an effective amount of niclosamide. The dependent claims refine this concept by specifying the immune checkpoint inhibitor as an antibody, including ipilimumab or tremelimumab, by specifying oral and rectal administration formats, and by adding a GI-versus-plasma compartment concentration constraint involving a mitochondrial uncoupling agent.
Treating CTLA-4-targeting checkpoint inhibitor-induced iatrogenic autoimmune colitis with niclosamide
A method for treating iatrogenic autoimmune colitis in a subject in need thereof, comprising administering an effective amount of niclosamide wherein the iatrogenic autoimmune colitis is induced by an immune checkpoint inhibitor that targets CTLA-4.
Using an antibody as the CTLA-4-targeting immune checkpoint inhibitor
The method wherein the immune checkpoint inhibitor is an antibody.
Using ipilimumab or tremelimumab as the antibody immune checkpoint inhibitor
The method wherein the antibody is ipilimumab or tremelimumab.
Oral administration of niclosamide
The method includes administering niclosamide by oral administration.
Rectal delivery formats for niclosamide
Niclosamide is administered via an enema, rectal gel, rectal foam, rectal aerosol, or suppository.
GI-tract niclosamide concentration higher than plasma mitochondrial uncoupling agent
After administration, the concentration of niclosamide in the GI tract is higher than the concentration of a mitochondrial uncoupling agent in the plasma compartment.
Across the claim set, the core coverage is a CTLA-4 immune checkpoint inhibitor-induced iatrogenic autoimmune colitis treatment using an effective amount of niclosamide, with refinements specifying the CTLA-4 inhibitor as an antibody, including ipilimumab or tremelimumab, specifying oral or rectal administration formats, and requiring a GI-versus-plasma compartment concentration relationship involving a mitochondrial uncoupling agent.
Stated Advantages
Improved local efficacy by using local administration approaches intended to reduce systemic exposure and/or toxicity.
Rectal administration is described as showing better efficacy than intraperitoneal administration in a TNBS colitis setting.
Selectively killing pathogenic or activated T cells via mitochondrial uncoupling that disrupts mitochondrial membrane potential and induces T-cell death.
Documented Applications
Treating iatrogenic autoimmune colitis in a subject induced by a CTLA-4-targeting immune checkpoint inhibitor, using an effective amount of niclosamide.
Treatment of inflammatory bowel disease contexts described as including ulcerative colitis and Crohn’s disease, including iatrogenic colitis.
Use of a TNBS colitis model to compare local versus systemic delivery effects, with rectal administration described as better than intraperitoneal administration.
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