Kits for increasing target specificity of mannosylated dextran therapeutic or diagnostic compounds

Abstract

Disclosed is a method for enhancing the target specificity of a mannosylated dextran therapeutic or diagnostic compound by administering at least a blocking composition comprising a scaffold and one or more CD206 targeting moieties attached thereto, and administering an effective amount of a mannosylated dextran therapeutic or diagnostic compound comprising a dextran scaffold and one or more CD206 targeting moieties and one or more therapeutic agents attached thereto.In an exemplary embodiment, the molecular mass of the blocking composition scaffold is at least about 2 times larger than the molecular mass of the mannosylated dextran scaffold compound.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) to U.S. Provisional Application No. 62 / 908,136, entitled "Compositions and Related Methods for Blocking Off-Target Localization of Mannosylated Dextrans and Other Cd206 Ligands," filed September 30, 2019, which is hereby incorporated by reference in its entirety for all purposes. [Background technology]

[0002] Macrophages contribute significantly to the pathobiology of many societally important diseases. Macrophages may occur in large numbers during the lesions of diseases in which macrophages are involved. Examples of diseases in which macrophages are involved include, but are not limited to, cancer, atherosclerosis, and rheumatoid arthritis. Macrophages respond to various stimuli in their local microenvironment by changing the expression patterns of many genes, potentially hundreds. Macrophages that have changed such phenotypes are said to be activated macrophages. Depending on which stimuli the macrophages are responding to, a wide range of activated phenotypic states can be achieved. Among the genes that can be differentially expressed upon macrophage activation is the macrophage mannose receptor CD206, which is highly upregulated in the majority of activated macrophages present at sites of inflammation, such as, but not limited to, tumors (i.e., tumor-associated macrophages, TAMs), atherosclerosis, and rheumatoid arthritis.

[0003] Because macrophages are not only abundant in the lesions of macrophage-associated diseases, but also contribute significantly to the pathobiology of these diseases, many investigators have targeted imaging agents to macrophages as a tool to diagnose these conditions (examples include), and / or therapeutic agents to macrophages as a strategy to treat macrophage-associated conditions (examples include). Also, because CD206 is typically highly expressed on activated macrophages present in the lesions of macrophage-associated diseases, many investigators have evaluated agents that target CD206 to image and / or treat these lesions or diseases.

[0004] CD206 is a transmembrane C-type lectin with high affinity for mannose, a binding ligand that displays multiple sugar moieties. CD206 is expressed on a variety of cell types, including myeloid lineage, including macrophages and myeloid-derived suppressor cells, as well as some populations of dendritic cells and microglia. Importantly, CD206 is expressed by Kupffer cells. Kupffer cells are resident macrophage-like cells of the liver that occur in large numbers along the walls of sinusoidal capillaries. Thus, Kupffer cells are in direct contact with the blood. Another important class of CD206-expressing cells consists of mesangial cells present in the glomerulus of the kidney. Mesangial cells are separated from the blood only by endothelial cells that do not have an associated basement membrane, allowing mesangial cells to have almost unhindered contact with macromolecules in the blood.

[0005] Tilmanocept is a synthetic molecular construct made by attaching mannose moieties and the chelator diethylenetriaminepentaacetic acid (DTPA) to a 10 kD dextran backbone via amine-terminated leashes. Tilmanocept has an average of 17 mannose moieties, 5 DTPA moieties, and a variable number of unoccupied amine-terminated leashes per dextran backbone molecule. Tilmanocept is a member of a class of related constructs called mannosylated dextrans. Mannosylated dextrans can be constructed using dextrans of various sizes with a variable number of mannose moieties attached to the dextran backbone by molecular leashes of various compositions. Many types of other moieties (DTPA as just one example) can be conjugated to these constructs. Mannosylated dextrans in general, and Tilmanocept in particular, are purposefully designed to be high affinity ligands for certain C-type lectins, in particular the macrophage mannose receptor CD206. However, non-specific localization by binding to CD206-expressing cells, particularly in the liver and kidney, has undesirable and / or dose-limiting consequences.Therefore, there is a need in the art for methods to increase the target specificity of mannosylated dextran-based therapeutic and diagnostic agents. Summary of the Invention

[0006] Disclosed is a method for increasing the target specificity of mannosylated dextran therapeutic or diagnostic compounds by administering at least a blocking composition comprising a scaffold and one or more CD206 targeting moieties attached thereto, and administering an effective amount of a mannosylated dextran therapeutic or diagnostic compound comprising a dextran scaffold and one or more CD206 targeting moieties and one or more therapeutic agents attached thereto.In an exemplary embodiment, the molecular mass of the blocking composition scaffold is at least 2 times larger than the molecular mass of the mannosylated dextran scaffold compound.

[0007] In certain embodiments, the mannosylated dextran therapeutic or diagnostic compound has formula (I):

[0008] [ka]

[0009] (In the formula, each X is independently H, L1-A, or L2-R; each L1 and L2 is independently a linker; each A independently comprises a therapeutic agent, a diagnostic agent, or H; each R independently comprises a mannose-binding C-type lectin receptor targeting moiety or H; n is an integer greater than zero, At least one R comprises a mannose-binding C-type lectin receptor targeting moiety selected from the group consisting of mannose, fucose, and n-acetylglucosamine, and at least one A comprises a therapeutic or diagnostic agent.

[0010] In certain embodiments, the blocking compound backbone is selected from dextran, cellulose, polyethylene glycol, or a polypeptide. In an exemplary implementation, the backbone is dextran.

[0011] In a further embodiment, one or more CD206 targeting moieties are attached to the blocking compound scaffold with leashes. According to certain embodiments, the blocking compound scaffold is at least about 35 kDa. In further embodiments, the blocking compound scaffold is between about 35 kDa and 180 kDa. In yet further embodiments, the blocking compound scaffold is between about 35 kDa and 500 kDa.

[0012] According to one particular embodiment, the blocking compound has formula (I):

[0013] [ka]

[0014] (In the formula, Each X is H or L2-R and each L2 is independently a linker; each R independently comprises a mannose-binding C-type lectin receptor targeting moiety or H; n is an integer greater than zero, At least one R is a compound comprising a mannose-binding C-type lectin receptor targeting moiety selected from the group consisting of mannose, fucose, and n-acetylglucosamine.

[0015] In certain embodiments, the blocking compound backbone is about 110 kDa and the dextran backbone of the mannosylated dextran therapeutic or diagnostic compound is about 10 kDa.

[0016] In certain embodiments, the blocking compound does not contain a therapeutic or diagnostic agent. In certain embodiments, the step of administering the blocking compound is followed by a time interval of about 1 second to 60 minutes before the step of administering the mannosylated dextran therapeutic or diagnostic compound. In further embodiments, the time interval is about 10 minutes to about 20 minutes. In certain alternative embodiments, the blocking compound and the mannosylated dextran therapeutic or diagnostic compound are administered simultaneously.

[0017] According to certain embodiments, the mannosylated dextran therapeutic or diagnostic compound comprises at least one therapeutic moiety. In certain embodiments, the percentage of the injected dose of the mannosylated dextran therapeutic or diagnostic compound that is localized in the desired target tissue other than the liver, kidney, and / or spleen is higher than the percentage of the mannosylated dextran therapeutic or diagnostic compound that is localized when the blocking compound is not administered.In further embodiments, the effective dose of the mannosylated dextran therapeutic or diagnostic compound is lower than the effective dose of the mannosylated dextran therapeutic or diagnostic compound when the blocking compound is not administered.In yet further embodiments, the blocking compound preferentially binds to CD206-expressing cells in the liver, kidney, and / or spleen.In further embodiments, the mannosylated dextran therapeutic or diagnostic compound reduces the binding of CD206 cells in the liver, kidney, and / or spleen compared to subjects administered an equivalent dose of the mannosylated dextran therapeutic or diagnostic compound without the blocking compound.

[0018] In certain embodiments, the subject has been diagnosed with an autoimmune disease, an inflammatory disease, or cancer. Further disclosed herein is a kit for diagnosis or treatment of a subject in need thereof, comprising a blocking compound comprising a scaffold and one or more CD206 targeting moieties attached thereto, and a mannosylated dextran therapeutic or diagnostic compound comprising a dextran scaffold and one or more CD206 targeting moieties and one or more therapeutic agents attached thereto, wherein the molecular mass of the blocking composition scaffold is at least two times greater than the molecular mass of the mannosylated dextran scaffold compound. In certain embodiments, the kit comprises a blocking compound having a structure represented by Formula (I):

[0019] [ka]

[0020] (In the formula, each X is independently H, L1-A, or L2-R; each L1 and L2 is independently a linker; each A independently comprises a therapeutic agent, a diagnostic agent, or H; each R independently comprises a mannose-binding C-type lectin receptor targeting moiety or H; n is an integer greater than zero, At least one R comprises a mannose-binding C-type lectin receptor targeting moiety selected from the group consisting of mannose, fucose, and n-acetylglucosamine, and at least one A comprises a mannosylated dextran therapeutic or diagnostic compound, which is a compound of the formula (comprising a therapeutic or diagnostic agent). In a further embodiment, the blocking compound backbone is about 110 kDa and the mannosylated dextran therapeutic or diagnostic compound dextran backbone is about 10 kDa. [Brief description of the drawings]

[0021] [Figure 1] FIG. 1 shows an autoradiograph of a section from a male Sprague Dawley rat injected IV (tail vein) one hour prior with 25 μg of 99mTc-tilmanocept labeled with 5 mCi of 99mTechnetium, showing strong localization to the liver (L) and kidney (K) according to certain embodiments. [Figure 2A] Exemplary false-color fluorescence images of Balb / C mice bearing 4T1 tumors that were IV-injected with Cy5-tilmanocept (A) or not (C). Image B shows the liver (L), kidney (K), spleen (S), and tumor (T) excised from the mouse shown in A. Note that the false-color scales in Figures 2A and 2B are different, and that the red areas in Figure 2B have the same level of fluorescence as the yellow areas in Figure 2A. [Figure 2B] Same as above. [Figure 2C] Same as above. [Diagram 3] Figure 2 shows a PET scan of a normal subject injected with Gallium 68, showing widespread localization to the spleen, liver and kidneys. Localization to the bladder is due to urinary excretion. [Figure 4A]Figure 4A and Figure 4B show dynamic PET+CT over 90 min. L; liver, K; kidney, S; spleen. Blocking agent reduces liver localization. In this example, Wistar rats were injected with 5 μg of [68Ga]DOTA-tilmanocept labeled with 300 μCi of [68Ga] (300 μL) via tail vein catheter. The blocking agent was a 350 kD mannosylated dextran administered (650 μL) immediately prior to [68Ga]DOTA-tilmanocept. [Figure 4B] Same as above. [Diagram 5] Liver localization of [68Ga]DOTA-tilmanocept visualized and quantified by PET-CT in Wistar rats. All rats received 5 μg of [68Ga]DOTA-tilmanocept labeled with 300 μCi of [68Ga] intravenously (IV). One rat received no blocking agent. Three rats received 2.5 mg of a 350 kD blocking agent IV immediately prior to administration of [68Ga]DOTA-tilmanocept. [Figure 6] Muscle localization of [68Ga]DOTA-tilmanocept visualized and quantified by PET-CT in Wistar rats. All rats received 5 μg of [68Ga]DOTA-tilmanocept labeled with 300 μCi of [68Ga] intravenously (IV). One rat received no blocking agent. Three rats received 2.5 mg of a 350 kD blocking agent IV immediately prior to administration of [68Ga]DOTA-tilmanocept. [Figure 7] Muscle / liver localization ratios (x100) of [68Ga]DOTA-tilmanocept (%ID / gram) in blocked and unblocked rats. In rats injected with [68Ga]DOTA-tilmanocept with and without blocking agent. Muscle / liver localization ratios (x100) of [68Ga]DOTA-tilmanocept show that the reduction in liver localization with the use of high molecular weight blocking agent is accompanied by an increase in relative localization to deep tissue macrophages in muscle. The increase in relative localization ranged from 2.7-fold to over 8-fold. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] Ranges may be expressed herein as "about" one particular value and / or to "about" another particular value. When such a range is expressed, a further embodiment includes from one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations by use of the antecedent "about," it is to be understood that the particular value forms a further embodiment. It is to be further understood that the endpoints of each range are significant in relation to the other endpoint and independently of the other endpoint. It is also to be understood that there are several values ​​disclosed herein, and that each value is also disclosed herein as "about" that particular value in addition to the value itself. For example, when the value "10" is disclosed, "about 10" is also disclosed. It is also to be understood that each unit between two particular units is also disclosed. For example, when 10 and 15 are disclosed, 11, 12, 13, and 14 are also disclosed.

[0023] A residue of a chemical species, as used herein and in the concluding claims, refers to a moiety that is a product resulting from a chemical species in a particular reaction scheme, or a subsequent formulation or chemical product, regardless of whether that moiety is actually derived from the chemical species. Thus, an ethylene glycol residue in a polyester refers to one or more -OCH2CH2O- units in the polyester, regardless of whether ethylene glycol is used to prepare the polyester. Similarly, a sebacic acid residue in a polyester refers to one or more -CO(CH2)8CO- moieties in the polyester, regardless of whether that residue is derived by reacting sebacic acid or an ester thereof to obtain the polyester.

[0024] As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Exemplary substituents include, for example, those described below. The permissible substituents can be one or more and can be the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. The terms "substituted" or "substituted with" also include the implicit proviso that such substitution is in accordance with the permissible valences of the substituted atom and substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, etc. It is also contemplated that in certain embodiments, unless expressly indicated otherwise, individual substituents may be further optionally substituted (i.e., further substituted or unsubstituted).

[0025] In defining various terms, "A1", "A2", "A3", and "A4" are used herein as general symbols to represent various specific substituents. These symbols are not limited to those disclosed herein and may be any substituent, and if they are defined as a certain substituent in one instance, they may be defined as some other substituent in another instance.

[0026] "R1", "R2", "R3", "Rn" (where n is an integer) as used herein can independently have one or more of the groups listed above. For example, when R1 is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can be optionally replaced with a hydroxyl group, an alkoxy group, an alkyl group, a halide, etc. Depending on the group selected, the first group can be incorporated within the second group, or alternatively, the first group can be pendant (i.e., attached) to the second group. For example, in the phrase "an alkyl group comprising an amino group", the amino group can be incorporated within the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group selected determines whether the first group is embedded or attached to the second group.

[0027] As described herein, the compounds of the present invention may contain "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally", means that one or more hydrogens of the specified moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at all positions. The combination of substituents envisioned by the present invention is preferably one that results in the formation of a stable or chemically feasible compound. In certain embodiments, it is also contemplated that individual substituents may be further optionally substituted (i.e., further substituted or not substituted), unless expressly indicated otherwise.

[0028] Certain of the materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, starting materials and reagents used in preparing the disclosed compounds and compositions are available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, NJ), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.), or may be readily obtained by direct marketing in a variety of formats, including, but not limited to, Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March's Advanced Organic Chemistry (John Wiley and Sons, 4th Edition); and Larock's Comprehensive Organic Transformations (VCH Publishers, 1997). These compounds can be prepared by methods known to those skilled in the art, either according to procedures described in references such as "The Journal of Chemistry, vol. 13, no. 1, pp. 111-119, 1999" or by methods known to those skilled in the art.

[0029] Disclosed are the components used to prepare the compositions of the present invention, and the compositions themselves used within the methods disclosed herein. When these and other materials are disclosed herein, and when combinations, subsets, interactions, groups, etc. of these materials are disclosed, it is understood that each is specifically contemplated and described herein, although specific references to each of the various individual and collective combinations and permutations of these compounds may not be explicitly disclosed. For example, when a particular compound is disclosed and discussed, and several modifications that may be made to several molecules that include the compound are discussed, all combinations and permutations of the compounds and possible modifications are expressly contemplated, unless specifically indicated otherwise. Thus, when classes of molecules A, B, and C are disclosed, as well as classes of molecules D, E, and F, and AD as an example of a combination molecule, each is considered to be individually and collectively contemplated, even if each is not individually listed, i.e., AE, AF, BD, BE, BF, CD, CE, and CF are disclosed. Similarly, any subset or combination of these is also disclosed. Thus, for example, the subgroups AE, BF, and CE will be considered to be disclosed. This concept applies to all aspects of this application, including but not limited to steps in methods of making and using the compositions of the invention. Thus, where there are various additional steps that may be performed, it is to be understood that each of these additional steps may be performed by any particular embodiment or combination of embodiments of the methods of the invention.

[0030] As used herein, the term "pharmaceutical acceptable carrier" or "carrier" refers to sterile aqueous or non-aqueous solutions, colloids, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions immediately prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial action can be ensured by the inclusion of various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical forms can be brought about by the inclusion of agents such as aluminum monostearate and gelatin which delay absorption. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters), and poly(anhydrides). The rate of drug release can be controlled depending on the ratio of drug to polymer and the nature of the particular polymer used. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium immediately prior to use. Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.

[0031] As used herein, the term "cancer" refers to cells with autonomous growth capabilities. Examples of such cells include cells with an abnormal state or condition characterized by rapidly proliferating cell growth. The term is meant to include cancerous growths, e.g., tumors, oncogenic processes, metastatic tissues, and malignantly transformed cells, tissues, or organs, regardless of histopathological type or stage of invasion. It also includes malignant tumors of various organ systems, such as the respiratory, cardiovascular, renal, reproductive, hematological, nervous, hepatic, gastrointestinal, and endocrine systems, as well as adenocarcinomas, including most colon, renal cell, prostate, and / or testicular cancers, non-small cell lung, small intestine, and esophageal cancers. "Naturally occurring" cancers include any cancer that is not experimentally induced by the implantation of cancer cells into a subject, including, for example, spontaneously induced cancers, cancers caused by exposure of a patient to a carcinogen, cancers resulting from the insertion of a transgenic cancer gene or knockout of a tumor suppressor gene, and cancers caused by infectious diseases, e.g., viral infections. The term "cancer" is art-recognized and refers to a malignant tumor of epithelial or endocrine tissue. In some embodiments, the method can be used to treat a subject having an epithelial cancer, e.g., a solid tumor of epithelial origin, e.g., lung cancer, breast cancer, ovarian cancer, prostate cancer, renal cancer, pancreatic cancer, or colon cancer.

[0032] As used herein, the term "subject" refers to the target of administration, e.g., an animal. Thus, the subject of the methods disclosed herein can be a vertebrate, such as a mammal, fish, bird, reptile, or amphibian. Alternatively, the subject of the methods disclosed herein can be a human, a non-human primate, a horse, a pig, a rabbit, a dog, a sheep, a goat, a cow, a cat, a guinea pig, or a rodent. The term does not indicate a particular age or sex. Thus, it is intended to include adult and newborn subjects, as well as fetuses of either sex. In one embodiment, the subject is a mammal. A patient refers to a subject suffering from a disease or disorder. The term "patient" includes human and animal subjects. In some embodiments of the disclosed methods, the subject has been diagnosed with a need for treatment of one or more cancer disorders prior to the administration step.

[0033] As used herein, the term "treatment" refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, condition, or disorder. The term includes active treatment, i.e., treatment specifically directed to ameliorate a disease, condition, or disorder, and also includes causal treatment, i.e., treatment directed to remove the cause of the associated disease, condition, or disorder. In addition, the term includes palliative treatment, i.e., treatment designed to reduce symptoms, but not cure, of a disease, condition, or disorder; preventive treatment, i.e., treatment directed to minimize or partially or completely inhibit the onset of the associated disease, condition, or disorder; and supportive treatment, i.e., treatment used to complement another specific therapy directed to ameliorate the associated disease, condition, or disorder. In various embodiments, the term encompasses any treatment of a subject, including a mammal (e.g., a human), including (i) preventing the onset of a disease in a subject who may be susceptible to the disease but has not yet been diagnosed as having it, (ii) inhibiting the disease, i.e., arresting its onset, or (iii) relieving the disease, i.e., causing regression of the disease. In one embodiment, the subject is a mammal such as a primate, and in a further embodiment, the subject is a human. The term "subject" also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cows, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mice, rabbits, rats, guinea pigs, fruit flies, etc.).

[0034] As used herein, the term "prevent" or "preventing" refers to preventing, avoiding, eliminating, forestalling, hindering, or impeding something from happening, especially by prior action. Where reduce, inhibit, or prevent are used herein, the use of the other two words is expressly disclosed unless specifically indicated otherwise.

[0035] As used herein, the term "diagnosed" means that one has undergone a physical examination by a person skilled in the art, e.g., a physician, and has been found to have a condition that can be diagnosed or treated by a compound, composition, or method disclosed herein. For example, "diagnosed with cancer" means that one has undergone a physical examination by a person skilled in the art, e.g., a physician, and has been found to have a condition that can be diagnosed or treated by a compound or composition that can reduce the size of a tumor or the rate of growth of a tumor. A subject having cancer, a tumor, or at least one cancer or tumor cell may be identified using methods known in the art. For example, the anatomical location, total size, and / or cellular composition of a cancer cell or tumor may be determined using contrast-enhanced MRI or CT. Additional methods for identifying cancer cells may include, but are not limited to, ultrasound, bone scans, surgical biopsies, and biological markers (e.g., serum protein levels and gene expression profiles). An imaging solution comprising the cell sensitizing composition of the present invention may be used in combination with MRI or CT, for example, to identify cancer cells.

[0036] As used herein, the terms "administering" and "administration" refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, intranasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including intravenous administration, intraarterial administration, administration to a specific organ by infiltration, intramuscular administration, intratumoral administration, and subcutaneous administration. Administration can be continuous or intermittent. In various embodiments, the preparation can be administered therapeutically, i.e., administered to treat an existing disease or condition. In further various embodiments, the preparation can be administered prophylactically, i.e., administered for the prevention of a disease or condition.

[0037] As used herein, the terms "effective amount" and "effective amount" refer to an amount sufficient to achieve a desired outcome or to affect an undesired condition. For example, a "therapeutically effective amount" refers to an amount sufficient to achieve a desired therapeutic outcome or to affect an undesired symptom, but generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend on a variety of factors, including the disorder being treated and the severity of the disorder, the particular composition used; the age, weight, general health, sex, and diet of the patient; the time of administration; the route of administration; the excretion rate of the particular compound used; the duration of treatment; drugs used in combination with or simultaneously with the particular compound used, and similar factors well known in the medical arts. For example, it is well within the skill of the art to start a dose of a compound at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. If desired, an effective daily dose can be divided into multiple doses for administration. Consequently, a single dose composition can contain such amounts or submultiples thereof to make up the daily dose. In the event of any contraindications, the dosage can be adjusted by the individual physician. Dosage may vary and may be administered in one or more doses per day for one or several days. Guidance can be found in the literature for appropriate dosages for a given class of pharmaceutical. In further various embodiments, the preparation can be administered in a "prophylactically effective amount", i.e., an amount effective for the prevention of a disease or condition.

[0038] Effective dosages may be initially estimated from in vitro assays. For example, initial dosages for use in animals may be formulated to achieve circulating blood or serum concentrations of active compounds that are equal to or greater than the IC50 of a particular compound as measured in in vitro assays. It is well within the capabilities of those skilled in the art to calculate dosages to achieve such circulating blood or serum concentrations, taking into account the bioavailability of a particular active agent. For guidance, readers are referred to Fingl & Woodbury, "General Principles," In: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46 (latest edition), Pergamagon Press (incorporated herein by reference in its entirety), and references cited therein.

[0039] The phrase "anti-cancer composition" can include compositions that exert antineoplastic, chemotherapeutic, antiviral, antimitotic, antitumor, antiangiogenic, antimetastatic, and / or immunotherapeutic effects, e.g., compositions that can prevent the development, maturation, or spread of tumor cells directly, e.g., by cytostatic or cytoablative effects, and indirectly through mechanisms such as biological response modification, on tumor cells. There are numerous anti-proliferative agents available in commercial use, clinical evaluation, and preclinical development that can be included in the present application through combination drug chemotherapy. For ease of discussion, antiproliferative agents are divided into the following classes, subtypes, and species: ACE inhibitors, alkylating agents, angiogenesis inhibitors, angiostatins, anthracyclines / DNA intercalators, anticancer antibiotics or antibiotic-type agents, antimetabolites, antimetabolites, antimetastatic compounds, asparaginase, bisphosphonates, cGMP phosphodiesterase inhibitors, calcium carbonate, cyclooxygenase-2 inhibitors, DHA derivatives, DNA topoisomerases, endostatins, epipodophyllotoxins, genistamines, and the like. , hormonal anticancer agents, hydrophilic bile acids (URSO), immunomodulatory or immunological agents, integrin antagonists, interferon antagonists or agents, MMP inhibitors, miscellaneous antineoplastic agents, monoclonal antibodies, nitrosoureas, NSAIDs, ornithine decarboxylase inhibitors, pBATT radiosensitizers / chemosensitizers / protectants, retinoids, selective inhibitors of endothelial cell proliferation and migration, endothelin proliferation inhibitors, selenium, stromelysin inhibitors, taxanes, vaccines, and vinca alkaloids.

[0040] The major categories into which some antiproliferative agents fall include antimetabolites, alkylating agents, antibiotic-type agents, hormonal anticancer agents, immunological agents, interferon-type agents, and various antineoplastic agents. Some antiproliferative agents function through multiple or unknown mechanisms and therefore can be classified into more than one category.

[0041] "Tilmanocept" refers to the non-radiolabeled precursor of the LYMPHOSEEK® diagnostic agent. Tilmanocept is a mannosylaminodextran. It has a dextran backbone with multiple amino-terminal leashes (-O(CH)) attached to its core glucose element. 2 ) 3 S(CH 2 ) 2 NH 2 In addition, mannose moieties may be conjugated to the amino groups of some leashes, and the chelator diethylenetriaminepentaacetic acid (DTPA) may be conjugated to the amino groups of other leashes that do not contain mannose. Tilmanocept generally has a dextran backbone in which multiple glucose residues comprise the amino-terminal leashes,

[0042] [ka]

[0043] The mannose moiety is conjugated to the amino group of the leash via an amidine linker;

[0044] [ka]

[0045] The chelating agent diethylenetriaminepentaacetic acid (DTPA) is conjugated to the amino groups of the leash via an amide linker.

[0046] [ka]

[0047] Tilmanocept has the chemical name dextran 3-[(2-aminoethyl)thio]propyl 17-carboxy-10,13,16-tris(carboxymethyl)-8-oxo-4-thia-7,10,13,16-tetraazaheptadec-1-yl 3-[[2-[[1-imino-2-(D-mannopyranosylthio)ethyl]amino]ethyl]thio]propyl ether complex and Tilmanocept Tc99m has the following molecular formula: [C 6 H 10 O 5 ] n· (C 19 H 28 N 4 O 9 S 99m Tc) b· (C 13 H 24 N 2 O 5 S 2 ) c· (C 5 H 11 N.S. a and contains 3-8 conjugated DTPA molecules (b), 12-20 conjugated mannose molecules (c), and 0-17 free amine side chains (a). Tilmanocept has the following general structure:

[0048] [ka]

[0049] Some of the glucose moieties may not have an amino-terminal leash attached. This disclosure describes compositions of polymeric mannosylated dextrans and methods of their use to block (i.e., eliminate through competition) the ability of smaller mannosylated dextrans carrying diagnostic and therapeutic moieties to bind to CD206 receptor-expressing cells in the liver and kidney without proportionally reducing the ability of these smaller mannosylated dextrans to bind to CD206 cells aggregated at the site of the pathological process. The utility of the disclosed invention is to allow robust localization of mannosylated dextrans carrying diagnostic and therapeutic moieties to the site of the pathological process while reducing or eliminating localization to non-specific sites such as the liver and kidney. Non-specific localization has undesirable and / or dose-limiting consequences. Also, other imaging and therapeutic agents bind to receptors that occur in the liver, kidney and / or other non-specific sites, as well as at the site of the pathological process. Similar to the situation with mannosylated dextrans, high molecular weight dextrans can be conjugated to these other imaging and / or therapeutic agents, either directly or by molecular leashes of various compositions, and used to block accumulation of these other imaging and / or therapeutic agents at non-specific sites while allowing localization of their unconjugated (smaller molecular weight) forms to pathological lesions.

[0050] In certain embodiments, a method is disclosed for increasing the target specificity of mannosylated dextran therapeutic or diagnostic compounds by administering at least a blocking composition comprising a scaffold and one or more CD206 targeting moieties attached thereto, and administering an effective amount of a mannosylated dextran therapeutic or diagnostic compound comprising a dextran scaffold and one or more CD206 targeting moieties and one or more therapeutic agents attached thereto.In exemplary implementations, the molecular mass of the blocking composition scaffold is at least 2 times larger than the molecular mass of the mannosylated dextran scaffold compound.

[0051] In certain embodiments, the disclosed method enhances the specificity of target tissues where CD206-expressing cells do not directly contact or have a smaller range of direct contact with circulating blood, such as in the case of liver Kupffer cells (e.g., the target tissue is not immersed in blood).Such targets can include joints (e.g., for the diagnosis of rheumatoid arthritis), and various cancers other than liver and kidney.The ability to enhance specificity to muscle will be understood by those skilled in the art as a proxy for the ability to enhance target specificity in other tissues with limited angiogenesis.

[0052] Mannosylated dextran therapeutic or diagnostic compound In certain embodiments, the compounds disclosed herein use carrier constructs that include a polymeric (e.g., carbohydrate) backbone with conjugated mannose-binding C-lectin type receptor targeting moiety (e.g., mannose) to deliver one or more active therapeutic agents. Examples of such constructs include mannosylaminodextran (MAD), which includes a dextran backbone with mannose molecules conjugated to the glucose residues of the backbone and with active pharmaceutical ingredients conjugated to the glucose residues of the backbone. Tilmanocept is a specific example of MAD. Tilmanocept derivatives, which are tilmanocept without DTPA conjugation, are a further example of MAD.

[0053] In certain implementations, the present disclosure provides compounds comprising a dextran-based moiety or scaffold having one or more mannose-binding C-type lectin receptor targeting moieties and one or more therapeutic agents attached thereto. The dextran-based moiety generally comprises a dextran backbone similar to that described in U.S. Pat. No. 6,409,990 ('990 patent), which is incorporated herein by reference. Thus, the backbone comprises a plurality of glucose moieties (i.e., residues) linked by α-1,6 glycosidic bonds. Other bonds, such as α-1,4 and / or α-1,3 bonds, may also be present. In some embodiments, not all backbone moieties are substituted. In some embodiments, the mannose-binding C-type lectin receptor targeting moieties are attached to about 10% to about 50% of the glucose residues of the dextran backbone, or about 20% to about 45% of the glucose residues, or about 25% to about 40% of the glucose residues. In some embodiments, the dextran backbone has a MW of about 1 to about 20 kDa, and in other embodiments, the dextran backbone has a MW of about 5 to about 15 kDa. In still other embodiments, the dextran backbone has a MW of about 8 to about 15 kDa, e.g., about 10 kDa. In other embodiments, the dextran backbone has a MW of about 1 to about 5 kDa, e.g., about 2 kDa.

[0054] According to further aspects, the mannose-binding C-type lectin receptor targeting moiety is selected from, but not limited to, mannose, fucose, and n-acetylglucosamine. In some embodiments, the targeting moiety is attached to about 10% to about 50% of the glucose residues of the dextran backbone, or about 20% to about 45% of the glucose residues, or about 25% to about 40% of the glucose residues. The MWs referred to herein, as well as the number and degree of conjugation of receptor substrates, leashes, and diagnostic / therapeutic moieties attached to the dextran backbone, refer to the average amount of a given amount of carrier molecule, as synthesis techniques result in some variation.

[0055] According to certain embodiments, the one or more mannose-binding C-type lectin receptor targeting moieties and the one or more therapeutic or diagnostic agents are attached to the dextran-based moiety via a linker. The linker may be attached to about 50% to about 100%, or about 70% to about 90% of the backbone moiety. The linkers may be the same or different. In some embodiments, the linker is an amino-terminated linker. In some embodiments, the linker may comprise -O(CH2)3S(CH2)2NH-. In some embodiments, the linker may be a chain of 1 to 20 member atoms selected from carbon, oxygen, sulfur, nitrogen, and phosphorus. The linker may be a straight chain or a branched chain. Linkers may also include, but are not limited to, halo groups, perfluoroalkyl groups, perfluoroalkoxy groups, alkyl groups such as C1-4 alkyl, alkenyl groups such as C1-4 alkenyl, alkynyl groups such as C1-4 alkynyl, hydroxy groups, oxo groups, mercapto groups, alkylthio groups, alkoxy groups, nitro groups, azidoalkyl groups, aryl or heteroaryl groups, aryloxy or heteroaryloxy groups, aralkyl or heteroaralkyl groups, aralkoxy or heteroaralkoxy groups, HO-(C=O)- groups, heptagonists, aryloxy groups ... It may be substituted with one or more substituents including tert-butyl cyclic alkyl groups, cycloalkyl groups, amino groups, alkyl- and dialkylamino groups, carbamoyl groups, alkylcarbonyl groups, alkylcarbonyloxy groups, alkoxycarbonyl groups, alkylaminocarbonyl groups, dialkylaminocarbonyl groups, arylcarbonyl groups, aryloxycarbonyl groups, alkylsulfonyl groups, arylsulfonyl groups, -NH-NH2; =NH; =N-alkyl; -SH; -S-alkyl; -NH-C(O)-; -NH-C(=N)-, etc. Other suitable linkers are possible, as will be apparent to one of skill in the art.

[0056] In some embodiments, one or more therapeutic agents are attached via a biodegradable linker. In some embodiments, the biodegradable linker comprises a pH-sensitive moiety such as a hydrazone. At lower (more acidic) pH, the hydrazone linker spontaneously hydrolyzes at a rate that increases as the pH decreases. When mannosylated dextran binds to CD206, it is internalized into endosomes that become increasingly acidic over time, thereby releasing the therapeutic agent payload into the cell.

[0057] According to further embodiments, the therapeutic agent is a cytotoxic agent (e.g., doxorubicin). In yet further embodiments, the therapeutic agent is an anti-cancer agent. In certain embodiments, a chelator can be attached or incorporated into the disclosed compounds and used to chelate therapeutic agents such as Cu(II). Exemplary chelators include, but are not limited to, DTPA (such as Mx-DTPA), DOTA, TETA, NETA, or NOTA. According to certain exemplary implementations, the chelator is DOTA.

[0058] Any of a variety of detectable moieties can be directly or indirectly bound to carrier molecules for a variety of purposes. As used herein, the term "detectable moiety" or "diagnostic moiety" (these terms can be used interchangeably) refers to an atom, isotope, or chemical structure that: (1) is capable of binding to carrier molecules; (2) is non-toxic to humans; and (3) provides a directly or indirectly detectable signal, particularly a signal that is not only measurable but whose intensity is related (e.g., proportional) to the amount of detectable moiety. The signal can be detected by any suitable means, including spectroscopic, electrical, optical, magnetic, auditory, radio signal, or tactile detection means, and the measurement process described herein.

[0059] Suitable detectable moieties include, but are not limited to, radioisotopes (radionuclides), fluorophores, chemiluminescent agents, bioluminescent agents, magnetic moieties (including paramagnetic moieties), metals (e.g., for use as imaging agents), RFID moieties, enzymatic reactants, colorimetric releasing agents, dyes, and particle forming agents.

[0060] By way of example, suitable diagnostic moieties include, but are not limited to, the following: · Paramagnetic and superparamagnetic materials such as contrast agents suitable for magnetic resonance imaging (MRI), such as gadolinium (Gd3+), superparamagnetic iron oxide; - contrast agents suitable for computed tomography (CT) imaging, such as the iodinated molecules, ytterbium and dysprosium; -99mTc, 210Bi, 212-n-213-n-214n·131n Ba,,,, 140n Ba,,, 11C,-, 14^C, 51, C-.r, 67^da,,, 68^a,,,, 153^d., 88vY, 90vY, 91vY, 123T 124T, Bi, Bi, Bi, 1, 1, 125I, 131I, i radioisotopes suitable for scintigraphic imaging (or scintigraphy), such as In, In, F, N, Rh, Sm, Cu, Ho, Lu, Ra, Rb, Re and Re, P, P, Sc, Se, Se, Sr, Ta, Te ... - Gamma ray emitting agents suitable for single photon emission computed tomography (SPECT), such as 99mTc, mIn, and 123I -Dyes and Fluorescent Agents Suitable for Optical Imaging -Agents suitable for positron emission tomography (PET), such as 18F.

[0061] The diagnostic moiety can be attached to the carrier molecule in a variety of ways, such as by direct attachment or using a chelator attached to the carrier molecule. In some embodiments, the diagnostic moiety can be attached using a leash attached to the carrier backbone. It can then be conjugated to the amino group of one or more leashes and used to attach a diagnostic moiety thereto, as described in connection with the case of direct attack. Note that in some cases, the glucose moiety may not have an aminothiol leash attached. Certain embodiments may include a single type of diagnostic moiety or a mixture of different diagnostic moieties. For example, embodiments of the compounds disclosed herein may include a contrast agent suitable for MRI and a radioisotope suitable for scintigraphic imaging, as well as further combinations of diagnostic moieties as described herein.

[0062] One or more diagnostic moieties can be attached to one or more leashes using a suitable chelating agent, including, but not limited to, those known to those of skill in the art or to be developed hereafter, such as tetraazacyclododecanetetraacetic acid (DOTA), mercaptoacetylglycylglycyl-glycine (MAG3), diethylenetriaminepentaacetic acid (DTPA), dimercaptosuccinic acid, diphenylethylenediamine, porphyrins, iminodiacetic acid, and ethylenediaminetetraacetic acid (EDTA).

[0063] In certain embodiments, the disclosed compounds are present in the form of a pharma- ceutically acceptable carrier. According to certain embodiments, the disclosed compounds have formula (I):

[0064] [ka]

[0065] wherein each X is independently H, L1-A, or L2-R; each L1 and L2 is independently a linker; each A independently comprises a therapeutic agent or H; each R independently comprises a mannose-binding C-type lectin receptor targeting moiety or H; n is an integer greater than zero, at least one R comprises a mannose-binding C-type lectin receptor targeting moiety selected from the group consisting of mannose, fucose, and n-acetylglucosamine, and at least one A comprises a therapeutic agent.

[0066] In certain embodiments, at least one L1 comprises -(CH2)pS(CH2)-NH-, where p and q are integers from 0 to 5. According to a further embodiment, at least one L2 is a C2-12 hydrocarbon chain optionally interrupted by up to three heteroatoms selected from the group consisting of O, S and N.

[0067] In still further embodiments, at least one L2 comprises -(CH2)pS(CH2)-NH-, where p and q are independently integers from 0 to 5. In a further embodiment, the disclosed composition is of formula (II):

[0068] [ka]

[0069] where * indicates the point at which a therapeutic or diagnostic agent is attached. In certain embodiments, the therapeutic agent is attached via a linker. According to certain embodiments, the disclosed compounds (e.g., mannosylated dextran therapeutic or diagnostic compounds, and / or blocking compounds) may include a pharma- ceutically acceptable carrier and the compounds disclosed herein, or pharma- ceutically acceptable salts of the compounds. The disclosed compounds, or pharma- ceutically acceptable salts thereof, may be included in a pharmaceutical composition in combination with one or more other therapeutically active compounds.

[0070] Blocking Compounds In certain aspects, the blocking compounds disclosed herein preferentially bind to CD206 expressed in the kidney and / or liver using a carrier construct comprising a polymeric (e.g., carbohydrate) backbone with a conjugated mannose-binding C-lectin type receptor targeting moiety (e.g., mannose). An example of such a construct includes mannosylaminodextran (MAD), which comprises a dextran backbone with mannose molecules conjugated to glucose residues of the backbone. In alternative embodiments, the blocking composition backbone may include any polymer suitable for safe administration to a subject and conjugated to a C-lectin type receptor targeting moiety (with or without a leash). Examples include, but are not limited to, cellulose, polyethylene glycol, and various polypeptides.

[0071] In certain embodiments, the blocking compound backbone is about 35-500 kD. The blocking compound backbone can be at least about 50 kD, at least about 60 kD, at least about 70 kD, at least about 80 kD, at least about 90 kD, at least about 100 kD, at least about 110 kD, at least about 120 kD, at least about 130 kD, at least about 140 kD, at least about 150 kD, at least about 150 kD, at least about 160 kD, at least about 170 kD, at least about 180 kD, at least about 190 kD, at least about 200 kD, at least about 210 kD, at least about 220 kD, at least about 230 kD, at least about 240 kD, and at least about 250 kD. The blocking compound backbone can be less than about 100 kD, less than about 90 kD, less than about 80 kD, less than about 70 kD, or less than about 60 kD.

[0072] According to certain embodiments, the blocking compound backbone has a molecular mass of about 1.5 to about 50 times that of the mannosylated dextran therapeutic or diagnostic compound backbone. In certain aspects, the blocking compound backbone has a molecular mass of about 2 to about 3 times that of the mannosylated dextran therapeutic or diagnostic compound backbone. In further embodiments, the blocking compound backbone has a molecular mass of about 2 times that of the mannosylated dextran therapeutic or diagnostic compound backbone.

[0073] In some embodiments, the mannose-binding C-type lectin receptor targeting moiety is selected from, but not limited to, mannose, fucose, and n-acetylglucosamine. In some embodiments, the targeting moiety is attached to about 10% to about 50% of the available residues of the blocking compound backbone, or about 20% to about 45% of the residues, or about 25% to about 40% of the residues.

[0074] According to certain embodiments, one or more mannose-binding C-type lectin receptor targeting moieties are attached to the backbone via a linker. The linker may be attached to about 50% to about 100%, or about 70% to about 90% of the backbone moieties. The linkers may be the same or different. In some embodiments, the linker is an amino-terminated linker. In some embodiments, the linker may comprise -O(CH2)3S(CH2)2NH-. In some embodiments, the linker may be a chain of 1 to 20 member atoms selected from carbon, oxygen, sulfur, nitrogen, and phosphorus. The linker may be linear or branched. Linkers may also include, but are not limited to, halo groups, perfluoroalkyl groups, perfluoroalkoxy groups, alkyl groups such as C1-4 alkyl, alkenyl groups such as C1-4 alkenyl, alkynyl groups such as C1-4 alkynyl, hydroxy groups, oxo groups, mercapto groups, alkylthio groups, alkoxy groups, nitro groups, azidoalkyl groups, aryl or heteroaryl groups, aryloxy or heteroaryloxy groups, aralkyl or heteroaralkyl groups, aralkoxy or heteroaralkoxy groups, HO-(C=O)- groups, heptagonists, aryloxy groups ... It may be substituted with one or more substituents, including terecyclyl group, cycloalkyl group, amino group, alkyl- and dialkylamino group, carbamoyl group, alkylcarbonyl group, alkylcarbonyloxy group, alkoxycarbonyl group, alkylaminocarbonyl group, dialkylaminocarbonyl group, arylcarbonyl group, aryloxycarbonyl group, alkylsulfonyl group, arylsulfonyl group, -NH-NH2;=NH;=N-alkyl;-SH;-S-alkyl;-NH-C(O)-;-NH-C(=N)- and the like.Other suitable linkers are possible, as will be apparent to those skilled in the art.In certain alternative embodiments, the targeting moiety is directly attached to the backbone without using a linker.

[0075] The pharmaceutical carrier used can be, for example, solid, liquid or gas.The examples of solid carrier include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid.The examples of liquid carrier include sugar syrup, peanut oil, olive oil and water.The examples of gas carrier include carbon dioxide and nitrogen.

[0076] In preparing the composition for oral dosage form, any convenient pharmaceutical medium can be used.For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc. can be used to form oral liquid preparations such as suspensions, elixirs and solutions, while carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, etc. can be used to form oral solid preparations such as powders, capsules and tablets.Because of their ease of administration, tablets and capsules are the preferred oral dosage units, whereby solid pharmaceutical carriers are used.Optionally, tablets can be coated by standard aqueous or non-aqueous techniques.

[0077] 10. The method of the preceding claims, wherein the blocking compound does not contain a therapeutic or diagnostic agent. According to certain embodiments, a method for increasing target specificity of mannosylated dextran therapeutic or diagnostic compounds is disclosed, comprising at least administering a blocking composition comprising a scaffold and one or more CD206 targeting moieties attached thereto, and administering an effective amount of mannosylated dextran therapeutic or diagnostic compounds comprising a dextran scaffold and one or more CD206 targeting moieties and one or more therapeutic agents attached thereto.In exemplary implementations, the molecular mass of the blocking composition scaffold is at least 2 times larger than the molecular mass of the mannosylated dextran scaffold compound.

[0078] In certain aspects, the step of administering the blocking compound is followed by a time interval prior to administration of the mannosylated dextran therapeutic or diagnostic compound. According to these embodiments, during this time interval, the blocking compound circulates throughout the subject's system and binds to CD206-expressing cells in the kidney and liver, allowing the mannosylated dextran therapeutic or diagnostic compound to be competitively excluded from subsequent binding to such cells. In certain aspects, the time interval is at least about 10 minutes. In further aspects, the time interval is about 10 minutes to about 60 minutes. In further aspects, the time interval is 10 minutes to about 30 minutes. In yet further aspects, the time interval is 10 minutes to about 20 minutes.

[0079] According to certain embodiments of the disclosed methods, the mannosylated dextran therapeutic or diagnostic compound comprises at least one therapeutic moiety. In certain exemplary implementations of these embodiments, the effective dose of the mannosylated dextran therapeutic or diagnostic compound is lower than the effective dose of the mannosylated dextran therapeutic or diagnostic compound in the absence of administration of the blocking compound.

[0080] According to further embodiments, the blocking compound preferentially binds to CD206 expressing cells in the liver and / or kidney. In an exemplary implementation, the mannosylated dextran therapeutic or diagnostic compound reduces binding to CD206 cells in the liver and / or kidney compared to subjects administered an equivalent dose of the mannosylated dextran therapeutic or diagnostic compound without the blocking compound.

[0081] In certain embodiments, the compound is administered in a therapeutically effective amount. The compound is administered in a prophylactically effective amount. In still further embodiments, the method further comprises administering the compound intravenously, intraperitoneally, intramuscularly, orally, subcutaneously, intraocularly, by intratumoral injection, or transdermally, or delivering directly to the tumor organ by invasive techniques.

[0082] The methods provided herein may be performed in an adjuvant setting. In some embodiments, the methods are performed in a neoadjuvant setting, i.e., the methods may be performed prior to primary / definitive treatment. In some embodiments, the methods are used to treat individuals who have been previously treated. Any of the treatment methods provided herein can be used to treat individuals who have not been previously treated. In some embodiments, the methods are used as a first line treatment. In some embodiments, the methods are used as a second line treatment.

[0083] According to certain embodiments, the subject has been diagnosed with melanoma, breast cancer, lung cancer, pancreatic carcinoma, renal cancer, ovarian cancer, prostate cancer or cervical carcinoma, glioblastoma, or colorectal cancer, brain and spinal cord tumors, head and neck cancer, thymic cancer, mesothelioma, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, bile duct cancer, bladder cancer, testicular cancer, germ cell cancer, ovarian cancer, cervical cancer, endometrial cancer, lymphoma, acute leukemia, chronic leukemia, multiple myeloma, sarcoma, or any combination thereof.

[0084] In certain embodiments, the method further comprises administering the composition as a bolus and / or at regular intervals. In certain embodiments, the disclosed method further comprises administering the composition intravenously, intraperitoneally, intramuscularly, orally, subcutaneously, intratumorally, or transdermally.

[0085] According to certain further embodiments, the method further comprises diagnosing the subject with cancer. In a further aspect, the subject is diagnosed with cancer prior to administration of the composition. According to yet a further aspect, the method further comprises evaluating the effectiveness of the composition. In a still further aspect, evaluating the effectiveness of the composition comprises measuring a tumor size prior to administration of the composition and measuring a tumor size after administration of the compound. In a still further aspect, evaluating the effectiveness of the composition is performed at regular intervals. According to certain aspects, the disclosed method further comprises optionally adjusting at least one aspect of the method. In a still further aspect, adjusting at least one aspect of the method comprises changing the dose of the composition, the frequency of administration of the composition, or the route of administration of the compound.

[0086] According to certain alternative embodiments, the subject has been diagnosed with a disease associated with elevated levels of CD206+ macrophages and / or MDSCs. Such diseases or conditions include acquired immune deficiency syndrome (AIDS), acute disseminated encephalomyelitis (ADEM), Addison's disease, agammaglobulinemia, allergic diseases, alopecia, Alzheimer's disease, amyotrophic lateral sclerosis, ankylosing spondylitis, antiphospholipid syndrome, antisynthetase syndrome, arterial plaque disorders, asthma, atherosclerosis, atopic allergy, atopic dermatitis, autoimmune aplastic anemia, autoimmune cardiomyopathy, autoimmune enteropathy, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune hypothyroidism. autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, peripheral neuropathy, autoimmune pancreatitis, autoimmune polyendocrine syndrome, autoimmune progesterone dermatitis, autoimmune thrombocytopenic purpura, autoimmune urticaria, autoimmune uveitis, Baro's disease / Baro's concentric sclerosis, Behçet's disease, Buerger's disease, Bickerstaff encephalitis, Blau syndrome, bullous pemphigoid, Castleman's disease, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, chronic relapsing multiple osteomyelitis, chronic obstructive pulmonary disease, chronic venous congestion ulcers, Churg-Strauss syndrome, cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, complement component 2 deficiency, contact dermatitis, cranial arteritis, CREST syndrome, Crohn's disease, Cushing's syndrome, cutaneous leukocytoclastic vasculitis, Degos disease, Dercum's disease, dermatitis herpetiformis, dermatomyositis, diabetes mellitus type I, diabetes mellitus type II, diffuse cutaneous systemic sclerosis, Dressler's syndrome, drug-induced lupus, discoid lupus erythematosus, eczema, emphysema, endometriosis, enthesitis-related arthritis, eosinophilic fasciitis, eosinophilic gastroenteritis, eosinophilic pneumonia, Epidermolysis bullosa acquisita, erythema nodosum, erythroblastosis fetalis, essential mixed cryoglobulinemia, Evans syndrome, fibrodysplasia ossificans progressiva, fibrous alveolitis (or idiopathic pulmonary fibrosis), gastritis, peptic pemphigoid, Gaucher disease, glomerulonephritis, Goodpasture syndrome, Graves disease, Guillain-Barré syndrome (GBS), Hashimoto's encephalopathy, Hashimoto's thyroiditis, heart disease, Henoch-Schönlein purpura, herpes gestationis (also known as pemphigoid gestationis), hidradenitis suppurativa, HIV infection, Hughes-Stobin syndrome, hypogammaglobulinemia,Infectious diseases (including bacterial infections), idiopathic inflammatory demyelinating diseases, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura, IgA nephropathy, inclusion body myositis, inflammatory arthritis, inflammatory bowel disease, inflammatory dementia, interstitial cystitis, interstitial pneumonia, juvenile idiopathic arthritis (also known as juvenile rheumatoid arthritis), Kawasaki disease, Lambert-Eaton myasthenic syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, linear immunoglobulin A disease (LAD), lupoid hepatitis (also known as autoimmune hepatitis), lupus erythematosus, lymphomatoid granulomatosis, Majeed syndrome, malignancies including cancer (e.g. sarcomas) , Kaposi's sarcoma, lymphoma, leukemia, carcinoma and melanoma), Meniere's disease, microscopic polyangiitis, Miller Fisher syndrome, mixed connective tissue disease, morphea, Mucha-Habermann disease (also known as acute pityriasis lichenoidis), multiple sclerosis, gravitational myasthenia, myositis, narcolepsy, neuromyelitis optica (also known as Devic's disease), neuromyotonia, ocular cicatricial pemphigoid, Ord's thyroiditis, relapsing rheumatism, PANDAS (pediatric autoimmune neuropsychiatric disorder associated with streptococcus), paraneoplastic cerebellar degeneration, Parkinson's disease, paroxysmal nocturnal hemoglobinopathy (PNHAS), Robinuria (PNH), Parry-Romberg syndrome, Parsonage-Turner syndrome, pars planitis, pemphigus vulgaris, peripheral arterial disease, pernicious anemia, perivenous encephalitis, POEMS syndrome, polyarteritis nodosa, polymyalgia rheumatica, polymyositis, primary biliary cirrhosis, primary sclerosing cholangitis, progressive inflammatory neuropathy, psoriasis, psoriatic arthritis, pyoderma gangrenosum, pure red cell aplasia, Rasmussen encephalitis, Raynaud's phenomenon, relapsing polychondritis, Reiter's syndrome, restenosis, restless legs syndrome, retroperitoneal fibrosis, rheumatoid arthritis, rheumatic fever, sarcoidosis, schizophrenia, Schmidt's syndrome Syndrome, Schnitzler's syndrome, Scleritis, Scleroderma, Sepsis, Serum sickness, Sjögren's syndrome, Spondyloarthropathy, Still's disease (adult onset), Stiff body syndrome, Stroke, Subacute bacterial endocarditis (SBE), Susac's syndrome, Sweet's syndrome, Sydenham's chorea, Sympathetic ophthalmia, Systemic lupus erythematosus, Takayasu's arteritis, Temporal arteritis (also known as "giant cell arteritis"), Thrombocytopenia, Tolosa-Hunt syndrome, Transplant (e.g. heart / lung transplant) rejection, Transverse myelitis, Tuberculosis, Ulcerative colitis, Undifferentiated connective tissue disease, Undifferentiated spondyloarthropathy, Urticarial vasculitis, Vasculitis, Vitiligo,and Wegener's granulomatosis.

[0087] Also provided herein is a pharmaceutical preparation kit containing the disclosed compound or composition.The kit can be constructed to represent a single preparation or a combination of preparations.The composition can be subdivided to contain an appropriate amount of the compound.The unit dose can be a packaged composition, such as a packaged powder, a vial, an ampoule, a pre-filled syringe, or a sachet containing liquid.

[0088] The compounds or compositions described herein may be single doses, or may be for continuous or periodic discontinuous administration.For continuous administration, the kit may contain the compound in each dosage unit.For periodic discontinuation, the kit may contain a placebo during the period when the compound is not delivered.If it is desired to change the concentration of the composition, the components of the composition, or the relative ratio of the compound or other agent in the composition over time, the kit may contain a series of dosage units.

[0089] The kit may include a package or container with the compound formulated for the desired delivery route. The kit may also include administration instructions, a package insert for the compound, instructions for monitoring circulating levels of the compound, or a combination thereof. The kit may further include materials for practicing with the compound, including but not limited to reagents, well plates, containers, markers or labels, and the like. Such kits are packaged in a manner suitable for treating the desired indication. Other suitable components to be included in such kits will be readily apparent to those skilled in the art, taking into account the desired indication and delivery route. The kit may also include or be packaged with an instrument to aid in the injection / administration or placement of the compound in the subject's body. Such instruments include, but are not limited to, inhalants, syringes, pipettes, forceps, measuring spoons, eye drops, or any such medically approved means of delivery. Other instruments may include devices that allow for reading or monitoring of reactions in vitro.

[0090] The compounds or compositions of these kits may also be provided in dry, lyophilized, or liquid form. When reagents or components are provided in dry form, reconstitution is generally performed by adding a solvent. The solvent may be provided in another packaging means and may be selected by the skilled artisan.

[0091] Several packages or kits for dispensing pharmaceutical agents are known to those of skill in the art. In one embodiment, the package is a labeled blister package, a dial dispenser package, or a bottle.

[0092] In certain embodiments, the kits disclosed herein comprise a blocking compound comprising a backbone and one or more CD206 targeting moieties attached thereto, and a mannosylated dextran therapeutic or diagnostic compound comprising a dextran backbone and one or more CD206 targeting moieties and one or more therapeutic agents attached thereto, wherein the molecular mass of the blocking composition backbone is at least two times greater than the molecular mass of the mannosylated dextran backbone compound. In certain embodiments, the kit comprises a blocking compound comprising a backbone and one or more CD206 targeting moieties attached thereto, and a mannosylated dextran therapeutic or diagnostic compound comprising a dextran backbone and one or more CD206 targeting moieties and one or more therapeutic agents attached thereto, wherein the molecular mass of the blocking composition backbone is at least two times greater than the molecular mass of the mannosylated dextran backbone compound.

[0093] [ka]

[0094] (In the formula, each X is independently H, L1-A, or L2-R; each L1 and L2 is independently a linker; each A independently comprises a therapeutic agent, a diagnostic agent, or H; each R independently comprises a mannose-binding C-type lectin receptor targeting moiety or H; n is an integer greater than zero, At least one R comprises a mannose-binding C-type lectin receptor targeting moiety selected from the group consisting of mannose, fucose, and n-acetylglucosamine, and at least one A comprises a mannosylated dextran therapeutic or diagnostic compound, which is a compound of the formula (comprising a therapeutic or diagnostic agent). In a further embodiment, the blocking compound backbone is about 110 kDa and the mannosylated dextran therapeutic or diagnostic compound dextran backbone is about 10 kDa. EXAMPLES

[0095] The following examples are presented to provide those of skill in the art with a complete disclosure and description of certain examples of how the compounds, compositions, articles, devices and / or methods claimed herein are made and evaluated, are intended to be purely exemplary of the invention, and are not intended to limit the scope of what the inventors regard as their invention. However, those of skill in the art, in light of this disclosure, will understand that numerous changes can be made in the specific embodiments that are disclosed and still obtain the same or similar results without departing from the spirit and scope of the invention.

[0096] Example 1: Due to their high affinity for CD206, mannosylated dextran in general and 99mTc-tilmanocept in particular have been investigated as either imaging agents or drug delivery vehicles for macrophage-involved diseases atherosclerosis, cancer and rheumatoid arthritis (unpublished results). Imaging studies have been performed using Lymphoseek (99mTc-tilmanocept) administered by intravenous (IV) injection, rather than the peritumoral or intradermal routes of administration used for SLN-related indications. The results of these studies have been generally positive, however, as shown in Figures 1 and 2, IV administration of 99mTc-tilmanocept resulted in highly significant uptake of mannosylated dextran by the liver and kidney. Figure 1 shows that 5 mCi of 99mAutoradiograms of sections from male Sprague Dawley rats that had been IV injected (tail vein) with 25 μg of technetium-labeled 99mTc-tilmanocept 1 hour prior are shown. Most of the injected radioactivity was excreted in the urine by 1 hour after injection (not shown in Figure 1). Among organs, the greatest localization of radioactivity occurred in the liver and kidneys (L and K, respectively, in Figure 1) due to the presence of many Kupffer cells and mesangial cells in these organs. There was also significant localization (although less) in the spleen, which is known to contain macrophages. The Sprague Dawley rats in this study were healthy and therefore did not have any disease lesions to which 99mTc-tilmanocept could be localized.

[0097] Example 2: In a second experiment, fluorescently labeled (Cy5) tilmanocept was injected into Balb / C mice bearing 4T1 syngeneic tumors. When excited, Cy5 fluoresces in the near infrared region of the light spectrum. Figure 2 provides a false color image obtained from this experiment, with yellow indicating areas with higher fluorescence than red regions. Figure 2A shows an image of a mouse injected with Cy5-tilmanocept, and Figure 2C shows an image of an animal that was not injected with any fluorescent material. Comparing Figure 2A to Figure 2C, it can be seen that there was considerable autofluorescence from the animal's hair and intestine (I). However, in animals injected with fluorescent mannosylated dextran, the localization of Cy5-tilmanocept in the tumor (T) is remarkably evident. The animal shown in Figure 2A was dissected, allowing the fluorescence of the liver, kidney, spleen and tumor to be examined (Figure 2B). In Figure 2B, it is evident that the tumor (T) specifically localized a significant amount of Cy5-tilmanocept due to CD206 expression in TAMs. The intensity of localization to the liver (L) and kidney (K) was higher than in the tumor due to the presence of CD206-expressing Kupffer cells and mesangial cells, respectively. The intensity of fluorescence in the spleen (S) and tumor was similar due to the presence of splenic macrophages and tumor TAMs. Nonspecific uptake by the liver and kidney may negatively affect localization to pathological lesions with large numbers of CD206-expressing macrophages, resulting in undesirable nonspecific toxicity for CD206-targeted mannosylated dextran drug delivery constructs.

[0098] Example 3: To block localization of low molecular weight mannosylated dextrans such as 99mTc-tilmanocept or similarly sized drug delivery vehicles to non-specific sites such as the liver or kidney, high molecular weight mannosylated dextrans can be synthesized. Dextran is a polymer of glucose with α-1,6 glycosidic linkages. Mannosylation of dextran is described in the '990 patent. Synthesis of tilmanocept is described in the '990 patent. In this example, tilmanocept is synthesized starting from a 10 kDa dextran backbone. High molecular weight mannosylated dextrans can be synthesized starting from a 110 kDa dextran backbone. For each of these backbones, amine-terminated leashes can be added to the dextran backbone, as in the aforementioned '990 patent. (In the case of tilmanocept, the chelator, DTPA, can then be added to some of the amine-terminated leashes. The large molecular weight constructs do not have a chelator or any other detection or therapeutic moieties attached. Finally, for both tilmanocept and the high molecular weight constructs, a variable number of sugars, mannose, can be added to some of the unoccupied amine-terminated leashes. Note that other sugars in addition to mannose can be attached to the amine-terminated leashes to generate constructs that bind to CD206, but attachment of multiple mannose moieties is necessary and sufficient to enable high affinity binding to CD206.

[0099] Example 4: High molecular weight mannosylated dextran administered intravenously (IV) immediately prior to IV administration of gallium-68 labeled DOTA-tilmanocept results in selective blocking (i.e., reduction) of liver localization and increased localization to deep tissue macrophages in muscle.

[0100] A tilmanocept derivative was synthesized that carries the chelator dodecanetetraacetic acid (DOTA) instead of diethylenetriaminepentaacetic acid (DTPA). This construct, designated DOTA-tilmanocept, is identical to commercially available tilmanocept, except that the DTPA in commercially available tilmanocept has been replaced with DOTA. This replacement of DTPA with DOTA allows the construct DOTA-tilmanocept to be coupled to gallium 68 [ 68 This was done to allow for efficient labeling with a variety of ions, including gallium. 68 allows imaging by positron emission tomography (PET), which was the imaging modality used in this example. DOTA-tilmanocept has an average molecular weight of approximately 20 kD.

[0101] Four Wistar rats (approximately 250 grams) were given 300 μCi of gallium. 68 5 μg of [ 68 Experiments were performed with intravenous (IV) injection of [Ga]DOTA-tilmanocept. Dynamic PET imaging was performed from the time of injection until 90 min post-injection. Standard uptake values ​​(SUV) were calculated to determine the biodistribution of the radiolabel to various organs and reported as percent of the injected dose per gram (%ID / g) for each organ. In this example, results from two organs are reported: liver and thigh muscle. Thigh muscle is a muscle that is known to mediate the expression of [Ga]DOTA-tilmanocept to tissue macrophages that are not directly exposed to blood. 68 The tumor-associated macrophages and macrophages associated with the pathobiology of rheumatoid arthritis are two examples among many tissue macrophages. In contrast, the liver contains a large number of Kupffer cells, which express CD206 and are directly exposed to the blood circulation. Kupffer cells show significant precipitation of mannosylated dextran injected into the blood.

[0102] A high molecular weight (HMW) mannosylated dextran (Mw approx. 350 kD) was synthesized using the same chemical procedures used to make tilmanocept or DOTA-tilmanocept, except that the starting dextran backbone was 150 kD instead of 10 kD and no chelator was conjugated to the resulting mannosylated dextran. This HMW construct binds to CD206 on Kupffer cells, thereby [ 68 The HMW construct is designed to block [Ga]DOTA-tilmanocept localization to the liver, but also to leave the bloodstream and penetrate inefficiently into tissues due to its relatively large size. The relatively poor penetration into tissues may be due to the fact that the HMW construct is unable to localize to tissue macrophages. 68 Ga]DOTA-tilmanocept. 68 Because Ga]DOTA-tilmanocept is localized in Kupffer cells, more 68 Ga]DOTA-tilmanocept is available to exit the circulation and bind to CD206 expressed on tissue macrophages.

[0103] In the experiments described in this example, 68 Immediately prior to IV administration of [Ga]DOTA-tilmanocept, three of the four rats were IV injected with 2.5 mg of the HMW blocking construct. In Figure 4A and Figure 4B, representative PET-CT images from 80-90 min of a rat not administered HMW blocking agent (Figure 4A) and a rat administered HMW blocking agent (Figure 4B) are shown. Qualitative assessment of the images indicates that the HMW blocking agent is able to inhibit [Ga]DOTA-tilmanocept delivery to the liver. 68 Figure 5 shows that the HMW blocking agent reduced the localization of [Ga]DOTA-tilmanocept to the liver, expressed as %ID / g, in unblocked rats and three rats that received the HMW blocking agent. 68 Figure 6 shows a graph of the localization of [Ga]DOTA-tilmanocept in the thigh muscle of four rats. On average, rats treated with HMW blocking agent showed 26.7% localization, which was comparable to unblocked rats. Figure 6 shows the localization of [Ga]DOTA-tilmanocept in the thigh muscle of four rats, expressed as %ID / g. 68Figure 7 shows the localization of [Ga]DOTA-tilmanocept. Results varied, but on average, rats treated with HMW blocking agent showed 29.7% higher localization than was observed in rats that did not receive blocking agent. The third graphical representation of the results (Figure 7) shows the thigh muscle / liver %ID / g ratio (x100) for each of the four rats. All rats treated with HMW blocking agent showed higher muscle / liver ratios, ranging from 2.7- to 8.5-fold higher than those observed in rats that did not receive blocking agent. These results suggest that the HMW mannosylated dextran blocking agent significantly increased the localization of [Ga]DOTA-tilmanocept to the liver. 68 Ga]DOTA-tilmanocept selectively inhibited binding to macrophages in the thigh muscle. 68 These results indicate that it did not decrease, and possibly increase, the localization of [Ga]DOTA-tilmanocept. Other sites of tissue macrophages, such as sites of pathological lesions involving macrophages, are expected to function similarly.

[0104] Although the present invention has been described with reference to preferred embodiments, workers skilled in the art will recognize that changes may be made in form and detail without departing from the spirit and scope of the invention.

Claims

1. A kit for increasing the target specificity of a mannosylated dextran therapeutic or diagnostic compound, comprising: a. a blocking compound comprising a scaffold and one or more CD206 targeting moieties attached thereto; b. an effective amount of said mannosylated dextran therapeutic or diagnostic compound comprising a dextran backbone and attached thereto one or more CD206 targeting moieties and one or more therapeutic or diagnostic agents; A kit, wherein the molecular mass of the backbone of said blocking compound is at least two times greater than the molecular mass of the backbone of said mannosylated dextran therapeutic or diagnostic compound.

2. The mannosylated dextran therapeutic or diagnostic compound is a compound of formula (I), 【Chemistry 1】 During the ceremony, each X is independently H, L1-A, or L2-R; each L1 and L2 is independently a linker; each A independently comprises a therapeutic agent, a diagnostic agent, or H; each R independently comprises a mannose-binding C-type lectin receptor targeting moiety or H; n is an integer greater than zero, 2. The kit of claim 1, wherein at least one R comprises a mannose-binding C-type lectin receptor targeting moiety selected from the group consisting of mannose, fucose, and n-acetylglucosamine, and at least one A comprises a therapeutic or diagnostic agent.

3. The kit of claim 1 , wherein the backbone of the blocking compound is selected from the list consisting of dextran, cellulose, polyethylene glycol, and polypeptide.

4. 2. The kit of claim 1, wherein the one or more CD206 targeting moieties are attached to the backbone of the blocking compound via (-O(CH 2 ) 3 S(CH 2 ) 2 NH 2 ).

5. The kit of claim 1, wherein the backbone of the blocking compound is between 35 kDa and 500 kDa.

6. The blocking compound is a compound of formula (I), 【Chemistry 2】 During the ceremony, each X is H or L2-R; each L2 is independently a linker; each R independently comprises a mannose-binding C-type lectin receptor targeting moiety or H; n is an integer greater than zero, 6. The kit of claim 5, wherein at least one R comprises a mannose-binding C-type lectin receptor targeting moiety selected from the group consisting of mannose, fucose, and n-acetylglucosamine.

7. 6. The kit of claim 5, wherein the backbone of the blocking compound is 110 kDa and the dextran backbone of the mannosylated dextran therapeutic or diagnostic compound is 10 kDa.

8. The kit of claim 5 , wherein the blocking compound does not contain a therapeutic or diagnostic agent.

9. 2. The kit of claim 1, wherein the blocking compound is administered to the subject followed by a time interval of at least 0 to 60 minutes before the mannosylated dextran therapeutic or diagnostic compound is administered to the subject.

10. The kit of claim 9, wherein the time interval is between 10 minutes and 20 minutes.

11. The kit of claim 1 , wherein the blocking compound and the mannosylated dextran therapeutic or diagnostic compound are administered simultaneously.

12. The kit of claim 1 , wherein the mannosylated dextran therapeutic or diagnostic compound comprises at least one therapeutic moiety.

13. The kit of claim 12, wherein the percentage of the mannosylated dextran therapeutic or diagnostic compound that is localized in a desired target tissue other than the liver, kidney, and / or spleen is higher than the percentage of the mannosylated dextran therapeutic or diagnostic compound that is localized in the absence of administration of the blocking compound.

14. The kit of claim 12, wherein the effective dose of the mannosylated dextran therapeutic or diagnostic compound is lower than the effective dose of the mannosylated dextran therapeutic or diagnostic compound in the absence of administration of the blocking compound.

15. The kit of claim 1 , wherein the blocking compound preferentially binds to CD206-expressing cells in at least one of the liver, kidney, and spleen.

16. The kit of claim 15, wherein binding of the mannosylated dextran therapeutic or diagnostic compound to CD206 cells in at least one of the liver, kidney, and spleen is reduced compared to a subject administered an equivalent dose of the mannosylated dextran therapeutic or diagnostic compound without administering the blocking compound.

17. 10. The kit of claim 9, wherein the subject has been diagnosed with an autoimmune disease, an inflammatory disease, or cancer.

18. A kit for increasing the target specificity of a mannosylated dextran therapeutic or diagnostic compound, comprising: a. a blocking compound comprising a scaffold and one or more CD206 targeting moieties attached thereto, said blocking compound being between 35 kDa and 500 kDa; b. an effective amount of said mannosylated dextran therapeutic or diagnostic compound comprising a dextran backbone and attached thereto one or more CD206 targeting moieties and one or more therapeutic or diagnostic agents; A kit, wherein the molecular mass of the backbone of said blocking compound is at least two times greater than the molecular mass of the backbone of said mannosylated dextran therapeutic or diagnostic compound.

19. 1. A kit for diagnosis or treatment of a subject in need thereof, comprising: a. a blocking compound comprising a scaffold and one or more CD206 targeting moieties attached thereto; b. a mannosylated dextran therapeutic or diagnostic compound comprising a dextran backbone and one or more CD206 targeting moieties and one or more therapeutic agents attached thereto; A kit, wherein the molecular mass of the backbone of said blocking compound is at least two times greater than the molecular mass of the backbone of said mannosylated dextran therapeutic or diagnostic compound.

20. The mannosylated dextran therapeutic or diagnostic compound is a compound of formula (I), 【Chemistry 3】 During the ceremony, each X is independently H, L1-A, or L2-R; each L1 and L2 is independently a linker; each A independently comprises a therapeutic agent, a diagnostic agent, or H; each R independently comprises a mannose-binding C-type lectin receptor targeting moiety or H; n is an integer greater than zero, 20. The kit of claim 19, wherein at least one R comprises a mannose-binding C-type lectin receptor targeting moiety selected from the group consisting of mannose, fucose, and n-acetylglucosamine, and at least one A comprises a therapeutic or diagnostic agent.

21. 20. The kit of claim 19, wherein the backbone of the blocking compound is 110 kDa and the dextran backbone of the mannosylated dextran therapeutic or diagnostic compound is 10 kDa.

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