WO2020023389A1 - Compositions à exposition réduite de modulation de cibles thérapeutiques - Google Patents

Compositions à exposition réduite de modulation de cibles thérapeutiques Download PDF

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WO2020023389A1
WO2020023389A1 PCT/US2019/042825 US2019042825W WO2020023389A1 WO 2020023389 A1 WO2020023389 A1 WO 2020023389A1 US 2019042825 W US2019042825 W US 2019042825W WO 2020023389 A1 WO2020023389 A1 WO 2020023389A1
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target site
conjugate
polymer
condition
active entity
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PCT/US2019/042825
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English (en)
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Silvio Traversa
Valentina Mainero
Raffaella Bagnod
Todd James Harris
Luisa Bertarione RAVA ROSSA
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Sienna Biopharmaceuticals, Inc.
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Publication of WO2020023389A1 publication Critical patent/WO2020023389A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • polymer conjugates comprising active agents linked to polymers, and therapeutic uses thereof. More particularly, polymer conjugates for treating target sites within the skin, eye, and gastrointestinal system which exhibit reduced exposure to non-target sites and inhibit mediators, such as kinase mediators, of various dermatological, ophthalmic, and/or gastrointestinal conditions are described. Other conjugates for treating the eye, dermatological target sites and target sites within the gastrointestinal system are also described.
  • Inhibitors of kinase mediators of various ophthalmic, dermatological, and gastrointestinal conditions have been described for possible therapeutic use in the prevention, alleviation and treatment of kinase-associated ophthalmic, dermatological, gastrointestinal pathologies.
  • such compounds are associated with broad kinase specificity, as well as undesirable and toxic effects, in particular at non-target sites. Accordingly, strategies to render these active kinase inhibitors or other drugs more specific, less toxic, and more targeted to sites within the eye, skin, and gastrointestinal system are needed.
  • Effective delivery of pharmacologically active agents may be hindered by unwanted exposure of those agents to non-desired locations (such as the systemic circulation and/or lymphatic system).
  • injectable and topical agents useful in treating various skin, eye, and gastrointestinal disorders may result in toxic side effects because of systemic exposure.
  • One issue with delivering compositions comprising one or more active agents topically (or non-topically) is the concern that such agents should be delivered in an amount and at a location sufficient to have a therapeutic effect.
  • exposure e.g., absorption or longevity of the composition in the systemic circulation, lymphatic system, or other non-targeted sites
  • the compositions described herein are both therapeutically efficacious and minimize non-target (e.g., systemic or bloodstream) exposure.
  • the active agents are PEGylated or otherwise coupled to large molecules, and surprisingly, are effective in crossing biological membranes such that the active agents are effectively delivered to the target location.
  • inflammatory bowel diseases, inflammatory skin diseases, and ophthalmic conditions are disclosed in several embodiments, other embodiments are used to treat dermal and eye inflammation, as well as other several conditions (e.g., those conditions that would benefit from treatment with reduced exposure at non-target sites). Ophthalmic treatments are provided in some embodiments.
  • the compositions and technology described herein are used in the gastrointestinal systems. Inflammatory and non-inflammatory conditions are contemplated herein.
  • compositions for treating joints are provided. Treatment of the nose and ear are provided in other embodiments.
  • Reduced exposure compounds and compositions are provided in several embodiments.
  • “Reduced exposure” compounds are those compounds that, when delivered to a target location, are formulated to act at the target location with reduced exposure (e.g., entry and/or longevity) in non-target sites. Exposure is reduced as compared to active agents not formulated according to the embodiments described herein. As a non-limiting example, a PEGylated topical dermal, ophthalmic or gastrointestinal active agent has reduced exposure to the bloodstream as compared to the active agent alone.
  • Reduced exposure compounds include topical compounds that can be delivered to body surfaces and cavities, such as the skin, eyes, ears, nose, mouth, vagina, rectum, etc.
  • Non-desired target sites include, for example, the systemic system, the lymphatic system, non-target tissue, etc.
  • Reduced exposure compositions comprise or consist essentially of one or more “reduced exposure compounds.”
  • a reduced exposure composition is delivered orally, e.g., for treatment of the gastrointestinal system, eye, or skin.
  • the active agent remains in the eye, the skin, or the lining of the gastrointestinal tract and is able to achieve pharmacological specificity.
  • a reduced exposure composition is delivered topically, e.g., for treatment of the skin.
  • the active agent remains in the targeted layer of the skin and is able to achieve pharmacological specificity. Because the active agent is conjugated with PEG or another molecule as described herein, the active agent is absorbed more slowly into the non-target site (e.g., the systemic circulation and/or lymphatic system).
  • the active agent is absorbed into the non-target site (e.g., systemic circulation and/or lymphatic system). Further, once the composition enters the systemic circulation and/or lymphatic system, clearance (e.g., by the kidney) occurs at a much faster rate.
  • compositions formulated according to the methods described herein for treating the lungs (e.g., via inhalants), joints (e.g., via injectables), eye (e.g., via eye drops), nasal passageways, and the ear (such as the ear canal and other structures).
  • Vaginal and rectal tissues are treated in some embodiments via, for example suppositories.
  • reduced exposure compostions suitable for topical application to the eye e.g., ointment or eye drop.
  • the reduced exposure compsotions disclosed herein are administered by intraocular and periocular injection such as, for example, direct intravitreal injection, subconjunctival injection, subtenon injection, and peribulbar injection.
  • reduced exposure compostions which can be administered via intraocular implantable devices known to one of skill in the art.
  • reduced exposure at the tear ducts reduces the amount of active agent that is removed (e.g., drained) from the eye, and accordingly allows a higher concernation of active agent to remain at the target site in the eye.
  • a polymer conjugate comprising a warhead (e.g., at least one active agent) linked to a polymer, wherein the warhead comprises an inhibitor, antagonist, or inverse agonist of, for example, c-Src.
  • at least one inhibitor, antagonist, or inverse agonist of c-Src comprises or consists of a composition that includes any one of compounds 1-71 (and derivatives thereof) disclosed herein in Table 1 coupled to a polymer.
  • the warhead of the polymer conjugate is compound 1 of Table 1.
  • the polymer conjugate is CT101 , wherein CT101 has the following formula:
  • a polymer conjugate comprising a warhead (e.g., at least one active agent) linked to a polymer, wherein the warhead comprises an inhibitor, antagonist, or inverse agonist of, for example, a mediator of a gastrointestinal, dermatological, and/or ophthalmic condition.
  • at least one inhibitor, antagonist, or inverse agonist of a mediator of a gastrointestinal, dermatological and/or ophthalmic condition comprises or consists of a composition that includes any one of compounds 1-264 (and derivatives thereof) disclosed herein in Table 3 coupled to a polymer.
  • the warhead of the polymer conjugate is compound 1 in Table 3.
  • the LSE polymer conjugate is CT352, wherein CT352 has the following formula below:
  • a polymer conjugate comprising a warhead (e.g., at least one active agent) linked to a polymer, wherein the warhead comprises an inhibitor, antagonist, or inverse agonist of, for example, a vascular endothelial growth factor receptor (VEGFR).
  • the warhead comprises or consists of a composition that includes any one of compounds 1-59 (and derivatives thereof) disclosed herein in Table 2 coupled to a polymer.
  • the warhead of the polymer conjugate is compound 1 of Table 2.
  • the polymer conjugate is CT103, wherein the composition has the formula:
  • a non-target site such as the systemic circulation and/or lymphatic system
  • exposure at a non-target site is less than 90%, 75%, 50%, 25%, 15%, 10%, 5% or 2% (or less) of the polymer conjugate as compared to a similar active entity that has not been produced according to the embodiments described herein.
  • desirable rate of clearance from the non-target site (e.g., systemic circulation and/or lymphatic system) for the compositions described herein is increased by at least 10%, 25%, 50%, or 75% or more as compared to non-conjugated controls.
  • a PEGylated active agent described herein not only penetrates the desired membranes to reach a desired target, but has reduced non-target exposure by at least 20-80% or more as compared to the non-PEGylated active agent.
  • blood concentrations measured post administration of the compositions described herein are less than about 0.1 ng/ml, less than 1 ng/ml, or less than 10 ng/ml after, e.g., 15 minutes, 30 minutes, 1 hour, 6 hours or 12 hours.
  • reduced exposure at non-target sites contributes to enhanced efficacy.
  • Efficacy may be enhanced because lower concentrations/amounts/dosing schedules are required to achieve the same or similar therapeutic efficacy at the target site (because, for example, the active ingredient stays at the desired target site for a longer time).
  • concentrations/amounts/dosing schedules are reduced by 25%-75% or more.
  • More rapid clearance rates of the active agent once in the non-target site(s) are also beneficial because this may allow for a higher concentration or more doses to be delivered. This is especially beneficial for active agents in which a subject would benefit from a higher dose but cannot tolerate the higher dose due to toxicity at the non-target site (e.g., systemic toxicity). Faster clearance rates would permit the desired higher dose to be delivered according to the desired schedule. For example, a subject may be able to tolerate daily doses rather than weekly doses because of the reduced exposure.
  • the active agents of the compositions described herein are measured in non-target sites (e.g., the systemic circulation and/or lymphatic system) at less than amounts found when the active agent is delivered without conjugation (e.g., less than 0.5%, 1 % or 2% after 6 or 12 hours, as compared with 3-15% (e.g., 3-6%) when the active agent is delivered without conjugation).
  • non-target sites e.g., the systemic circulation and/or lymphatic system
  • the active agents of the compositions described herein are measured in non-target sites (e.g., the systemic circulation and/or lymphatic system) at less than 0.5%, 1 % or 2% after 3-24 hours, as compared to an amount 2-20 times greater when the active agent is delivered without conjugation.
  • non-target sites e.g., the systemic circulation and/or lymphatic system
  • clearance of the compositions occurs within minutes of exposure to the non-target site (e.g., systemic circulation and/or lymphatic system), as opposed to hours.
  • 50% clearance of the conjugated polymer compounds occurs in less than 5 minutes, 15 minutes, 30 minutes, 1 hour, 6 hours, and 12 hours of exposure to the systemic circulation and/or lymphatic system. Clearance times of the conjugated polymer compounds are reduced by more than 25%, 50%, 75% and 90%, as compared to the non-conjugated active agents or other formulations. These reduced clearance times are beneficial to reduce toxicity and undesired side effects.
  • an active agent may be increasingly toxic as it is metabolized in the non-target site (e.g., systemic circulation and/or lymphatic system) because the metabolites exhibit more toxicity than the original agent.
  • the term“active entity” as used herein should not be understood as limiting the participation of the polymer itself and/or the chemical linking moiety between the polymer and the warhead in defining the pharmacology of the polymer conjugate.
  • the polymer influences the selectivity and/or inhibitory activity of the polymer conjugate.
  • the chemical linking moiety between the polymer and warhead influences the selectivity and/or inhibitory activity of the polymer conjugate.
  • the polymer conjugates exhibit no change in selectivity or inhibitory activity against the therapeutic target in comparison with the unconjugated active agent. In some embodiments, the polymer conjugates exhibit a significant increase in selectivity against the therapeutic target in comparison with the unconjugated active agent. In some embodiments, the polymer conjugates exhibit a significant increase in inhibitory activity against the therapeutic target in comparison with the unconjugated active agent. In some embodiments, the polymer conjugates exhibit a significant increase in selectivity and inhibitory activity against the therapeutic target in comparison with the unconjugated active agent. In some embodiments, the increased selectivity and/or inhibitory activity of the polymer conjugate against the therapeutic target in comparison with the unconjugated active agent causes decrease in undesired biological effects.
  • the increased selectivity of the polymer conjugate is caused by an increase of the hydrodynamic volume resulting from the conjugated polymer chain.
  • the polymer chain creates a higher steric hindrance which allows discrimination among the diverse shapes and sizes of the binding sites of different proteins, thus improving selectivity with respect to the active agent alone.
  • age-related macular degeneration is treated.
  • diabetic retinopathy is treated.
  • corneal edema is treated.
  • macular edema is treated.
  • dry eye is treated.
  • various inflammatory skin diseases are treated.
  • the inflammatory skin disease comprises, in some embodiments, psoriasis, psoriasis guttata, inverse psoriasis, pustular psoriasis, psoriatic erythroderma, acute febrile neutrophilic dermatosis, eczema, xerotic eczema, dyshidrotic eczema, vesicular palmar eczema, acne vulgaris, atopic dermatitis, contact dermatitis, allergic contact dermatitis, dermatomyositis, exfoliative dermatitis, hand eczema, pompholyx, keloids, rosacea, rosacea due to sarcoidosis, rosacea due to scleroderma, rosacea due to Sweet syndrome, rosacea due to systemic lupus erythematosus, rosacea due to ur
  • various skin neoplasias are treated.
  • the skin neoplasia comprises, in some embodiments, squamous cell carcinoma, basal cell carcinoma, malignant melanoma, malignant cutaneous lymphoma, Kaposi's sarcoma, Merkel cell skin cancer, and non-melanoma skin cancer.
  • various vascular tumors are treated.
  • the vascular tumor comprises, in some embodiments, hemangiomas, Kaposi's sarcoma, lymphangioma, glomangioma, angiosarcoma, hemangioendothelioma, and infantile hemangiomas.
  • the bullous disease comprises, in some embodiments, bullous pemphigoid, erythema multiforme, dermatitis herpetiformis, epidermolysis bullosa acquisita, linear Immunoglobulin A disease, mucous membrane pemphigoid, pemphigoid gestationis, pemphigus foliaceus, and pemphigus vulgaris.
  • the conjugates provided herein are useful in treating a dermal condition in a subject in need thereof.
  • the dermal condition is pruritus, skin neoplasia, vascular tumor, inflammatory dermatosis, scarring, a bullous disease, UV irradiation therapy, alopecia areata, or vitiligo.
  • the pruritus is pruritus due to psoriasis, pruritus due to atopic dermatitis, or prurigo nodularis.
  • the skin neoplasia is squamous cell carcinoma, basal cell carcinoma, malignant melanoma, or malignant cutaneous lymphomas.
  • the vascular tumor is angiosarcoma, Kaposi’s sarcoma, infantile hemangioma, or hemangioendothelioma.
  • the inflammatory dermatosis is dermatitis, psoriasis, keloid, or rosacea.
  • the dermatitis is atopic dermatitis or irritant contact dermatitis.
  • the bullous disease is bullous pemphigoid or erythema multiforme.
  • the conjugates provided herein are useful in treating a gastrointestinal system condition in a subject in need thereof.
  • the gastrointestinal system condition is ulcerative colitis, Crohn’s disease, intestinal fibrosis, or colorectal cancer.
  • the conjugates provided herein are useful in treating an ocular condition in a subject in need thereof.
  • the ocular condition is age-related macular degeneration, diabetic retinopathy, edema, dry eye, uveitis, pterygia, conjunctivitis, graft versus host disease, glaucoma, or retinopathy of prematurity.
  • the age-related macular degeneration is wet age- related macular degeneration or dry age-related macular degeneration.
  • the edema is macular edema or corneal edema. In some embodiments, the macular edema is diabetic macular edema.
  • dry eye is spontaneous dry eye or aqueous deficiency dry eye.
  • the uveitis is juvenile idiopathic arthritis uveitis or posterior uveitis.
  • the conjunctivitus is vernal keratocunjunctivitis (allergic conjunctivitis).
  • the graft versus host disease is ophthalmic graft versus host disease.
  • the glaucoma is primary open angle glaucoma.
  • the conjugates provided herein are useful in treating a respiratory condition in a subject in need thereof.
  • the respiratory condition is asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, or cough.
  • the cough is chronic cough.
  • the conjugates provided herein are useful in treating rheumatoid arthritis, osteoarthritis, neuropathic pain, or neuropathic itch in a subject in need thereof.
  • the polymer conjugates are administered in combination with UV irradiation therapy.
  • the polymer conjugates configured for reduced exposure are administered to other areas of the body besides the skin.
  • administration comprises treatment of the lung and respiratory conditions via inhalation of the polymer conjugates.
  • Eye drops are provided in some embodiments to treat eye inflammation or ophthalmic disorders and diseases. Treatment to the joints to treat inflammation or other joint conditions is also provided.
  • administration comprises treatment of the gastro-intestinal tract via, for example, an enteric coated capsule comprising the polymer conjugates taken orally.
  • Reduced exposure provides benefits in these applications.
  • Applications for the nose and ear, such as inhalants, ointments and drops are provided in several embodiments. Treatment to the nasal passage to treat allergies or allergic rhinitis is also provided.
  • Vaginal and rectal compounds are provided in some embodiments, including as suppositories, creams, ointments, etc.
  • various inflammatory bowel diseases are treated.
  • the inflammatory bowel disease comprises, in some embodiments, Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behget's syndrome, and indeterminate colitis.
  • polymer conjugates wherein the polymer is polyethylene glycol (PEG) or methoxy-polyethylene glycol (m-PEG).
  • PEG polyethylene glycol
  • m-PEG methoxy-polyethylene glycol
  • a pharmaceutical composition comprising or consisting essentially of a polymer conjugate disclosed herein that is formulated for topical and non-topical administration.
  • methods of making and using the compositions described herein are provided.
  • the invention comprises a reduced exposure composition comprising at least one active entity linked to at least one polymer, wherein the composition has reduced exposure at a non-target site as compared to the active entity delivered without the polymer.
  • the non-target site comprises the systemic system, the lymphatic system and/or another non-target tissue site in some embodiments.
  • the active entity comprises an inhibitor, an antagonist, or an inverse agonist.
  • the active entity may be an inhibitor, antagonist, or inverse agonist of a mediator of inflammation.
  • the active entity may be an inhibitor, antagonist, or inverse agonist of a mediator of an inflammatory bowel disease an inflammatory skin disease, and/or inflammatory ophthalmic condition.
  • the active entity may be an inhibitor, antagonist, or inverse agonist of a gastrointestinal, dermatological, and/or ophthalmic condition
  • the active entity may be an inhibitor, antagonist, or inverse agonist of JAK and/or ST AT family proteins.
  • the active entity comprises or consists essentially of any one or more of compounds 1-264 of Table 3 in some embodiments.
  • the active entity comprises compound 1 of Table 3 in some embodiments.
  • the reduced exposure composition comprises CT352 in some embodiments.
  • the active entity comprises an indolocarbazole compound. In some embodiments, the active entity comprises a derivative of K252a. In some embodiments, the composition comprises SNA-125. In some embodiments, the composition comprises SNA-120.
  • the active entity binds to a tropomyosin-receptor-kinase A (TrkA) in some embodiments.
  • the active entity binds to a Janus Kinase (JAK) family member in some embodiments.
  • the active entity binds to one or more of Janus Kinase 1 (JAK1), Janus Kinase 2 (JAK2), Janus Kinase 3 (JAK3), and/or Tyrosine kinase 2 (TYK2) in some embodiments.
  • the active entity binds to mitogen-activated protein kinase kinase (MAP2K) in some embodiments.
  • the active entity binds to mitogen-activated protein kinase kinase 3 (MAP2K3) in some embodiments.
  • the binding may be partially or fully inhibitory or not.
  • the active entity comprises an inhibitor, an antagonist, or an inverse agonist.
  • the active entity may be an inhibitor, antagonist, or inverse agonist of c-Src.
  • inflammatory conditions are treated.
  • non-inflammatory conditions are treated.
  • the active entity comprises or consists essentially of any one or more of compounds 1-71 of Table 1 in some embodiments.
  • the active entity comprises compound 1 of Table 1.
  • the composition comprises CT101.
  • the active entity binds to c-Src in some embodiments.
  • the binding may be partially or fully inhibitory or not.
  • the active entity comprises an inhibitor, an antagonist, or an inverse agonist.
  • the active entity may be an inhibitor, antagonist, or inverse agonist of a VEGFR.
  • the active entity comprises or consists essentially of any one or more of compounds 1-59 in some embodiments.
  • the active entity comprises compound 1 of Table 2.
  • the composition comprises CT103.
  • the active entity binds to a VEGFR in some embodiments.
  • the active entity binds to VEGFR-1 in some embodiments.
  • the active entity binds to VEGFR-2 in some embodiments.
  • the active entity binds to VEGFR-3 in some embodiments.
  • the binding may be partially or fully inhibitory or not.
  • the polymer used in the reduced exposure compounds comprises polyethylene glycol (PEG) and/or methoxy-polyethylene glycol (m-PEG).
  • PEG polyethylene glycol
  • m-PEG methoxy-polyethylene glycol
  • the active entity has one or more carboxyl, hydroxyl, amino and/or sulfhydryl groups
  • the active entity is PEGylated (or conjugated/coupled to another polymer) at one or more of said carboxyl, hydroxyl, amino and/or sulfhydryl groups.
  • the reduced exposure compositions described herein are formulated for topical administration, such as eye drops, gels, ointments, liquids, etc. in several embodiments.
  • Inhalants, injectables, nasal sprays, oral administration etc. are provided in some embodiments.
  • the reduced exposure compositions described herein are formulated for oral administration in several embodiments.
  • Inhalants, injectables, eye drops, nasal sprays, topical administration etc. are provided in some embodiments.
  • methods of treating one or more of the following are provided: non-dermal inflammation, inflammatory bowel disease, inflammatory skin diseases, wounds, scars, autoimmune disorders, and cancerous or pre-cancerous lesions.
  • Kits comprising one or more compounds and devices for administration (syringes, eye droppers, containers, inhalers, etc.) as well as instructions for use, are provided in certain embodiments.
  • compositions may be administered via at least two routes of administration, either simultaneously or sequentially according to some embodiments.
  • the composition is administered via a first (e.g. oral, topical dermal) route to a subject, wherein the subject further receives an additional agent via a second (e.g., injectable, non-dermal) route to achieve synergetic effects.
  • methods for reducing exposure of a composition at at least one non-target site comprise applying a composition comprising at least one active entity linked to at least one polymer, wherein the combination of the active entity and polymer reduces exposure at the non-target site by more than 50% as compared to the active entity without the polymer.
  • the composition may be applied topically, injected, inhaled, or administered orally.
  • the nontarget site includes non-target tissue at which pharmacological activity is not desired and/or not achieved.
  • Non-target sites can include the bloodstream or systemic system.
  • Non-target sites can also include the lymphatic system.
  • methods of treating a respiratory disease in a subject via delivery of the polymer conjugates e.g., wherein the warhead is a small molecule targeting a JAK and/or STAT family protein
  • Delivery routes may include for example intratracheal instillation or inhalation.
  • the formulation may include liquids, nebulized or aerosolized liquids or suspensions, dry powder, nanocomposites, nanoparticles or microparticles, etc.
  • Respiratory disorders include treatable obstructive, restrictive or inflammatory airways diseases of whatever type, etiology, or pathogenesis.
  • Non-limiting examples of respiratory conditions include: acute bronchitis; acute laryngotracheal bronchitis; arachidic bronchitis; catarrhal bronchitis; croupus bronchitis; dry bronchitis; infectious asthmatic bronchitis; productive bronchitis; staphylococcus or streptococcal bronchitis; vesicular bronchitis; cylindric bronchiectasis; sacculated bronchiectasis; fusiform bronchiectasis; capillary bronchiectasis; cystic bronchiectasis; dry bronchiectasis; follicular bronchiectasis; chronic obstructive pulmonary disease (COPD), chronic obstructive lung disease (COLD), chronic obstructive airways disease (COAD) or small airways obstruction of whatever type, etiology, or pathogenesis,
  • pneumoconiosis of whatever type, etiology, or pathogenesis in particular pneumoconiosis that is a member selected from the group consisting of aluminosis or bauxite workers' disease, anthracosis or miners' asthma, asbestosis or steam-fitters' asthma, chalicosis or flint disease, ptilosis caused by inhaling the dust from ostrich feathers, siderosis caused by the inhalation of iron particles, silicosis or grinders' disease, byssinosis or cotton-dust asthma and talc pneumoconiosis; interstitial lung diseases (ILD) or pulmonary fibrosis of whatever type, etiology
  • ILD interstitial lung diseases
  • pulmonary fibrosis of whatever type, etiology
  • Respiratory disorders also include, in some embodiments, malignancies and tumors of the respiratory system, nonlimiting examples of which include lung adenocarcinoma, squamous cell carcinoma, large cell carcinoma, bronchioloalveolar carcinoma (BAC), pulmonary adenocarcinoma (AIS), non-small-cell carcinoma, small cell carcinoma, and mesothelioma.
  • malignancies and tumors of the respiratory system nonlimiting examples of which include lung adenocarcinoma, squamous cell carcinoma, large cell carcinoma, bronchioloalveolar carcinoma (BAC), pulmonary adenocarcinoma (AIS), non-small-cell carcinoma, small cell carcinoma, and mesothelioma.
  • a reduced exposure composition for inhibiting the activity of a therapeutic target at a target site is provided.
  • Methods for treating diseases, conditions, and disorders are also provided.
  • the composition comprises or consists essentially of a conjugate comprising or consists essentially of an active entity coupled (e.g., linked) to at least one polymer.
  • the active entity may have, for example, selectivity and/or an inhibitory activity against the therapeutic target.
  • the conjugate has increased selectivity and/or inhibitory activity compared to the unconjugated active entity.
  • the polymer can include, for example, polyethylene glycol (PEG) and/or methoxy-polyethylene glycol (m-PEG).
  • a pharmaceutically acceptable carrier formulated for delivering the conjugate to the target site is also provided.
  • the conjugate has reduced exposure at a non-target site as compared to the unconjugated active entity.
  • the non-target site includes for example the systemic system, the lymphatic system and/or other non-target tissue sites.
  • the conjugate may have, in some embodiments, reduced systemic exposure and toxicity when delivered to the target site as compared to the unconjugated active entity.
  • the target site includes cells and or tissues localized within one or more of the following: skin, scalp, eye, Gl tract, joint and/or lung.
  • the non-target site comprises any site at which pharmacological activity is not desired and/or not achieved.
  • the conjugate has increased permeability across at least one of a nuclear and plasma membrane compared to the unconjugated active entity.
  • the conjugate can advantageously traverse plasma membranes of cells at the target site, thereby promoting interactions between the active entity and the therapeutic target. This traversal may include the crossing of cellular lipid bilayers to, e.g., distribute the active entity among both lipophilic and hydrophilic cellular compartments.
  • Membranes include the lipid bilayer, plasma membrane and the nuclear membrane as examples.
  • the conjugate interacts with a kinase associated with the plasma membrane, cytoplasm and/or nucleus.
  • the conjugate may exhibit a depot effect across cellular compartments, thereby reducing the dose of the active entity adequate to inhibit the cellular kinase compared to the unconjugated active entity.
  • the conjugate is selected from:
  • n is about 2-2270 (e.g., about 4-1 170, 4-10, 10-20, 20-40, 40-60, 60-80, 80-100, 125-150-150-175, 175-200, 200-300, 300-400, 400-500, 500-600, 600-700,
  • n is about 35-65. In some embodiments, n is about 40- 60. In some embodiments, n is about 41-48. In some embodiments, n is about 42-48. In some embodiments, n is about 40-46. In some embodiments, n is about 44-47. In some embodiments, n is about 44-46. In some embodiments, n is about 44-45. In some embodiments, n is about 45-46. In some embodiments, n is about 42-45. In some embodiments, n is about 42-44. In some embodiments, n is about 42-43. In some embodiments, n is about 43-44. In some embodiments, n is about 45. In some embodiments, n is about 44. In some embodiments, n is about 43.
  • SNA-352 (CT352) is of the formula:
  • n 42—47 (e.g., about 43-45, e.g, about 43, e.g., about 44, e.g., about
  • SNA-101 (CT101) is of the formula:
  • n 42—47 (e.g., about 43-45, e.g, about 43, e.g., about 44, e.g., about
  • SNA-103 (CT 103) is of the formula:
  • n 42—47 (e.g., about 43-45, e.g, about 43, e.g., about 44, e.g., about
  • the therapeutic target may be a mediator of a condition, such as, for example, a respiratory condition, a gastrointestinal condition, an inflammatory condition.
  • the therapeutic target may be, for example, one or more of VEGFR, c-Src, TkrA, MAP2K3, a JAK family kinase and/or a ST AT family protein.
  • the active entity and/or conjugate may have a longer residence time within a cell or other tissue at the target site compared to the active entity without conjugation to the polymer.
  • the residence time of the active entity and/or conjugate within a cell or other tissue at the target site is, as compared to the active entity without conjugation to the polymer, (i) at least 25% (e.g., 25-50%, 50-75%, 75-100%, 100-150%, or higher and overlapping ranges therein) longer and/or (ii) at least 2-20 fold (e.g., 2-10 fold, 2-4 fold, 4-6 fold, 6-8 fold, 8-10 fold, 10-12 fold, 12-14 fold, 14-
  • the residence time is over 100 fold longer.
  • the conjugate increased residence time at the target site results in lower concentrations and/or lower frequency of administration.
  • a smaller dose of the conjugate may be adequate to achieve a therapeutic effect comparable to the active entity without conjugation to the polymer.
  • the dose of the conjugate sufficient to achieve a therapeutic effect comparable to the active entity without conjugation to the polymer is at least 10% (e.g., 10-15%, 15-20%, 20-25%, 25-30%, 30-40%, 40-50%, 50- 60%, 60-70%, 70-80%, 80-90%, 90-100%, 100%-125%, 125-150%, or higher and overlapping ranges therein) lower. In one embodiment, the dose is over 200% lower. In some embodiments, fewer doses and/or smaller doses of the conjugate are sufficient as compared to the active entity delivered without the polymer.
  • the active entity and/or conjugate may have reduced concentration, activity and/or bioavailability within a cell or tissue at a non-target site compared to the active entity without conjugation to the polymer.
  • the active entity and/or conjugate is present at a biologically inactive concentration within a cell or tissue at a non-target site.
  • reduced concentration, activity and/or bioavailability within a cell or tissue at a non-target site e.g., the systemic system, the lymphatic system, bone marrow, the circulatory system
  • the active entity and/or conjugate has reduced systemic absorption and/or little or no systemic toxicity when the composition is administered.
  • the reduced exposure composition is formulated for topical delivery, oral delivery, respiratory delivery or injection into target sites, e.g., eyes and joints.
  • Administration by topical delivery, oral delivery, rectal delivery, inhalation or instillation, and/or injection is provided in several embodiments.
  • Topical delivery to body surfaces, such as, for example skin, eyes, ears, nose, mouth, lungs, vagina and/or rectum, is provided in some embodiments.
  • effective amounts of the active entity are delivered to a subject (e.g., human or veterinary).
  • the composition may further comprise one or more additional ingredients, such as, for example, an antibiotic agent, an anti-angiogenesis agent, a preventive or therapeutic agent for inflammatory bowel disease, an antifungal agent, an antiviral agent, an antiprotozoal agent, an anesthetic agent, a steroidal anti-inflammatory agent, a nonsteroidal anti-inflammatory agent, an antipruritic agent, an additional antioxidant agent, a chemotherapeutic agent, an anti-histamine agent, a vitamin or vitamin complex, and/or a hormone.
  • additional ingredients such as, for example, an antibiotic agent, an anti-angiogenesis agent, a preventive or therapeutic agent for inflammatory bowel disease, an antifungal agent, an antiviral agent, an antiprotozoal agent, an anesthetic agent, a steroidal anti-inflammatory agent, a nonsteroidal anti-inflammatory agent, an antipruritic agent, an additional antioxidant agent, a chemotherapeutic agent, an anti-histamine agent, a vitamin or vitamin complex, and/
  • the method of treatment and/or use of the compositions described herein are provided for the prophylaxis or treatment of one or more of the following gastrointestinal conditions: inflammatory bowel disease, Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behget's syndrome, indeterminate colitis, irritable bowel syndrome and/or small intestinal bacterial overgrowth.
  • the method of treatment and/or use of the compositions described herein are provided for the prophylaxis or treatment of one or more of the following ophthalmic conditions: macular degeneration, age related macular degeneration (ARMD), choroidal neovascularization, retinopathy, diabetic retinopathy, acute macular neuroretinopathy, chronic macular neuroretinopathy, central serous chorioretinopathy, macular edema, cystoid macular edema, diabetic macular edema, acute multifocal placoid pigment epitheliopathy, Behcet's disease, birdshot retinochoroidopathy, uveitis, intermediate uveitis (pars planitis), anterior uveitis, multifocal choroiditis, multiple evanescent white dot syndrome (MEWDS), ocular sarcoidosis, posterior scleritis, serpignous choroiditis, subretinal fibrosis, uveit
  • the method of treatment and/or use of the compositions described herein are provided for the prophylaxis or treatment of one or more of the following dermal conditions: psoriasis, psoriasis guttata, inverse psoriasis, pustular psoriasis, psoriatic erythroderma, acute febrile neutrophilic dermatosis, eczema, xerotic eczema, dyshidrotic eczema, vesicular palmar eczema, acne vulgaris, atopic dermatitis, contact dermatitis, allergic contact dermatitis, dermatomyositis, exfoliative dermatitis, hand eczema, pompholyx, keloids, rosacea, rosacea due to sarcoidosis, rosacea due to scleroderma, rosacea due to Sweet syndrome, rosacea due to systemic lup
  • a reduced exposure composition for treating a target site with the gastrointestinal system is provided.
  • Methods for treating the Gl and/or gastrointestinal conditions are also provided.
  • the composition comprises or consists essentially of a conjugate comprising or consists essentially of an active entity coupled (e.g., linked) to at least one polymer.
  • the active entity may be for example, an inhibitor, antagonist, or inverse agonist of a mediator of a gastrointestinal condition.
  • the polymer can include, for example, polyethylene glycol (PEG) and/or methoxy-polyethylene glycol (m-PEG).
  • a pharmaceutically acceptable carrier formulated for delivering the conjugate to the target site is also provided.
  • the conjugate has reduced exposure at a non-target site as compared to the active entity delivered without the polymer.
  • the non-target site includes for example the systemic system, the lymphatic system and/or other non-target tissue sites.
  • the non-target site comprises any site at which pharmacological activity is not desired and/or not achieved.
  • the conjugate can advantageously traverse plasma membranes of cells at the target site, thereby promoting interactions between the active entity and the mediator of the gastrointestinal condition.
  • This traversal may include the crossing of cellular lipid bilayers to, e.g., distribute the active entity among both lipophilic and hydrophilic cellular compartments.
  • Membranes include the lipid bilayer, plasma membrane and the nuclear membrane as examples.
  • the conjugate interacts with mediator associated with the plasma membrane, cytoplasm and/or nucleus.
  • the conjugate may exhibit a depot effect across cellular compartments, thereby reducing the dose of the active entity required to inhibit the cellular mediator compared to the active entity without conjugation to the polymer.
  • the conjugate penetrates one or more physical barriers of the Gl, one or more physiological barriers of the Gl, and/or one or more biological barriers of the Gl (e.g. the epithelial barrier and/or intestinal mucosa).
  • the conjugate can under transcytosis across the intestinal epithelium.
  • the active entity and/or conjugate may be an inhibitor, antagonist, and/or inverse agonist of a protein mediator of a condition (e.g., a kinase). In some embodiments, the active entity and/or conjugate may be an inhibitor, antagonist, and/or inverse agonist of a mediator of a gastrointestinal condition.
  • a protein mediator of a condition e.g., a kinase
  • the active entity and/or conjugate may be an inhibitor, antagonist, and/or inverse agonist of a mediator of a gastrointestinal condition.
  • the mediator is one or more of c-Src, a VEGFR protein (e.g., VEGFR-1 , VEGFR-2, VEGFR-3), a JAK protein (e.g., of JAK1 , JAK2, JAK3, and Tyrosine kinase 2 (TYK2)), STAT, NF-Kappa B, TrkA, MAPK, MAP2K and/or MAP2K3.
  • the active entity and/or conjugate is an inhibitor, antagonist, and/or inverse agonist of a mediator of inflammation.
  • the mediator of inflammation may be, for example, a mediator of an inflammatory bowel disease.
  • the active entity and/or conjugate reduces inflammation at the target site within the Gl.
  • the reduced inflammation at the target site treats an inflammatory bowel disease (e.g. Crohn's disease, ulcerative colitis).
  • the reduced exposure composition comprises one or more of conjugates SNA-101 , SNA- 103, SNA-352, SNA-120 and/or SNA-125.
  • the active entity and/or conjugate exhibits greater access to the mediator compared to the active entity without conjugation to the polymer.
  • the reduced exposure composition may be formulated for topical, oral, or suppository delivery.
  • Topical, oral, and suppository administration is provided in several embodiments. In several embodiments, the administration is daily.
  • effective amounts of the active entity are delivered to a subject (e.g., human or veterinary).
  • the composition may further comprise one or more additional ingredients, such as, for example, antibiotic agent, an anti-angiogenesis agent, a preventive or therapeutic agent for inflammatory bowel disease, an antifungal agent, an antiviral agent, an antiprotozoal agent, an anesthetic agent, a steroidal antiinflammatory agent, a non-steroidal anti-inflammatory agent, an antipruritic agent, an additional antioxidant agent, a chemotherapeutic agent, an anti-histamine agent, a vitamin or vitamin complex, and/or a hormone.
  • additional ingredients such as, for example, antibiotic agent, an anti-angiogenesis agent, a preventive or therapeutic agent for inflammatory bowel disease, an antifungal agent, an antiviral agent, an antiprotozoal agent, an anesthetic agent, a steroidal antiinflammatory agent, a non-steroidal anti-inflammatory agent, an antipruritic agent, an additional antioxidant agent, a chemotherapeutic agent, an anti-histamine agent, a vitamin or vitamin complex, and/or
  • the active entity and/or conjugate may have an increased concentration, activity and/or bioavailability within a cell or tissue at the target site compared to the active entity without conjugation to the polymer. In some such embodiments, the therapeutically effective amount of the active entity is at the target site.
  • the concentration, activity and/or bioavailability within a cell or other tissue at the target site is, as compared to the active entity without conjugation to the polymer, at least 2-20 fold (e.g., 2-4 fold, 4-6 fold, 6-8 fold, 8-10 fold, 10-12 fold, 14-16 fold, 18-20 fold, 20-30 fold, 30-40 fold, 40-50 fold, 50-100 fold, and overlapping ranges therein) greater than within a cell or tissue at a non-target site (e.g., the systemic system, the lymphatic system, bone marrow, outside the gastrointestinal tract).
  • the concentration, activity and/or bioavailability within a cell or tissue at the target site is over 100 fold greater.
  • the active entity and/or conjugate may have reduced concentration, activity and/or bioavailability within a cell or tissue at a non-target site compared to the active entity without conjugation to the polymer.
  • the active entity and/or conjugate is present at a biologically inactive concentration within a cell or tissue at a non-target site.
  • reduced concentration, activity and/or bioavailability within a cell or tissue at a non-target site advantageously reduces toxicity and/or other side effects, such as, for example, immunosuppression.
  • the active entity and/or conjugate has reduced systemic absorption and/or little or no systemic toxicity when the composition is formulated for oral delivery and is administered orally (e.g., a single administration, administration on a daily basis).
  • the active entity and/or conjugate may have a greater activity and/or bioavailability within a cell or other tissue at the target site (e.g., gastrointestinal tract) than within a cell or other tissue at a non-target site (e.g., outside the gastrointestinal tract).
  • target site e.g., gastrointestinal tract
  • non-target site e.g., outside the gastrointestinal tract
  • the activity and/or bioavailability of the active entity and/or conjugate within a cell or other tissue at the target site is, as compared to within a cell or other tissue at a non-target site, (i) at least 25% (e.g., 25-50%, 50-75%, 75-100%, 100-150%, or higher and overlapping ranges therein) greater and/or (ii) at least 2-20 fold (e.g., 2-10 fold, 2-4 fold, 4-6 fold, 6-8 fold, 8-10 fold, 10-12 fold, 12-14 fold, 14-16 fold, 16-18 fold, 18-20 fold, 20-30 fold, 40-50 fold, 10-50 fold, 50-100 fold, and overlapping ranges therein) greater.
  • the activity and/or bioavailability is over 100 fold greater within a cell or other tissue at the target site than within a cell or other tissue at a non-target site.
  • the active entity and/or conjugate may have a longer residence time within a cell or other tissue at the target site (e.g., intestinal lamina basement) compared to the active entity without conjugation to the polymer.
  • the residence time of the active entity and/or conjugate within a cell or other tissue at the target site is, as compared to the active entity without conjugation to the polymer, (i) at least 25% (e.g., 25-50%, 50-75%, 75-100%, 100-150%, or higher and overlapping ranges therein) longer and/or (ii) at least 2-20 fold (e.g., 2-10 fold, 2-4 fold, 4-6 fold, 6-8 fold, 8-10 fold, 10-12 fold, 12-14 fold, 14-16 fold, 16-18 fold, 18-20 fold, 20-30 fold, 40-50 fold, 10-50 fold, 50-100 fold, and overlapping ranges therein) longer.
  • the residence time is over 100 fold longer.
  • the increased residence time is in one or more of the gastrointestinal
  • the active entity and/or conjugate may have a shorter residence time within a cell or other tissue at a non-target site compared to the active entity without conjugation to the polymer.
  • the residence time of the active entity and/or conjugate within a cell or other tissue at a non-target site is, as compared to the active entity without conjugation to the polymer, at least 2-20 fold (e.g., 2-10 fold, 2-4 fold, 4-6 fold, 6-8 fold, 8-10 fold, 10-12 fold, 12-14 fold, 14-16 fold, 16-18 fold, 18-20 fold, 20-30 fold, 40-50 fold, 10-50 fold, 50-100 fold, and overlapping ranges therein) shorter.
  • the residence time is over 100 fold shorter.
  • a smaller dose of the conjugate may be adequate to achieve a therapeutic effect comparable to the active entity without conjugation to the polymer.
  • the dose of the conjugate sufficient to achieve a therapeutic effect comparable to the active entity without conjugation to the polymer is at least 10% (e.g., 10-15%, 15-20%, 20-25%, 25-30%, 30-40%, 40-50%, 50- 60%, 60-70%, 70-80%, 80-90%, 90-100%, 100%-125%, 125-150%, or higher and overlapping ranges therein) lower. In one embodiment, the dose is over 200% lower. In some embodiments, fewer doses and/or smaller doses of the conjugate are required as compared to the active entity delivered without the polymer.
  • the active entity and/or conjugate may have diminished systemic absorption compared to the active entity without conjugation to the polymer.
  • the systemic absorption of the active entity and/or conjugate, as compared to the active entity without conjugation to the polymer is at least 2-20 fold (e.g., 2-10 fold, 2-4 fold, 4-6 fold, 6-8 fold, 8-10 fold, 10-12 fold, 12-14 fold, 14- 16 fold, 16-18 fold, 18-20 fold, 20-30 fold, 40-50 fold, 10-50 fold, 50-100 fold, and overlapping ranges therein) lower.
  • the systemic absorption is over 100 fold lower.
  • the active entity and/or conjugate may have minimal systemic absorption following oral administration.
  • the active entity and/or conjugate may have reduced clearance time from a non-target site compared to the active entity without conjugation to the polymer.
  • the clearance time of the active entity and/or conjugate from a non-target site, as compared to the active entity without conjugation to the polymer is at least 2-20 fold (e.g., 2-10 fold, 2-4 fold, 4-6 fold, 6-8 fold, 8-10 fold, 10-12 fold, 12-14 fold, 14-16 fold, 16-18 fold, 18-20 fold, 20-30 fold, 40-50 fold, 10-50 fold, 50-100 fold, and overlapping ranges therein) lower.
  • the clearance time is over 100 fold lower.
  • the active entity and/or conjugate displays rapid systemic elimination when administered by intravenous, intramuscular, transmucosal, subcutaneous or intraperitoneal injection and/or infusion.
  • the active entity and/or conjugate may have enhanced delivery to a cell or other tissue at the target site (e.g., Gl tract, intestinal lamina propria) compared to the active entity without conjugation to the polymer.
  • the target site e.g., Gl tract, intestinal lamina propria
  • at least 10% e.g., 10-15%, 15-20%, 20-25%, 25-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, 90-100%, and overlapping ranges therein
  • the conjugate may have enhanced delivery to the intestinal epithelium and/or intestinal laminalitis as compared to the active entity delivered without the polymer.
  • the conjugate is amphiphilic and/or amphipathic. In some embodiments, the conjugate is more amphiphilic and/or amphipathic than the active entity without conjugation to the polymer. For example, in several embodiments, the conjugate, as compared to the active entity without conjugation to the polymer, is at least 25% (e.g., 20-25%, 25-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, 90-100%, 100%-125%, 125-150%, or higher and overlapping ranges therein) more amphiphilic. In one embodiment, the amphiphilicity is over 200% greater.
  • the conjugate is more hydrophilic than the active entity without conjugation to the polymer.
  • the conjugate, as compared to the active entity without conjugation to the polymer is at least 25% (e.g., 20-25%, 25-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, 90-100%, 100%-125%, 125-150%, or higher and overlapping ranges therein) more hydrophilic.
  • the hydrophilicity is over 200% greater.
  • the greater hydrophilicity of the conjugate advantageously facilitates one or more of: non- compartmentalization within a cell or tissue at the target site; access to and activity in both the lipid bilayer and the cytosol of the cell; access to and/or activity in both the lipid bilayer and the cytoplasm of the cell; and/or access to and/or activity across the lipid bilayer.
  • the target site includes one or more of the following: intestinal epithelium, intestinal lamina intestinal, the lining of the gastrointestinal tract, immune cells residing within the intestinal lamina propria, muscularis mucosae, myenteric plexus, the submucosa, the muscular layer, intraperitoneal spaces, retroperitoneal spaces, serosa, adventitia.
  • the target site includes immune cells, and/or non-immune cells.
  • the conjugate targets immune cells residing within the Gl epithelial layer and/or intestinal laminalitis.
  • the target site includes the gastrointestinal tract and the non-target site includes non-gastrointestinal tract tissue.
  • the target site includes the small intestine and the non-target site includes one or more of the large intestine and stomach. In one embodiment, the target site includes the large intestine and the non-target site includes one or more of the small intestine and stomach. In some embodiments, the target site includes the small intestine and large intestine and the nontarget site includes the stomach. In one embodiment, the target site includes the intestinal lamina intestinal and the non-target site includes tissue contacting the intestinal lamina intestinal. In several embodiments, the target site includes immune cells of the intestinal lamina limbal, and the non-target site includes non-immune cells.
  • the target site includes the intestinal lamina intestinal and/or gastric parietal cells and the non-target site comprises sites other than intestinal lamina intestinal and/or gastric parietal cells.
  • the target site includes one or two of the duodenum, jejunum and ileum and the non- target site includes the remaining one or two.
  • the target site includes one or two of the ascending colon, transverse colon and the descending colon and the non- target site comprises the remaining one or two.
  • the method of treatment and/or use of the compositions described herein are provided for the prophylaxis or treatment of one or more of the following conditions: inflammatory bowel disease, irritable bowel syndrome, small intestinal bacterial overgrowth, Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behget's syndrome, small intestinal bacterial overgrowth, and indeterminate colitis.
  • the method of treatment and/or use of the compositions described herein are provided for reducing immunosuppression and/or an inflammatory response while treating a gastrointestinal condition in a subject in need thereof.
  • the method of treatment and/or use of the compositions described herein are provided for reducing reduce liver damage, neutropenia and/or lymphopenia while treating a gastrointestinal condition in a subject in need thereof.
  • a reduced exposure composition for treating a dermal target site e.g., the skin
  • a dermal target site e.g., the skin
  • Methods for treating the skin and/or dermal conditions are also provided.
  • the composition comprises or consists essentially of a conjugate comprising or consists essentially of an active entity coupled (e.g., linked) to at least one polymer.
  • the active entity may be for example, an inhibitor, antagonist, or inverse agonist of a mediator of a dermal condition.
  • the polymer can include, for example, polyethylene glycol (PEG) and/or methoxy-polyethylene glycol (m- PEG).
  • a pharmaceutically acceptable carrier formulated for delivering the conjugate to the target site is also provided.
  • the conjugate has reduced exposure at a non-target site as compared to the active entity delivered without the polymer.
  • the non-target site includes for example the systemic system, the lymphatic system and/or other non-target tissue sites.
  • the non-target site comprises any site at which pharmacological activity is not desired and/or not achieved.
  • the conjugate can advantageously traverse plasma membranes of cells at the target site, thereby promoting interactions between the active entity and the mediator of the dermal condition.
  • This traversal may include the crossing of cellular lipid bilayers to, e.g., distribute the active entity among both lipophilic and hydrophilic cellular compartments.
  • Membranes include the lipid bilayer, plasma membrane and the nuclear membrane as examples.
  • the conjugate interacts with mediator associated with the plasma membrane, cytoplasm and/or nucleus.
  • the conjugate may exhibit a depot effect across cellular compartments, thereby reducing the dose of the active entity required to inhibit the cellular mediator compared to the active entity without conjugation to the polymer.
  • the conjugate penetrates one or more physical barriers of the skin, one or more physiological barriers of the skin, and/or one or more biological barriers of the skin.
  • the active entity and/or conjugate may be an inhibitor, antagonist, and/or inverse agonist of a protein mediator of a condition (e.g., a kinase). In some embodiments, the active entity and/or conjugate may be an inhibitor, antagonist, and/or inverse agonist of a mediator of a dermal condition.
  • a protein mediator of a condition e.g., a kinase
  • the active entity and/or conjugate may be an inhibitor, antagonist, and/or inverse agonist of a mediator of a dermal condition.
  • the mediator is one or more of c-Src, a VEGFR protein (e.g., VEGFR-1 , VEGFR-2, VEGFR-3), a JAK protein (e.g., of JAK1 , JAK2, JAK3, and Tyrosine kinase 2 (TYK2)), STAT, NF-Kappa B, TrkA, MAPK, MAP2K and/or MAP2K3.
  • the active entity and/or conjugate is an inhibitor, antagonist, and/or inverse agonist of a mediator of inflammation.
  • the mediator of inflammation may be, for example, a mediator of an inflammatory skin condition.
  • the active entity and/or conjugate reduces inflammation at the target site.
  • the reduced inflammation at the target site treats an inflammatory skin condition.
  • the reduced exposure composition comprises one or more of conjugates SNA-101 , SNA-103, SNA-352, SNA-120 and/or SNA-125.
  • the active entity and/or conjugate exhibits greater access to the mediator compared to the active entity without conjugation to the polymer.
  • the reduced exposure composition is formulated for topical delivery.
  • Topical administration is provided in several embodiments. In several embodiments, the administration is daily.
  • effective amounts of the active entity are delivered to a subject (e.g., human or veterinary).
  • the composition may further comprise one or more additional ingredients, such as, for example, a protective agent, an emollient, an astringent, a humectant, a sun screening agent, a sun tanning agent, a UV absorbing agent, an antibiotic agent, an antiangiogenesis agent, a physiological cooling agent, an antifungal agent, an antiviral agent, an antiprotozoal agent, an anti-acne agent, an anesthetic agent, a steroidal antiinflammatory agent, a non-steroidal anti-inflammatory agent, an antipruritic agent, an additional antioxidant agent, a chemotherapeutic agent, an anti-histamine agent, a vitamin or vitamin complex, a hormone, an anti-dandruff agent, an anti-wrinkle agent, an anti-skin atrophy agent, a skin whitening agent, and/or a cleansing agent.
  • additional ingredients such as, for example, a protective agent, an emollient, an astringent, a humectant,
  • the active entity and/or conjugate may have an increased concentration, activity and/or bioavailability within a cell or tissue at the target site compared to the active entity without conjugation to the polymer. In some such embodiments, the therapeutically effective amount of the active entity is at the target site.
  • the concentration, activity and/or bioavailability within a cell or other tissue at the target site is, as compared to the active entity without conjugation to the polymer, at least 2-20 fold (e.g., 2-4 fold, 4-6 fold, 6-8 fold, 8-10 fold, 10-12 fold, 14-16 fold, 18-20 fold, 20-30 fold, 30-40 fold, 40-50 fold, 50-100 fold, and overlapping ranges therein) greater than within a cell or tissue at a non-target site (e.g., the systemic system, the lymphatic system, bone marrow, outside the skin).
  • the concentration, activity and/or bioavailability within a cell or tissue at the target site is over 100 fold greater.
  • the active entity and/or conjugate may have reduced concentration, activity and/or bioavailability within a cell or tissue at a non-target site compared to the active entity without conjugation to the polymer.
  • the active entity and/or conjugate is present at a biologically inactive concentration within a cell or tissue at a non-target site.
  • reduced concentration, activity and/or bioavailability within a cell or tissue at a non-target site e.g., the systemic system, the lymphatic system, bone marrow, outside the skin
  • the active entity and/or conjugate has reduced systemic absorption and/or little or no systemic toxicity when the composition is administered topically (e.g., a single administration, administration on a daily basis).
  • the active entity and/or conjugate may have a greater activity and/or bioavailability within a cell or other tissue at the target site (e.g., skin) than within a cell or other tissue at a non-target site.
  • the activity and/or bioavailability of the active entity and/or conjugate within a cell or other tissue at the target site is, as compared to within a cell or other tissue at a non-target site, (i) at least 25% (e.g., 25-50%, 50-75%, 75-100%, 100-150%, or higher and overlapping ranges therein) greater and/or (ii) at least 2-20 fold (e.g., 2-10 fold, 2-4 fold, 4-6 fold, 6-8 fold, 8- 10 fold, 10-12 fold, 12-14 fold, 14-16 fold, 16-18 fold, 18-20 fold, 20-30 fold, 40-50 fold, 10-50 fold, 50-100 fold, and overlapping ranges therein) greater.
  • the activity and/or bioavailability is over 100
  • the active entity and/or conjugate may have a longer residence time within a cell or other tissue at the target site (e.g., skin) compared to the active entity without conjugation to the polymer.
  • the residence time of the active entity and/or conjugate within a cell or other tissue at the target site is, as compared to the active entity without conjugation to the polymer, (i) at least 25% (e.g., 25-50%, 50-75%, 75-100%, 100-150%, or higher and overlapping ranges therein) longer and/or (ii) at least 2-20 fold (e.g., 2-10 fold, 2-4 fold, 4-6 fold, 6-8 fold, 8-10 fold, 10-12 fold, 12-14 fold, 14-16 fold, 16-18 fold, 18-20 fold, 20-30 fold, 40-50 fold, 10-50 fold, 50- 100 fold, and overlapping ranges therein) longer.
  • the residence time is over 100 fold longer.
  • the increased residence time is in the skin.
  • the active entity and/or conjugate may have a shorter residence time within a cell or other tissue at a non-target site compared to the active entity without conjugation to the polymer.
  • the residence time of the active entity and/or conjugate within a cell or other tissue at a non-target site is, as compared to the active entity without conjugation to the polymer, at least 2-20 fold (e.g., 2-10 fold, 2-4 fold, 4-6 fold, 6-8 fold, 8-10 fold, 10-12 fold, 12-14 fold, 14-16 fold, 16-18 fold, 18-20 fold, 20-30 fold, 40-50 fold, 10-50 fold, 50-100 fold, and overlapping ranges therein) shorter.
  • the residence time is over 100 fold shorter.
  • a smaller dose of the conjugate may be adequate to achieve a therapeutic effect comparable to the active entity without conjugation to the polymer.
  • the dose of the conjugate sufficient to achieve a therapeutic effect comparable to the active entity without conjugation to the polymer is at least 10% (e.g., 10-15%, 15-20%, 20-25%, 25-30%, 30-40%, 40-50%, 50- 60%, 60-70%, 70-80%, 80-90%, 90-100%, 100%-125%, 125-150%, or higher and overlapping ranges therein) lower. In one embodiment, the dose is over 200% lower. In some embodiments, fewer doses and/or smaller doses of the conjugate are required as compared to the active entity delivered without the polymer.
  • the active entity and/or conjugate may have diminished systemic absorption compared to the active entity without conjugation to the polymer.
  • the systemic absorption of the active entity and/or conjugate, as compared to the active entity without conjugation to the polymer is at least 2-20 fold (e.g., 2-10 fold, 2-4 fold, 4-6 fold, 6-8 fold, 8-10 fold, 10-12 fold, 12-14 fold, 14- 16 fold, 16-18 fold, 18-20 fold, 20-30 fold, 40-50 fold, 10-50 fold, 50-100 fold, and overlapping ranges therein) lower.
  • the systemic absorption is over 100 fold lower.
  • the active entity and/or conjugate may have minimal systemic absorption following epicutaneous administration.
  • the active entity and/or conjugate may have reduced clearance time from a non-target site compared to the active entity without conjugation to the polymer.
  • the clearance time of the active entity and/or conjugate from a non-target site, as compared to the active entity without conjugation to the polymer is at least 2-20 fold (e.g., 2-10 fold, 2-4 fold, 4-6 fold, 6-8 fold, 8-10 fold, 10-12 fold, 12-14 fold, 14-16 fold, 16-18 fold, 18-20 fold, 20-30 fold, 40-50 fold, 10-50 fold, 50-100 fold, and overlapping ranges therein) lower.
  • the clearance time is over 100 fold lower.
  • the active entity and/or conjugate displays rapid systemic elimination when administered by intravenous, intramuscular, transmucosal, subcutaneous or intraperitoneal injection and/or infusion.
  • the active entity and/or conjugate may have enhanced delivery to a cell or other tissue at the target site (e.g., dermis, epidermis, subcutis) compared to the active entity without conjugation to the polymer.
  • a cell or other tissue at the target site e.g., dermis, epidermis, subcutis
  • at least 10% (e.g., 10-15%, 15-20%, 20-25%, 25-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, 90-100%, and overlapping ranges therein) of the administered conjugate reaches a cell or other tissue at the target site.
  • the conjugate may have enhanced delivery to the epidermis, dermis, and/or subcutis as compared to the active entity delivered without the polymer.
  • the conjugate is amphiphilic and/or amphipathic. In some embodiments, the conjugate is more amphiphilic and/or amphipathic than the active entity without conjugation to the polymer. For example, in several embodiments, the conjugate, as compared to the active entity without conjugation to the polymer, is at least 25% (e.g., 20-25%, 25-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, 90-100%, 100%-125%, 125-150%, or higher and overlapping ranges therein) more amphiphilic. In one embodiment, the amphiphilicity is over 200% greater.
  • the conjugate is more hydrophilic than the active entity without conjugation to the polymer.
  • the conjugate, as compared to the active entity without conjugation to the polymer is at least 25% (e.g., 20-25%, 25-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, 90-100%, 100%-125%, 125-150%, or higher and overlapping ranges therein) more hydrophilic.
  • the hydrophilicity is over 200% greater.
  • the greater hydrophilicity of the conjugate advantageously facilitates one or more of: non- compartmentalization within a cell or tissue at the target site; access to and activity in both the lipid bilayer and the cytosol of the cell; access to and/or activity in both the lipid bilayer and the cytoplasm of the cell; and/or access to and/or activity across the lipid bilayer.
  • the target site includes cells localized within one or more of the following: the stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale layers, the papillary layer of the dermis, the reticular layer of the dermis, sebaceous glands, arrector pili muscles, sensory nerve fibers, hair follicles, hair roots, pacinian corpuscles, hair root plexus, eccrine sweat glands, the hypodermis and/or the superficial fascia.
  • the target cells may comprise immune cells, non-immune cells and/or keratinocytes.
  • the conjugate targets immune cells residing within dermis, epidermis, and/or subcutis.
  • the target site comprises immune cells of the epidermis or dermis and the non-target site comprises non-immune cells.
  • the target site includes the epidermis and the non-target site includes the dermis, gland, hypodermis and/or blood vessels.
  • the target site includes the dermis and the non-target site includes the epidermis, gland, hypodermis and/or blood vessels.
  • the target site includes the epidermis and the nontarget site includes the dermis, gland, blood vessels, and/or hypodermis.
  • the target site includes the dermis and the non-target site includes the epidermis, gland hypodermis and/or blood vessels.
  • the target site includes one or more of the epidermis, follicle, gland, blood vessels, dermis and subcutis, and the non-target site includes the remaining sites.
  • the target site includes the subcutis and the non-target site includes tissue contacting the subcutis.
  • the target site includes the skin and the non-target site includes non-integumentary tissue.
  • the conjugates, or compositions thereof, provided herein are useful in treating a dermal condition in a subject in need thereof.
  • the dermal condition is pruritus, skin neoplasia, vascular tumor, inflammatory dermatosis, scarring, a bullous disease, UV irradiation therapy, alopecia areata, or vitiligo.
  • the pruritus is pruritus due to psoriasis, pruritus due to atopic dermatitis, or prurigo nodularis.
  • the skin neoplasia is squamous cell carcinoma, basal cell carcinoma, malignant melanoma, or malignant cutaneous lymphomas.
  • the vascular tumor is angiosarcoma, Kaposi’s sarcoma, infantile hemangioma, or hemangioendothelioma.
  • the inflammatory dermatosis is dermatitis, psoriasis, keloid, or rosacea.
  • the dermatitis is atopic dermatitis or irritant contact dermatitis.
  • the bullous disease is bullous pemphigoid or erythema multiforme.
  • the dermal condition is selected from chronic actinic dermatitis, chronic mucocutaneous candidiasis, cutaneous T-cell lymphoma, cutaneous graft-versus-host disease, hypereosinophilic syndrome, mastocytosis and mast cell disease, sting vasculopathy, palmoplantar pustulosis, or polyarteritis nodosa.
  • the conjugates, or compositions thereof, provided herein are useful in treating a gastrointestinal system condition in a subject in need thereof.
  • the gastrointestinal system condition is ulcerative colitis, Crohn’s disease, intestinal fibrosis, or colorectal cancer.
  • the method of treatment and/or use of the compositions described herein are provided for the prophylaxis or treatment of one or more of the following conditions: psoriasis, psoriasis guttata, inverse psoriasis, pustular psoriasis, psoriatic erythroderma, acute febrile neutrophilic dermatosis, eczema, xerotic eczema, dyshidrotic eczema, vesicular palmar eczema, acne vulgaris, atopic dermatitis, contact dermatitis, allergic contact dermatitis, dermatomyositis, exfoliative dermatitis, hand eczema, pompholyx, keloids, rosacea, rosacea due to sarcoidosis, rosacea due to scleroderma, rosacea due to Sweet syndrome, rosacea due to systemic lupus
  • the method of treatment and/or use of the compositions described herein are provided for the prophylaxis or treatment of a vascular tumor, e.g., Kaposi's sarcoma, lymphangioma, glomangioma, angiosarcoma, hemangioendothelioma, and infantile hemangiomas.
  • a vascular tumor e.g., Kaposi's sarcoma, lymphangioma, glomangioma, angiosarcoma, hemangioendothelioma, and infantile hemangiomas.
  • the method of treatment and/or use of the compositions described herein are provided for the prophylaxis or treatment of a skin neoplasia, e.g., squamous cell carcinoma, basal cell carcinoma, malignant melanoma, malignant cutaneous lymphoma, Kaposi's sarcoma, Merkel cell skin cancer, and non-melanoma skin cancer.
  • a skin neoplasia e.g., squamous cell carcinoma, basal cell carcinoma, malignant melanoma, malignant cutaneous lymphoma, Kaposi's sarcoma, Merkel cell skin cancer, and non-melanoma skin cancer.
  • the method of treatment and/or use of the compositions described herein are provided for the prophylaxis or treatment of a bullous disease, e.g., bullous pemphigoid, erythema multiforme, dermatitis herpetiformis, epidermolysis bullosa acquisita, linear Immunoglobulin A disease, mucous membrane pemphigoid, pemphigoid gestationis, pemphigus foliaceus, and pemphigus vulgaris.
  • a bullous disease e.g., bullous pemphigoid, erythema multiforme, dermatitis herpetiformis, epidermolysis bullosa acquisita, linear Immunoglobulin A disease, mucous membrane pemphigoid, pemphigoid gestationis, pemphigus foliaceus, and pemphigus vulgaris.
  • the method of treatment and/or use of the compositions described herein are provided for the modulation of hair growth and cycling. In several embodiments, the method of treatment and/or use of the compositions described herein are provided for the prophylaxis or treatment of alopecia.
  • the conjugates, or compositions thereof, provided herein are useful in treating a respiratory condition in a subject in need thereof.
  • the respiratory condition is asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, or cough.
  • the cough is chronic cough.
  • the conjugates, or compositions thereof, provided herein are useful in treating rheumatoid arthritis, osteoarthritis, neuropathic pain, or neuropathic itch in a subject in need thereof.
  • a reduced exposure composition for treating a target site in the eye is provided.
  • Methods for treating the eye and/or ophthalmic conditions are also provided.
  • the composition comprises or consists essentially of a conjugate comprising or consists essentially of an active entity coupled (e.g., linked) to at least one polymer.
  • the active entity may be for example, an inhibitor, antagonist, or inverse agonist of a mediator of an ophthalmic condition.
  • the polymer can include, for example, polyethylene glycol (PEG) and/or methoxy-polyethylene glycol (m-PEG).
  • a pharmaceutically acceptable carrier formulated for delivering the conjugate to the target site is also provided.
  • the conjugate has reduced exposure at a non-target site as compared to the active entity delivered without the polymer.
  • the non-target site includes for example the systemic system, the lymphatic system and/or other non-target tissue sites.
  • the nontarget site comprises any site at which pharmacological activity is not desired and/or not achieved.
  • the conjugate can advantageously traverse plasma membranes of cells at the target site, thereby promoting interactions between the active entity and the mediator of the ophthalmic condition.
  • This traversal may include the crossing of cellular lipid bilayers to, e.g., distribute the active entity among both lipophilic and hydrophilic cellular compartments.
  • Membranes include the lipid bilayer, plasma membrane and the nuclear membrane as examples.
  • the conjugate may exhibit a depot effect across cellular compartments, thereby reducing the dose of the active entity required to inhibit the cellular mediator compared to the active entity without conjugation to the polymer.
  • the conjugate penetrates one or more physical barriers of the eye, one or more physiological barriers of the eye, and/or one or more biological barriers of the eye, such as, for example, the conjunctival epithelium, Tenon's fascia, episclera, sclera, and/or choroid.
  • the conjugates, or compositions thereof, provided herein are useful in treating an ocular condition in a subject in need thereof.
  • the ocular condition is age-related macular degeneration, diabetic retinopathy, edema, dry eye, uveitis, pterygia, conjunctivitis, graft versus host disease, glaucoma, or retinopathy of prematurity.
  • the age-related macular degeneration is wet age-related macular degeneration or dry age-related macular degeneration.
  • the edema is macular edema or corneal edema.
  • the macular edema is diabetic macular edema.
  • dry eye is spontaneous dry eye or aqueous deficiency dry eye.
  • the uveitis is juvenile idiopathic arthritis uveitis or posterior uveitis.
  • the conjunctivitus is vernal keratocunjunctivitis (allergic conjunctivitis).
  • the graft versus host disease is ophthalmic graft versus host disease.
  • the glaucoma is primary open angle glaucoma.
  • the active entity and/or conjugate may be an inhibitor, antagonist, and/or inverse agonist of a protein mediator of a condition (e.g., a kinase). In some embodiments, the active entity and/or conjugate may be an inhibitor, antagonist, and/or inverse agonist of a mediator of an ophthalmic condition.
  • a protein mediator of a condition e.g., a kinase
  • the active entity and/or conjugate may be an inhibitor, antagonist, and/or inverse agonist of a mediator of an ophthalmic condition.
  • the mediator is one or more of c-Src, a VEGFR protein (e.g., VEGFR-1 , VEGFR-2, VEGFR-3), a JAK protein (e.g., of JAK1 , JAK2, JAK3, and Tyrosine kinase 2 (TYK2)), STAT, NF-Kappa B, TrkA, MAPK, MAP2K and/or MAP2K3.
  • the active entity and/or conjugate is an inhibitor, antagonist, and/or inverse agonist of a mediator of inflammation.
  • the mediator of inflammation may be, for example, a mediator of an inflammatory ocular condition.
  • the active entity and/or conjugate reduces inflammation at the target site.
  • the reduced inflammation at the target site treats an inflammatory ocular condition, such as, for example, uveitis.
  • the reduced exposure composition comprises one or more of conjugates SNA-101 , SNA-103, SNA-352, SNA- 120 and/or SNA- 125.
  • the active entity and/or conjugate exhibits greater access to the mediator compared to the active entity without conjugation to the polymer.
  • the reduced exposure composition is formulated for local ocular delivery via a topical or injectable.
  • Intra-ocular admistration is provided in several embodiments.
  • the composition may be formulated for, e.g., subconjunctival, intravitreal, retrobulbar or intracameral delivery.
  • effective amounts of the active entity are delivered to a subject (e.g., human or veterinary).
  • the composition may further comprise one or more additional ingredients, such as, for example, an antibiotic agent, an anti-angiogenesis agent, a preventive or therapeutic agent for inflammatory bowel disease, an antifungal agent, an antiviral agent, an antiprotozoal agent, an anesthetic agent, a steroidal anti-inflammatory agent, a non-steroidal antiinflammatory agent, an antipruritic agent, an additional antioxidant agent, a chemotherapeutic agent, an anti-histamine agent, a vitamin or vitamin complex, and/or a hormone.
  • additional ingredients such as, for example, an antibiotic agent, an anti-angiogenesis agent, a preventive or therapeutic agent for inflammatory bowel disease, an antifungal agent, an antiviral agent, an antiprotozoal agent, an anesthetic agent, a steroidal anti-inflammatory agent, a non-steroidal antiinflammatory agent, an antipruritic agent, an additional antioxidant agent, a chemotherapeutic agent, an anti-histamine agent, a vitamin or vitamin complex, and/
  • the active entity and/or conjugate may have a longer residence time within a cell or other tissue at the target site compared to the active entity without conjugation to the polymer.
  • the residence time of the active entity and/or conjugate within a cell or other tissue at the target site is, as compared to the active entity without conjugation to the polymer, (i) at least 25% (e.g., 25-50%, 50-75%, 75-100%, 100-150%, or higher and overlapping ranges therein) longer and/or (ii) at least 2-20 fold (e.g., 2-10 fold, 2-4 fold, 4-6 fold, 6-8 fold, 8-10 fold, 10-12 fold, 12-14 fold, 14- 16 fold, 16-18 fold, 18-20 fold, 20-30 fold, 40-50 fold, 10-50 fold, 50-100 fold, and overlapping ranges therein) longer.
  • the residence time is over 100 fold longer.
  • the increased residence time is at the anterior segment of the eye and/or anterior segment of the eye.
  • the active entity and/or conjugate may have a shorter residence time within a cell or other tissue at a non-target site compared to the active entity without conjugation to the polymer.
  • the residence time of the active entity and/or conjugate within a cell or other tissue at a non-target site is, as compared to the active entity without conjugation to the polymer, at least 2-20 fold (e.g., 2-10 fold, 2-4 fold, 4-6 fold, 6-8 fold, 8-10 fold, 10-12 fold, 12-14 fold, 14-16 fold, 16-18 fold, 18-20 fold, 20-30 fold, 40-50 fold, 10-50 fold, 50-100 fold, and overlapping ranges therein) shorter.
  • the residence time is over 100 fold shorter.
  • a smaller dose of the conjugate may be adequate to achieve a therapeutic effect comparable to the active entity without conjugation to the polymer.
  • the dose of the conjugate sufficient to achieve a therapeutic effect comparable to the active entity without conjugation to the polymer is at least 10% (e.g., 10-15%, 15-20%, 20-25%, 25-30%, 30-40%, 40-50%, 50- 60%, 60-70%, 70-80%, 80-90%, 90-100%, 100%-125%, 125-150%, or higher and overlapping ranges therein) lower. In one embodiment, the dose is over 200% lower. In some embodiments, fewer doses and/or smaller doses of the conjugate are required as compared to the active entity delivered without the polymer.
  • the active entity and/or conjugate may have diminished systemic absorption compared to the active entity without conjugation to the polymer.
  • the systemic absorption of the active entity and/or conjugate, as compared to the active entity without conjugation to the polymer is at least 2-20 fold (e.g., 2-10 fold, 2-4 fold, 4-6 fold, 6-8 fold, 8-10 fold, 10-12 fold, 12-14 fold, 14- 16 fold, 16-18 fold, 18-20 fold, 20-30 fold, 40-50 fold, 10-50 fold, 50-100 fold, and overlapping ranges therein) lower.
  • the systemic absorption is over 100 fold lower.
  • the active entity and/or conjugate may have reduced clearance time from a non-target site compared to the active entity without conjugation to the polymer.
  • the clearance time of the active entity and/or conjugate from a non-target site, as compared to the active entity without conjugation to the polymer is at least 2-20 fold (e.g., 2-10 fold, 2-4 fold, 4-6 fold, 6-8 fold, 8-10 fold, 10-12 fold, 12-14 fold, 14-16 fold, 16-18 fold, 18-20 fold, 20-30 fold, 40-50 fold, 10-50 fold, 50-100 fold, and overlapping ranges therein) lower.
  • the clearance time is over 100 fold lower.
  • the active entity and/or conjugate may have enhanced delivery to a cell or other tissue at the target site compared to the active entity without conjugation to the polymer.
  • at least 10% e.g., 10- 15%, 15-20%, 20-25%, 25-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, 90-100%, and overlapping ranges therein
  • the conjugate may have enhanced delivery to the posterior segment of the eye and/or anterior segment of the eye as compared to the active entity delivered without the polymer.
  • the active entity and/or conjugate may have an increased concentration, activity and/or bioavailability within a cell or tissue at the target site compared to the active entity without conjugation to the polymer. In some such embodiments, the therapeutically effective amount of the active entity is at the target site.
  • the concentration, activity and/or bioavailability within a cell or other tissue at the target site is, as compared to the active entity without conjugation to the polymer, at least 2-20 fold (e.g., 2-4 fold, 4-6 fold, 6-8 fold, 8-10 fold, 10-12 fold, 14-16 fold, 18-20 fold, 20-30 fold, 30-40 fold, 40-50 fold, 50-100 fold, and overlapping ranges therein) greater than within a cell or tissue at a non-target site (e.g., the systemic system, the lymphatic system, bone marrow, outside the eye).
  • the concentration, activity and/or bioavailability within a cell or tissue at the target site is over 100 fold greater.
  • the active entity and/or conjugate may have reduced concentration, activity and/or bioavailability within a cell or tissue at a non-target site compared to the active entity without conjugation to the polymer.
  • the active entity and/or conjugate is present at a biologically inactive concentration within a cell or tissue at a non-target site.
  • reduced concentration, activity and/or bioavailability within a cell or tissue at a non-target site advantageously reduces toxicity and/or other side effects, such as, for example, immunosuppression.
  • the conjugate is amphiphilic and/or amphipathic. In some embodiments, the conjugate is more amphiphilic and/or amphipathic than the active entity without conjugation to the polymer. For example, in several embodiments, the conjugate, as compared to the active entity without conjugation to the polymer, is at least 25% (e.g., 20-25%, 25-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, 90-100%, 100%-125%, 125-150%, or higher and overlapping ranges therein) more amphiphilic. In one embodiment, the amphiphilicity is over 200% greater.
  • the conjugate is more hydrophilic than the active entity without conjugation to the polymer.
  • the conjugate, as compared to the active entity without conjugation to the polymer is at least 25% (e.g., 20-25%, 25-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, 90-100%, 100%-125%, 125-150%, or higher and overlapping ranges therein) more hydrophilic.
  • the hydrophilicity is over 200% greater.
  • the greater hydrophilicity of the conjugate advantageously facilitates one or more of: non- compartmentalization within a cell or tissue at the target site; access to and activity in both the lipid bilayer and the cytosol of the cell; access to and/or activity in both the lipid bilayer and the cytoplasm of the cell; and/or access to and/or activity across the lipid bilayer.
  • the target site includes one or more of the following: the anterior segment of the eye, the posterior segment of the eye, an anterior sub-Tenon space, an anterior suprachoroidal space, an anterior intrascleral space, a posterior sub- Tenon space, a posterior suprachoroidal space and a posterior intrascleral space, the conjunctival epithelium, Tenon's fascia, episclera, sclera, choroid, the cornea, lens, sclera, anterior chamber, iris, posterior chamber, choroid, retina, Bowman's layer, stroma, Descemet's membrane, the endothelium, Tenon's Capsule and any combination thereof.
  • the target site includes target immune cells residing within the anterior segment of the eye and/or posterior segment of the eye.
  • the method of treatment and/or use of the compositions described herein are provided for the prophylaxis or treatment of one or more of the following conditions: glaucoma, allergic conditions, inflammatory conditions of the anterior segment and cornea, allergic conditions of the anterior segment and cornea, infectious conditions of the anterior segment and cornea, and corneal angiogenesis, corneal edema, macular edema, dry eye, uveitis, macular degeneration, age related macular degeneration (ARMD), diabetic retinopathy, inflammatory conditions of the posterior segment, infectious conditions of the posterior segment, neurodegenerative disease, and vascular disease of the posterior segment, choroidal neovascularization, retinopathy, diabetic retinopathy, acute macular neuroretinopathy, chronic macular neuroretinopathy, central serous chorioretinopathy, macular edema, cystoid macular edema, or diabetic macular edema, acute multifocal placoid pigment epitheliopathy, Behcet's
  • the method of treatment and/or use of the compositions described herein are provided for the prophylaxis or treatment of tears (e.g., retinal tear, giant retinal tear), laceration, abrasion, retinal detachment, macular hole, floaters, etc.
  • tears e.g., retinal tear, giant retinal tear
  • laceration e.g., abrasion, retinal detachment, macular hole, floaters, etc.
  • the method of treatment and/or use of the compositions described herein are provided for the prophylaxis or treatment of a retinal disease associated with tumors, congenital hypertrophy of the RPE, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined hamartoma of the retina and retinal pigmented epithelium, retinoblastoma, vasoproliferative tumors of the ocular fundus, retinal astrocytoma, or intraocular lymphoid tumors.
  • the method of treatment and/or use of the compositions described herein are provided for the prophylaxis or treatment of punctate inner choroidopathy, acute posterior multifocal placoid pigment epitheliopathy, myopic retinal degeneration, or acute retinal pigment epithelitis.
  • a reduced exposure composition for inhibiting the activity of a therapeutic target in the respiratory tract is provided.
  • Methods and uses for treating respiratory conditions are also provided.
  • the composition comprises or consists essentially of a conjugate comprising or consists essentially of an active entity coupled (e.g., linked) to at least one polymer.
  • the active entity may be for example, an inhibitor, antagonist, or inverse agonist of a mediator of a respiratory condition.
  • the active entity can have a selectivity and/or an inhibitory activity against the therapeutic target.
  • the conjugate has increased selectivity and/or inhibitory activity compared to the unconjugated active entity.
  • the polymer can include, for example, polyethylene glycol (PEG) and/or methoxy-polyethylene glycol (m-PEG).
  • a pharmaceutically acceptable carrier formulated for delivering the conjugate to the target site is also provided.
  • the conjugate has reduced exposure at a non-target site as compared to the unconjugated active entity.
  • the non-target site includes for example the systemic system, the lymphatic system and/or other non-target tissue sites.
  • the non-target site comprises any site at which pharmacological activity is not desired and/or not achieved.
  • the conjugate can advantageously traverse plasma membranes of cells at the target site compared to the unconjugated active entity, thereby promoting interactions between the active entity and the mediator of a respiratory condition.
  • This traversal may include the crossing of cellular lipid bilayers to, e.g., distribute the active entity among both lipophilic and hydrophilic cellular compartments.
  • Membranes include the lipid bilayer, plasma membrane and the nuclear membrane as examples.
  • the method of treatment and/or use of the compositions described herein are provided for the prophylaxis or treatment of one or more of the following conditions: acute bronchitis; acute laryngotracheal bronchitis; arachidic bronchitis; catarrhal bronchitis; croupus bronchitis; dry bronchitis; infectious asthmatic bronchitis; productive bronchitis; staphylococcus or streptococcal bronchitis; vesicular bronchitis; cylindric bronchiectasis; sacculated bronchiectasis; fusiform bronchiectasis; capillary bronchiectasis; cystic bronchiectasis; dry bronchiectasis; follicular bronchiectasis; chronic obstructive pulmonary disease (COPD), chronic obstructive lung disease (COLD), chronic o
  • COPD
  • pneumoconiosis of whatever type, etiology, or pathogenesis in particular pneumoconiosis that is a member selected from the group consisting of aluminosis or bauxite workers' disease, anthracosis or miners' asthma, asbestosis or steam-fitters' asthma, chalicosis or flint disease, ptilosis caused by inhaling the dust from ostrich feathers, siderosis caused by the inhalation of iron particles, silicosis or grinders' disease, byssinosis or cotton-dust asthma and talc pneumoconiosis; interstitial lung diseases (ILD) or pulmonary fibrosis of whatever type, etiology
  • ILD interstitial lung diseases
  • pulmonary fibrosis of whatever type, etiology
  • Respiratory disorders also include, in some embodiments, malignancies and tumors of the respiratory system, nonlimiting examples of which include lung adenocarcinoma, squamous cell carcinoma, large cell carcinoma, bronchioloalveolar carcinoma (BAC), pulmonary adenocarcinoma (AIS), non-small-cell carcinoma, small cell carcinoma, and/or mesothelioma.
  • lung adenocarcinoma squamous cell carcinoma, large cell carcinoma, bronchioloalveolar carcinoma (BAC), pulmonary adenocarcinoma (AIS), non-small-cell carcinoma, small cell carcinoma, and/or mesothelioma.
  • BAC bronchioloalveolar carcinoma
  • AIS pulmonary adenocarcinoma
  • non-small-cell carcinoma small cell carcinoma
  • mesothelioma mesothelioma.
  • the reduced exposure composition comprises a conjugate comprising an active entity linked to at least one polymer
  • the active entity is an inhibitor, antagonist, or inverse agonist of a mediator of the dermal condition
  • the at least one polymer is polyethylene glycol (PEG) or methoxy-polyethylene glycol (m-PEG); and
  • a pharmaceutically acceptable carrier formulated for delivering the conjugate to the target site
  • the conjugate has reduced exposure at a non-target site as compared to the active entity delivered without the polymer, wherein the non-target site comprises the systemic system, the lymphatic system and/or another non-target tissue site; the conjugate can traverse cellular membranes and distribute among both lipophilic and hydrophilic cellular compartments, thereby promoting interactions between the active entity and the cellular mediator of a condition; and
  • the conjugate is selected from SNA-101 , SNA-103, or SNA-352.
  • a reduced exposure composition for treating a condition in a subject in need thereof, wherein:
  • the reduced exposure composition comprises a conjugate comprising an active entity linked to at least one polymer
  • the active entity is an inhibitor, antagonist, or inverse agonist of a mediator of the dermal condition
  • the at least one polymer is polyethylene glycol (PEG) or methoxy-polyethylene glycol (m-PEG); and
  • a pharmaceutically acceptable carrier formulated for delivering the conjugate to the target site
  • the conjugate has reduced exposure at a non-target site as compared to the active entity delivered without the polymer, wherein the non-target site comprises the systemic system, the lymphatic system and/or another non-target tissue site; and
  • the conjugate can traverse cellular membranes and distribute among both lipophilic and hydrophilic cellular compartments, thereby promoting interactions between the active entity and the cellular mediator of a condition.
  • the conjugate penetrates one or more physical, physiological and/or biological barriers of the skin.
  • the conjugate exhibits enhanced delivery to the epidermis as compared to delivery of the active entity without conjugation to the polymer.
  • the conjugate exhibits enhanced delivery to the dermis as compared to delivery of the active entity without conjugation to the polymer.
  • the conjugate exhibits enhanced delivery to the subcutis as compared to delivery of the active entity without conjugation to the polymer.
  • the conjugate exhibits increased residence time in the skin as compared to the active entity delivered without conjugation to the polymer.
  • the conjugate targets immune cells residing within the dermal target site.
  • the reduced exposure composition exhibits fewer side effects as compared to the active entity administered without conjugation to the polymer.
  • the reduced exposure composition requires fewer and/or lower doses to achieve an effective amount as compared to the active entity administered without conjugation to the polymer.
  • the reduced exposure composition provides 2-20 fold more activity and/or bioavailability of the active entity at the target site than at the non-target site.
  • the reduced exposure composition provides at least 25 % or 50 % more activity and/or bioavailability of the active entity at the target site than at the non-target site.
  • the target site comprises the epidermis and the non-target site comprises the dermis, gland, hypodermis and/or blood vessels.
  • the target site comprises the dermis and the non-target site comprises the epidermis, gland, hypodermis and/or blood vessels.
  • the target site comprises one or two of the epidermis, dermis, gland, blood vessels, and subcutis, and the non-target site comprises the remaining sites.
  • the target site comprises the subcutis and the non-target site comprises tissue contacting the subcutis.
  • the target site comprises immune cells of the epidermis or dermis and the non-target site comprises non-immune cells.
  • the target site comprises the skin and the non-target site comprises non-integumentary tissue.
  • the condition is a dermal condition, a gastrointestinal condition, an ophthalmological condition, a respiratory condition, or a combination thereof.
  • the dermal condition is pruritus (e.g., pruritus due to psoriasis, pruritus due to atopic dermatitis, or prurigo nodularis), skin neoplasia (e.g., squamous cell carcinoma, basal cell carcinoma, malignant melanoma, or malignant cutaneous lymphoma), vascular tumor (e.g., angiosarcoma, Kaposi’s sarcoma, infantile hemangioma, or hemangioendothelioma), inflammatory dermatosis (e.g., dermatitis (e.g., atopic dermatitis or irritant contact dermatitis), psoriasis, keloid, or rosacea), scarring, a bullous disease (e.g., bullous pemphigoid or erythema multiforme), UV irradiation therapy
  • skin neoplasia e
  • the dermal condition is angiosarcoma, Kaposi’s sarcoma, infantile hemangioma, hemangioendothelioma, irritant contact dermatitis, rosacea, bullous pemphigoid, erythema multiforme, UV irradiation therapy, alopecia areata, vitiligo, or a combination thereof.
  • the dermal condition is pruritus, prurigo nodularis, postherpetic neuralgia, seborrheic dermatitis, lichen simplex chronicus, Grover’s disease, neurodermatitis, pemphigoid, bullous pemphigoid, epidermolysis bullosa, alopecia areata, atopic dermatitis, chronic actinic dermatitis, chronic mucocutaneous candidiasis, cutaneous t-cell lymphoma, dermatomyositis, erythema multiforme, graft-versus-host disease (cutaneous), hypereosinophilic syndrome, lupus erythematosus, mastocytosis and mast cell disease, STING vasculopathy, palmoplantar pustulosis, polyarteritis nodosa, psoriasis, vitiligo, dry skin pruritus in the elderly, warts
  • the dermal condition is pruritus due to intrahepatic cholestasis, posthepatic cholestasis, drug- induced cholestasis, chronic renal failure, dialysis treatment, diabetes mellitus, systemic parasitosis, Sjogren’s syndrome, AIDS, drug eruption, pregnancy, a psychogenic condition, sclerosis multiplex, stroke, delusion of parasitosis, lymphoma, mastocytosis, polycythemia vera, iron-deficiency anemia, hyperthyroidism, hyperparathyroidism, brain tumor, myxoedema, acute eczema, chronic eczema, monetary eczema, sebaceous deficiency eczema, contact dermatitis, atopic dermatitis, seborrheic dermatitis, neurodermatitis, acute prurigo (strofus, urticaria, lichen ur
  • the gastrointestinal condition is ulcerative colitis, Crohn’s disease, intestinal fibrosis, colorectal cancer, irritable bowel syndrome, visceral pain, or a combination thereof.
  • the ophthalmological condition is age-related macular degeneration (e.g., wet age-related macular degeneration or dry age-related macular degeneration), diabetic retinopathy, edema (e.g., macular edema (e.g., diabetic macular edema) or corneal edema), dry eye (e.g., spontaneous dry eye or aqueous deficiency dry eye), uveitis (e.g., juvenile idiopathic arthritis uveitis or posterior uveitis), pterygia, conjunctivitis (e.g., vernal keratocunjunctivitis (allergic conjunctivitis) or atopic keratoconjunctivitis), graft versus host disease (e.g., ophthalmic graft versus host disease), glaucoma (e.g., primary open angle glaucom
  • the ophthalmological condition is age-related macular degeneration (e.g., wet age-related macular degeneration or dry age-related macular degeneration), edema (e.g., macular edema (e.g., diabetic macular edema) or corneal edema), dry eye (e.g., spontaneous dry eye or aqueous deficiency dry eye), juvenile idiopathic arthritis uveitis, posterior uveitis, pterygia, conjunctivitis (e.g., vernal keratoconjunctivitis (allergic conjunctivitis) or atopic keratoconjunctivitis), ophthalmic graft versus host disease, glaucoma (e.g., primary open angle glaucoma), retinopathy of prematurity, diabetic retinopathy, or a combination thereof.
  • age-related macular degeneration e.g., wet age-
  • the respiratory condition is asthma (e.g., T H 2 asthma or non-T H 2 asthma), chronic obstructive pulmonary disease, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis), pulmonary hypertension, sinusitis with nasal polyposis, allergic rhinitis, cough (e.g., chronic cough), lymphangioleiomyomatosis, or a combination thereof.
  • asthma e.g., T H 2 asthma or non-T H 2 asthma
  • chronic obstructive pulmonary disease e.g., chronic obstructive pulmonary disease
  • pulmonary fibrosis e.g., idiopathic pulmonary fibrosis
  • pulmonary hypertension pulmonary hypertension
  • sinusitis with nasal polyposis e.g., allergic rhinitis
  • cough e.g., chronic cough
  • lymphangioleiomyomatosis e.g., chronic cough
  • the condition is rheumatoid arthritis, osteoarthritis, neuropathic pain, neuropathic itch, or a combination thereof.
  • Figure 1 depicts the BioMAP profile of SNA-101 in the Diversity PLUS Panel at the indicated concentrations.
  • the X-axis lists the quantitative protein-based biomarker readouts measured in each system.
  • the grey region around the Y-axis represents the 95% significance envelope generated from historical vehicle controls.
  • Biomarker activities are annotated when 2 or more consecutive concentrations change in the same direction relative to vehicle controls, are outside of the significance envelope, and have at least one concentration with an effect size > 20% (
  • Biomarker key activities are described as modulated if these activities increase in some systems, but decrease in others.
  • Cytotoxicity is indicated on the profile plot by a thin black arrow above the X-axis, and antiproliferative effects are indicated by a thick grey arrow. Cytotoxicity and antiproliferative arrows may only require one concentration to meet the indicated threshold for profile annotation. Other BioMAP profiles disclosed herein are also depicted in a similar manner.
  • Figure 2 depicts a Reference Benchmark Overlay of SNA-101 and Benchmark Apremilast. Common biomarker readouts are annotated when the readout for both profiles is outside of the significance envelope with an effect size > 20% (
  • Figure 3 depicts an overlay of SNA-101 (29 mM) and Topiramate (3.3 mM), which was the top similarity match from a search of the BioMAP Reference Database of > 4,000 agents.
  • Common biomarker readouts are annotated when the readout for both profiles is outside of the significance envelope with an effect size > 20% (
  • Figure 4 depicts Mechanism HeatMAP Analysis for SNA-101. HeatMAP analysis of the 148 biomarker readouts (rows) within the Diversity PLUS panel by SNA-101 in comparison to 19 consensus mechanism class profiles (columns). Horizontal grey lines separate the 12 Diversity PLUS systems, while the vertical grey line separates SNA-101 from the 19 consensus mechanism profiles. Biomarker activities outside of the significance envelope are red if protein levels are increased, blue if protein levels are decreased and white if levels are within the envelope or unchanged. Darker shades of color represent greater change in biomarker activity relative to vehicle control.
  • Figure 5 depicts the BioMAP profile of SNA-101 in the Diversity PLUS Panel at the indicated concentrations.
  • the X-axis lists the quantitative protein-based biomarker readouts measured in each system.
  • the grey region around the Y-axis represents the 95% significance envelope generated from historical vehicle controls.
  • Biomarker activities are annotated when 2 or more consecutive concentrations change in the same direction relative to vehicle controls, are outside of the significance envelope, and have at least one concentration with an effect size > 20% (
  • Biomarker key activities are described as modulated if these activities increase in some systems, but decrease in others.
  • Cytotoxicity is indicated on the profile plot by a thin black arrow above the X-axis, and antiproliferative effects are indicated by a thick grey arrow. Cytotoxicity and antiproliferative arrows may only require one concentration to meet the indicated threshold for profile annotation.
  • Other BioMAP profiles disclosed herein are also depicted in a similar manner.
  • Figure 6 depicts a Reference Benchmark Overlay of SNA-101 and Benchmark Staurosporine. Common biomarker readouts are annotated when the readout for both profiles is outside of the significance envelope with an effect size > 20% (
  • Figure 7 depicts an overlay of SNA-101 (300 mM) and N037 (490 ng/ml), which was the top similarity match from a search of the BioMAP Reference Database of > 4,000 agents for SNA-101 (300 mM).
  • Common biomarker readouts are annotated when the readout for both profiles is outside of the significance envelope with an effect size > 20% (
  • Figure 8 depicts an overlay of SNA-101 (100 mM) and Infliximab (30000 ng/ml), which was the top similarity match from a search of the BioMAP Reference Database of > 4,000 agents for SNA-101 (100 mM).
  • Common biomarker readouts are annotated when the readout for both profiles is outside of the significance envelope with an effect size > 20% (
  • Figure 9 depicts Mechanism HeatMAP Analysis for SNA-101. HeatMAP analysis of the 148 biomarker readouts (rows) within the Diversity PLUS panel by SNA-101 in comparison to 19 consensus mechanism class profiles (columns). Horizontal grey lines separate the 12 Diversity PLUS systems, while the vertical grey line separates SNA-101 from the 19 consensus mechanism profiles. Biomarker activities outside of the significance envelope are red if protein levels are increased, blue if protein levels are decreased and white if levels are within the envelope or unchanged. Darker shades of color represent greater change in biomarker activity relative to vehicle control.
  • Figure 10 depicts the BioMAP profile of SNA-103 in the Diversity PLUS Panel.
  • the X-axis lists the quantitative protein-based biomarker readouts measured in each system.
  • the grey region around the Y- axis represents the 95% significance envelope generated from historical vehicle controls.
  • Biomarker activities are annotated when 2 or more consecutive concentrations change in the same direction relative to vehicle controls, are outside of the significance envelope, and have at least one concentration with an effect size > 20% (
  • Biomarker key activities are described as modulated if these activities increase in some systems, but decrease in others.
  • Cytotoxicity is indicated on the profile plot by a thin black arrow above the X-axis, and antiproliferative effects are indicated by a thick grey arrow. Cytotoxicity and antiproliferative arrows may only require one concentration to meet the indicated threshold for profile annotation. Other BioMAP profiles disclosed herein are also depicted in a similar manner.
  • Figure 11 depicts a Reference Benchmark Overlay of SNA- 103 and Benchmark Calcipotriene. Common biomarker readouts are annotated when the readout for both profiles is outside of the significance envelope with an effect size > 20% (
  • Figure 12 depicts an overlay of SNA-103 (230 mM) and Apoptolidin (1 mM), which was the top similarity match from a search of the BioMAP Reference Database of > 4,000 agents for SNA-103 (230 mM).
  • Common biomarker readouts are annotated when the readout for both profiles is outside of the significance envelope with an effect size > 20% (
  • Figure 13 depicts Mechanism HeatMAP Analysis for SNA-103.
  • Horizontal grey lines separate the 12 Diversity PLUS systems, while the vertical grey line separates SNA-103 from the 19 consensus mechanism profiles.
  • Biomarker activities outside of the significance envelope are red if protein levels are increased, blue if protein levels are decreased and white if levels are within the envelope or unchanged. Darker shades of color represent greater change in biomarker activity relative to vehicle control.
  • Figure 14 depicts clustering of test agent profiles following pairwise correlation analysis and clustering of the most similar profiles.
  • Each colored circle represents the BioMAP profile of a compound at a specific concentration, with larger circles representing higher concentrations.
  • Figure 15 depicts the BioMAP profile of SNA-352 in the Diversity PLUS Panel.
  • the X-axis lists the quantitative protein-based biomarker readouts measured in each system.
  • the grey region around the Y- axis represents the 95% significance envelope generated from historical vehicle controls.
  • Biomarker activities are annotated when 2 or more consecutive concentrations change in the same direction relative to vehicle controls, are outside of the significance envelope, and have at least one concentration with an effect size > 20% (
  • Biomarker key activities are described as modulated if these activities increase in some systems, but decrease in others.
  • Cytotoxicity is indicated on the profile plot by a thin black arrow above the X-axis, and antiproliferative effects are indicated by a thick grey arrow. Cytotoxicity and antiproliferative arrows may only require one concentration to meet the indicated threshold for profile annotation. Other BioMAP profiles disclosed herein are also depicted in a similar manner.
  • Figure 16 depicts a Reference Benchmark Overlay of SNA-352 and Benchmark Cyclosporin A. Common biomarker readouts are annotated when the readout for both profiles is outside of the significance envelope with an effect size > 20% (
  • Figure 17 depicts the changes in secretion of (a) IL-17F (b) IgG, (c) IL-17A, and (d) TNFa in the BioMAP BT system mediated by SNA-352 (3.9 mM), Tofacitinib (3.3 mM), Apremilast (3.3 mM), SR221 1 (3.3 mM), and Cyclosporin A (3.3 mM).
  • Figure 18 depicts an overlay of SNA-352 (3.9 mM) and Deferoxamine Mesylate (4.4 mM), which was the top similarity match from a search of the BioMAP Reference Database of > 4,000 agents.
  • Common biomarker readouts are annotated when the readout for both profiles is outside of the significance envelope with an effect size > 20% (
  • Figure 19 depicts Mechanism HeatMAP Analysis for SNA-352.
  • Horizontal grey lines separate the 12 Diversity PLUS systems, while the vertical grey line separates SNA-352 from the 19 consensus mechanism profiles.
  • Biomarker activities outside of the significance envelope are red if protein levels are increased, blue if protein levels are decreased and white if levels are within the envelope or unchanged. Darker shades of color represent greater change in biomarker activity relative to vehicle control.
  • Figure 20 depicts the SNA-352 kinase inhibition profile at test concentrations of 100nM and 200nM for the top inhibited kinases as well as those kinases in the middle in the inhibition spectrum.
  • Figure 21 depicts a JAK2 vs Staurosporine concentration-%inhibition curve used to derive the slope (1.853), R 2 (1.00), and IC 5 o (4.30E-10).
  • Figure 22 depicts a JAK2 vs CT340 concentration-%inhibition curve used to derive the slope (1.147), R 2 (1.00), and IC 5 o (1.35E-07).
  • Figure 23 depicts a JAK3 vs Staurosporine concentration-%inhibition curve used to derive the slope (1.597), R 2 (1.00), and IC 50 (2.78E-10).
  • Figure 24 depicts a JAK3 vs CT340 concentration-%inhibition curve used to derive the slope (1.164), R 2 (1.00), and IC 50 (3.87E-08).
  • Figure 25 depicts a PDGFRb vs Staurosporine concentration-%inhibition curve used to derive the slope (2.900), R 2 (1.00), and IC 5 o (3.87E-10).
  • Figure 26 depicts a PDGFRb vs CT340 concentration-%inhibition curve used to derive the slope (1.165), R 2 (1.00), and IC 50 (1.12E-07).
  • Figure 27 depicts a TRKA vs Staurosporine concentration-%inhibition curve used to derive the slope (2.106), R 2 (1.00), and IC 50 (5.02E-10).
  • Figure 28 depicts a TRKA vs CT340 concentration-%inhibition curve used to derive the slope (1.159), R 2 (1.00), and IC 5 o (2.55E-08).
  • Figure 29 depicts a MAP2K1 vs Staurosporine concentration-%inhibition curve used to derive the slope (1.287), R 2 (1.00), and IC 5 o (1.39E-09).
  • Figure 30 depicts a MAP2K1 vs CT340 concentration-%inhibition curve used to derive the slope (1.434), R 2 (1.00), and IC 50 (1.96E-08).
  • Figure 31 depicts a MAP2K3 vs Staurosporine concentration-%inhibition curve used to derive the slope (1.402), R 2 (1.00), and IC 5 o (1.13E-09).
  • Figure 32 depicts a MAP2K3 vs CT340 concentration-%inhibition curve used to derive the slope (1.41 1), R 2 (1.00), and IC 50 (1.26E-08).
  • Figure 33 depicts a TAK1-TAB1 vs Staurosporine concentration-%inhibition curve used to derive the slope (1.369), R 2 (.98), and IC 5 o (4.14E-08).
  • Figure 34 depicts a TAK1-TAB1 vs CT340 concentration-%inhibition curve used to derive the slope (1.480), R 2 (.98), and IC 50 (2.19E-07).
  • Figure 35 depicts the BioMAP profile of SNA-120 in the Diversity PLUS Panel.
  • the X-axis lists the quantitative protein-based biomarker readouts measured in each system.
  • the grey region around the Y- axis represents the 95% significance envelope generated from historical vehicle controls.
  • Biomarker activities are annotated when 2 or more consecutive concentrations change in the same direction relative to vehicle controls, are outside of the significance envelope, and have at least one concentration with an effect size > 20% (
  • Biomarker key activities are described as modulated if these activities increase in some systems, but decrease in others.
  • Cytotoxicity is indicated on the profile plot by a thin black arrow above the X-axis, and antiproliferative effects are indicated by a thick grey arrow. Cytotoxicity and antiproliferative arrows may only require one concentration to meet the indicated threshold for profile annotation. Other BioMAP profiles disclosed herein are also depicted in a similar manner.
  • Figure 36 depicts a Reference Benchmark Overlay of SNA- 120 and Benchmark SR221 1.
  • Common biomarker readouts are annotated when the readout for both profiles is outside of the significance envelope with an effect size > 20% (
  • Figure 37 depicts an overlay of SNA-120 (28 mM) and GSK690693 (10 mM), which was the top similarity match from a search of the BioMAP Reference Database of > 4,000 agents for SNA-120 (28 mM).
  • Common biomarker readouts are annotated when the readout for both profiles is outside of the significance envelope with an effect size > 20% (
  • Figure 38 depicts Mechanism HeatMAP Analysis for SNA-120. HeatMAP analysis of the 148 biomarker readouts (rows) within the Diversity PLUS panel by SNA- 120 in comparison to 19 consensus mechanism class profiles (columns). Horizontal grey lines separate the 12 Diversity PLUS systems, while the vertical grey line separates SNA-120 from the 19 consensus mechanism profiles. Biomarker activities outside of the significance envelope are red if protein levels are increased, blue if protein levels are decreased and white if levels are within the envelope or unchanged. Darker shades of color represent greater change in biomarker activity relative to vehicle control.
  • Figure 39 depicts the BioMAP profile of SNA-125 in the Diversity PLUS Panel.
  • the X-axis lists the quantitative protein-based biomarker readouts measured in each system.
  • the grey region around the Y- axis represents the 95% significance envelope generated from historical vehicle controls.
  • Biomarker activities are annotated when 2 or more consecutive concentrations change in the same direction relative to vehicle controls, are outside of the significance envelope, and have at least one concentration with an effect size > 20% (
  • Biomarker key activities are described as modulated if these activities increase in some systems, but decrease in others.
  • Cytotoxicity is indicated on the profile plot by a thin black arrow above the X-axis, and antiproliferative effects are indicated by a thick grey arrow. Cytotoxicity and antiproliferative arrows may only require one concentration to meet the indicated threshold for profile annotation. Other BioMAP profiles disclosed herein are also depicted in a similar manner.
  • Figure 40 depicts a Reference Benchmark Overlay of SNA- 125 and Benchmark Tofacitinib. Common biomarker readouts are annotated when the readout for both profiles is outside of the significance envelope with an effect size > 20% (
  • Figure 41 depicts an overlay of SNA-125 (3.9 mM) and SB203580 (10 mM), which was the top similarity match from a search of the BioMAP Reference Database of > 4,000 agents for SNA-125 (3.9 mM).
  • Common biomarker readouts are annotated when the readout for both profiles is outside of the significance envelope with an effect size > 20% (
  • Figure 42 depicts Mechanism HeatMAP Analysis for SNA-125. HeatMAP analysis of the 148 biomarker readouts (rows) within the Diversity PLUS panel by SNA- 125 in comparison to 19 consensus mechanism class profiles (columns). Horizontal grey lines separate the 12 Diversity PLUS systems, while the vertical grey line separates SNA-125 from the 19 consensus mechanism profiles. Biomarker activities outside of the significance envelope are red if protein levels are increased, blue if protein levels are decreased and white if levels are within the envelope or unchanged. Darker shades of color represent greater change in biomarker activity relative to vehicle control.
  • Figure 43 depicts the BioMAP profile of SNA-125 in the Diversity PLUS Panel.
  • the X-axis lists the quantitative protein-based biomarker readouts measured in each system.
  • the grey region around the Y- axis represents the 95% significance envelope generated from historical vehicle controls.
  • Biomarker activities are annotated when 2 or more consecutive concentrations change in the same direction relative to vehicle controls, are outside of the significance envelope, and have at least one concentration with an effect size > 20% (
  • Biomarker key activities are described as modulated if these activities increase in some systems, but decrease in others.
  • Cytotoxicity is indicated on the profile plot by a thin black arrow above the X-axis, and antiproliferative effects are indicated by a thick grey arrow. Cytotoxicity and antiproliferative arrows may only require one concentration to meet the indicated threshold for profile annotation. Other BioMAP profiles disclosed herein are also depicted in a similar manner.
  • Figure 44 depicts a Reference Benchmark Overlay of SNA- 125 and Benchmark K252a. Common biomarker readouts are annotated when the readout for both profiles is outside of the significance envelope with an effect size > 20% (
  • Figure 45 depicts an overlay of SNA-125 (30 mM) and IKK 16 (370 nM), which was the top similarity match from a search of the BioMAP Reference Database of > 4,000 agents for SNA-125 (30 mM).
  • Common biomarker readouts are annotated when the readout for both profiles is outside of the significance envelope with an effect size > 20% (
  • Figure 46 depicts Mechanism HeatMAP Analysis for SNA-125. HeatMAP analysis of the 148 biomarker readouts (rows) within the Diversity PLUS panel by SNA- 125 in comparison to 19 consensus mechanism class profiles (columns). Horizontal grey lines separate the 12 Diversity PLUS systems, while the vertical grey line separates SNA-125 from the 19 consensus mechanism profiles. Biomarker activities outside of the significance envelope are red if protein levels are increased, blue if protein levels are decreased and white if levels are within the envelope or unchanged. Darker shades of color represent greater change in biomarker activity relative to vehicle control.
  • Figure 47 depicts a BioMAP profile overlay of SNA-125 (10 mM), Methotrexate 10 mM), and Tofacitinib (10 mM).
  • Figure 48 depicts representative chromatograms detected using UV analysis (A) and MS analysis (B).
  • Figure 49 depicts chromatograms of a CT101 plasma standard extract (100 mg/mL) detected using SIR (TIC, upper) and UV (lower).
  • Figure 50 depicts method validation.
  • Figure 51 depicts individual chromatograms used for the analysis of CT101 (sample: plasma spiked with CT101 for 100 mg/mL). Top chromatogram: 1 167.5; middle chromatogram: 778.6, bottom chromatogram: 584.2.
  • Figure 52 depicts mouse plasma concentrations of CT101. Data are presented as Mean ⁇ Cl 95%.
  • Figure 53 depicts representative chromatograms showing CT101 in extracted murine plasma following intra-venous administration. Top chromatogram: 2 hours. Middle chromatogram: 10 minutes, bottom chromatogram: blank murine plasma.
  • Figure 54 depicts representative chromatograms showing CT101 in extracted murine plasma following epicutaneous administration. Top chromatogram: 8 hours, middle chromatogram: 0 hours, bottom chromatogram: blank murine plasma.
  • Figure 55 depicts Chromatograms of a CT103 plasma standard extract (50 mg/mL) detected using SIR (TIC, upper) and UV at 337 nm (lower).
  • Figure 57 depicts method validation. Arrows denote peaks of LOO and LOQ.
  • Figure 58 depicts individual chromatograms of SIR channels used for the analysis of compound (sample: plasma spiked with compound at 50 mg/mL). Top chromatogram: 794; middle chromatogram: 595.8, bottom chromatogram: 476.8.
  • Figure 60 depicts mouse plasma concentrations of CT103. Data are presented as Mean ⁇ Cl 95%.
  • Figure 61 depicts plasma levels after intravenous dosing.
  • Figure 62 depicts body weight versus day of study - males.
  • Figure 63 depicts body weight versus day of study - males.
  • Figure 64 depicts plasma levels after intravenous dosing - Day 1.
  • Figure 65 depicts plasma levels after intravenous dosing - Week 2.
  • Figure 66 depicts body weight versus day of study - Males.
  • Figure 67 depicts body weight versus day of study - Males.
  • Figure 68 depicts body weight versus day of study (Main phase) - Males.
  • Figure 69 depicts body weight versus day of study (Main phase) - Males.
  • Figure 70 depicts CT327 calibration curves in rat plasma used to determine pharmacokinetic plasma levels (dotted lines represent upper and lower confidence limits).
  • Figure 71 depicts mean plasma concentration-time after dose profile of CT327 (SNA-120) after a single intravenous administration at 18 mg/kg. Open symbols represent the average measured values ( ⁇ 95% Cl, vertical bar), while filled-in symbols represent interpolated values.
  • Figure 72 depicts raw luminescence values for a CT101 pre-incubation time of 6 hours and a stimulation time of 24 hours. Each symbol represents an individual well. Each condition was tested in sextuplicate.
  • Figure 73 depicts fold induction of Luciferase above non-stimulated cells for a CT101 pre-incubation time of 6 hours and a stimulation time of 24 hours.
  • Figure 74 depicts raw luminescence values for a CT101 pre-incubation time of 18 hours and a stimulation time of 24 hours. Each condition was tested in sextuplicate except for Jurkat cells were conditions were tested in triplicate.
  • Figure 75 depicts fold induction of Luciferase above non-stimulated cells for a CT101 pre-incubation time of 18 hours and a stimulation time of 24 hours.
  • Figure 76 depicts raw luminescence values for a CT101 pre-incubation time of 24 hours and a stimulation time of 24 hours. Each condition was tested in sextuplicate except for Jurkat cells where conditions were tested in triplicate.
  • Figure 77 depicts fold induction of Luciferase above non-stimulated cells for a CT101 pre-incubation time of 24 hours and a stimulation time of 24 hours.
  • Figure 78 depicts raw luminescence values for a CT101 pre-incubation time of 6 hours and a stimulation time of 6 hours. Each condition was tested in sextuplicate.
  • Figure 79 depicts fold induction of Luciferase above non-stimulated cells for a CT101 pre-incubation time of 6 hours and a stimulation time of 6 hours.
  • Figure 80 depicts raw luminescence values for a CT101 pre-incubation time of 18 hours and a stimulation time of 6 hours. Each condition was tested in sextuplicate except for Jurkat cells were conditions were tested in triplicate.
  • Figure 81 depicts fold induction of Luciferase above non-stimulated cells for a CT101 pre-incubation time of 18 hours and a stimulation time of 6 hours.
  • Figure 82 depicts raw luminescence values for a CT101 pre-incubation time of 24 hours and a stimulation time of 6 hours. Each condition was tested in sextuplicate.
  • Figure 83 depicts fold induction of Luciferase above non-stimulated cells for a CT101 pre-incubation time of 24 hours and a stimulation time of 6 hours.
  • Figure 84 depicts percentage cytotoxicity for a CT101 pre-incubation time of 6 hours and a stimulation time of 24 hours.
  • Figure 85 depicts percentage cytotoxicity for a CT101 pre-incubation time of 18 hours and a stimulation time of 24 hours.
  • Figure 86 depicts percentage cytotoxicity for a CT101 pre-incubation time of 24 hours and a stimulation time of 24 hours.
  • Figure 87 depicts percentage cytotoxicity for a CT101 pre-incubation time of 24 hours and a stimulation time of 6 hours.
  • Figure 88 depicts percentage cytotoxicity for a CT101 pre-incubation time of 6 hours and a stimulation time of 6 hours.
  • Figure 89 depicts tritiated thymidine incorporation in corrected counts per minute (CCPM). Data are presented as Mean ⁇ SEM.
  • Figure 90 depicts Tritiated thymidine incorporation in corrected counts per minute (CCPM). Data are presented as Mean ⁇ SEM.
  • Figure 91 depicts tritiated thymidine incorporation in corrected counts per minute (CCPM).
  • CCPM corrected counts per minute
  • Figure 92 depicts percentage inhibition by CT103 with 18 hour pre-incubation time ,5x103 cells per well and 50ng/mL VEGF stimulation. Percentage inhibition of VEGF induced proliferation by CT103. Proliferation in the absence of VEGF (0 ng/mL VEGF) was subtracted from VEGF induced proliferation (50 ng/mL) and divided by 50 ng/mL VEGF stimulated cell proliferation in the absence of drug (DMSO).
  • DMSO drug
  • Figure 93 depicts tritiated thymidine incorporation in corrected counts per minute (CCPM). Data are presented as Mean ⁇ SEM.
  • Figure 94 depicts non-linear fit of transformed normalised maximal response for IC50 calculation.
  • the DMSO (0 mM CT103) treated VEGF-induced HUVEC proliferation was excluded from the IC50 calculation as it was lower than the 3 lowest concentrations of CT103, which had reached a consistent plateau as can be seen above.
  • the IC50 was calculated as 18.5 mM.
  • Figure 95 depicts percentage inhibition of VEGF induced proliferation by CT103. Proliferation in the absence of VEGF was subtracted from VEGF induced proliferation and divided by VEGF stimulated cell proliferation in the absence of drug (DMSO).
  • Figure 96 depicts luciferase activity of THP1 cells stimulated with a concentration range of HKLM or LPS, calculated relative to unstimulated cells.
  • Figure 98 depicts the inhibition of proliferation by K252a, CT327 and CT340. Column bar graphs of proliferation assay results expressed as Absorbance at 570 nm with reference at 650 nm.
  • Figure 99 depicts the inhibition of proliferation by K252a, CT327 and CT340.
  • Figure 100 depicts the inhibition of proliferation by K252a, CT327 and CT340. Column bar graphs of proliferation assay results expressed as Absorbance at 570 nm with reference at 650 nm.
  • Figure 101 depicts (a) colitis development was evaluated monitoring colon shortening at mice sacrifice, (b) weight loss during the experiment, and (c) colitis clinical score at sacrifice.
  • CT100 and CT300 data points refer to 100 and 300 mg/kg CT352 in vehicle.
  • CsA data points refer to 25 mg/kg cyclsporin A (positive control).
  • Figure 102 depicts qRTPCR analysis of inflammatory cytokines and chemokines expression.
  • RNA from whole proximal and distal colon was analysed and an increased expression of cytokines (IL6, IL17) and chemokines (MIP1 a and MIP2) related to inflammation was detected in DSS treated mice, while this response was counteracted by CsA (positive control) and CT352 administration at the same time.
  • Figure 103 depicts histological analysis of colon samples. The extension and the degree of the colitis were determined in blind and the score assigned to each samples reported in the colitis clinical score graph (a). A representative sample image from each group was reported (4X magnification) (b).
  • Figure 104 depicts the (A) colon dissection diagram and (B) fields and scoring order employed in the oxazolone-induced colitis mouse study.
  • Figure 105 depicts the effect of SNA- 125, SNA-352, tofacitinib, and prednisolone on the body weight of animals challenged with oxazolone. Compounds or vehicle controls were dosed BID as indicated intracecally (IC) or orally (PO).
  • Figure 105A depicts percent body weight change from Day -1 to Day 4 of the study.
  • Figure 105B depicts the area under the curve (AUC) of the percent weight change depicted in Figure 105A.
  • Figure 106 depicts the effect of SNA- 125, SNA-352, tofacitinib, and prednisolone on the body weight of animals challenged with oxazolone according to last observation carried forward analysis. Compounds or vehicle controls were dosed BID as indicated intracecally (IC) or orally (PO).
  • Figure 106A depicts percent body weight change from Day -1 to Day 4 of the study.
  • Figure 106B depicts the area under the curve (AUC) of the percent weight change depicted in Figure 106A.
  • Figure 107 depicts the effect of SNA-125, SNA-352, tofacitinib, and prednisolone on the Day 2 endoscopy score of animals challenged with oxazolone by (A) bar chart and (B) dot plot. Compounds or vehicle controls were dosed BID as indicated intracecally (IC) or orally (PO).
  • Figure 108 depicts the effect of SNA- 125, SNA-352, tofacitinib, and prednisolone on the Day 2 stool consistency score of animals challenged with oxazolone by (A) bar chart and (B) dot plot. Compounds or vehicle controls were dosed BID as indicated intracecally (IC) or orally (PO).
  • Figure 109 depicts the effect of SNA- 125, SNA-352, tofacitinib, and prednisolone on the Day 4 endoscopy score of animals challenged with oxazolone by (A) bar chart and (B) dot plot. Compounds or vehicle controls were dosed BID as indicated intracecally (IC) or orally (PO).
  • Figure 1 10 depicts the effect of SNA-125, SNA-352, tofacitinib, and prednisolone on the Day 4 stool consistency score of animals challenged with oxazolone by (A) bar chart and (B) dot plot. Compounds or vehicle controls were dosed BID as indicated intracecally (IC) or orally (PO).
  • Figure 1 1 1 depicts the effect of SNA-125, SNA-352, tofacitinib, and prednisolone on the disease activity index (DAI) score of animals at (A) Day 2 and (B) Day 4 following challenge with oxazolone.
  • DAI disease activity index
  • Compounds or vehicle controls were dosed BID as indicated intracecally (IC) or orally (PO).
  • Figure 1 12 depicts the effect of SNA-125, SNA-352, tofacitinib, and prednisolone on the colon weight/length ratio of animals challenged with oxazolone.
  • Compounds or vehicle controls were dosed BID as indicated intracecally (IC) or orally (PO).
  • Figure 1 13 depicts the effect of SNA-125, SNA-352, tofacitinib, and prednisolone on the colon inflammation histopathology scores of animals challenged with oxazolone.
  • Compounds or vehicle controls were dosed BID as indicated intracecally (IC) or orally (PO). Group means with standard error of the mean (SEM) bars are depicted.
  • Figure 1 14 depicts the effect of SNA-125, SNA-352, tofacitinib, and prednisolone on the colon edema histopathology scores of animals challenged with oxazolone.
  • Compounds or vehicle controls were dosed BID as indicated intracecally (IC) or orally (PO). Group means with standard error of the mean (SEM) bars are depicted.
  • Figure 1 15 depicts the effect of SNA-125, SNA-352, tofacitinib, and prednisolone on the colon mucosal necrosis/loss histopathology scores of animals challenged with oxazolone.
  • Compounds or vehicle controls were dosed BID as indicated intracecally (IC) or orally (PO). Group means with standard error of the mean (SEM) bars are depicted.
  • Figure 1 16 depicts the effect of SNA-125, SNA-352, tofacitinib, and prednisolone on the summed colon histopathology scores of animals challenged with oxazolone.
  • Compounds or vehicle controls were dosed BID as indicated intracecally (IC) or orally (PO). Group means with standard error of the mean (SEM) bars are depicted.
  • Figure 1 17 depicts representative control animal H&E-stained colon histopathology micrographs at 40x and 100x magnifications.
  • Figure 1 18 depicts representative H&E-stained colon histopathology micrographs at 40x and 100x magnifications for animals administered BID
  • A Vehicle PO
  • B 15 mg/kg Tofacitinib PO
  • C 1 mg/kg Prednisolone PO
  • D 400 mg/kg SNA- 125 PO
  • E 400 mg/kg SNA-352 PO.
  • Moderate inflammation unfilled black arrows
  • edema filled red arrows
  • multifocal ulceration (brackets) are indicated.
  • Figure 1 19 depicts representative H&E-stained colon histopathology micrographs at 40x and 100x magnifications for animals administered BID
  • A Vehicle IC
  • B 1 mg/kg Tofacitinib IC
  • C 400 mg/kg SNA-125 IC
  • D 400 mg/kg SNA-352 IC.
  • Figure 120 depicts the effect of SNA- 125, SNA-352, tofacitinib, and prednisolone on the proein levels of IFNy in colon tissue homogenate supernatants of animals following challenge with oxazolone.
  • Compounds or vehicle controls were dosed BID as indicated intracecally (IC) or orally (PO). Group means with standard error of the mean (SEM) bars are depicted.
  • Figure 121 depicts the effect of SNA-125, SNA-352, tofacitinib, and prednisolone on the protein levels of TNFa in colon tissue homogenate supernatants of animals following challenge with oxazolone.
  • Compounds or vehicle controls were dosed BID as indicated intracecally (IC) or orally (PO). Group means with standard error of the mean (SEM) bars are depicted, with outliers removed (A), or present (B).
  • Figure 122 depicts the effect of SNA- 125, SNA-352, tofacitinib, and prednisolone on the protein levels of IL-6 in colon tissue homogenate supernatants of animals following challenge with oxazolone.
  • Compounds or vehicle controls were dosed BID as indicated intracecally (IC) or orally (PO).
  • Group means with standard error of the mean (SEM) bars are depicted, with outliers removed (A), or present (B).
  • Figure 123 depicts the effect of SNA- 125, SNA-352, tofacitinib, and prednisolone on the protein levels of IL-10 in colon tissue homogenate supernatants of animals following challenge with oxazolone.
  • Compounds or vehicle controls were dosed BID as indicated intracecally (IC) or orally (PO).
  • Group means with standard error of the mean (SEM) bars are depicted, with outliers removed (A), or present (B).
  • Figure 124 depicts bodyweights. Data are presented as Mean ⁇ SEM percentages of the initial bodyweights. # p ⁇ 0.05 and ### p ⁇ 0.001 when compared to Day 0. ° p ⁇ 0.05, °° p ⁇ 0.01 and **** p ⁇ 0.0001 when compared to the vehicle-treated group.
  • Figure 125 depicts ear swelling. Data are presented as Mean ⁇ SEM. ### p ⁇ 0.0001 in the vehicle-treated group when compared to Day 0. °° p ⁇ 0.01 , °°° p ⁇ 0.001 and when compared to the vehicle-treated group. Betamethasone 0.1
  • Figure 126 depicts macroscopic scores. Data are presented as Mean ⁇ SEM.
  • Figure 127 depicts cytokine levels in ears (mg/ml).
  • A. IL-1 b B. IFN-y C. IL-4 D. IL- 10.
  • Data are presented as Mean ⁇ SEM. **** p ⁇ 0.0001 , ** p ⁇ 0.001 , * p ⁇ 0.01 when compared to the Vehicle treated group. //////// p ⁇ 0.0001 , ### p ⁇ 0.001 when compared to the right ear within the same group.
  • Figure 128 depicts bodyweights. Data are presented as Mean ⁇ SEM of the initial (Day -13) bodyweights. * p ⁇ 0.05, ** p ⁇ 0.01.
  • Figure 129 depicts ear swelling. Data are presented as Mean ⁇ SEM of the difference between ovalbumin challenged and contralateral (saline-injected) ears. Statistical significances: # p ⁇ 0.05, ## p ⁇ 0.01 , ### p ⁇ 0.001 when compared to the baseline (0 hours) values. * p ⁇ 0.05, ** p ⁇ 0.01 , *** p ⁇ 0.001 when comparing to the Control group.
  • Figure 130 depicts ear swelling at peak disease (fifteen minutes after the ovalbumin challenge). Data are presented as Mean ⁇ SEM of the difference between ovalbumin-challenged and contralateral (saline-injected) ears. Statistical significances: * p ⁇ 0.05, ** p ⁇ 0.01 , *** p ⁇ 0.001 when compared to the vehicle-treated group.
  • Figure 131 depicts erythema scores (Challenged ears). Data are presented as Mean ⁇ SEM.
  • Figure 132 depicts erythema scores (Challenged ears). Data are presented as Mean ⁇ SEM.
  • Figure 133 depicts histopathology scores (Left ears). Data are presented as Mean ⁇ SEM. ** p ⁇ 0.01 , *** p ⁇ 0.001 when compared to the Control group.
  • Figure 134 depicts representative histopathology pictures. Left panel: Left ears. Right panel: Right ears. Top line: Control Group. Middle line: Betamethasone 0.1 %- treated group. Bottom line: Vehicle-treated group. Magnification: x100.
  • Figure 135 depicts representative histopathology pictures. Left panel: Left ears. Right panel: Right ears. Top line: CT101_5%-treated group. Middle line: CT101_10%- treated group. Bottom line: CT101_20%-treated group. Magnification: x100.
  • Figure 136 depicts bodyweights. Data are presented as Mean ⁇ SEM percentages of the initial bodyweights. * p ⁇ 0.05, *** p ⁇ 0.001 , **** p ⁇ 0.0001 when compared to the vehicle-treated group; # # # p ⁇ 0.001 , # # # # p ⁇ 0.0001 when compared to Day 0.
  • Figure 137 depicts erythema scores. Data are presented as Mean ⁇ SEM. * p ⁇ 0.05, ** p ⁇ 0.01 , *** p ⁇ 0.001 , **** p ⁇ 0.0001 when compared to the vehicle-treated group.
  • Figure 138 depicts scaling scores. Data are presented as Mean ⁇ SEM. * p ⁇ 0.05, *** p ⁇ 0.01 and **** p ⁇ 0.0001 when compared to the vehicle-treated group.
  • Figure 139 depicts thickness scores. Data are presented as Mean ⁇ SEM. * p ⁇ 0.05, *** p ⁇ 0.001 , **** p ⁇ 0.0001.
  • Figure 140 depicts clinical scores. Data are presented as Mean ⁇ SEM. * p ⁇ 0.05, ** p ⁇ 0.01 , *** p ⁇ 0.001 and **** p ⁇ 0.0001 when compared to the vehicle-treated group.
  • Figure 141 depicts normalized body weight trends.
  • Figure 142 depicts scar formation; SEI of saline-injected scars (Group 1 , Left Ears). Values are expressed as mean ⁇ StdDev.
  • Figure 143 depicts scar formation; SEI of vehicle-treated scars (Group 1 , Right Ears). Values are expressed as mean ⁇ StdDev.
  • Figure 144 depicts scar formation; SEI of CT340-injected scars (Group 2). Values are expressed as mean ⁇ StdDev.
  • Figure 145 depicts Scar Formation; SEI of CT340 topical-dosed scars (Group 3). Values are expressed as mean ⁇ StdDev.
  • Figure 146 depicts Scar Formation; SEI of TACA-treated scars (Group 4). Values are expressed as mean ⁇ StdDev.
  • Figure 147 depicts scar formation; summary of SEI. Values are expressed as mean ⁇ StdDev.
  • Figure 148 depicts scar formation following intra-lesion injections with CT340 or
  • Figure 149 depicts scar formation following topical dosing with CT340
  • Figure 150 depicts scar formation SEI of CT340-treated scars, Values are expressed as mean ⁇ StdDev.
  • Figure 151 depicts scar inflammation scores following intra-lesion injections with CT340 or TACA. Values are expressed as mean ⁇ StdDev.
  • Figure 152 depicts scar inflammation scores following topical dosing with CT340, Values are expressed as mean ⁇ StdDev.
  • Figure 156 depicts anti-NGF antibody effect on Capsaicin responses. Inhibition of capsaicin responses in DRG neurons by anti-NGF was between 37.4 ⁇ 7.7% (100 ng/ml), and 63.3 ⁇ 9.7% (10 mg/ml). Results are given as mean (percent inhibition) ⁇ s.e.m.
  • Figure 157 depicts the effect of compound incubation on neurite length. Treatment with CT327 and CT340 at 1 nM, 10 nM, 100 nM, 1 mM and 10 mM concentrations did not affect neurite length of neurons compared with control. Treatment with GW441756 resulted in vesiculation and reduced neurite length at the higher concentrations of 1 mM and 10 mM. Anti-NGF antibody treatment at 1 and 10 mg/ml concentrations also did not affect neurite length. Neurite lengths were normalized to controls and are given as mean percent of control ⁇ s.e.m.
  • Figure 158 depicts the effect of CT327 incubation on neurite length. 24 hour Incubation with CT327 did not have any effect on neurite length. Neurite lengths are expressed as mean percent of control ⁇ s.e.m.
  • Figure 159 depicts the effect of CT340 incubation on neurite length. 24 hour Incubation with CT340 did not significantly affect neurite length compared to control. Neurite lengths are expressed as mean percent of control ⁇ s.e.m.
  • Figure 160 depicts the effect of GW441756 incubation on neurite length.
  • Neurons treated with 0.33% ethanol (solvent for GW441756) had similar neurite length compared with NGF-treated controls. Neurite lengths are expressed as mean percent of control ⁇ s.e.m.
  • Figure 161 depicts the effect of anti-NGF antibody incubation on neurite length. Neurons treated with anti-NGF at 1 or 10 mg/ml did not show a significant change in neurite length compared to control. Neurite lengths are expressed as mean percent of control ⁇ s.e.m.
  • Figure 162 depicts TrkA/Gap43 immunostaining in DRG neurons: A) Merged image showing co-localization of TrkA and Gap43 immunostaining in DRG neuron; B) Gap43 was strongly localized in cell bodies and neurites; C) TrkA immunostaining was observed to be densely localized in the cell bodies, while neurites were very faint.
  • Figure 163 depicts representative PGP9.5-immunoreactive intra-epithelial nerve fibres (IEFN) (arrowed) in untreated control skin (top panel) and treated skin region (bottom panel) mini-pig skin using an antibody dilution of 1 :40,000, magnification x40.
  • IEFN intra-epithelial nerve fibres
  • Figure 164 depicts a scatter plot showing the PGP9.5 intra epithelial fibre counts in untreated and treated mini-pig skin from the various groups. The median value is indicated.
  • C control; L, low dose; M, medium dose; H high dose; R, recovery; ut untreated area; t treated area.
  • Figure 165 depicts the design of the IMQ-induced psoriasis mouse study.
  • Animal shaving, IMQ cream application, treatment, left ear biopsy punch, body weight measurements, ear thickness measurements, psoriasis clinical scoring, and termination were performed at the indicated tiem points.
  • Figure 166 depicts the change in animal body weight throughout the IMQ-induced psoriasis mouse study.
  • Figure 167 depicts the changes in the total psoriasis score throughout the IMQ- induced psoriasis mouse study.
  • the difference between SNA-125 at 5% and the vehicle is statistically significant from day 7.
  • the differences between SNA- 125 at 0.5% and 1 % and the vehicle are statistically significant on day 10.
  • Figure 168 depicts the changes in the Erythema score throughout the IMQ- induced psoriasis mouse study.
  • SNA-125 at 5% is statistically significant from the vehicle from day 7.
  • SNA- 125 at 0.5% and 1 % are statistically significant on day 10.
  • Figure 169 depicts the changes in the plaque score throughout the IMQ-induced psoriasis mouse study. SNA-125 at 5% is statistically significant from the vehicle on day 10.
  • Figure 170 depicts the changes in the punctate redness/scabbing score throughout the IMQ-induced psoriasis mouse study.
  • Figure 171 depicts the changes in spleen thickness throughout the IMQ-induced psoriasis mouse study
  • Figure 172 depicts the changes in ear thickness throughout the IMQ-induced psoriasis mouse study.
  • Figure 173 depicts the levels of cytokines (a) IL-22, (b) IL-17A, (c) IL17F, and (d) TNFa, in ear samples at Day 4.
  • Figure 174 depicts a schematic showing how the IMQ-induced psoriasis study was performed.
  • Figure 175 depicts the total psoriasis clinical scores over time for all groups (A), the SNA-101 group (B), the SNA-125 group (C), and the SNA-352 group (D). The mean score for each group is displayed for each day +/- SEM.
  • Figure 176 depicts the erythema scores over time for all groups (A), the SNA-101 group (B), the SNA-125 group (C), and the SNA-352 group (D). The mean score for each group is displayed for each day +/- SEM.
  • Figure 177 depicts the plaque scores over time for all groups (A), the SNA-101 group (B), the SNA-125 group (C), and the SNA-352 group (D). The mean score for each group is displayed for each day +/- SEM.
  • Figure 178 depicts the punctate redness/scabbing scores over time for all groups (A), the SNA-101 group (B), the SNA-125 group (C), and the SNA-352 group (D).
  • the mean score for each group is displayed for each day +/- SEM.
  • Figure 179A depicts the weight of spleens upon experimental termination on day 10. Mean spleen weight for each group is displayed +/- SEM.
  • Figure 179B depicts left ear thickness as measured with a caliper on days 0, 4, 6, 8, and 10. Mean thickness for each group is displayed for each day +/- SEM.
  • Figure 179C depicts the daily weight of mice. Body weight changes are displayed for each day as a percent of their weight measured on day 0. Mean values for each group are displayed +/- SEM.
  • Figure 180 depicts the levels of IL-17F (A), TNF-a (B), IL-22 (C), and IL-17A (D) as measured in left ears biopunched on day 4. After tissue homogenization, the cytokine levels in tissue lysates were measured via multiplex and then normalized with total protein amounts. Mean values for each group are displayed +/- SEM.
  • Figure 181 depicts a schematic of the IL-23-induced psoriasis mouse model study.
  • Figure 182 depicts the effect SNA-120 and SNA-325 in an IL-23-induced psoriasis mouse model.
  • Figure 182A depicts the total psoriasis clinical scores for each group over time. The mean score for each group is displayed for each day +/- SEM.
  • Figure 182B depicts the right ear thickness of each group at the indicated time points. Mean thickness for each group is displayed for each day +/- SEM.
  • Figure 182C depicts body weight of each group over the course of the study. Body weight changes are displayed for each day as a percent of their weight measured on day 0. Mean values for each group are displayed +/- SEM.
  • Figure 183 depicts the concentration vs. %lnhibition curves of staurosporine (A) and SNA-352 (B) against LIMK1. The calculated slope and IC50(M) are also depicted).
  • Figure 184 depicts the concentration vs. %lnhibition curves of staurosporine (A) and SNA-352 (B) against MAP2K6. The calculated slope and IC50(M) are also depicted).
  • Figure 185 depicts the concentration vs. %lnhibition curves of staurosporine (A) and SNA-352 (B) against MLK1. The calculated slope and IC50(M) are also depicted).
  • Figure 186 depicts the concentration vs. %lnhibition curves of staurosporine (A) and SNA-352 (B) against MLK3. The calculated slope and IC50(M) are also depicted).
  • Figure 187 depicts representative Day 2 endoscopy images of naive control, vehicle control (PO), vehicle control (IC), and tofacitinib (15 mg/kg PO) animals. Animals underwent video endoscopy on Day 2 and colitis severity was scored on a scale of 0-4. Images were captured from each animal during the procedure and representative images from each treatment group are presented. All doses were administered twice a day (BID).
  • Figure 188 depicts representative Day 2 endoscopy images of tofacitinib (15 mg/kg IC), prednisolone (1 mg/kg PO), SNA-125 (400 mg/kg PO), and SNA-352 (400mg/kg PO) animals. Animals underwent video endoscopy on Day 2 and colitis severity was scored on a scale of 0-4. Images were captured from each animal during the procedure and representative images from each treatment group are presented. All doses were administered twice a day (BID).
  • Figure 214 shows representatives of two possible scenarios for the assignment of test fields as referred to in Example 51.
  • Figure 218 shows the relative percent improvement in disease transcriptome of day 12 lesional tissue versus day 1 lesional tissue as referred to in Example 51. Histogram groupings are, left to right, IMP1 (2 % SNA-125), IMP2 (0.2 % SNA-125), IMP3 (0.5 % SNA-120), and IMP4 (vehicle).
  • Figure 220 shows in life assessment stool consistency scores for day 2 of Example 56.
  • Figure 221 shows in life assessment stool consistency scores for day 4 of Example 56.
  • Figure 222 shows in life assessment colitis severity by endoscopy scores for day 2 of Example 56.
  • Figure 223 shows in life assessment colitis severity by endoscopy scores for day 4 of Example 56.
  • Figure 224 shows in life assessment composite endoscopy DAI scores for day 2 of Example 56.
  • Figure 225 shows in life assessment composite endoscopy DAI scores for day 4 of Example 56.
  • Figure 226 shows terminal assessment body weight change results of Example 56.
  • Figure 227 shows terminal assessment colon weight to length ratio results of Example 56.
  • Figure 228 shows terminal assessment composite DAI scores of Example 56. DETAILED DESCRIPTION
  • LSE platform creates polymer conjugates optimized for topical applications.
  • the polymer conjugates developed by LSE or more generally the reduced exposure technology exhibit enhanced penetration.
  • the enhanced penetration leads to delivery of a high local concentration of the drug.
  • the polymer conjugates show a limited non-target absorption upon topical administration due to their increased molecular size and amphiphilicity and/or amphipathicity.
  • side-effects are minimized by limiting or eliminating non-target (e.g., systemic) absorption.
  • the polymer conjugate comprises a“warhead” linked to a polymer.
  • the warhead is a pharmacologically active entity selected according to the particular target or pathway of interest.
  • polymer conjugates for use in the treatment of conditions including but not limited to inflammatory bowel diseases, dermatological diseases, and ophthalmic conditions).
  • the polymer is directly coupled to the warhead without a separate chemical linking moiety between the polymer and the warhead; such direct coupling may involve without limitation ester, ether, acetal, ketal, vinyl ether, carbamate, urea, amine, amide, enamine, imine, oxime, amidine, iminoester, carbonate, orthoester, phosphonate, phosphinate, sulfonate, sulfinate, sulfide, sulfate, disulfide, sulfinamide, sulfonamide, thioester, aryl, silane, siloxane, heterocycles, thiocarbonate, thiocarbamate, and phosphonamide bonds.
  • the linker is a separate chemical linking moiety between the polymer and the warhead.
  • the polymer is polyethylene glycol (PEG), wherein the terminal OH group can optionally be modified e.g. with C 1 -C5 alkyl or C 1 -C5 acyl groups, e.g., with C 1 -, C2- or C3-alkyl groups or C 1 -, C2- or C3 groups.
  • the modified PEG is a terminally alkoxy-substituted PEG.
  • the modified PEG is a methoxy-PEG (mPEG).
  • the polymer has a molecular weight ranging from about 100 to about 100,000 Da.
  • the polymer is polydisperse with respect to molecular weight (e.g., has a distribution of molecular weights) and the indicated molecular weight of the polymer represents an average molecular weight. In other embodiments, the polymer has a molecular weight ranging from about 200 to about 50,000 Da. In several embodiments, the polymer has a molecular weight ranging from about 500 to about 10,000 Da (e.g., 500-1000, 1000- 2000, 2000-3000, 3000-5000,5000-7000, 7000-10,000 Da, and overlapping ranges therein).
  • the polymer is a short-chain PEG, and in some embodiments a terminally alkoxy-substituted PEG, such as a mPEG with a molecular weight ranging from about 200 to about 4,000 Da, from about 400 to about 3,000 Da, from about 500 to about 2,000 Da, from about 700 to about 3,000 Da, from about 900 to about 4,000 Da, or from about 1 ,000 to about 5,000 Da.
  • the short-chain PEG or mPEG has an average molecular weight of about 1 ,000-3,000 Da. (e.g., 2,000 Da).
  • the polymer is a long-chain PEG.
  • the long-chain PEG may be a terminally alkoxy-substituted PEG, such as methoxy-substituted PEG, with a molecular weight ranging greater than about 4,000 Da. In several embodiments, the molecular weight ranges from about 4,500-10,000Da (e.g., 4,500 to about 5,500 Da). In several embodiments, the long-chain PEG or mPEG has an average molecular weight of about 2,000 Da or of about 5,000 Da. In several embodiments, the polymer is of natural or semi-synthetic or synthetic origin. In several embodiments, the polymer has a linear or branched structure.
  • the polymer is selected from poly(alkylene oxides) or from (polyethylene) oxides.
  • the polymer selected may include, without limitation, one or more of the following: polyacrylic acid, polyacrylates, polyacrylamide or N-alkyl derivatives thereof, polymethacrylic acid, polymethacrylates, polyethylacrylic acid, polyethylacrylates, polyvinylpyrrolidone, poly(vinylalcohol), polyglycolic acid, polylactic acid, poly(lactic-co-glycolic) acid, dextran, chitosan, and hydroxyethyl starch.
  • administration comprises treatment of the gastro-intestinal tract via, for example, an enteric coated capsule comprising the polymer conjugates taken orally.
  • the polymer conjugates provided herein treat inflammatory bowel diseases.
  • conjugating the warhead to a polymer (e.g., PEG) in the disclosed molecular weight ranges may slow diffusion of the molecule in the tissue, thereby potentially increasing residence time of the molecule in the target tissue, e.g. certain regions of the eye, epithelial and sub-epithelial layers in the eye, the epidermis and dermis for skin, the lining of the Gl tract, associated epithelial and sub-epithelial layers in other topical surfaces like gut, eye, lungs, the intestinal epithelium, the intestinal lamina limba, intestinal mucosa, etc.
  • This “depot” effect may also lead to lower concentrations needing to be applied or for products to be applied with lower frequency, or both.
  • the polymer conjugates provided herein are administered to the skin by topical application. In one embodiment, the polymer conjugates provided herein treat inflammatory skin diseases.
  • Eye drops are provided in some embodiments to treat eye inflammation or ophthalmic disorders and diseases.
  • conjugating the warhead to a polymer in the disclosed molecular weight ranges may be useful in reducing the diffusion or extravasation of the molecule out of the circulatory system after it enters it via injection and or diffusion from the target tissue.
  • a polymer e.g., PEG
  • conjugating the warhead to a polymer in the disclosed molecular weight ranges may be useful in reducing the diffusion or extravasation of the molecule out of the circulatory system after it enters it via injection and or diffusion from the target tissue.
  • the PEGylated drug has a volume of distribution that is largely restricted to the blood, indicating that very little extravasation occurs with the polymer conjugates prior to being renally cleared. This reduced extravasation may explain at least in part the observed shorter half-life for the polymer conjugates.
  • compositions described herein may be combined with other modalities to achieve synergic effects.
  • these other modalities include, but are not limited to, energy delivery (such as laser, radiofrequency, ultrasound, microwave, etc.), thermal therapy, light therapy, radiation, intravenous chemotherapy, and others.
  • the compositions are applied with pressure, heat, massage etc. to facilitate localization to the desired target site.
  • the compositions are administered in combination with one or more additional therapeutics that may not be reduced exposure compounds.
  • the polymer conjugate exhibits unexpected permeability across the nuclear membrane. In several embodiments, the polymer conjugate exhibits unexpected permeability across both the nuclear and plasma membranes. Accordingly, in Example 30, two polymer conjugates, SNA-125 and SNA-120, were surprisingly shown to penetrate the keratinocyte cellular membrane and interact with the target kinases intracellularly within the cytoplasm, thereby leading to inhibition of proliferation of keratinocytes in a non-toxic manner.
  • the reduced exposure compounds comprising a hydrophobic drug conjugated to a short chain PEG, exhibit surprising accessibility across cellular compartments, compared to the unconjugated drug.
  • the conjugate can cross and reside within the lipid bilayer of the cell membrane, accumulate within the cytosol, and even traverse the nuclear envelope - thereby providing access both membrane, cytosolic and nuclear molecular targets in several embodiments.
  • This property of the reduced exposure compounds result in excellent depo’ing, longer residence times within target cells, and/or relative non-compartmentalization in several embodiments. Consequently, in many embodiments, these compounds are biologically active at lower concentrations and require less frequent dosing - thereby reducing potential drug toxicity.
  • the invention comprises a reduced exposure composition for treating a target site within the gastrointestinal system, skin, or eye comprising a conjugate comprising one or more active entitites linked to one or more polymers, wherein the active entity is a mediator of a gastrointestinal condition, ophthalmic condition, and/or dermatological condition and has reduced exposure in the systemic system as compared to the gastrointestinal system based on the ability of the conjugate to cross the lipid bilayer and into the cytoplasm and/or cytosol of a plurality of cells within the gastrointestinal system.
  • the invention comprises a reduced exposure composition for treating a dermatological target site comprising a conjugate comprising one or more active entitites linked to one or more polymers, wherein the active entity is a mediator of a dermatological condition and has reduced exposure in the systemic system as compared to the skin based on the ability of the conjugate to cross the lipid bilayer and into the cytoplasm and/or cytosol of a plurality of cells within the target site.
  • the concentration and/or bioavailability of the activity entity in the systemic system in one embodiment, is at an amount that is not active systemically and therefore does not result in undesired systemic side effects.
  • the active entity has little or no exposure to the lymphatic system, thus resulting in little or no immunosuppression. Damage to organs such as the kidney or liver is also nominal because of the reduced exposure to non-target tissue.
  • the warhead employed in the LSE polymer conjugate is an indolocarbazole compound.
  • a polymer conjugate comprising a warhead (e.g., at least one active agent) linked to a polymer, wherein the warhead comprises an indolocarbazole compound.
  • the polymer conjugate comprises an indolocarbazole compound of formula (I) or of formula (II):
  • R 1 and R 2 are the same or a different residue and are each independently selected from the group consisting of:
  • R 5 and R 6 are each independently selected from hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted lower alkylaminocarbonyl, substituted or unsubstituted lower arylaminocarbonyl, alkoxycarbonyl, carbamoyl,
  • R 7 is selected from the group consisting of hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, - (CH 2 ) a CO 2 R 1 ° (wherein a is 1 or 2, and wherein R 10 is selected from the group consisting of hydrogen and substituted or unsubstituted lower alkyl) and -(CH 2 ) a CO 2 NR 5 R 6 ,
  • R 8 is selected from hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl
  • (f) -CH CH(CH 2 )mR 16 , wherein m is 0 to 4, and R 16 is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -COOR 15 , -OR 15 (wherein R 15 is as defined above) - CONR 5 R 6 or -NR 5 R 6 (wherein R 5 and R 6 are as defined above);
  • R 3 is hydrogen, halogen, acyl, carbamoyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted lower alkynyl or amino;
  • W 1 and W 2 are independently hydrogen, hydroxy or W 1 and W 2 together represent oxygen;
  • X is a polymer moiety, either linear or branched
  • A represents -U-X'
  • B represents -L 2 -Y', wherein at least one of X' and Y' is a polymer moiety, either linear or branched, which is bound by L 1 and/or L 2 to the tetrahydrofuran ring of the compound of formula (II);
  • L 1 and/or L 2 are a covalent chemical bond or a linker group
  • R 19 or R 20 are each independently selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl or R 19 or R 20 are independently the residue of an a-amino acid in which the hydroxy group of the carboxyl group is excluded, or R 19 or R 20 are combined with a nitrogen atom to form a heterocyclic group; and
  • L 2 is a covalent chemical bond and Y' is selected from hydroxy, lower alkoxy, aralkyloxy, or acyloxy;
  • the polymer moiety X, X or/and Y' covalently attached to the indolocarbazole compound of formulae (I) and (II) has to be biocompatible, can be of natural or semisynthetic or synthetic origin and can have a linear or branched structure.
  • the polymer moiety X, X or/and Y' is selected from poly(alkylene oxides), in particular from (polyethylene) oxides.
  • polymers include without limitation polyacrylic acid, polyacrylates, polyacrylamide or N-alkyl derivatives thereof, polymethacrylic acid, polymethacrylates, polyethylacrylic acid, polyethylacrylates, polyvinylpyrrolidone, poly(vinylalcohol), polyglycolic acid, polylactic acid, poly(lactic-co-glycolic) acid, dextran, chitosan, polyaminoacids, hydroxyethyl starch.
  • the polymer moiety X, X' or/and Y' is a polyethylene glycol (PEG) moiety, wherein the terminal OH group can optionally be modified e.g. with C 1 - C 5 alkyl or C 1 - C 5 acyl groups. In some embodiments, the terminal OH group is optionally modified with C 1 -, C 2 - or C 3 -alkyl groups or C 1 -, C 2 - or C 3 groups. In some embodiments, the modified polyethylene glycol is a terminally alkoxy-substituted polyethylene glycol. In some embodiments, the polymer moiety is methoxy-polyethylene- glycol (mPEG).
  • mPEG methoxy-polyethylene- glycol
  • body surface area includes the face, scalp, intertriginous, and genital areas, exclusive of the mucosa, palms, and soles, of the subject.
  • lower alkyl when used alone or in combination with other groups, means a straight chained or branched lower alkyl group containing from 1-6 carbon atoms, preferably from 1-5, more preferably from 1-4 and especially preferably 1-3 or 1-2 carbon atoms.
  • These groups include, in some embodiments, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, amyl, isoamyl, neopentyl, 1 - ethylpropyl, hexyl, and the like.
  • lower alkyl moiety of the "lower alkoxy”, the “lower alkoxycarbonyl”, the “lower akylaminocarbonyl’, “lower hydroxyalkyl' and of the “tri-lower alkylsilyl’ groups has the same meaning as "lower alkyl” defined above.
  • the "lower alkenyl” groups are defined as C 2 -C 6 alkenyl groups which may be straight chained or branched and may be in the Z or E form. Such groups include vinyl, propenyl, 1 -butenyl, isobutenyl, 2-butenyl, 1 -pentenyl, (Z)-2- pentenyl, (E)-2-pentenyl, (Z)-4-methyl-2-pentenyl, (E)-4-methyl-2-pentenyl, pentadienyl, e.g., 1 , 3 or 2,4- pentadienyl, and the like.
  • the C 2 -C 6 - alkenyl groups are C 2 -C 5 -, C 2 -C 4 -alkenyl groups. In other embodiments, the C 2 -C 6 - alkenyl groups are C 2 -C 3 -alkenyl groups.
  • lower alkynyl groups refers to C 2 -C 6 -alkynyl groups which may be straight chained or branched and include ethynyl, propynyl, 1 -butynyl, 2- butynyl, 1 - pentynyl, 2-pentynyl, 3-methyl-1 -pentynyl, 3-pentynyl, 1 -hexynyl, 2-hexynyl, 3-hexynyl and the like.
  • C 2 -C 6 -alkynyl groups are C 2 -C 5 -, C 2 -C 4 -alkynyl groups.
  • C 2 -C 6 -alkynyl groups are C 2 -C 3 -alkynyl groups.
  • aryl group refers to C 6 -C 14 -aryl groups which contain from 6 up to 14 ring carbon atoms. These groups may be mono-, bi- or tricyclic and are fused rings. In some embodiments, the aryl groups include phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl and the like. The aryl moiety of the "arylcarbonyl” and the “arylaminocarbonyl” groups has the same meaning as defined above.
  • heteroaryl may contain 1 to 3 heteroatoms independently selected from nitrogen, sulfur or oxygen and refers C 3 -C 13 -heteroaryl groups. These groups may be mono-, bi- or tricyclic.
  • the C 3 -C 13 heteroaryl groups include heteroaromatics and saturated and partially saturated heterocyclic groups. These heterocyclics may be monocyclic, bicyclic, or tricyclic.
  • the 5 or 6-membered heterocyclic groups are thienyl, furyl, pyrrolyl, pyridyl, pyranyl, morpholinyl, pyrazinyl, methyl pyrrolyl, and pyridazinyl.
  • the C 3 -C 13 - heteroaryl may be a bicyclic heterocyclic group.
  • the bicyclic heterocyclic groups are benzofuryl, benzothienyl, indolyl, imidazolyl, and pyrimidinyl.
  • the C 3 -C 13 -heteroaryls are furyl and pyridyl.
  • lower alkoxy includes alkoxy groups containing from 1 to 6 carbon atoms, in some embodiments from 1 to 5, in other embodiments from 1 -4 and in yet other embodiments 1 to 3 or 1 to 2 carbon atoms and may be straight chained or branched. These groups include methoxy, ethoxy, propoxy, butoxy, isopropoxy, tert- butoxy, pentoxy, hexoxy and the like.
  • acyl includes lower alkanoyl containing 1 to 6 carbon atoms, in some embodiments from 1 to 5, from 1 to 4, from 1 to 3 or from 1 to 2 carbon atoms and may be straight chained or branched. These groups include, in some embodiments, formyl, acetyl, propionyl, butyryl, isobutyryl, tertiary butyryl, pentanoyl and hexanoyl.
  • the acyl moiety of the "acyloxy" group has the same meaning as defined above.
  • halogen includes fluoro, chloro, bromo, iodio, and the like.
  • aralkyl refers C 7 -C 15 -aralkyl wherein the alkyl group is substituted by an aryl.
  • the alkyl group and aryl may be selected from the C 1 -C 6 alkyl groups and the C 6 -C 14 -aryl groups as defined above, wherein the total number of carbon atoms is between 7 and 15.
  • the C 7 -C 15 -aralkyl groups are benzyl, phenylethyl, phenylpropyl, phenylisopropyl, phenylbutyl, diphenylmethyl, 1 ,1 - diphenylethyl, 1 ,2-diphenylethyl.
  • the aralkyl moiety of the "aralkyloxy" groups has the same meaning as defined above.
  • the substituted lower alkyl, alkenyl and alkynyl groups have 1 to 3 independently selected substituents, such as lower alkyl, hydroxy, lower alkoxy, carboxyl, lower alkoxycarbonyl, nitro, halogen, amino, mono- or di- lower alkylamino, dioxolane, dioxane, dithiolane, and dithione.
  • the lower alkyl substituent moiety of the substituted lower alkyl, alkenyl and alkynyl groups, and the lower alkyl moiety of the lower alkoxy, the lower alkoxycarbonyl, and the mono- or di-lower alkylamino substituents of the substituted lower alkyl, alkenyl and alkynyl groups have the same meaning as "lower alkyl” defined above.
  • the substituted aryl, the substituted heteroaryl and the substituted aralkyl groups each has 1 to 3 independently selected substituents, such as lower alkyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, nitro, amino, mono- or di-lower alkylamino, and halogen.
  • the lower alkyl moiety of the lower alkyl, the lower alkoxy, the lower alkoxycarbonyl, and the mono- or di- lower alkylamino groups among the substituents has the same meaning as‘lower alkyl’ defined
  • the heterocyclic group formed by R 5 and R 6 combined with a nitrogen atom includes pyrrolidinyl, piperidinyl, piperidino, morpholinyl, morpholino, thiomorpholino, N- methylpiperazinyl, indolyl, and isoindolyl.
  • each of R 1 and R 2 is hydrogen.
  • the residue R 14 is selected from phenyl, pyridyl, imidazolyl, thiazolyl, tetrazolyl, -COOR 15 , -OR 15 (wherein R 15 is in some embodiments selected from hydrogen, methyl, ethyl, phenyl or acyl), -SR 7 (wherein R 7 is in some embodiments selected from substituted or unsubstituted lower alkyl, 2-thiazoline and pyridyl) and -NR 5 R 6 (wherein R 5 and R 6 are in some embodiments selected from hydrogen, methyl, ethyl, phenyl, carbamoyl and lower alkylaminocarbonyl).
  • the residue R 16 is selected from hydrogen, methyl, ethyl, phenyl, imidazole, thiazole, tetrazole, -COOR 15 , -OR 15 and -NR 5 R 6 (wherein the residues R 15 , R 5 and R 6 have the meanings as described above).
  • the residue R 7 is selected from the group consisting of substituted or unsubstituted lower alkyl, substituted or unsubstituted phenyl, pyridyl, pyrimidinyl, thiazole and tetrazole.
  • k is 2, 3 or 4
  • j is 1 or 2
  • m and n are independently 0 or 1.
  • R 3 is hydrogen or acetyl. Furthermore, in some embodiments, each W 1 and W 2 is hydrogen.
  • X' when Y' is a polymer moiety and X' is not a polymer moiety, X' is selected from carboxy, hydroxymethyl or a lower alkoxycarbonyl. In some embodiments X is selected from methoxycarbonyl.
  • Y' is selected from hydroxy or acetyloxy.
  • the warhead of the polymer conjugate is a derivative of K252a, which has the formula: or a pharmaceutically acceptable salt thereof.
  • the polymer conjugate is SNA-125, wherein the composition has the formula:
  • the polymer conjugate is SNA-120, wherein the composition has the formula:
  • the active entity comprises an indolocarbazole compound. In some embodiments, the active entity comprises a derivative of K252a. In some embodiments, the composition comprises SNA-125.
  • n 2-2270.
  • a reduced exposure composition for treating a target site comprising a conjugate comprising at least one active entity linked to at least one polymer, wherein the conjugate has reduced exposure at a non-target site as compared to the active entity delivered without the polymer, wherein the non-target site comprises the systemic system, the lymphatic system and/or another non-target tissue site, wherein the conjugate has the formula:
  • n 2-2270
  • a pharmaceutically acceptable carrier formulated for delivery of the conjugate to the target site.
  • a reduced exposure composition for treating a cell within a target site comprising a conjugate, the conjugate comprising an active entity linked to at least one polymer, and a pharmaceutically acceptable carrier formulated for delivery of the conjugate to the target site;
  • composition has reduced exposure at a non-target site as compared to the active entity delivered without the polymer;
  • the active entity is an inhibitor, antagonist, or inverse agonist of a cellular kinase
  • the active entity comprises or consists essentially of any one or more of compounds 1-40;
  • the at least one polymer is polyethylene glycol (PEG) or methoxy- polyethylene glycol (m-PEG); and
  • conjugate can traverse the cell membrane and distribute among both lipophilic and hydrophilic cellular compartments within the cell, thereby promoting interactions between the active entity and the cellular kinase.
  • the non-target site includes non-target tissue at which pharmacological activity is not desired and/or not achieved.
  • the active entity comprises compound 1.
  • the composition comprises SNA-352.
  • the cellular kinase is a JAK family protein or a STAT family protein.
  • the active entity binds to a JAK family protein.
  • the active entity inhibits a JAK family protein.
  • the JAK protein comprises one or more of JAK1 , JAK2, JAK3, and Tyrosine kinase 2 (TYK2).
  • the active entity binds to a STAT family protein.
  • the active entity inhibits a STAT family protein.
  • the active entity has one or more carboxyl, hydroxyl, amino and/or sulfhydryl groups.
  • the at least one polymer is conjugated to the active entity at the one or more carboxyl, hydroxyl, amino and/or sulfhydryl groups.
  • the conjugate has a longer residence time within the cell compared to the active entity without conjugation to the polymer. In some embodiments, the residence time of the conjugate is at least 25% longer as compared to the active entity without conjugation to the polymer.
  • the residence time of the conjugate is at least 2-20 fold longer as compared to the active entity without conjugation to the polymer.
  • the conjugate exhibits greater access to the kinase compared to the active entity without conjugation to the polymer.
  • the conjugate exhibits a depo effect across cellular compartments, thereby reducing the dose of the active entity required to inhibit kinase activity compared to the active entity without conjugation to the polymer.
  • the dose of the conjugate needed to achieve a comparable therapeutic effect is 10-90% lower as compared to the active entity without conjugation to the polymer.
  • the activity entity has a concentration, activity and/or bioavailability at the target site that is at least 2-20 fold greater than at a non-target site, wherein the non-target site comprises the circulatory system.
  • the activity entity has a concentration, activity and/or bioavailability at the target site that is at least 2-20 fold greater than at a non-target site, wherein the non-target site comprises the lymphatic system.
  • the reduced concentration, activity and/or bioavailability reduces toxicity.
  • the activity entity has a concentration, activity and/or bioavailability at the target site that is at least 2-20 fold greater than at a non-target site, wherein the non-target site comprises bone marrow.
  • the reduced concentration, activity and/or bioavailability in the bone marrow reduces immunosuppression.
  • the conjugate is present at a biologically inactive concentration at a non-target site.
  • the conjugate is amphiphilic
  • the conjugate is at least 25% more amphiphilic than the active entity without conjugation to the polymer.
  • the conjugate is at least 25% more hydrophilic than the active entity without conjugation to the polymer, thus facilitating non- compartmentalization within the cell.
  • the conjugate is at least 25% more hydrophilic than the active entity without conjugation to the polymer, thus facilitating access to and activity in both the lipid bilayer and the cytosol of the cell. In some embodiments, the conjugate is at least 25% more hydrophilic than the active entity without conjugation to the polymer, thus facilitating access to and/or activity in both the lipid bilayer and the cytoplasm of the cell.
  • the conjugate is at least 25% more hydrophilic than the active entity without conjugation to the polymer, thus facilitating access to and/or activity across the lipid bilayer.
  • the composition is formulated for topical administration.
  • the composition is formulated as an inhalant.
  • the composition is formulated as an injectable.
  • the composition is formulated as an eye drop.
  • the composition is formulated for oral administration.
  • said composition is administered via at least two routes of administration, either simultaneously or sequentially.
  • composition is administered via a topical route to a subject, and wherein the subject further receives an additional agent via a non-topical route to achieve synergetic effects.
  • the composition further comprises one or more additional ingredients from the group consisting of a protective agent, an emollient, an astringent, a humectant, a sun screening agent, a sun tanning agent, a UV absorbing agent, an antibiotic agent, an anti-angiogenesis agent, a preventive or therapeutic agent for inflammatory bowel disease, a physiological cooling agent, an antifungal agent, an antiviral agent, an antiprotozoal agent, an anti-acne agent, an anesthetic agent, a steroidal anti-inflammatory agent, a non-steroidal anti-inflammatory agent, an antipruritic agent, an additional antioxidant agent, a chemotherapeutic agent, an anti-histamine agent, a vitamin or vitamin complex, a hormone, an anti-dandruff agent, an anti-wrinkle agent, an anti-skin atrophy agent, a skin whitening agent, and a cleansing agent.
  • a protective agent an emollient, an astringent, a humec
  • provided herein are methods for treating an inflammatory condition in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition provided herein.
  • provided herein are methods for treating any one or more of inflammatory bowel disease, irritable bowel syndrome or small intestinal bacteria overgrowth in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition provided herein.
  • provided herein are methods for treating ulcerative colitis in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition provided herein.
  • methods for treating Crohn’s disease in a subject in need thereof the method comprising administering to the subject an effective amount of a composition provided herein.
  • provided herein are methods for treating an inflammatory skin disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition provided herein.
  • provided herein are methods for treating a wound in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition provided herein.
  • provided herein are methods for treating a scar in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition provided herein.
  • provided herein are methods for treating a cancerous or pre- cancerous lesion in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition provided herein.
  • provided herein are methods for treating a lung in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition provided herein.
  • provided herein are methods for treating the gastrointestinal system in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition provided herein.
  • provided herein are methods for treating an autoimmune disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition provided herein.
  • provided herein are methods for treating an eye in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition provided herein.
  • provided herein are methods for treating a joint in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition provided herein.
  • provided herein are methods for treating or preventing one or more of the following conditions: inflammatory bowel disease, irritable bowel syndrome, small intestinal bacterial overgrowth, Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behget's syndrome, indeterminate colitis, alopecia, alopecia areata, androgenic alopecia, or dry eye, the method comprising administering to the subject an effective amount of a composition provided herein.
  • methods of treating multifocal inflammation caused by a gastrointestinal system condition in a subject in need thereof comprising administering to the subject a compound having the formula:
  • n 2-2270.
  • edema caused by a gastrointestinal system condition in a subject in need thereof, comprising administering to the subject a compound having the formula:
  • n 2-2270.
  • kits for treating mucosal necrosis caused by a gastrointestinal system condition in a subject in need thereof comprising administering to the subject a compound having the formula:
  • n 2-2270.
  • edema caused by a gastrointestinal system condition in a subject in need thereof, comprising administering to the subject a compound having the formula:
  • n 2-2270.
  • kits for treating blood in the stool caused by a gastrointestinal system condition in a subject in need thereof comprising administering to the subject a compound having the formula:
  • n 2-2270.
  • provided herein are methods of treating diarrhea caused by a gastrointestinal system condition in a subject in need thereof, comprising administering to the subject a compound having the formula:
  • n 2-2270.
  • n 2-2270.
  • the gastrointestinal system condition is inflammatory bowel disease, irritable bowel syndrome, small intestinal bacterial overgrowth, Crohn's disease, colitis, intestinal fibrosis, or colorectal cancer.
  • the gastrointestinal system is colitis.
  • the colitis is ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, or indeterminate colitis.
  • kits for treating a condition in a subject in need thereof comprising administering to the subject an effective amount of a compound having the formula:
  • n 2-2270.
  • the condition is a dermal condition, a gastrointestinal condition, an ophthalmological condition, a respiratory condition, or a combination thereof.
  • the dermal condition is pruritus (e.g., pruritus due to psoriasis, pruritus due to atopic dermatitis, or prurigo nodularis), skin neoplasia (e.g., squamous cell carcinoma, basal cell carcinoma, malignant melanoma, or malignant cutaneous lymphoma), vascular tumor (e.g., angiosarcoma, Kaposi’s sarcoma, infantile hemangioma, or hemangioendothelioma), inflammatory dermatosis (e.g., dermatitis (e.g., atopic dermatitis or irritant contact dermatitis), psoriasis, keloid, or rosacea), scarring
  • pruritus e.g., pr
  • the dermal condition is angiosarcoma, Kaposi’s sarcoma, infantile hemangioma, hemangioendothelioma, irritant contact dermatitis, rosacea, bullous pemphigoid, erythema multiforme, UV irradiation therapy, alopecia areata, vitiligo, or a combination thereof.
  • the dermal condition is pruritus, prurigo nodularis, postherpetic neuralgia, seborrheic dermatitis, lichen simplex chronicus, Grover’s disease, neurodermatitis, pemphigoid, bullous pemphigoid, epidermolysis bullosa, alopecia areata, atopic dermatitis, chronic actinic dermatitis, chronic mucocutaneous candidiasis, cutaneous t-cell lymphoma, dermatomyositis, erythema multiforme, graft-versus-host disease (cutaneous), hypereosinophilic syndrome, lupus erythematosus, mastocytosis and mast cell disease, STING vasculopathy, palmoplantar pustulosis, polyarteritis nodosa, psoriasis, vitiligo, dry skin pruritus in the elderly, warts, or a combination
  • the dermal condition is pruritus due to intrahepatic cholestasis, posthepatic cholestasis, drug-induced cholestasis, chronic renal failure, dialysis treatment, diabetes mellitus, systemic parasitosis, Sjogren’s syndrome, AIDS, drug eruption, pregnancy, a psychogenic condition, sclerosis multiplex, stroke, delusion of parasitosis, lymphoma, mastocytosis, polycythemia vera, iron-deficiency anemia, hyperthyroidism, hyperparathyroidism, brain tumor, myxoedema, acute eczema, chronic eczema, monetary eczema, sebaceous deficiency eczema, contact dermatitis, atopic dermatitis, seborrheic dermatitis, neurodermatitis, acute prurigo (strofus, urticaria, lichen urticatus), suba
  • the gastrointestinal condition is ulcerative colitis, Crohn’s disease, intestinal fibrosis, colorectal cancer, irritable bowel syndrome, visceral pain, or a combination thereof.
  • the ophthalmological condition is age- related macular degeneration (e.g., wet age-related macular degeneration or dry age- related macular degeneration), diabetic retinopathy, edema (e.g., macular edema (e.g., diabetic macular edema) or corneal edema), dry eye (e.g., spontaneous dry eye or aqueous deficiency dry eye), uveitis (e.g., juvenile idiopathic arthritis uveitis or posterior uveitis), pterygia, conjunctivitis (e.g., vernal keratocunjunctivitis (allergic conjunctivitis) or atopic keratoconjunctivitis), graft versus host disease (e.g., ophthalmic graft versus host disease), glaucoma (e.g., primary open angle glaucoma), retin
  • the ophthalmological condition is age- related macular degeneration (e.g., wet age-related macular degeneration or dry age- related macular degeneration), edema (e.g., macular edema (e.g., diabetic macular edema) or corneal edema), dry eye (e.g., spontaneous dry eye or aqueous deficiency dry eye), juvenile idiopathic arthritis uveitis, posterior uveitis, pterygia, conjunctivitis (e.g., vernal keratoconjunctivitis (allergic conjunctivitis) or atopic keratoconjunctivitis), ophthalmic graft versus host disease, glaucoma (e.g., primary open angle glaucoma), retinopathy of prematurity, diabetic retinopathy, or a combination thereof.
  • age- related macular degeneration e.g., wet age-
  • the respiratory condition is asthma (e.g., T h 2 asthma or non-T H 2 asthma), chronic obstructive pulmonary disease, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis), pulmonary hypertension, sinusitis with nasal polyposis, allergic rhinitis, cough (e.g., chronic cough), lymphangioleiomyomatosis, or a combination thereof.
  • asthma e.g., T h 2 asthma or non-T H 2 asthma
  • chronic obstructive pulmonary disease e.g., chronic obstructive pulmonary disease
  • pulmonary fibrosis e.g., idiopathic pulmonary fibrosis
  • pulmonary hypertension e.g., sinusitis with nasal polyposis
  • allergic rhinitis e.g., chronic cough
  • lymphangioleiomyomatosis e.g., chronic cough
  • the condition is rheumatoid arthritis, osteoarthritis, neuropathic pain, neuropathic itch, or a combination thereof.
  • provided herein are methods of treating a condition in a subject in need thereof, comprising administering to the subject an effective amount of a compound having the formula:
  • n 4-1 140;
  • the condition is a dermal condition, a gastrointestinal condition, an ophthalmological condition, a respiratory condition, or a combination thereof.
  • the dermal condition is pruritus (e.g., pruritus due to psoriasis, pruritus due to atopic dermatitis, or prurigo nodularis), skin neoplasia (e.g., squamous cell carcinoma, basal cell carcinoma, malignant melanoma, or malignant cutaneous lymphoma), vascular tumor (e.g., angiosarcoma, Kaposi’s sarcoma, infantile hemangioma, or hemangioendothelioma), inflammatory dermatosis (e.g., dermatitis (e.g., atopic dermatitis or irritant contact dermatitis), psoriasis, keloid, or
  • the dermal condition is angiosarcoma, Kaposi’s sarcoma, infantile hemangioma, hemangioendothelioma, irritant contact dermatitis, rosacea, bullous pemphigoid, erythema multiforme, UV irradiation therapy, alopecia areata, vitiligo, or a combination thereof.
  • the dermal condition is pruritus, prurigo nodularis, postherpetic neuralgia, seborrheic dermatitis, lichen simplex chronicus, Grover’s disease, neurodermatitis, pemphigoid, bullous pemphigoid, epidermolysis bullosa, alopecia areata, atopic dermatitis, chronic actinic dermatitis, chronic mucocutaneous candidiasis, cutaneous t-cell lymphoma, dermatomyositis, erythema multiforme, graft-versus-host disease (cutaneous), hypereosinophilic syndrome, lupus erythematosus, mastocytosis and mast cell disease, STING vasculopathy, palmoplantar pustulosis, polyarteritis nodosa, psoriasis, vitiligo, dry skin pruritus in the elderly, warts, or
  • the dermal condition is pruritus due to intrahepatic cholestasis, posthepatic cholestasis, drug-induced cholestasis, chronic renal failure, dialysis treatment, diabetes mellitus, systemic parasitosis, Sjogren’s syndrome, AIDS, drug eruption, pregnancy, a psychogenic condition, sclerosis multiplex, stroke, delusion of parasitosis, lymphoma, mastocytosis, polycythemia vera, iron-deficiency anemia, hyperthyroidism, hyperparathyroidism, brain tumor, myxoedema, acute eczema, chronic eczema, monetary eczema, sebaceous deficiency eczema, contact dermatitis, atopic dermatitis, seborrheic dermatitis, neurodermatitis, acute prurigo (strofus, urticaria, lichen urticatus
  • the gastrointestinal condition is ulcerative colitis, Crohn’s disease, intestinal fibrosis, colorectal cancer, irritable bowel syndrome, visceral pain, or a combination thereof.
  • the ophthalmological condition is age-related macular degeneration (e.g., wet age-related macular degeneration or dry age-related macular degeneration), diabetic retinopathy, edema (e.g., macular edema (e.g., diabetic macular edema) or corneal edema), dry eye (e.g., spontaneous dry eye or aqueous deficiency dry eye), uveitis (e.g., juvenile idiopathic arthritis uveitis or posterior uveitis), pterygia, conjunctivitis (e.g., vernal keratocunjunctivitis (allergic conjunctivitis) or a
  • the ophthalmological condition is age-related macular degeneration (e.g., wet age-related macular degeneration or dry age-related macular degeneration), edema (e.g., macular edema (e.g., diabetic macular edema) or corneal edema), dry eye (e.g., spontaneous dry eye or aqueous deficiency dry eye), juvenile idiopathic arthritis uveitis, posterior uveitis, pterygia, conjunctivitis (e.g., vernal keratoconjunctivitis (allergic conjunctivitis) or atopic keratoconjunctivitis), ophthalmic graft versus host disease, glaucoma (e.g., primary open angle glaucoma), retinopathy of prematurity, diabetic retinopathy, or a combination thereof.
  • age-related macular degeneration e.g., wet age-
  • the respiratory condition is asthma (e.g., T H 2 asthma or non-T H 2 asthma), chronic obstructive pulmonary disease, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis), pulmonary hypertension, sinusitis with nasal polyposis, allergic rhinitis, cough (e.g., chronic cough), lymphangioleiomyomatosis, or a combination thereof.
  • asthma e.g., T H 2 asthma or non-T H 2 asthma
  • chronic obstructive pulmonary disease e.g., chronic obstructive pulmonary disease
  • pulmonary fibrosis e.g., idiopathic pulmonary fibrosis
  • pulmonary hypertension pulmonary hypertension
  • sinusitis with nasal polyposis e.g., allergic rhinitis
  • cough e.g., chronic cough
  • lymphangioleiomyomatosis e.g., chronic cough
  • the condition is rheumatoid arthritis, osteoarthritis, neuropathic pain, neuropathic itch, or a combination thereof.
  • provided herein are methods of treating a condition in a subject in need thereof, comprising administering to the subject an effective amount of a compound having the formula:
  • n 4-1 140;
  • the condition is a dermal condition, a gastrointestinal condition, an ophthalmological condition, a respiratory condition, or a combination thereof.
  • the dermal condition is pruritus (e.g., pruritus due to psoriasis, pruritus due to atopic dermatitis, or prurigo nodularis), skin neoplasia (e.g., squamous cell carcinoma, basal cell carcinoma, malignant melanoma, or malignant cutaneous lymphoma), vascular tumor (e.g., angiosarcoma, Kaposi’s sarcoma, infantile hemangioma, or hemangioendothelioma), inflammatory dermatosis (e.g., dermatitis (e.g., atopic dermatitis or irritant contact dermatitis), psoriasis, keloid, or rosacea), scarring, a bullous disease (e.g., bullous pemphigoid or erythema multiforme), UV irradiation therapy,
  • skin neoplasia
  • the dermal condition is angiosarcoma, Kaposi’s sarcoma, infantile hemangioma, hemangioendothelioma, irritant contact dermatitis, rosacea, bullous pemphigoid, erythema multiforme, UV irradiation therapy, alopecia areata, vitiligo, or a combination thereof.
  • the dermal condition is pruritus, prurigo nodularis, postherpetic neuralgia, seborrheic dermatitis, lichen simplex chronicus, Grover’s disease, neurodermatitis, pemphigoid, bullous pemphigoid, epidermolysis bullosa, alopecia areata, atopic dermatitis, chronic actinic dermatitis, chronic mucocutaneous candidiasis, cutaneous t-cell lymphoma, dermatomyositis, erythema multiforme, graft-versus-host disease (cutaneous), hypereosinophilic syndrome, lupus erythematosus, mastocytosis and mast cell disease, STING vasculopathy, palmoplantar pustulosis, polyarteritis nodosa, psoriasis, vitiligo, dry skin pruritus in the elderly, warts, or
  • the dermal condition is pruritus due to intrahepatic cholestasis, posthepatic cholestasis, drug-induced cholestasis, chronic renal failure, dialysis treatment, diabetes mellitus, systemic parasitosis, Sjogren’s syndrome, AIDS, drug eruption, pregnancy, a psychogenic condition, sclerosis multiplex, stroke, delusion of parasitosis, lymphoma, mastocytosis, polycythemia vera, iron-deficiency anemia, hyperthyroidism, hyperparathyroidism, brain tumor, myxoedema, acute eczema, chronic eczema, monetary eczema, sebaceous deficiency eczema, contact dermatitis, atopic dermatitis, seborrheic dermatitis, neurodermatitis, acute prurigo (strofus, urticaria, lichen urticatus
  • the gastrointestinal condition is ulcerative colitis, Crohn’s disease, intestinal fibrosis, colorectal cancer, irritable bowel syndrome, visceral pain, or a combination thereof.
  • the ophthalmological condition is age-related macular degeneration (e.g., wet age-related macular degeneration or dry age-related macular degeneration), diabetic retinopathy, edema (e.g., macular edema (e.g., diabetic macular edema) or corneal edema), dry eye (e.g., spontaneous dry eye or aqueous deficiency dry eye), uveitis (e.g., juvenile idiopathic arthritis uveitis or posterior uveitis), pterygia, conjunctivitis (e.g., vernal keratocunjunctivitis (allergic conjunctivitis) or atopic keratoconjunctivitis), graft versus host disease (e.g., ophthalmic graft versus host disease), glaucoma (e.g., primary open angle glaucoma),
  • glaucoma e.
  • the ophthalmological condition is age-related macular degeneration (e.g., wet age-related macular degeneration or dry age-related macular degeneration), edema (e.g., macular edema (e.g., diabetic macular edema) or corneal edema), dry eye (e.g., spontaneous dry eye or aqueous deficiency dry eye), juvenile idiopathic arthritis uveitis, posterior uveitis, pterygia, conjunctivitis (e.g., vernal keratoconjunctivitis (allergic conjunctivitis) or atopic keratoconjunctivitis), ophthalmic graft versus host disease, glaucoma (e.g., primary open angle glaucoma), retinopathy of prematurity, diabetic retinopathy, or a combination thereof.
  • age-related macular degeneration e.g., wet age-
  • the respiratory condition is asthma (e.g., T H 2 asthma or non-T H 2 asthma), chronic obstructive pulmonary disease, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis), pulmonary hypertension, sinusitis with nasal polyposis, allergic rhinitis, cough (e.g., chronic cough), lymphangioleiomyomatosis, or a combination thereof.
  • the condition is rheumatoid arthritis, osteoarthritis, neuropathic pain, neuropathic itch, or a combination thereof.
  • the active entity binds to a tropomyosin-receptor-kinase A (TrkA) in some embodiments.
  • the active entity binds to a Janus Kinase (JAK) family member in some embodiments.
  • the active entity binds to one or more of Janus Kinase 1 (JAK1), Janus Kinase 2 (JAK2), Janus Kinase 3 (JAK3), and/or Tyrosine kinase 2 (TYK2) in some embodiments.
  • the active entity binds to mitogen-activated protein kinase kinase (MAP2K) in some embodiments.
  • the active entity binds to mitogen-activated protein kinase kinase 3 (MAP2K3) in some embodiments.
  • the binding may be partially or fully inhibitory or not.
  • compositions comprising an indolocarbazole compound are used, in several embodiments, as inhibitors, antagonists, and inverse agonists of TkrA, Jak3, and/or MAP2K3.
  • Several embodiments relate to polymer conjugates of an indolocarbazole compound, optimized for topical applications while also minimizing side-effects caused by exposure at non-target sites (e.g., systemic absorption). Non-topical applications are provided in other embodiments.
  • the conjugates, or compositions thereof, provided herein selectively inhibit TrkA, the high-affinity receptor of NGF, that blocks nerve growth factor- (NGF) dependent over-activation of TRPV1 (transient receptor potential vanilloid 1), a key mediator of peripheral itch in psoriasis. Reducing the severity of itch is considered an important treatment goal for patients.
  • the conjugates, or compositions thereof, provided herein are useful in treating itch (pruritus, e.g., moderate to severe pruritus) associated with psoriasis (e.g., moderate to severe psoriasis).
  • the conjugates, or compositions thereof, provided herein are provided as a topical nonsteroidal therapy (e.g., and ointment) to treat itch (pruritus, e.g., moderate to severe pruritus) associated with psoriasis (e.g., moderate to severe psoriasis) in a subject in need thereof.
  • itch e.g., moderate to severe pruritus
  • psoriasis e.g., moderate to severe psoriasis
  • the warhead of the polymer conjugate is an indolocarbazole compound or derivative thereof.
  • methods of treating an inflammatory bowel disease in a subject comprising administering to the subject an effective amount of an LSE polymer conjugate wherein the warhead is an indolocarbazole compound.
  • the warhead of the LSE polymer conjugate is a derivative of K252a.
  • the LSE polymer conjugate is SNA-125.
  • the LSE polymer conjugate is SNA-120.
  • Oral delivery is contemplated in several embodiments suitable for gastrointestinal disorders, and thus several embodiments relate to polymer conjugates of an indolocarbaozle, optimized for oral delivery to treat the gastrointestinal system while also minimizing side-effects caused by exposure at non-target sites (e.g., systemic absorption). Topical applications are provided in other embodiments.
  • the warhead of the polymer conjugate is an indolocarbazole compound or derivative thereof.
  • methods of treating an ophthalmic condition in a subject comprising administering to the subject an effective amount of an LSE polymer conjugate wherein the warhead is an indolocarbazole compound.
  • the warhead of the LSE polymer conjugate is a derivative of K252a.
  • the LSE polymer conjugate is SNA-125.
  • the LSE polymer conjugate is SNA-120.
  • non-inflammatory ophthalmic conditions may also be treated.
  • the warhead of the polymer conjugate is an indolocarbazole compound or derivative thereof.
  • methods of treating an inflammatory skin disease in a subject comprising administering to the subject an effective amount of an LSE polymer conjugate wherein the warhead is an indolocarbazole compound.
  • the warhead of the LSE polymer conjugate is a derivative of K252a.
  • the LSE polymer conjugate is SNA-125.
  • the LSE polymer conjugate is SNA-120.
  • non-inflammatory dermatological conditions may also be treated.
  • Topical delivery is contemplated in several embodiments suitable for dermal pathologies, and thus several embodiments relate to polymer conjugates of an indolocarbaozle, optimized for topical delivery to treat the skin while also minimizing side-effects caused by exposure at non-target sites (e.g., systemic absorption).
  • Nontopical applications are provided in other embodiments.
  • the dermal condition affects at least about 20 % of the body surface area of the subject.
  • the ointment is administered to at least about 20 % of the body surface area of the subject affected by the dermal condition.
  • a dosage of the conjugate, or composition thereof is topically administered to the subject twice in a day.
  • a dosage of the conjugate, or composition thereof is topically administered to the subject at a frequency of about every 12 hours.
  • the conjugate, or composition thereof is formulated in an ointment.
  • the conjugate, or composition thereof is administered daily for about four weeks.
  • the conjugate, or composition thereof is administered daily for at least four weeks.
  • the conjugate, or composition thereof is administered once or twice daily for about four weeks, and the PASI score of the subject is reduced by about 50 % to about 75 % as compared to the PASI score of the subject without administration of the conjugate, or composition thereof.
  • about 30 mg to about 100 mg of the conjugate, or composition thereof, is administered.
  • the conjugate, or composition thereof is administered twice in a day.
  • the conjugate, or composition thereof is administered once in a day.
  • the composition is administered topically and the composition is a pharmaceutical composition that is a cream, an ointment, a lotion, or a gel.
  • compositions comprising an indolocarbazole compound are used, in several embodiments, as inhibitors, antagonists, and inverse agonists of TkrA, Jak3, and/or MAP2K3.
  • Several embodiments relate to polymer conjugates of an indolocarbazole compound, optimized for topical applications while also minimizing side-effects caused by exposure at non-target sites (e.g., systemic absorption). Non-topical applications are provided in other embodiments.
  • the warhead of the polymer conjugate is an indolocarbazole compound or derivative thereof.
  • methods of treating an inflammatory bowel disease in a subject comprising administering to the subject an effective amount of an LSE polymer conjugate wherein the warhead is an indolocarbazole compound.
  • the warhead of the LSE polymer conjugate is a derivative of K252a.
  • the LSE polymer conjugate is SNA-125.
  • the LSE polymer conjugate is SNA- 120.
  • the warhead employed in the LSE polymer conjugate is a small molecule targeting mediator(s) of gastrointestinal conditions.
  • methods of treating an inflammatory bowel disease in a subject comprising administering to the subject an effective amount of a polymer conjugate, wherein the warhead is a small molecule targeting mediator(s) of gastrointestinal conditions.
  • the gastrointestinal condition is an inflammatory bowel disease.
  • inflammatory bowel diseases include Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behget's syndrome, and indeterminate colitis.
  • JAK and/or STAT family proteins are mediator(s) of gastrointestinal conditions.
  • the warhead employed in the LSE polymer conjugate is a small molecule a targeting a JAK and/or STAT family protein.
  • kits for treating an inflammatory condition in a subject in need thereof comprising administering to the subject an effective amount of a conjugate, or composition thereof, provided herein.
  • provided herein are methods for treating any one or more of inflammatory bowel disease, irritable bowel syndrome or small intestinal bacteria overgrowth in a subject in need thereof, the method comprising administering to the subject an effective amount of a conjugate, or composition thereof, provided herein.
  • kits for treating ulcerative colitis in a subject in need thereof comprising administering to the subject an effective amount of a conjugate, or composition thereof, provided herein.
  • kits for treating Crohn’s disease in a subject in need thereof comprising administering to the subject an effective amount of a conjugate, or composition thereof, provided herein.
  • provided herein are methods for treating an inflammatory skin disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a conjugate, or composition thereof, provided herein.
  • kits for treating a wound in a subject in need thereof comprising administering to the subject an effective amount of a conjugate, or composition thereof, provided herein.
  • provided herein are methods for treating a scar in a subject in need thereof, the method comprising administering to the subject an effective amount of a conjugate, or composition thereof, provided herein.
  • provided herein are methods for treating a cancerous or pre- cancerous lesion in a subject in need thereof, the method comprising administering to the subject an effective amount of a conjugate, or composition thereof, provided herein.
  • provided herein are methods for treating a lung in a subject in need thereof, the method comprising administering to the subject an effective amount of a conjugate, or composition thereof, provided herein.
  • methods for treating the gastrointestinal system in a subject in need thereof the method comprising administering to the subject an effective amount of a conjugate, or composition thereof, provided herein.
  • provided herein are methods for treating an autoimmune disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a conjugate, or composition thereof, provided herein.
  • kits for treating an eye in a subject in need thereof comprising administering to the subject an effective amount of a conjugate, or composition thereof, provided herein.
  • provided herein are methods for treating a joint in a subject in need thereof, the method comprising administering to the subject an effective amount of a conjugate, or composition thereof, provided herein.
  • inflammatory bowel disease irritable bowel syndrome, small intestinal bacterial overgrowth, Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behget's syndrome, indeterminate colitis, alopecia, alopecia areata, androgenic alopecia, or dry eye
  • the method comprising administering to the subject an effective amount of a conjugate, or composition thereof, provided herein.
  • kits for treating multifocal inflammation caused by a gastrointestinal system condition in a subject in need thereof comprising administering to the subject a conjugate, or composition thereof, provided herein.
  • provided herein are methods of treating edema caused by a gastrointestinal system condition in a subject in need thereof, comprising administering to the subject a conjugate, or composition thereof, provided herein.
  • kits for treating mucosal necrosis caused by a gastrointestinal system condition in a subject in need thereof comprising administering to the subject a conjugate, or composition thereof, provided herein.
  • provided herein are methods of treating edema caused by a gastrointestinal system condition in a subject in need thereof, comprising administering to the subject a conjugate, or composition thereof, provided herein.
  • provided herein are methods of treating blood in the stool caused by a gastrointestinal system condition in a subject in need thereof, comprising administering to the subject a conjugate, or composition thereof, provided herein.
  • provided herein are methods of treating diarrhea caused by a gastrointestinal system condition in a subject in need thereof, comprising administering to the subject a conjugate, or composition thereof, provided herein.
  • provided herein are methods of treating body weight loss caused by a gastrointestinal system condition in a subject in need thereof, comprising administering to the subject a conjugate, or composition thereof, provided herein.
  • the gastrointestinal system condition is inflammatory bowel disease, irritable bowel syndrome, small intestinal bacterial overgrowth, Crohn's disease, colitis, intestinal fibrosis, or colorectal cancer.
  • the gastrointestinal system is colitis.
  • the colitis is ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, or indeterminate colitis.
  • provided herein are methods of treating a gastrointestinal system condition in a subject in need thereof, comprising administering to the subject a conjugate, or composition thereof, provided herein.
  • kits for treating multifocal inflammation caused by a gastrointestinal system condition in a subject in need thereof comprising administering to the subject a conjugate, or composition thereof, provided herein.
  • provided herein are methods of treating edema caused by a gastrointestinal system condition in a subject in need thereof, comprising administering to the subject a conjugate, or composition thereof, provided herein.
  • kits for treating mucosal necrosis caused by a gastrointestinal system condition in a subject in need thereof comprising administering to the subject a conjugate, or composition thereof, provided herein.
  • provided herein are methods of treating edema caused by a gastrointestinal system condition in a subject in need thereof, comprising administering to the subject a conjugate, or composition thereof, provided herein.
  • provided herein are methods of treating blood in the stool caused by a gastrointestinal system condition in a subject in need thereof, comprising administering to the subject a conjugate, or composition thereof, provided herein.
  • kits for treating diarrhea caused by a gastrointestinal system condition in a subject in need thereof comprising administering to the subject a conjugate, or composition thereof, provided herein
  • provided herein are methods of treating body weight loss caused by a gastrointestinal system condition in a subject in need thereof, comprising administering to the subject a conjugate, or composition thereof, provided herein.
  • methods of treating a dermal condition in a subject in need thereof comprising administering to the subject a conjugate, or composition thereof, provided herein.
  • kits for reducing the psoriasis area and severity index (PASI) score of a subject suffering from a dermal condition comprising administering to the subject a conjugate, or composition thereof, provided herein.
  • PASI psoriasis area and severity index
  • provided herein are methods of reducing the body surface area affected by a dermal condition in a subject affected thereby, comprising administering to the subject a conjugate, or composition thereof, provided herein.
  • provided herein are methods of reducing the investigator global assessment (IGA) score of a subject suffering from a dermal condition, comprising administering to the subject a conjugate, or composition thereof, provided herein.
  • IGA investigator global assessment
  • a conjugate, or composition thereof provided herein, wherein:
  • the conjugate, or composition thereof treats the dermal condition; and the threshold level is about 5.0 ng/mL.
  • the dermal condition is selected from chronic actinic dermatitis, chronic mucocutaneous candidiasis, cutaneous T-cell lymphoma, cutaneous graft-versus-host disease, hypereosinophilic syndrome, mastocytosis and mast cell disease, stimulator of interferon genes (STING)-associated vasculopathy with onset in infance (SAVI), palmoplantar pustulosis, or polyarteritis nodosa.
  • STING stimulator of interferon genes
  • the JAK kinase family is a cytoplasmic protein kinase family comprising the members JAK1 , JAK2, JAK3 and TYK2.
  • JAK1 cytoplasmic protein kinase family
  • JAK2 JAK3
  • TYK2 cytoplasmic protein kinase family
  • ligand binding to a receptor leads to receptor dimerization or oligomerization, which leads to JAK recruitment and activation either through autophosphorylation or phosphorylation by other JAK kinases or by other tyrosine kinases, which in turn leads to tyrosine phosphorylation of the receptors as well as downstream substrates of JAK.
  • Growth factor or cytokine receptors that recruit JAK kinases include the interferon receptors, interleukin receptors (receptors for the cytokines IL-2 to IL-7, IL-9 to IL-13, IL-15, IL-23), various hormone receptors (erythropoietin (Epo) receptor, the thrombopoietin (Tpo) receptor, the leptin receptor, the insulin receptor, the prolactin (PRL) receptor, the Granulocyte Colony-Stimulating Factor (G-CSF) receptor and the growth hormone receptor), receptor protein tyrosine kinases (such as EGFR and PDGFR), and receptors for other growth factors such as leukemia inhibitory factor (LIF), Oncastatin M (OSM), IFNa/b/g, Granulocyte-macrophage colony-stimulating factor (GM-CSF), Ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-I) (
  • autoimmune diseases and disease associated with chronic inflammation, as well as acute responses have been linked to excessive or unregulated production or activity of one or more cytokines, the signaling of which depend on JAK kinases.
  • diseases include gastrointestinal conditions, which may be treated according to several embodiments described herein.
  • Phosphorylated receptors serve as docking sites for other SH-2 domain containing signaling molecules that interact with JAKs such as the STAT family of transcription factors, Src family of kinases, MAP kinases PB kinase and protein tyrosine phosphatases (Rane S.G. and Reddy E.P., Oncogene 2000 19, 5662-5679).
  • JAKs such as the STAT family of transcription factors, Src family of kinases, MAP kinases PB kinase and protein tyrosine phosphatases (Rane S.G. and Reddy E.P., Oncogene 2000 19, 5662-5679).
  • the family of latent cytoplasmic transcription factors, STATS are the most well characterized downstream substrates for JAKs.
  • the STAT proteins bind to phosphorylated cytokine receptors through their SH2 domains to become phosphorylated by JAKs, which event leads to their dimerization and release and
  • STAT3 Signal transducer and activator of transcription 3
  • STAT3 is a transcription factor that regulates the expression of a variety of genes involved in many cellular processes such as cell growth, apoptosis, cell motility, and cytokine production.
  • STAT3 is activated by JAK kinases and translocates to the nucleus to act as a transcriptional activator.
  • JAK kinases JAK kinases and translocates to the nucleus to act as a transcriptional activator.
  • IBD Inflammatory bowel diseases
  • IBS irritable bowel syndrome
  • SIBO small intestinal bacterial overgrowth
  • methods of treating IBD, IBS and/or (SIBO) in a subject comprising administering to the subject an effective amount of a polymer conjugate, wherein the warhead is a small molecule targeting mediator(s) of gastrointestinal conditions.
  • the warhead employed in the LSE polymer conjugate is a small molecule targeting a JAK and/or STAT family protein.
  • Non-limiting examples of inflammatory bowel diseases include Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behget's syndrome, and indeterminate colitis.
  • the warhead employed in the LSE polymer conjugate is a small molecule targeting c-Src.
  • methods of treating an inflammatory bowel disease in a subject comprising administering to the subject an effective amount of a polymer conjugate, wherein the warhead is a small molecule targeting c-Src.
  • the c-Src kinase is the most widely studied member of the largest family of nonreceptor protein tyrosine kinases, known as the Src family kinases (SFKs).
  • Src family kinases Other SFK members include Lyn, Fyn, Lck, Hck, Fgr, Blk, Yrk, and Yes.
  • the Src kinases can be grouped into two sub-categories, those that are ubiquitously expressed (Src, Fyn, and Yes), and those which are found primarily in hematopoietic cells (Lyn, Lck, Hck, Blk, Fgr). (Benati, D. Src Family Kinases as Potential Therapeutic Targets for Malignancies and Immunological Disorders.
  • SFKs are key messengers in many cellular pathways, including those involved in regulating proliferation, differentiation, survival, motility, and angiogenesis.
  • the activity of SFKs is highly regulated intramolecularly by interactions between the SH2 and SH3 domains and intermolecularly by association with cytoplasmic molecules. This latter activation may be mediated by focal adhesion kinase (FAK) or its molecular partner Crk- associated substrate (CAS), which plays a prominent role in integrin signaling, and by ligand activation of cell surface receptors, e.g. epidermal growth factor receptor (EGFR).
  • FAK focal adhesion kinase
  • CAS molecular partner Crk- associated substrate
  • Src can also be activated by dephosphorylation of tyrosine residue Y530.
  • maximal Src activation requires the autophosphorylation of tyrosine residue Y419 (in the human protein) present within the catalytic domain.
  • Elevated Src activity may be caused by increased transcription or by deregulation due to overexpression of upstream growth factor receptors such as EGFR, HER2, platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), vascular endothelial growth factor receptor, ephrins, integrin, or FAK.
  • upstream growth factor receptors such as EGFR, HER2, platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), vascular endothelial growth factor receptor, ephrins, integrin, or FAK.
  • compositions comprising compounds Nos 1-71 shown in Table 1 are used, in several embodiments, as inhibitors, antagonists, and inverse agonists of c-Src.
  • Several embodiments relate to polymer conjugates of compounds 1-71 , optimized for topical applications while also minimizing side-effects caused by exposure at non-target sites (e.g., systemic absorption). Non-topical applications are provided in other embodiments.
  • the warhead of the polymer conjugate is a small molecule disclosed in Table 1 targeting c-Src.
  • methods of treating an inflammatory bowel disease in a subject comprising administering to the subject an effective amount of an LSE polymer conjugate wherein the warhead is a small molecule disclosed in Table 1 targeting c-Src.
  • the warhead of the LSE polymer conjugate is compound 1 of Table 1.
  • the LSE polymer conjugate is CT101.
  • the warhead employed in the LSE polymer conjugate is a small molecule targeting a vascular endothelial growth factor receptor (VEGFR).
  • VEGFR vascular endothelial growth factor receptor
  • Angiogenesis the process of sprouting new blood vessels from existing vasculature, and arteriogenesis, the remodeling of small vessels into larger conduit vessels, are both physiologically important aspects of vascular growth in adult tissues.
  • These processes of vascular growth are involved, in some cases, for beneficial processes such as tissue repair, wound healing, recovery from tissue ischemia and menstrual cycling. They are also involved, in some cases, for the development of pathological conditions such as the growth of neoplasias, diabetic retinopathy, rheumatoid arthritis, psoriasis, certain forms of macular degeneration, and certain inflammatory pathologies.
  • the inhibition of vascular growth in these contexts has also shown beneficial effects in preclinical animal models.
  • angiogenesis For example, inhibition of angiogenesis by blocking vascular endothelial growth factor or its receptor has resulted in inhibition of tumor growth and in retinopathy. Also, the development of pathological pannus tissue in rheumatoid arthritis involves angiogenesis and might be blocked by inhibitors of angiogenesis.
  • Certain diseases are known to be associated with deregulated angiogenesis, for example ocular neovascularization, such as retinopathies (including diabetic retinopathy), age-related macular degeneration, psoriasis, hemangioblastoma, hemangioma, arteriosclerosis, inflammatory disease, such as a rheumatoid or rheumatic inflammatory disease, especially arthritis (including rheumatoid arthritis), or other chronic inflammatory disorders, such as chronic asthma, arterial or post- transplantational atherosclerosis, endometriosis, and neoplastic diseases, for example so-called solid tumors and liquid tumors (such as leukemias).
  • retinopathies including diabetic retinopathy
  • age-related macular degeneration psoriasis
  • hemangioblastoma hemangioma
  • arteriosclerosis arteriosclerosis
  • inflammatory disease such as a rheumatoid or r
  • VEGF Vascular endothelial growth factor
  • vasculogenesis the de novo formation of the embryonic circulatory system
  • angiogenesis the growth of blood vessels from pre-existing vasculature.
  • VEGF activity has been mostly studied on cells of the vascular endothelium, although it does have effects on a number of other cell types (e.g., stimulation monocyte/macrophage migration, neurons, cancer cells, kidney epithelial cells, keratinocytes).
  • VEGF has been shown to stimulate endothelial cell mitogenesis and cell migration.
  • VEGF is also a vasodilator and increases microvascular permeability and was originally referred to as vascular permeability factor.
  • VEGF vascular endothelial growth factor
  • the broad term“VEGF” covers a number of proteins from two families, that result from alternate splicing of mRNA from a single, 8 exon, VEGF gene.
  • the two different familes are referred to according to their terminal exon (exon 8) splice site— the proximal splice site (denoted VEGFxxx) or distal splice site (VEGFxxxb).
  • these domains have functional consequences for the VEGF splice variants as the terminal (exon 8) splice site determines whether the proteins are pro-angiogenic (proximal splice site, expressed during angiogenesis) or anti-angiogenic (distal splice site, expressed in normal tissues).
  • exons 6 and 7 mediate interactions with heparan sulfate proteoglycans (HSPGs) and neuropilin co-receptors on the cell surface, enhancing their ability to bind and activate VEGFRs.
  • HSPGs heparan sulfate proteoglycans
  • neuropilin co-receptors enhancing their ability to bind and activate VEGFRs.
  • VEGFRs tyrosine kinase receptors
  • the VEGF receptors have an extracellular portion consisting of 7 immunoglobulin-like domains, a single transmembrane spanning region and an intracellular portion containing a split tyrosine-kinase domain.
  • VEGF-A binds to VEGFR- 1 (Flt-1) and VEGFR-2 (KDR/Flk-1). VEGFR-2 appears to mediate almost all of the known cellular responses to VEGF.
  • VEGFR-1 The function of VEGFR-1 is less well defined, although it is thought to modulate VEGFR-2 signaling. Another function of VEGFR-1 may be to act as a dummy/decoy receptor, sequestering VEGF from VEGFR-2 binding (this appears to be involved during vasculogenesis in the embryo). VEGF-C and VEGF-D, but not VEGF-A, are ligands for a third receptor (VEGFR-3), which mediates lymphangiogenesis.
  • VEGFR-3 third receptor
  • Increased vascular permeability is one of the earliest manifestations of inflammation, resulting in extravasation of protein-rich plasma into the effected tissue.
  • Acute vascular permeability allows the deposition of circulating plasma matrix proteins including fibrin and fibronectin (FN) which facilitate cell migration in the inflamed area. This process also provides an access point for immune cells and immunoglobulins to enter the tissue and fight foreign antigens (Nagy et al, Cold Spring Harb. Perspect. Med. 2:a006544, 2012).
  • chronic vascular hyperpermeability is suggested to sustain the inflammatory response and retard resolution, further promoting the development of chronic inflammation (Nagy et al, Cold Spring Harb. Perspect. Med.
  • vascular hyperpermeability underlies the pathogenesis of a large number of chronic disorders including rheumatoid arthritis (RA), psoriasis, ocular disease, cancer and chronic wounds (Nagy et al, Cold Spring Harb. Perspect. Med. 2:a006544, 2012; Costa et al, Angiogenesis 10:149-166, 2007).
  • RA rheumatoid arthritis
  • psoriasis ocular disease
  • cancer chronic wounds
  • VEGF is a potent vascular permeabilizing agent that is highly expressed during chronic inflammation (Nagy et al, Annu. Rev. Pathol. 2:251-275, 2007). Low microenvironmental levels of VEGF are desired in order to maintain stable vascular integrity and promote endothelial cell survival through autocrine mechanisms (Lee et al, Cell 130:691-703, 2007). Whereas elevated levels of VEGF induce vascular leakages by activating VEGF receptor 2 (VEGFR2) in endothelial cells (EC) leading to the opening of intercellular and/or intracellular pathways that facilitate plasma extravasation (Koch and Claesson-Welsh, Cold Spring Harb. Perspect. Med. 2:a006502, 2012).
  • VAGFR2 VEGF receptor 2
  • VEGF may serve as a pro-inflammatory mediator as it can enhance T cell (Xia et al, Blood 102:161-168, 2003), and monocyte (Murakami et al, Blood 108:1849-1856, 2006) migration as well as promote pro-inflammatory chemokines expression by EC including MCP-1 , and IL-8, leading to further immune recruitment.
  • Cellular sources for VEGF during inflammation can include macrophages and mast cells; however it can also be expressed by endothelial cells and acts in a paracrine and autocrine fashion.
  • VEGF plays a major role in promoting chronic inflammation by inducing vascular permeability and contributing to immune cell recruitment.
  • compositions comprising compounds Nos 1-59 shown in Table 2 are used, in several embodiments, as inhibitors, antagonists, and inverse agonists of a VEGFR.
  • Several embodiments relate to polymer conjugates of compounds 1 -59, optimized for topical applications while also minimizing side-effects caused by exposure at non-target sites (e.g., systemic absorption). Non-topical applications are provided in other embodiments.
  • the warhead of the polymer conjugate is a small molecule disclosed in Table 2 targeting a VEGFR.
  • methods of treating an inflammatory bowel disease in a subject comprising administering to the subject an effective amount of an LSE polymer conjugate wherein the warhead is a small molecule disclosed in Table 2 targeting a VEGFR.
  • the warhead of the LSE polymer conjugate is compound 1 of Table 2.
  • the LSE polymer conjugate is CT103.
  • compositions comprising compounds shown in Tables 1-3 are used, in several embodiments, as inhibitors, antagonists, and inverse agonists of the mediator(s) of gastrointestinal conditions, such as, but not limited to, inflammatory bowel diseases, IBS or SIBO are disclosed herein.
  • compositions comprising compounds shown in Tablse 1-3 are used as inhibitors, antagonists, and inverse agonists of JAK and/or STAT family proteins.
  • the warhead of the polymer conjugate is compound 1 of Table 3.
  • the LSE polymer conjugate is CT352.
  • Allergic inflammatory diseases are characterized by an immune response against a sensitizing agent, such as an allergen, resulting in the release of inflammatory mediators that recruit cells involved in inflammation in a subject, potentially leading to tissue damage and sometimes death.
  • a sensitizing agent such as an allergen
  • Methods of treating allergic inflammatory diseases of the gastrointestinal tract are provided herein.
  • methods of treating an allergic inflammatory disease in a subject comprising administering to the subject an effective amount of a polymer conjugate, wherein the warhead is a small molecule targeting a JAK and/or STAT family protein.
  • methods of treating the following conditions in a subject comprising administering to the subject an effective amount of a polymer conjugate, wherein the warhead is a small molecule targeting a JAK and/or STAT family protein: ulcerative colitis; Crohn’s disease; colorectal cancer; celiac disease; and intestinal fibrosis
  • LSE polymer conjugates wherein the warhead (e.g., one or more pharmacologically active agents) is a selective inhibitor, antagonist, or inverse agonist of JAK1.
  • the warhead of the LSE polymer conjugate is JNJ-54781532 (ASP015K, Peficitinb).
  • the warhead of the LSE polymer conjugate is Upadacitinib (ABT-494).
  • the warhead of the LSE polymer conjugate is GSK2586184.
  • LSE polymer conjugates wherein the warhead is an inhibitor, antagonist, or inverse agonist of LTA4H.
  • the warhead of the LSE polymer conjugate is JNJ-26993135 (1-[4-(benzothiazol-2-yloxy)-benzyl]-piperidine-4- carboxylic acid).
  • Colony-stimulating factor-1 receptor (CSF1 R; FMS) is a tyrosine kinase receptor that plays an essential role in promoting macrophage and dendritic cell differentiation, recruitment, activation, and proliferation.
  • the differentiation of dendritic cells and macrophages and their migration to intestinal mucosa is a component of inflammatory bowel diseases, particularly Crohn’s disease.
  • LSE polymer conjugates wherein the warhead is an inhibitor, antagonist, or inverse agonist of FMS.
  • the warhead of the LSE polymer conjugate is JNJ-40346527 (PRV-6527).
  • Acute and chronic inflammation of the bowel is caused by a number of diseases, and typically the epithelial cells on the surface of mucosal tissue have an induced state of hypoxia due to the presence of inflammation.
  • the body's response to this hypoxic condition is to increase the presence of hypoxia inducible factor- 1 alpha (HIF-1 a) which drives the expression of downstream HIF-1 target genes, inter alia, erythropoietin.
  • HIF-1 a is a mediator in the body's response to inflammation.
  • the cellular concentration of HIF-1 a is regulated by prolyl hydroxylase enzymes that serve to destabilize HIF-1 a during periods of normoxia, resulting in the destruction of this protein.
  • HIF-1 a prolyl hydroxylase thus leads to increased stabilization of HIF-1a, in turn resulting in an upregulation of HIF-1 a that leads to a corresponding increased response to inflammation.
  • treatment with one or more effective HIF-1 a prolyl hydroxylase inhibitors can increase the level of the body's cellular inflammatory response.
  • HIF-1 a prolyl hydroxylase inhibitors can increase the amount of epithelial cell healing over that which the body would normally provide.
  • LSE polymer conjugates wherein the warhead is a HIF-1 a stabilizer.
  • selective inhibitors, antagonists, and inverse agonists of HIF-1a prolyl hydroxylase are provided, in several embodiments.
  • the warhead of the LSE polymer conjugate is JNJ5169 (AKB-5169).
  • the warhead of the LSE polymer conjugate is a compound having the formula:
  • Z is phenyl substituted with from 1 to 5 halogens chosen from fluorine and chlorine;
  • R 4 is C 1 -C4 linear alkyl or C3-C4 branched alkyl
  • the warhead of the LSE polymer conjugate is a compound having the formula:
  • L is chosen from CH 2 or S02;
  • R represents from 0 to 5 substitutions for hydrogen
  • n is an integer from 0 to 5;
  • R 1 and R 2 are each independently chosen from:
  • R 1 and R 2 can be taken together to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring having from form 2 to 20 carbon atoms and from 1 to 7 heteroatoms; or a pharmaceutically acceptable salt thereof.
  • the a4 integrin a4b7 plays an essential role in lymphocyte migration throughout the gastrointestinal tract. It is expressed on most leukocytes, including B and T lymphocytes, where it mediates cell adhesion via binding to its ligand mucosal addressin cell adhesion molecule (MAdCAM). If left unchecked, integrin-mediated adhesion process can lead to chronic inflammation and autoimmune disease. Inhibitors of specific integrin-ligand interactions have been shown effective as anti-inflammatory agents for the treatment of various autoimmune diseases. Accordingly, there is provided, in several embodiments, LSE polymer conjugates wherein the warhead is an inhibitor, antagonist, or inverse agonist of alpha-4- beta-7 integrin.
  • MAdCAM mucosal addressin cell adhesion molecule
  • the warhead of the LSE polymer conjugate is PTG-100. In several embodiments, the warhead of the LSE polymer conjugate is a peptide dimer compound comprising two monomer subunits, wherein each monomer subunit comprises the amino acid sequence:
  • the present invention includes a peptide dimer compound comprising two linked monomer subunits of Formula (I):
  • Xaa 1 is absent, Ac, or any amino acid
  • Xaa 2 is absent, Ac, or any amino acid
  • Xaa 3 is absent, Ac, or any amino acid
  • Xaa 4 is any amino acid capable of forming a bond with Xaa 10 ;
  • Xaa 5 is selected from the group consisting of: N-Me-Arg, Arg, N-Me-Lys, Phe(4- guanidinoguanidino), Phe(4-carbomyl), Cit, Phe(4-NH 2 ), N-Me-homoArg, homoArg, Tyr, Dap, Dab, Arg-Me-sym, Arg-Me-asym, Cav, and His;
  • Xaa 6 is Ser, Gly, Thr or lie;
  • Xaa 7 is Asp, Asp(OMe) or N-Me-Asp;
  • Xaa 8 is selected from the group consisting of: Thr, Val, lie, Leu, homoLeu, Gin, Ser, Asp, Pro, Gly, His, Ala, Phe, Lys, Arg, Asn, Glu, Tyr, Trp, Met, Nle, and N- methyl amino acids, including N-Me-Thr;
  • Xaa 9 is selected from the group consisting of: Gin, Ser, Asp, Pro, Gly, Ala, Phe, Glu, lie, Val, N-butyl Ala, N-pental Ala, N-hexyl Ala, cyclobutyl Ala, cyclopentylAla, Leu, Nle, Cba, homoLeu, Cpa, Aoc, and N-Me-Leu;
  • Xaa 10 is any amino acid capable of forming a bond with Xaa 4 ;
  • Xaa 11 is absent or selected from the group consisting of: aromatic amino acids, substituted aromatic amino acids, and Tic;
  • Xaa 12 is absent or selected from the group consisting of: aromatic amino acids, substituted aromatic amino acids, Glu, D-Glu, homoGlu, Asp, D-Asp, D-homoGlu, Gla, beta-homoGlu, Tic, Aic, Gin, Cit, Glu(OMe), Asn, D-His, Tic, Phe(3-COOH), D-Arg, Bip, D-Trp, Phe, D-Phe, D-Val, D-Thr, D-Tyr, D-Lys, D-lle, D-His, N-Me- Glu, N-Me-Asp, alpha-homoGlu, Biphenyl-Gly, Biphenyl-Ala, Homo-Phe, D-1-Nal, D-2-Nal, Thr, and Val, and corresponding D-amino acids and isosteres;
  • Xaa 13 is absent or Pro or any amino acid
  • Xaa 14 is selected from the group consisting of: any amino acid with an amine side chain, Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, HomoLys, D-Dap, D-Dab, D- Orn, Cys, HomoCys, Pen, D-HomoCys, D-Cys, D-Pen, Asp, Glu, D-Asp, D-Glu and HomoSer, HomoGlu, D-homoGlu, N-Me-Glu, N-Me-Asp, N-Me-D-Glu, and N-Me-D-Asp; wherein Xaa 4 and Xaa 10 are both Pen or Cys; wherein: Xaa 5 is selected from the group consisting of Cit, Phe(4-carbomylamino), and N-Me-homoArg; Xaa 8
  • the interleukin-23 (IL-23) cytokine has been implicated as playing a crucial role in the pathogenesis of inflammatory bowel diseases.
  • IL-23R is expressed on various adaptive and innate immune cells including Th17 cells, gd T cells, natural killer (NK) cells, dendritic cells, macrophages, and innate lymphoid cells, which are found abundantly in the intestine. At the intestine mucosal surface, the gene expression and protein levels of IL-23R are found to be elevated in IBD patients.
  • IL-23 Production of IL-23 is enriched in the intestine, where it is believed to play a key role in regulating the balance between tolerance and immunity through T-cell-dependent and T-cell-independent pathways of intestinal inflammation through effects on T-helper 1 (Th1) and Th17-associated cytokines, as well as restraining regulatory T-cell responses in the gut, favoring inflammation.
  • Th1 T-helper 1
  • Th17-associated cytokines T-helper 1
  • IL-23R polymorphisms in the IL-23 receptor
  • Binding of IL-23 to IL-23R activates the JAK-STAT signaling.
  • LSE polymer conjugates wherein the warhead is an inhibitor, antagonist, or inverse agonist of Interleukin-23 receptor.
  • the warhead of the LSE polymer conjugate is PTG-200.
  • the warhead of the LSE polymer conjugate comprises a peptide inhibitor of Interleukin-23 receptor.
  • the warhead of the LSE polymer conjugate comprises the amino acid sequence of Formula II:
  • X1 is any amino acid or absent
  • X2 is any amino acid or absent
  • X3 is any amino acid or absent
  • X4 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Met, Glu, Asp, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys, Sec, 2-chloromethylbenzoic acid, mercapto- propanoic acid, mercapto-butyric acid, 2-chloro-acetic acid, 3-choro-propanoic acid, 4- chloro-butyric acid, 3-chloro-isobutyric acid, Abu, b-azido-Ala-OH, propargylglycine, 2- (3'-butenyl)glycine, 2-allylglycine, 2-(3'-butenyl)glycine, 2-(4'-pentenyl)glycine, 2-(5'- hexenyl)glycine, or absent;
  • X5 is any amino acid
  • X6 is any amino acid
  • X7 is Trp, Glu, Gly, lie, Asn, Pro, Arg, Thr or OctGly, or a corresponding a-methyl amino acid form of any of the foregoing;
  • X8 is any amino acid
  • X9 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Glu, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys, Asp, Leu, Val, Phe, Ser, Sec, Abu, b-azido-Ala-OH, propargylglycine, 2-2-allylglycine, 2-(3'-butenyl)glycine, 2-(4'-pentenyl)glycine, Ala, hCys, Met, MeCys, (D)Tyr or 2-(5'-hexenyl)glycine;
  • X10 is Tyr, Phe(4-0Me), 1-Nal, 2-Nal, Aic, a-MePhe, Bip, (D)Cys, Cha, DMT, (D)Tyr, Glu, His, hPhe
  • X1 1 is 2-Nal, 1-Nal, 2,4-dimethylPhe, Bip, Phe(3,4-CI2), Phe (3.4-F2), Phe(4- C02H), bhPhe(4-F), a-Me-Trp, 4-phenylcyclohexyl, Phe(4-CF3), Phe(3,4-OMe2), a- MePhe, bhPhe, bhTyr, bhTrp, Nva(5-phenyl), Phe, His, hPhe, Tic, Tqa, Trp, Tyr, Phe(4- OMe), Phe(4-Me), Trp(2,5,7-tri-tert-Butyl), Phe(4-Oallyl), Tyr(3-tBu), Phe(4-tBu), Phe(4- guanidino, Phe(4-OBzl), Octgly, Glu(Bzl), 4-Phenylbenzyla
  • X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, t-butyl-Ala, a-MeLys, D-Ala, (D)Asn, (D)Asp, (D)Leu, (D)Phe, (D)Tyr, Aib, a-MeLeu, a-MeOrn, b-Aib, b-Ala, bhAla, bhArg, bhLeu, bhVal, b-spiro-pip, Glu, hArg, lie, Lys, N-MeLeu, N-MeArg, Ogl, Orn, Pro, Gin, Ser, Thr, Tie, t-butyl-Gly, 4-amino-4-carboxy-tetrahydropyran (THP), Ache Acpc, Acbc, Acvc,
  • X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Asn, Cit, Lys, Arg, Orn, Val, bhAla, Lys(Ac), (D)Asn, (D)Leu, (D)Phe, (D)Thr, Ala, a-MeLeu, Aib, b-Ala, b-Glu, bhLeu, bhVal, b-spiro- pip, Cha, Chg, Asp, Dab, Dap, a-DiethylGly, hLeu, Asn, Ogl, Pro, Gin, Ser, b-spiro-pip, Thr, Tba, Tie or Aib, or a corresponding a-methyl amino acid form of any of the foregoing;
  • X14 is Phe, Tyr, Glu, Gly, His, Lys, Leu, Met, Asn, Lys(Ac), Dap(Ac), Asp, Pro, Gin, Arg, Ser, Thr, Tic or bhPhe, or a corresponding a-methyl amino acid form of any of the foregoing;
  • X15 is Gly, Ser, Thr, Gin, Ala, (D)Ala, (D)Asn, (D)Asp, (D)Leu, (D)Phe, (D)Thr, Aea, Asp, Asn, Glu, Phe, Gly, Lys, Leu, Pro, Arg, b-Ala, or Sarc, or a corresponding a- methyl amino acid form of any of the foregoing;
  • X16 is any amino acid or absent
  • X17 is any amino acid or absent
  • X18 is any amino acid or absent
  • X19 is any amino acid or absent
  • X20 is any amino acid or absent
  • peptide inhibitor is cyclized via a bond between X4 and X9.
  • the warhead of the LSE polymer conjugate comprises the amino acid sequence of Formula III:
  • XI is any amino acid or absent
  • X2 is any amino acid or absent
  • X3 is any amino acid or absent
  • X4 is Pen, Cys or homo-Cys
  • X5 is any amino acid
  • X6 is any amino acid
  • X7 is Trp, Bip, Gin, His, Glu(Bzl), 4-Phenylbenzylalanine, Tic, Phe[4-(2- aminoethoxy)], Phe(3,4-CI 2 ), Phe(4-OMe), 5-Hydroxy-Trp, 6-Chloro-Trp, N-MeTrp, a-Me- Trp, 1 ,2,3,4-tetrahydro-norharman, Phe(4-CO 2 H), Phe(4-CONH 2 ), Phe(3,4-Dimethoxy), Phe(4-CF 3 ), Phe(4-tBu), bb-diPheAla, Glu, Gly, lie, Asn, Pro, Arg, Thr or Octgly, or a corresponding a-methyl amino acid form of any of the foregoing;
  • X8 is any amino acid
  • X9 is Pen, Cys or hCys
  • X10 is 1-Nal, 2-Nal, Aic, Bip, (D)Cys, Cha, DMT, (D)Tyr, Glu, Phe, His, Trp, Thr, Tic, Tyr, 4-pyridylAla, Octgly, a Phe analog or a Tyr analog, or a corresponding a-methyl amino acid form of any of the foregoing;
  • XI I is 2-Nal, 1-Nal, 2,4-dimethylPhe, Bip, Phe(3,4-CI 2 ), Phe (3,4-F 2 ), Phe(4-
  • X12 is a-MeLys, a-MeOrn, a-MeLeu, a-MeVal, 4-amino-4-carboxy- tetrahydropyran, Ache Acpc, Acbc, Acvc, MeLeu, Aib, (D)Ala, (D)Asn, (D)Leu, (D)Asp, (D)Phe, (D)Thr, 3-Pal, Aib, b-Ala, bhGlu, bhAla, bhLeu, bhVal, b-spiro-pip, Cha, Chg, Asp, Dab, Dap, a-diethylGly, Glu, Phe, hLeu, hArg, hLeu, lie, Lys, Leu, Asn, N-MeLeu, N-MeArg, Ogl, Orn, Pro, Gin, Arg, Ser, Thr or Tie, or a
  • X13 is Lys(Ac), (D)Asn, (D)Leu, (D)Thr, (D)Phe, Ala, Aib, a-MeLeu, b-Ala, bhGlu, bhAla, bhLeu, bhVal, b-spiro-pip, Cha, Chg, Asp, Lys, Arg, Orn, Dab, Dap, a-diethylGly, Glu, Phe, hLeu, Lys, Leu, Asn, Ogl, Pro, Gin, Asp, Arg, Ser, spiro-pip, Thr, Tba, Tic, Val or Tyr, or a corresponding a-methyl amino acid form of any of the foregoing;
  • X14 is Asn, Glu, Phe, Gly, His, Lys, Leu, Met, Asn, Pro, Gin, Arg, Ser, Thr, Tic or Tyr, Lys(Ac), Orn or a corresponding a-methyl amino acid form of any of the foregoing;
  • X15 is Gly, (D)Ala, (D)Asn, (D)Asp, Asn, (D)Leu, (D)Phe, (D)Thr, Ala, Asn, Ser, AEA, Asp, Glu, Phe, Gly, Lys, Leu, Pro, Gin, Arg or Ser, b-Ala, Arg or a corresponding a- methyl amino acid form of any of the foregoing;
  • X16 is absent, Gly, Ala, Asp, Ser, Pro, Asn or Thr, or a corresponding a-methyl amino acid form of any of the foregoing;
  • X17 is absent, Glu, Ser, Gly or Gin, or a corresponding a-methyl amino acid form of any of the foregoing;
  • X18 is absent or any amino acid
  • X19 is absent or any amino acid
  • X20 is absent or any amino acid
  • the peptide inhibitor comprises a disulfide bond between X4 and X9.
  • Inflammatory bowel diseases are characterized by an aberrant immune response occurring in a genetically predisposed host in response to microbes and/or microbial compounds found in the gut microbiota.
  • a pathotype of E. coli called "AIEC” for "adherent- invasive Escherichia coli”
  • AIEC are able to adhere to the intestinal epithelium and colonize gut mucosa where they participate to IBD onset.
  • AIEC's adhesion to mucosal epithelial cells is mediated by proteinaceous, rod-like organelles that are called type-1 fimbriae.
  • Type-1 fimbriae carry an adhesin at the edge of a flexible tip fibrillum.
  • This adhesin, FimH is a lectin having a strong affinity for highly mannosylated glycoproteins.
  • AIEC bacteria adhere specifically to the carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), a mannosylated glycoprotein which is abnormally expressed in the ileal mucosa of 35% of CD patients.
  • CEACAM6 carcinoembryonic antigen-related cell adhesion molecule 6
  • Overexpression of these CEACAM6 molecules in CD patients acting as receptors for E. coli adhesion in the gut, favors ileal and colonic AIEC invasion and their intracellular survival and replication within the mucosal tissues, thereby amplifying immune responses in IBD patients.
  • LSE polymer conjugates wherein the warhead is an inhibitor, antagonist, or inverse agonist of FimH.
  • the warhead of the LSE polymer conjugate is EB8018.
  • the warhead of the LSE polymer conjugate is compound of the following formula:
  • Ri represents H, CO-(C 1 -C 6 )-alkyl or CO-alkylaryl, preferably H, COMe or COChhPh,
  • Y represents a single bond, CH 2 , O, NR 3 , S, preferably a single bond, CH 2 , NR 3 ,
  • A represents O, NH or S, preferably O or S,
  • X represents H and X' represents OH or X and X' taken together with the carbon atom bearing them form a CO group
  • R 2 represents H, a linear or branched (C 1 -C 6 )-alkyl or CF 3 ,
  • R 3 represents H, a d-C 6 alkyl, a CO-(C 1 -C 6 )-alkyl, CF 3 or COCF 3 , preferably H, CH 3 , COCH 3 , CF 3 or OCF 3 , and
  • R represents: a (C 1 -C 6 )-alkyl, a (C 2 -C 6 )-alkenyl, a (C 2 -C 6 )-alkynyl, a (C 3 -C 1 o)- cycloalkyl, a (C 5 -C 1 o)-cycloalkenyl, a heterocycloalkyl, a heterocycloalkenyl, an arylan alkyl aryl, CF 3 , adamantyl, OR a , or NR b R c ,
  • R a represents H, a (C 1 -C 6 )-alkyl, a (C 2 -C 6 )-alkenyl, a (C 2 -C 6 )-alkynyl, a (C 3 -C 6 )-cycloalkyl, a (C 3 -C 6 )-cycloalkenyl, a heterocycloalkyl, a heterocycloalkenyl, an aryl, a alkylaryl, a CHO, a CO-(C 1 -C 6 )-alkyl, or CO-aryl, a CO 2 H, a CO 2 -(C 1 -C 6 )-alkyl, or a CONH-( C 1 -C e )-alkyl,
  • R b and R c represent independently from each other any of the groups defined for R a , R b representing in particular H, said (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 10 )-cycloalkyl, (C 5 -C 10 )- cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, CO-(C 1 -C 6 )-alkyl, CO 2 -(C 1 -C 6 )-alkyl, CONH-(C 1 -C 6 )-alkyl, aryl, alkylaryl, CO-aryl and CO-alkylaryl being optionally substituted by one or more, preferably 1 to 4, more preferably 1 or 2 substituent(s) R', each independently selected from:
  • T represents a monovalent cation such as a mineral monovalent cation, in particular an alkaline cation preferably selected from Li + , Na + , K + and even more preferable Na + and wherein T’ is a monovalent anion, such as a halogenide, in particular chloride, bromide or iodide, preferably chloride,
  • aryl optionally substituted by one or more, preferably one to three substituents selected from a halogen, NH 2 , OH, CF 3 , a C 1 -C 6 alkyl preferably substituted by a carbohydrate, CH 2 S0 3 T, CH 2 COOT or N(R g ) 3 T, wherein R g , T and T' are as defined above,
  • alkyl aryl optionally substituted by one or more, preferably one to three substituents selected from a halogen, NH 2 , OH, CF 3 , a C 1 -C 6 alkyl preferably substituted by a carbohydrate, CH 2 S0 3 T, CH 2 COOT or N(R g ) 3 T', wherein R g , T and T' are as defined above,
  • NH-alkyl aryl optionally substituted by one or more, preferably one to three substituents selected from a halogen, NH 2 , OH, CF 3) a C 1 -C 6 alkyl preferably substituted by a carbohydrate, CH 2 S0 3 T, CH 2 COOT or N(R g ) 3 T, wherein R g , T and T’ are as defined above,
  • CO-aryl optionally substituted by one or more, preferably one to three substituents selected from a halogen, NH 2 , OH, CF 3 , a C 1 -C 6 alkyl preferably substituted by a carbohydrate, CH 2 S0 3 T, CH 2 COOT or N(R g ) 3 T, wherein R g , T and T’ are as defined above,
  • R d represents: H, a (C 1 -C 6 )-alkyl, a (C 3 -C 10 )-cycloalkyl, CO(C 1 -C 6 )- alkyl, or CO-aryl optionally substituted by one or more, preferably one to three substituents selected from a halogen, CF 3 , a C C 6 alkyi preferably substituted by a carbohydrate,
  • R e and R f represent independently from each other: H, a (C 1 - C 6 )-alkyl, a (C 3 -C 1 0)-cycloalkyl, CO-(C 1 -C 6 )-alkyl, or CO-aryl optionally substituted by one or more, preferably one to three substituents selected from a halogen, CF 3 , a C 1 -C 6 alkyl preferably substituted by a carbohydrate,
  • LSE polymer conjugates wherein the warhead is an inhibitor, antagonist, or inverse agonist of PDE4.
  • the warhead of the LSE polymer conjugate is Tetilomast (OPC-6535).
  • LSE polymer conjugates wherein the warhead is an inhibitor, antagonist, or inverse agonist of cytokines interleukin-12 (IL-12) and/or interleukin-23 (IL-23), which can mediate the progression of inflammatory bowel diseases.
  • the warhead of the LSE polymer conjugate is Apilimod (STA-5326).
  • LSE polymer conjugates wherein the warhead is an inhibitor, antagonist, or inverse agonist of a P38 mitogen-activated protein kinase.
  • the warhead of the LSE polymer conjugate is Doramapimod (BIRB 796).
  • the warhead of the LSE polymer conjugate is Semapimod (CNI-1493).
  • the warhead of the LSE polymer conjugate comprises an antibiotic selected from sulfonamides (e.g., 4-amino-N-(5- methyl-3-isoxazolyl)benzenesulfonamide); vancomycin; amoxicillin; tetracyclines; clarithromycin; clindamycin; a member of the cephlosporin antibiotic family (e.g., cefaclor, cefadroxil, cefixime, cefprozil, ceftriaxone, cefuroxime, cephalexin, loracarbef, and the like); a member of the penicillin family of antibiotics (e.g., ampicillin, amoxicillin/clavulanate, bacampicillin, cloxicillin, penicillin VK, and
  • the warhead of the LSE polymer conjugate comprises a non-systemic antibiotic that is minimally absorbed and has high local concentrations in the Gl tract after oral administration. Accordingly, in some embodiments, the LSE polymer conjugate comprises rifaximin.
  • Antibiotics delivered (e.g., orally) according to several embodiments described herein may be particularly useful to treat the small intestine (for example to treat SIBO or small intestinal bacterial overgrowth).
  • Such delivery compositions are able to, in some embodiments, deliver localized doses of antibiotics (or other antimicrobials) to the intestinal tract without significant exposure to other tissue which, advantageously, limits the side effects (such as dysbiosis or the destruction of good bacteria) that is caused by some antibiotics/antimicrobials.
  • localized and precision-based treatment permits lower doses of the antibiotics/antimicrobials to be ingested, which in some embodiments may reduce or avoid toxicity, adverse immune effects, tolerance, destruction of probiotics, etc.
  • Anti-fungals and anti-parasitic agents may also be delivered (orally, injected, topical, or by other means) according to the reduced systemic exposure embodiments described herein.
  • systemic exposure and/or exposure to a non-target tissue of antimicrobials is reduced by at least 25%, 50%, 75% or more using the embodiments described herein (e.g., LSE polymer conjugates) as compared with administration of the same antimicrobial without the polymer conjugates described herein.
  • the use of the compositions described herein results in a reduced negative impact on the natural healthy microbiome of a subject because of reduced exposure to non-target tissue.
  • Oral delivery is contemplated in several embodiments suitable for gastrointestinal disorders, and thus several embodiments relate to polymer conjugates of compounds in Tables 1-3, optimized for oral delivery to treat the gastrointestinal system while also minimizing side-effects caused by exposure at non-target sites (e.g., systemic absorption). Topical applications are provided in other embodiments.
  • the warhead of the polymer conjugate is a small molecule disclosed in Table 3 targeting mediator(s) of gastrointestinal conditions.
  • methods of treating an inflammatory bowel disease in a subject comprising administering to the subject an effective amount of an LSE polymer conjugate wherein the warhead is a small molecule disclosed in Table 3 targeting mediator(s) of gastrointestinal conditions.
  • JAK and/or STAT family proteins are mediator(s) of gastrointestinal conditions.
  • the warhead employed in the LSE polymer conjugate is a small molecule targeting a JAK and/or STAT family protein.
  • the warhead of the polymer conjugate is compound 1 of Table 3.
  • the LSE polymer conjugate is CT352.
  • compositions comprising an indolocarbazole compound are used, in several embodiments, as inhibitors, antagonists, and inverse agonists of a VEGFR, c-Src, TkrA, MAP2K3, a JAK and/or STAT family protein.
  • Several embodiments relate to polymer conjugates of an indolocarbazole compound, optimized for topical applications while also minimizing side-effects caused by exposure at non-target sites (e.g., systemic absorption).
  • Non-topical applications are provided in other embodiments.
  • the warhead of the polymer conjugate is an indolocarbazole compound or derivative thereof.
  • methods of treating an inflammatory skin disease in a subject comprising administering to the subject an effective amount of an LSE polymer conjugate wherein the warhead is an indolocarbazole compound.
  • the warhead of the LSE polymer conjugate is a derivative of K252a.
  • the LSE polymer conjugate is SNA-125.
  • the LSE polymer conjugate is SNA-120.
  • the LSE polymer conjugate is SNA-125.
  • the warhead employed in the LSE polymer conjugate is a small molecule targeting mediator(s) of dermatological conditions.
  • methods of treating an inflammatory skin disease in a subject comprising administering to the subject an effective amount of a polymer conjugate, wherein the warhead is a small molecule targeting mediator(s) of dermatological conditions.
  • the dermatological condition is an inflammatory skin disease.
  • JAK and/or STAT family proteins are mediator(s) of dermatological conditions.
  • the warhead employed in the LSE polymer conjugate is a small molecule targeting a VEGFR, c-Src, TkrA, MAP2K3, a JAK and/or STAT family protein .
  • methods of treating dermatological conditions in a subject comprising administering to the subject an effective amount of a polymer conjugate, wherein the warhead is a small molecule targeting mediator(s) of dermatological conditions.
  • the warhead employed in the LSE polymer conjugate is a small molecule targeting a VEGFR, c-Src, TkrA, MAP2K3, a JAK and/or STAT family protein.
  • the warhead employed in the LSE polymer conjugate is a small molecule targeting a JAK and/or STAT family protein.
  • methods of treating an inflammatory skin disease in a subject comprising administering to the subject an effective amount of a polymer conjugate, wherein the warhead is a small molecule targeting a JAK and/or STAT family protein.
  • the JAK kinase family is a cytoplasmic protein kinase family comprising the members JAK1 , JAK2, JAK3 and TYK2.
  • JAK1 cytoplasmic protein kinase family
  • JAK2 JAK3
  • TYK2 cytoplasmic protein kinase family
  • ligand binding to a receptor leads to receptor dimerization or oligomerization, which leads to JAK recruitment and activation either through autophosphorylation or phosphorylation by other JAK kinases or by other tyrosine kinases, which in turn leads to tyrosine phosphorylation of the receptors as well as downstream substrates of JAK.
  • Growth factor or cytokine receptors that recruit JAK kinases include the interferon receptors, interleukin receptors (receptors for the cytokines IL-2 to IL-7, IL-9 to IL-13, IL-15, IL-23), various hormone receptors (erythropoietin (Epo) receptor, the thrombopoietin (Tpo) receptor, the leptin receptor, the insulin receptor, the prolactin (PRL) receptor, the Granulocyte Colony-Stimulating Factor (G-CSF) receptor and the growth hormone receptor), receptor protein tyrosine kinases (such as EGFR and PDGFR), and receptors for other growth factors such as leukemia inhibitory factor (LIF), Oncastatin M (OSM), IFNa/b/g, Granulocyte-macrophage colony-stimulating factor (GM-CSF), Ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-I) (
  • autoimmune diseases and disease associated with chronic inflammation, as well as acute responses have been linked to excessive or unregulated production or activity of one or more cytokines, the signaling of which depend on JAK kinases.
  • diseases include rheumatoid arthritis (RA) such as moderate to severe RA, systemic lupus erythematosus (SLE), multiple sclerosis (MS), Crohn's disease such as moderate to severe Crohn's disease, psoriasis such as moderate to severe chronic plaque psoriasis, ulcerative colitis such as moderate to severe ulcerative colitis, ankylosing spondilytis (AS), psoriatic arthritis, Juvenile Idiopathic Arthritis (JIA) such as moderate to severe polyarticular JIA, systemic lupus erythematosus (SLE), diabetic nephropathy, dry eye syndrome, Sjogren's Syndrome, alopecia areata, vitiligo, or atopic dermatiti
  • Phosphorylated receptors serve as docking sites for other SH-2 domain containing signaling molecules that interact with JAKs such as the STAT family of transcription factors, Src family of kinases, MAP kinases PB kinase and protein tyrosine phosphatases (Rane S.G. and Reddy E.P., Oncogene 2000 19, 5662-5679).
  • JAKs such as the STAT family of transcription factors, Src family of kinases, MAP kinases PB kinase and protein tyrosine phosphatases (Rane S.G. and Reddy E.P., Oncogene 2000 19, 5662-5679).
  • the family of latent cytoplasmic transcription factors, STATS are the most well characterized downstream substrates for JAKs.
  • the STAT proteins bind to phosphorylated cytokine receptors through their SH2 domains to become phosphorylated by JAKs, which event leads to their dimerization and release and
  • STAT3 Signal transducer and activator of transcription 3
  • STAT3 is a transcription factor that regulates the expression of a variety of genes involved in many cellular processes such as cell growth, apoptosis, cell motility, and cytokine production.
  • STAT3 is activated by JAK kinases and translocates to the nucleus to act as a transcriptional activator.
  • JAK kinases JAK kinases and translocates to the nucleus to act as a transcriptional activator.
  • the warhead employed in the LSE polymer conjugate is a small molecule targeting c-Src.
  • methods of treating an inflammatory skin disease in a subject comprising administering to the subject an effective amount of a polymer conjugate, wherein the warhead is a small molecule targeting c-Src.
  • the c-Src kinase is the most widely studied member of the largest family of nonreceptor protein tyrosine kinases, known as the Src family kinases (SFKs).
  • Src family kinases Other SFK members include Lyn, Fyn, Lck, Hck, Fgr, Blk, Yrk, and Yes.
  • the Src kinases can be grouped into two sub-categories, those that are ubiquitously expressed (Src, Fyn, and Yes), and those which are found primarily in hematopoietic cells (Lyn, Lck, Hck, Blk, Fgr). (Benati, D. Src Family Kinases as Potential Therapeutic Targets for Malignancies and Immunological Disorders.
  • SFKs are key messengers in many cellular pathways, including those involved in regulating proliferation, differentiation, survival, motility, and angiogenesis.
  • the activity of SFKs is highly regulated intramolecularly by interactions between the SH2 and SH3 domains and intermolecularly by association with cytoplasmic molecules. This latter activation may be mediated by focal adhesion kinase (FAK) or its molecular partner Crk- associated substrate (CAS), which plays a prominent role in integrin signaling, and by ligand activation of cell surface receptors, e.g. epidermal growth factor receptor (EGFR).
  • FAK focal adhesion kinase
  • CAS molecular partner Crk- associated substrate
  • Src can also be activated by dephosphorylation of tyrosine residue Y530.
  • maximal Src activation requires the autophosphorylation of tyrosine residue Y419 (in the human protein) present within the catalytic domain.
  • Elevated Src activity may be caused by increased transcription or by deregulation due to overexpression of upstream growth factor receptors such as EGFR, HER2, platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), vascular endothelial growth factor receptor, ephrins, integrin, or FAK.
  • upstream growth factor receptors such as EGFR, HER2, platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), vascular endothelial growth factor receptor, ephrins, integrin, or FAK.
  • compositions comprising compounds Nos 1-71 shown in Table 1 are used, in several embodiments, as inhibitors, antagonists, and inverse agonists of c-Src.
  • Several embodiments relate to polymer conjugates of compounds 1-71 , optimized for topical applications while also minimizing side-effects caused by exposure at non-target sites (e.g., systemic absorption). Non-topical applications are provided in other embodiments.
  • the warhead of the polymer conjugate is a small molecule disclosed in Table 1 targeting c-Src.
  • methods of treating an inflammatory skin disease in a subject comprising administering to the subject an effective amount of an LSE polymer conjugate wherein the warhead is a small molecule disclosed in Table 1 targeting c-Src.
  • the warhead of the LSE polymer conjugate is compound 1 of Table 1.
  • the LSE polymer conjugate is CT101.
  • the warhead employed in the LSE polymer conjugate is a small molecule targeting a vascular endothelial growth factor receptor (VEGFR).
  • VEGFR vascular endothelial growth factor receptor
  • Angiogenesis the process of sprouting new blood vessels from existing vasculature, and arteriogenesis, the remodeling of small vessels into larger conduit vessels, are both physiologically important aspects of vascular growth in adult tissues.
  • These processes of vascular growth are involved, in some cases, for beneficial processes such as tissue repair, wound healing, recovery from tissue ischemia and menstrual cycling. They are also involved, in some cases, for the development of pathological conditions such as the growth of neoplasias, diabetic retinopathy, rheumatoid arthritis, psoriasis, certain forms of macular degeneration, and certain inflammatory pathologies.
  • the inhibition of vascular growth in these contexts has also shown beneficial effects in preclinical animal models.
  • angiogenesis For example, inhibition of angiogenesis by blocking vascular endothelial growth factor or its receptor has resulted in inhibition of tumor growth and in retinopathy. Also, the development of pathological pannus tissue in rheumatoid arthritis involves angiogenesis and might be blocked by inhibitors of angiogenesis.
  • Certain diseases are known to be associated with deregulated angiogenesis, for example ocular neovascularization, such as retinopathies (including diabetic retinopathy), age-related macular degeneration, psoriasis, hemangioblastoma, hemangioma, arteriosclerosis, inflammatory disease, such as a rheumatoid or rheumatic inflammatory disease, especially arthritis (including rheumatoid arthritis), or other chronic inflammatory disorders, such as chronic asthma, arterial or post- transplantational atherosclerosis, endometriosis, and neoplastic diseases, for example so-called solid tumors and liquid tumors (such as leukemias).
  • retinopathies including diabetic retinopathy
  • age-related macular degeneration psoriasis
  • hemangioblastoma hemangioma
  • arteriosclerosis arteriosclerosis
  • inflammatory disease such as a rheumatoid or r
  • VEGF Vascular endothelial growth factor
  • vasculogenesis the de novo formation of the embryonic circulatory system
  • angiogenesis the growth of blood vessels from pre-existing vasculature.
  • VEGF activity has been mostly studied on cells of the vascular endothelium, although it does have effects on a number of other cell types (e.g., stimulation monocyte/macrophage migration, neurons, cancer cells, kidney epithelial cells, keratinocytes).
  • VEGF has been shown to stimulate endothelial cell mitogenesis and cell migration.
  • VEGF is also a vasodilator and increases microvascular permeability and was originally referred to as vascular permeability factor.
  • VEGF vascular endothelial growth factor
  • the broad term“VEGF” covers a number of proteins from two families, that result from alternate splicing of mRNA from a single, 8 exon, VEGF gene.
  • the two different familes are referred to according to their terminal exon (exon 8) splice site— the proximal splice site (denoted VEGFxxx) or distal splice site (VEGFxxxb).
  • these domains have functional consequences for the VEGF splice variants as the terminal (exon 8) splice site determines whether the proteins are pro-angiogenic (proximal splice site, expressed during angiogenesis) or anti-angiogenic (distal splice site, expressed in normal tissues).
  • exons 6 and 7 mediate interactions with heparan sulfate proteoglycans (HSPGs) and neuropilin co-receptors on the cell surface, enhancing their ability to bind and activate VEGFRs.
  • HSPGs heparan sulfate proteoglycans
  • neuropilin co-receptors enhancing their ability to bind and activate VEGFRs.
  • VEGFRs tyrosine kinase receptors
  • the VEGF receptors have an extracellular portion consisting of 7 immunoglobulin-like domains, a single transmembrane spanning region and an intracellular portion containing a split tyrosine-kinase domain.
  • VEGF-A binds to VEGFR- 1 (Flt-1) and VEGFR-2 (KDR/Flk-1). VEGFR-2 appears to mediate almost all of the known cellular responses to VEGF.
  • VEGFR-1 The function of VEGFR-1 is less well defined, although it is thought to modulate VEGFR-2 signaling. Another function of VEGFR-1 may be to act as a dummy/decoy receptor, sequestering VEGF from VEGFR-2 binding (this appears to be involved during vasculogenesis in the embryo). VEGF-C and VEGF-D, but not VEGF-A, are ligands for a third receptor (VEGFR-3), which mediates lymphangiogenesis.
  • VEGFR-3 third receptor
  • Increased vascular permeability is one of the earliest manifestations of inflammation, resulting in extravasation of protein-rich plasma into the effected tissue.
  • Acute vascular permeability allows the deposition of circulating plasma matrix proteins including fibrin and fibronectin (FN) which facilitate cell migration in the inflamed area. This process also provides an access point for immune cells and immunoglobulins to enter the tissue and fight foreign antigens (Nagy et al, Cold Spring Harb. Perspect. Med. 2:a006544, 2012).
  • chronic vascular hyperpermeability is suggested to sustain the inflammatory response and retard resolution, further promoting the development of chronic inflammation (Nagy et al, Cold Spring Harb. Perspect. Med.
  • vascular hyperpermeability underlies the pathogenesis of a large number of chronic disorders including rheumatoid arthritis (RA), psoriasis, ocular disease, cancer and chronic wounds (Nagy et al, Cold Spring Harb. Perspect. Med. 2:a006544, 2012; Costa et al, Angiogenesis 10:149-166, 2007).
  • RA rheumatoid arthritis
  • psoriasis ocular disease
  • cancer chronic wounds
  • VEGF is a potent vascular permeabilizing agent that is highly expressed during chronic inflammation (Nagy et al, Annu. Rev. Pathol. 2:251-275, 2007). Low microenvironmental levels of VEGF are desired in order to maintain stable vascular integrity and promote endothelial cell survival through autocrine mechanisms (Lee et al, Cell 130:691-703, 2007). Whereas elevated levels of VEGF induce vascular leakages by activating VEGF receptor 2 (VEGFR2) in endothelial cells (EC) leading to the opening of intercellular and/or intracellular pathways that facilitate plasma extravasation (Koch and Claesson-Welsh, Cold Spring Harb. Perspect. Med. 2:a006502, 2012).
  • VAGFR2 VEGF receptor 2
  • VEGF may serve as a pro-inflammatory mediator as it can enhance T cell (Xia et al, Blood 102:161-168, 2003), and monocyte (Murakami et al, Blood 108:1849-1856, 2006) migration as well as promote pro-inflammatory chemokines expression by EC including MCP-1 , and IL-8, leading to further immune recruitment.
  • Cellular sources for VEGF during inflammation can include macrophages and mast cells; however it can also be expressed by endothelial cells and acts in a paracrine and autocrine fashion.
  • VEGF plays a major role in promoting chronic inflammation by inducing vascular permeability and contributing to immune cell recruitment.
  • compositions comprising compounds Nos 1-59 shown in Table 2 are used, in several embodiments, as inhibitors, antagonists, and inverse agonists of a VEGFR.
  • Several embodiments relate to polymer conjugates of compounds 1-59, optimized for topical applications while also minimizing side-effects caused by exposure at non-target sites (e.g., systemic absorption). Non-topical applications are provided in other embodiments.
  • the warhead of the polymer conjugate is a small molecule disclosed in Table 2 targeting a VEGFR.
  • methods of treating an inflammatory skin disease in a subject comprising administering to the subject an effective amount of an LSE polymer conjugate wherein the warhead is a small molecule disclosed in Table 2 targeting a VEGFR.
  • the warhead of the LSE polymer conjugate is compound 1 of Table 2.
  • the LSE polymer conjugate is CT103.
  • compositions comprising compounds shown in Tables 1-3 are used, in several embodiments, as inhibitors, antagonists, and inverse agonists of the mediator(s) of dermatological conditions, such as, but not limited to, inflammatory skin diseases, bullous dises, or skin neoplasias are disclosed herein.
  • compositions comprising compounds shown in Table 3 are used as inhibitors, antagonists, and inverse agonists of JAK and/or STAT family proteins.
  • the warhead of the polymer conjugate is compound 1 of Table 3.
  • the LSE polymer conjugate is CT352.
  • AD Atopic dermatitis
  • Histopathology reveals spongiosis, hyper and focal parakeratosis in acute lesions, whereas marked epidermal hyperplasia with hyper and parakeratosis, acanthosis/hypergranulosis and perivascular infiltration of the dermis with lymphocytes and abundant mast cells are the hallmarks of chronic lesions.
  • Psoriasis is characterized by frequent episodes of redness, itching, and thick, dry, silvery scales on the skin. Psoriasis comprises lesions that can involve primary and secondary alterations in epidermal proliferation, inflammatory responses of the skin, and an expression of regulatory molecules such as lymphokines and inflammatory factors. Psoriatic skin is morphologically characterized by an increased turnover of epidermal cells, thickened epidermis, abnormal keratin ization, inflammatory cell infiltrates into the epidermis and polymorphonuclear leukocyte and lymphocyte infiltration into the epidermis layer. Psoriasis is often associated with other inflammatory disorders, for example arthritis, including rheumatoid arthritis, inflammatory bowel disease (IBD), and Crohn's disease.
  • IBD inflammatory bowel disease
  • active agents useful for stimulating hair follicles are provided as oral applications or topical applications for the scalp.
  • Hair removal agents and ant-acne agents are provided in other embodiments.
  • Hair growth, hair removal and anti-acne therapies can all involve active agents that, if exposed to the non-target site (e.g., systemic circulation and/or lymphatic system) for long periods, result in toxicity or undesired side effects.
  • the non-target site e.g., systemic circulation and/or lymphatic system
  • the reduced exposure compositions described herein provides benefits for these applications as well.
  • active agents useful for stimulating hair follicles are provided as oral applications or topical applications for the scalp.
  • Hair removal agents and anti-acne agents are provided in other embodiments.
  • Hair growth, hair removal and anti-acne therapies can all involve active agents that, if exposed to the non-target site (e.g., systemic circulation and/or lymphatic system) for long periods, result in toxicity or undesired side effects.
  • the reduced exposure compositions described herein provides benefits for these applications as well.
  • the polymer conjugates provided herein modulate hair growth and cycling.
  • the polymer conjugates provided herein treat alopecia.
  • Allergic inflammatory diseases are characterized by an immune response against a sensitizing agent, such as an allergen, resulting in the release of inflammatory mediators that recruit cells involved in inflammation in a subject, potentially leading to tissue damage and sometimes death.
  • Allergic inflammatory diseases of the eye, skin, gastrointestinal tract, upper and lower airways, and lung including, but not limited to, atopic dermatitis, atopic keratoconjunctivitis, allergic conjunctivitis, asthma, and allergic rhinitis.
  • methods of treating an allergic inflammatory disease in a subject comprising administering to the subject an effective amount of a polymer conjugate, wherein the warhead is a small molecule targeting a VEGFR, c-Src, TkrA, MAP2K3, a JAK and/or ST AT family protein.
  • methods of treating the following conditions in a subject comprising administering to the subject an effective amount of a polymer conjugate, wherein the warhead is a small molecule targeting a VEGFR, c-Src, TkrA, MAP2K3, a JAK and/or STAT family protein: nail dystrophy; seborrheic keratosis; androgenic alopecia; contact dermatitis; actinic keratosis; acne; asthma; eczema (atopic derm); onychomycosis; sinusitis; allergic rhinitis; rosacea; COPD; pruritus; early AMD; urticaria; diabetic retinopathy; psoriasis; alopecia areata; dry eye; vitiligo; glaucoma; late AMD; ulcerative colitis; Crohn's disease; ocular rosacea; hair growth and cycling; skin neo
  • vascular tumors include hemangiomas, Kaposi's sarcoma, lymphangioma, glomangioma, angiosarcoma, hemangioendothelioma, and infantile hemangiomas.
  • Angiogenesis in the skin is also implicated in a number of other diseases that are characterized by macroscopically visible, prominent blood vessels, including rosacea and basal cell carcinoma.
  • methods of treating a skin neoplasia in a subject comprising administering to the subject an effective amount of a polymer conjugate, wherein the warhead is a small molecule targeting a VEGFR, c-Src, TkrA, MAP2K3, a JAK and/or STAT family protein.
  • skin neoplasias include squamous cell carcinoma, basal cell carcinoma, malignant melanoma, malignant cutaneous lymphoma, Kaposi's sarcoma, Merkel cell skin cancer, and non-melanoma skin cancer.
  • methods of treating an inflammatory skin disease in a subject comprising administering to the subject an effective amount of a polymer conjugate, wherein the warhead is a small molecule a VEGFR, c- Src, TkrA, MAP2K3, a JAK and/or STAT family protein.
  • Non-limiting examples of inflammatory skin diseases include psoriasis, psoriasis guttata, inverse psoriasis, pustular psoriasis, psoriatic erythroderma, acute febrile neutrophilic dermatosis, eczema, xerotic eczema, dyshidrotic eczema, vesicular palmar eczema, acne vulgaris, atopic dermatitis, contact dermatitis, allergic contact dermatitis, dermatomyositis, exfoliative dermatitis, hand eczema, pompholyx, keloids, rosacea, rosacea due to sarcoidosis, rosacea due to scleroderma, rosacea due to Sweet syndrome, rosacea due to systemic lupus erythematosus, rosacea due to urticaria, rosacea due to herpetic pain,
  • Bullous diseases are skin disorders characterized by blistering that often have an autoimmune etiology.
  • VEGF has been found to be upregulated in two bullous diseases, bullous pemphigoid and erythema multiforme. Brown, Lawrence F., et al. Journal of Investigative Dermatology 104.5 (1995): 744-749.
  • Bullous pemphigoid is a subepidermal disorder which manifests as subepidermal blisters with a dermal infiltrate of neutrophils and eosinophils.
  • Erythema multiforme is an inflammatory eruption characterized by symmetric erythematous, edematous, or bullous lesions of the skin or mucous membranes.
  • methods of treating a bullous disease in a subject comprising administering to the subject an effective amount of a polymer conjugate, wherein the warhead is a small molecule a VEGFR, c-Src, TkrA, MAP2K3, a JAK and/or ST AT family protein.
  • bullous diseases include bullous pemphigoid, erythema multiforme, dermatitis herpetiformis, epidermolysis bullosa acquisita, linear Immunoglobulin A disease, mucous membrane pemphigoid, pemphigoid gestationis, pemphigus foliaceus, and pemphigus vulgaris.
  • VEGF vascular endothelial growth factor
  • methods of modulating hair growth and cycling in a subject comprising administering to the subject an effective amount of a polymer conjugate, wherein the warhead is a small molecule targeting a VEGFR, c-Src, TkrA, MAP2K3, a JAK and/or STAT family protein.
  • methods of treating alopecia in a subject comprising administering to the subject an effective amount of a polymer conjugate, wherein the warhead is a small molecule targeting a VEGFR, c-Src, TkrA, MAP2K3, a JAK and/or STAT family protein.
  • a combination therapy comprising administering to the subject an effective amount of a polymer conjugate in conjunction with UV irradiation therapy, wherein the warhead is a small molecule targeting a VEGFR, c-Src, TkrA, MAP2K3, a JAK and/or STAT family protein.
  • alopecia is treated.
  • Non-limiting examples include androgenic alopecia and alopecia areata.
  • Androgenic alopecia also known as hereditary baldness, male pattern baldness, and seborrheic alopecia
  • Alopecia areata is known to be associated with autoimmune activities; hence, topically administered immunomodulatory compounds demonstrate efficacy for treating that type of hair loss.
  • hair regeneration compositions are in the form of a liquid.
  • hair regeneration compositions are in the form of a lotion.
  • hair regeneration compositions are in the form of a cream.
  • hair regeneration compositions are in the form of a gel.
  • the hair regeneration composition is administered twice daily. In other embodiments, the hair regeneration composition is administered one daily.
  • the hair regeneration composition is administered once weekly. In some embodiments, the hair regeneration composition is administered directly to the scalp. In some embodiments, the hair regeneration composition is administered directly non-scalp areas.
  • Oral delivery is contemplated in several embodiments suitable for dermal pathologies, and thus several embodiments relate to polymer conjugates of compounds in Tables 1-3, optimized for oral delivery to treat the skin while also minimizing side- effects caused by exposure at non-target sites (e.g., systemic absorption). Topical applications are provided in other embodiments.
  • the warhead of the polymer conjugate is a small molecule disclosed in Tables 1-3 targeting mediator(s) of dermatological conditions.
  • methods of treating an inflammatory skin disease or other dermal pathology in a subject comprising administering to the subject an effective amount of an LSE polymer conjugate wherein the warhead is a small molecule disclosed in Tables 1-3 targeting mediator(s) of dermatological conditions.
  • a VEGFR, c-Src, TkrA, MAP2K3, a JAK and/or STAT family protein are mediator(s) of dermatological conditions.
  • the warhead employed in the LSE polymer conjugate is a small molecule a VEGFR, c-Src, TkrA, MAP2K3, a JAK and/or STAT family protein.
  • the warhead of the polymer conjugate is compound 1 of Table 1.
  • the polymer conjugate is SNA-101 .
  • the warhead of the polymer conjugate is compound 1 of Table 2.
  • the polymer conjugate is SNA-103.
  • the warhead of the polymer conjugate is compound 1 of Table 3.
  • the LSE polymer conjugate is SNA-352.
  • an inflammatory skin disease a vascular tumor, a bullous disease, a skin neoplasia, a vascular tumor, or a scar may also be treated.
  • compositions comprising an indolocarbazole compound are used, in several embodiments, as inhibitors, antagonists, and inverse agonists of a VEGFR, c-Src, TkrA, MAP2K3, a JAK and/or STAT family protein.
  • Several embodiments relate to polymer conjugates of an indolocarbazole compound, optimized for topical applications (e.g., eye drops) while also minimizing side-effects caused by exposure at non-target sites (e.g., systemic absorption).
  • Non-topical applications are provided in other embodiments.
  • the reduced exposure compsotions disclosed herein are administered by direct intravitreal injection.
  • the reduced exposure compsotions are administered by subconjunctival injection. In other embodiments, the reduced exposure compsotions are administered by subtenon injection. In still further embodiments, the compostions are administered by peribulbar injection. Also provided, in several embodiments, are reduced exposure compostions which can be administered via intraocular implantable devices known to one of skill in the art.
  • the warhead of the polymer conjugate is an indolocarbazole compound or derivative thereof.
  • methods of treating an ophthalmic condition in a subject comprising administering to the subject an effective amount of an LSE polymer conjugate wherein the warhead is an indolocarbazole compound.
  • the warhead of the LSE polymer conjugate is a derivative of K252a.
  • the LSE polymer conjugate is SNA-125.
  • the LSE polymer conjugate is SNA- 120.
  • methods of treating an ophthalmic condition in a subject comprising administering to the subject an effective amount of a polymer conjugate, wherein the warhead is a small molecule targeting a VEGFR, c-Src, TkrA, MAP2K3, a JAK and/or STAT family protein.
  • Non-limiting examples of ophthalmic conditions include macular degeneration, age related macular degeneration (ARMD), choroidal neovascularization, retinopathy, diabetic retinopathy, acute macular neuroretinopathy, chronic macular neuroretinopathy, central serous chorioretinopathy, macular edema, cystoid macular edema, diabetic macular edema., acute multifocal placoid pigment epitheliopathy, Behcet's disease, birdshot retinochoroidopathy, uveitis, intermediate uveitis (pars planitis), anterior uveitis, multifocal choroiditis, multiple evanescent white dot syndrome (MEWDS), ocular sarcoidosis, posterior scleritis, serpignous choroiditis, subretinal fibrosis, uveitis syndrome, Vogt-Koyanagi-Harada syndrome, retinal arterial occlusive disease, central retinal vein
  • the c-Src kinase is the most widely studied member of the largest family of nonreceptor protein tyrosine kinases, known as the Src family kinases (SFKs).
  • Src family kinases Other SFK members include Lyn, Fyn, Lck, Hck, Fgr, Blk, Yrk, and Yes.
  • the Src kinases can be grouped into two sub-categories, those that are ubiquitously expressed (Src, Fyn, and Yes), and those which are found primarily in hematopoietic cells (Lyn, Lck, Hck, Blk, Fgr). (Benati, D. Src Family Kinases as Potential Therapeutic Targets for Malignancies and Immunological Disorders.
  • SFKs are key messengers in many cellular pathways, including those involved in regulating proliferation, differentiation, survival, motility, and angiogenesis.
  • the activity of SFKs is highly regulated intramolecularly by interactions between the SH2 and SH3 domains and intermolecularly by association with cytoplasmic molecules. This latter activation may be mediated by focal adhesion kinase (FAK) or its molecular partner Crk- associated substrate (CAS), which plays a prominent role in integrin signaling, and by ligand activation of cell surface receptors, e.g. epidermal growth factor receptor (EGFR).
  • FAK focal adhesion kinase
  • CAS molecular partner Crk- associated substrate
  • Src can also be activated by dephosphorylation of tyrosine residue Y530.
  • maximal Src activation requires the autophosphorylation of tyrosine residue Y419 (in the human protein) present within the catalytic domain.
  • Elevated Src activity may be caused by increased transcription or by deregulation due to overexpression of upstream growth factor receptors such as EGFR, HER2, platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), vascular endothelial growth factor receptor, ephrins, integrin, or FAK.
  • upstream growth factor receptors such as EGFR, HER2, platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), vascular endothelial growth factor receptor, ephrins, integrin, or FAK.
  • compositions comprising compounds Nos 1-71 shown in Table 1 are used, in several embodiments, as inhibitors, antagonists, and inverse agonists of c-Src.
  • Several embodiments relate to polymer conjugates of compounds 1-71 , optimized for topical applications (e.g., eye drops) while also minimizing side-effects caused by exposure at non-target sites (e.g., systemic absorption).
  • Non-topical applications e.g., intraocular injection, periocular injection, release from drug delivery devices
  • the warhead of the polymer conjugate is a small molecule disclosed in Table 1 targeting c-Src.
  • methods of treating an ophthalmic condition in a subject comprising administering to the subject an effective amount of an LSE polymer conjugate wherein the warhead is a small molecule disclosed in Table 1 targeting c-Src.
  • the warhead of the LSE polymer conjugate is compound 1 of Table 1.
  • the LSE polymer conjugate is CT101.
  • compositions comprising compounds shown in Table 3 are used as inhibitors, antagonists, and inverse agonists of JAK and/or STAT family proteins.
  • the warhead of the polymer conjugate is compound 1 of Table 3.
  • the LSE polymer conjugate is CT352.
  • the JAK kinase family is a cytoplasmic protein kinase family comprising the members JAK1 , JAK2, JAK3 and TYK2.
  • JAK1 cytoplasmic protein kinase family
  • JAK2 JAK3
  • TYK2 cytoplasmic protein kinase family
  • ligand binding to a receptor leads to receptor dimerization or oligomerization, which leads to JAK recruitment and activation either through autophosphorylation or phosphorylation by other JAK kinases or by other tyrosine kinases, which in turn leads to tyrosine phosphorylation of the receptors as well as downstream substrates of JAK.
  • Growth factor or cytokine receptors that recruit JAK kinases include the interferon receptors, interleukin receptors (receptors for the cytokines IL-2 to IL-7, IL-9 to IL-13, IL-15, IL-23), various hormone receptors (erythropoietin (Epo) receptor, the thrombopoietin (Tpo) receptor, the leptin receptor, the insulin receptor, the prolactin (PRL) receptor, the Granulocyte Colony-Stimulating Factor (G-CSF) receptor and the growth hormone receptor), receptor protein tyrosine kinases (such as EGFR and PDGFR), and receptors for other growth factors such as leukemia inhibitory factor (LIF), Oncastatin M (OSM), IFNa/b/g, Granulocyte-macrophage colony-stimulating factor (GM-CSF), Ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-I) (
  • autoimmune diseases and disease associated with chronic inflammation, as well as acute responses have been linked to excessive or unregulated production or activity of one or more cytokines, the signaling of which depend on JAK kinases.
  • diseases include dry eye syndrome and other inflammatory ophthalmic conditions.
  • Phosphorylated receptors serve as docking sites for other SH-2 domain containing signaling molecules that interact with JAKs such as the STAT family of transcription factors, Src family of kinases, MAP kinases PB kinase and protein tyrosine phosphatases (Rane S.G. and Reddy E.P., Oncogene 2000 19, 5662-5679).
  • JAKs such as the STAT family of transcription factors, Src family of kinases, MAP kinases PB kinase and protein tyrosine phosphatases (Rane S.G. and Reddy E.P., Oncogene 2000 19, 5662-5679).
  • the family of latent cytoplasmic transcription factors, STATS are the most well characterized downstream substrates for JAKs.
  • the STAT proteins bind to phosphorylated cytokine receptors through their SH2 domains to become phosphorylated by JAKs, which event leads to their dimerization and release and
  • STAT3 Signal transducer and activator of transcription 3
  • STAT3 is a transcription factor that regulates the expression of a variety of genes involved in many cellular processes such as cell growth, apoptosis, cell motility, and cytokine production.
  • STAT3 is activated by JAK kinases and translocates to the nucleus to act as a transcriptional activator.
  • JAK kinases JAK kinases and translocates to the nucleus to act as a transcriptional activator.
  • the warhead employed in the LSE polymer conjugate is a small molecule targeting a vascular endothelial growth factor receptor (VEGFR).
  • VEGFR vascular endothelial growth factor receptor
  • Angiogenesis the process of sprouting new blood vessels from existing vasculature, and arteriogenesis, the remodeling of small vessels into larger conduit vessels, are both physiologically important aspects of vascular growth in adult tissues.
  • These processes of vascular growth are involved, in some cases, for beneficial processes such as tissue repair, wound healing, recovery from tissue ischemia and menstrual cycling. They are also involved, in some cases, for the development of pathological conditions such as the growth of neoplasias, diabetic retinopathy, rheumatoid arthritis, psoriasis, certain forms of macular degeneration, and certain inflammatory pathologies.
  • the inhibition of vascular growth in these contexts has also shown beneficial effects in preclinical animal models.
  • angiogenesis For example, inhibition of angiogenesis by blocking vascular endothelial growth factor or its receptor has resulted in inhibition of tumor growth and in retinopathy. Also, the development of pathological pannus tissue in rheumatoid arthritis involves angiogenesis and might be blocked by inhibitors of angiogenesis.
  • Certain diseases are known to be associated with deregulated angiogenesis, for example ocular neovascularization, such as retinopathies (including diabetic retinopathy), age-related macular degeneration, psoriasis, hemangioblastoma, hemangioma, arteriosclerosis, inflammatory disease, such as a rheumatoid or rheumatic inflammatory disease, especially arthritis (including rheumatoid arthritis), or other chronic inflammatory disorders, such as chronic asthma, arterial or post- transplantational atherosclerosis, endometriosis, and neoplastic diseases, for example so-called solid tumors and liquid tumors (such as leukemias).
  • retinopathies including diabetic retinopathy
  • age-related macular degeneration psoriasis
  • hemangioblastoma hemangioma
  • arteriosclerosis arteriosclerosis
  • inflammatory disease such as a rheumatoid or r
  • VEGF Vascular endothelial growth factor
  • vasculogenesis the de novo formation of the embryonic circulatory system
  • angiogenesis the growth of blood vessels from pre-existing vasculature.
  • VEGF activity has been mostly studied on cells of the vascular endothelium, although it does have effects on a number of other cell types (e.g., stimulation monocyte/macrophage migration, neurons, cancer cells, kidney epithelial cells, keratinocytes).
  • VEGF has been shown to stimulate endothelial cell mitogenesis and cell migration.
  • VEGF is also a vasodilator and increases microvascular permeability and was originally referred to as vascular permeability factor.
  • VEGF vascular endothelial growth factor
  • the broad term“VEGF” covers a number of proteins from two families, that result from alternate splicing of mRNA from a single, 8 exon, VEGF gene.
  • the two different familes are referred to according to their terminal exon (exon 8) splice site— the proximal splice site (denoted VEGFxxx) or distal splice site (VEGFxxxb).
  • these domains have functional consequences for the VEGF splice variants as the terminal (exon 8) splice site determines whether the proteins are pro-angiogenic (proximal splice site, expressed during angiogenesis) or anti-angiogenic (distal splice site, expressed in normal tissues).
  • exons 6 and 7 mediate interactions with heparan sulfate proteoglycans (HSPGs) and neuropilin co-receptors on the cell surface, enhancing their ability to bind and activate VEGFRs.
  • HSPGs heparan sulfate proteoglycans
  • neuropilin co-receptors enhancing their ability to bind and activate VEGFRs.
  • VEGFRs tyrosine kinase receptors
  • the VEGF receptors have an extracellular portion consisting of 7 immunoglobulin-like domains, a single transmembrane spanning region and an intracellular portion containing a split tyrosine-kinase domain.
  • VEGF-A binds to VEGFR- 1 (Flt-1) and VEGFR-2 (KDR/Flk-1). VEGFR-2 appears to mediate almost all of the known cellular responses to VEGF.
  • VEGFR-1 The function of VEGFR-1 is less well defined, although it is thought to modulate VEGFR-2 signaling. Another function of VEGFR-1 may be to act as a dummy/decoy receptor, sequestering VEGF from VEGFR-2 binding (this appears to be involved during vasculogenesis in the embryo). VEGF-C and VEGF-D, but not VEGF-A, are ligands for a third receptor (VEGFR-3), which mediates lymphangiogenesis.
  • VEGFR-3 third receptor
  • Increased vascular permeability is one of the earliest manifestations of inflammation, resulting in extravasation of protein-rich plasma into the effected tissue.
  • Acute vascular permeability allows the deposition of circulating plasma matrix proteins including fibrin and fibronectin (FN) which facilitate cell migration in the inflamed area. This process also provides an access point for immune cells and immunoglobulins to enter the tissue and fight foreign antigens (Nagy et al, Cold Spring Harb. Perspect. Med. 2:a006544, 2012).
  • chronic vascular hyperpermeability is suggested to sustain the inflammatory response and retard resolution, further promoting the development of chronic inflammation (Nagy et al, Cold Spring Harb. Perspect. Med.
  • VEGF is a potent vascular permeabilizing agent that is highly expressed during chronic inflammation (Nagy et al, Annu. Rev. Pathol. 2:251-275, 2007). Low microenvironmental levels of VEGF are desired in order to maintain stable vascular integrity and promote endothelial cell survival through autocrine mechanisms (Lee et al, Cell 130:691-703, 2007). Whereas elevated levels of VEGF induce vascular leakages by activating VEGF receptor 2 (VEGFR2) in endothelial cells (EC) leading to the opening of intercellular and/or intracellular pathways that facilitate plasma extravasation (Koch and Claesson-Welsh, Cold Spring Harb. Perspect. Med. 2:a006502, 2012).
  • VAGFR2 VEGF receptor 2
  • VEGF may serve as a pro-inflammatory mediator as it can enhance T cell (Xia et al, Blood 102:161-168, 2003), and monocyte (Murakami et al, Blood 108:1849-1856, 2006) migration as well as promote pro-inflammatory chemokines expression by EC including MCP-1 , and IL-8, leading to further immune recruitment.
  • Cellular sources for VEGF during inflammation can include macrophages and mast cells; however it can also be expressed by endothelial cells and acts in a paracrine and autocrine fashion.
  • VEGF plays a major role in promoting chronic inflammation by inducing vascular permeability and contributing to immune cell recruitment.
  • compositions comprising compounds Nos 1-59 shown in Table 2 are used, in several embodiments, as inhibitors, antagonists, and inverse agonists of a VEGFR.
  • Several embodiments relate to polymer conjugates of compounds 1-59, optimized for topical applications (e.g., eye drops) while also minimizing side-effects caused by exposure at non-target sites (e.g., systemic absorption).
  • Non-topical applications e.g., intraocular injection, periocular injection release from drug delivery devices
  • the warhead of the polymer conjugate is a small molecule disclosed in Table 2 targeting a VEGFR.
  • methods of treating an ophthalmic condition in a subject comprising administering to the subject an effective amount of an LSE polymer conjugate wherein the warhead is a small molecule disclosed in Table 2 targeting a VEGFR.
  • the warhead of the LSE polymer conjugate is compound 1 of Table 2.
  • the LSE polymer conjugate is CT103.
  • methods of treating dry eye in a subject comprising administering to the subject an effective amount of a polymer conjugate, wherein the warhead is a small molecule targeting a VEGFR, c-Src, TkrA, MAP2K3, a JAK and/or STAT family protein.
  • the composition is formulated as an eye drop.
  • one or two drops of the composition are used per application.
  • three or four drops of the composition are used per application.
  • six drops of the composition are used per application.
  • the composition is applied for a period of 60 seconds before flushing. In other embodiments, the composition is applied for a period of 120 seconds before flushing. In additional embodiments, the composition is applied for a period of 360 seconds before flushing. In some embodiments, the composition may be administered one or more times a day. In some embodiments, the composition is administered daily. In some embodiments, the composition may be administered once a week.
  • methods of treating maculopathies and/or retinal degeneration diseases in a subject comprising administering to the subject an effective amount of a polymer conjugate, wherein the warhead is a small molecule targeting a VEGFR, c-Src, TkrA, MAP2K3, a JAK and/or STAT family protein.
  • Non-limiting examples of maculopathies and/or retinal degeneration diseases include macular degeneration, age related macular degeneration (ARMD), non-exudative age related macular degeneration, exudative age related macular degeneration, choroidal neovascularization, retinopathies, diabetic retinopathy, acute and chronic macular neuroretinopathy, central serous chorioretinopathy, macular edema, cystoid macular edema, and diabetic macular edema.
  • AMD age related macular degeneration
  • non-exudative age related macular degeneration exudative age related macular degeneration
  • choroidal neovascularization retinopathies
  • diabetic retinopathy acute and chronic macular neuroretinopathy
  • central serous chorioretinopathy macular edema
  • cystoid macular edema cystoid macular edema
  • diabetic macular edema diabetic macular edema
  • methods of treating uveitis, retinitis and/or choroiditis in a subject comprising administering to the subject an effective amount of a polymer conjugate, wherein the warhead is a small molecule targeting a VEGFR, c-Src, TkrA, MAP2K3, a JAK and/or STAT family protein.
  • Non- limiting examples of uveitis, retinitis and/or choroiditis include acute multifocal placoid pigment epitheliopathy, Behcet's disease, birdshot retinochoroidopathy, infectious ocular diseases (e.g., syphilis, lyme, tuberculosis, toxoplasmosis), uveitis, intermediate uveitis (pars planitis), and anterior uveitis, multifocal choroiditis, multiple evanescent white dot syndrome (MEWDS), ocular sarcoidosis, posterior scleritis, serpignous choroiditis, subretinal fibrosis, uveitis syndrome, and Vogt-Koyanagi-Harada syndrome.
  • infectious ocular diseases e.g., syphilis, lyme, tuberculosis, toxoplasmosis
  • uveitis intermediate uveitis (par
  • methods of treating vascular diseases and/or exudative ocular diseases in a subject comprising administering to the subject an effective amount of a polymer conjugate, wherein the warhead is a small molecule targeting a VEGFR, c-Src, TkrA, MAP2K3, a JAK and/or STAT family protein.
  • Non-limiting examples of vascular diseases and/or exudative ocular diseases include retinal arterial occlusive disease, central retinal vein occlusion, disseminated intravascular coagulopathy, branch retinal vein occlusion, hypertensive fundus changes, ocular ischemic syndrome, retinal arterial microaneurysms, Coat's disease, parafoveal telangiectasis, hemi-retinal vein occlusion, papillophlebitis, central retinal artery occlusion, branch retinal artery occlusion, carotid artery disease (CAD), frosted branch angitis, sickle cell retinopathy and other hemoglobinopathies, angioid streaks, familial exudative vitreoretinopathy, and Eales disease.
  • CAD carotid artery disease
  • methods of treating traumatic and/or surgical ocular conditions in a subject comprising administering to the subject an effective amount of a polymer conjugate, wherein the warhead is a small molecule targeting a VEGFR, c-Src, TkrA, MAP2K3, a JAK and/or STAT family protein.
  • traumatic and/or surgical ocular conditions include sympathetic ophthalmia, uveitic retinal disease, retinal detachment, trauma, laser, PDT, photocoagulation, hypoperfusion during surgery, radiation retinopathy, and bone marrow transplant retinopathy.
  • methods of treating a proliferative ocular disorder in a subject comprising administering to the subject an effective amount of a polymer conjugate, wherein the warhead is a small molecule targeting a VEGFR, c-Src, TkrA, MAP2K3, a JAK and/or STAT family protein.
  • a proliferative ocular disorders include proliferative vitreal retinopathy and epiretinal membranes, proliferative diabetic retinopathy.
  • methods of treating infectious ocular disorders in a subject comprising administering to the subject an effective amount of a polymer conjugate, wherein the warhead is a small molecule targeting a VEGFR, c-Src, TkrA, MAP2K3, a JAK and/or STAT family protein.
  • Non-limiting examples of infectious ocular disorders include ocular histoplasmosis, ocular toxocariasis, presumed ocular histoplasmosis syndrome (POHS), endophthalmitis, toxoplasmosis, retinal diseases associated with HIV infection, choroidal disease associated with HIV infection, uveitic disease associated with HIV Infection, viral retinitis, acute retinal necrosis, progressive outer retinal necrosis, fungal retinal diseases, ocular syphilis, ocular tuberculosis, diffuse unilateral subacute neuroretinitis, and myiasis.
  • infectious ocular disorders include ocular histoplasmosis, ocular toxocariasis, presumed ocular histoplasmosis syndrome (POHS), endophthalmitis, toxoplasmosis, retinal diseases associated with HIV infection, choroidal disease associated with HIV infection, uveitic disease associated with HIV Infection, viral retinitis, acute retinal
  • methods of treating an ocular genetic disorder in a subject comprising administering to the subject an effective amount of a polymer conjugate, wherein the warhead is a small molecule targeting a VEGFR, c-Src, TkrA, MAP2K3, a JAK and/or STAT family protein.
  • Non-limiting examples of ocular genetic disorders include retinitis pigmentosa, systemic disorders with associated retinal dystrophies, congenital stationary night blindness, cone dystrophies, Stargardt's disease and fundus flavimaculatus, Bests disease, pattern dystrophy of the retinal pigmented epithelium, X-linked retinoschisis, Sorsby's fundus dystrophy, benign concentric maculopathy, Bietti's crystalline dystrophy, and pseudoxanthoma elasticum.
  • methods of treating a retinal hole or tear in a subject comprising administering to the subject an effective amount of a polymer conjugate, wherein the warhead is a small molecule targeting a VEGFR, c- Src, TkrA, MAP2K3, a JAK and/or STAT family protein.
  • a polymer conjugate wherein the warhead is a small molecule targeting a VEGFR, c- Src, TkrA, MAP2K3, a JAK and/or STAT family protein.
  • retinal holes or tears include retinal detachment, macular hole, and giant retinal tear.
  • methods of treating an ocular tumor- associated condition in a subject comprising administering to the subject an effective amount of a polymer conjugate, wherein the warhead is a small molecule targeting a VEGFR, c-Src, TkrA, MAP2K3, a JAK and/or STAT family protein.
  • Nonlimiting examples of ocular tumor-associated condition include retinal disease associated with tumors, congenital hypertrophy of the RPE, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined hamartoma of the retina and retinal pigmented epithelium, retinoblastoma, vasoproliferative tumors of the ocular fundus, retinal astrocytoma, intraocular lymphoid tumors.
  • methods of treating punctate inner choroidopathy, acute posterior multifocal placoid pigment epitheliopathy, myopic retinal degeneration, and acute retinal pigment epithelitis in a subject comprising administering to the subject an effective amount of a polymer conjugate, wherein the warhead is a small molecule targeting a VEGFR, c-Src, TkrA, MAP2K3, a JAK and/or STAT family protein.

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Abstract

La présente invention concerne des conjugués polymères comprenant un agent actif lié à un polymère, l'agent actif comprenant un inhibiteur, un antagoniste ou un agoniste inverse d'un médiateur d'une cible thérapeutique associée à une affection, comprenant, par exemple, une affection ophtalmique, une affection dermatologique, une maladie inflammatoire de l'intestin ou d'autres affections gastro-intestinales et une affection respiratoire. Les conjugués polymères selon l'invention réduisent l'exposition de l'agent actif au niveau de sites non ciblés.
PCT/US2019/042825 2018-07-23 2019-07-22 Compositions à exposition réduite de modulation de cibles thérapeutiques WO2020023389A1 (fr)

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