Use of inhibitors of insulin-like growth factor receptor-1 for multiple sclerosis

Abstract

Provided are methods of treating multiple sclerosis comprising administering one or more compounds that inhibit insulin¬ like growth factor receptor- 1 (IGF-1R). Specifically, the disclosure provides a method for treating a subject having multiple sclerosis, comprising administering to the subject, in need thereof, a therapeutically effective amount of one or more compounds that inhibits IGF-1R. Further disclosed are IGF-1R inhibitor compounds used for the method.

Description

USE OF INHIBITORS OF INSULIN-LIKE GROWTH FACTOR RECEPTOR- 1 FOR MULTIPLE SCLEROSISBACKGROUND OF THE INVENTION

[0001] Multiple Sclerosis is an autoimmune disease of the central nervous system characterized by progressive neurodegeneration and inflammation. Treatment options for multiple sclerosis are partially effective towards reducing relapse; however, therapies are not able to prevent disease progression. An effective treatment for multiple sclerosis is still required.BRIEF SUMMARY OF THE INVENTION

[0002] In certain aspects, the present disclosure provides methods of treating a subject having multiple sclerosis, comprising administering to the subject, in need thereof, a therapeutically effective amount of one or more compounds that inhibits insulin-like growth factor receptor- 1 (IGF-1R).

[0003] In some aspects, the one or more compounds is an antibody, or an antigen binding fragment thereof, or a small molecule or a salt or polymorph thereof. The one or more compounds can be selected from the group consisting of teprotumumab, ganitumab, figitumumab, MEDI-573, cixutumumab, dalotuzumab, robatumumab, AVE1642, BIIB022, xentuzumab, istiratumab, lonigutamab, dalotuzumab, linsitinib, ceritinib, osimertinib, luminespib, brigatinib, picropodophyllin, ginsenoside, IDR-E804, nordihydroguaiaretic acid, BMS-754807, BMS-536924, BMS-554417, GSK1838705A, GSK1904529A, NVP-AEW541, NVP-ADW742, GTx-134, AG1024, KW-2450, PL- 2258, INSM-18, AZD3463, AZD9362, BI885578, BI893923, TT-100, XL-228, VRDN- 001, AG-1024, AZ12253801, TAE 226, AZ7550, PQ401, NBL31772, AG 538, NT157, and A-928605, or a salt or polymorph of any of the foregoing. The one or more compounds can be an antibody, or an antigen binding fragment thereof, e.g., teprotumumab and VRDN-001. The one or more compounds can be a human, chimeric human, or humanized monoclonal antibody, or an antigen binding fragment thereof, suitable for human therapy. The one or more compounds can be a small molecule, e.g., linsitinib.

[0004] In some aspects, the one or more compounds is administered orally, intradermally, subcutaneously (SC), intravenously (IV), or by inhalation.

[0005] In some aspects, the IGF-1R is a human, chimeric human, or humanized monoclonal antibody, or an antigen binding fragment thereof, suitable for human therapy. In some aspects, the human, chimeric human, or humanized monoclonal antibody, or an antigen binding fragment thereof that inhibits IGF-1R is administered one or more times per month. In some aspects, the human, chimeric human, or humanized monoclonal antibody, or an antigen binding fragment thereof that inhibits IGF-1R is administered one, two, three, or four times per month.

[0006] In some aspects, the one or more compounds that inhibit IGF-1R is a small molecule (e.g., linsitinib). In some aspects, the small molecule (e.g., linsitinib) that inhibits IGF-1R is administered one or more times per day. In some aspects, the small molecule (e.g., linsitinib) that inhibits IGF-1R is administered orally four times per day, three times per day, twice per day or once per day.

[0007] It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only, and do not restrict the scope of the claims.BRIEF DESCRIPTION OF THE FIGURES

[0008] FIG. l is a graph showing the percentage of CD4+ cells following immunization of mice with P-Gal (control), thyroid stimulating hormone receptor (TSHR), or TSHR and linsitinib.

[0009] FIG. 2A shows the percentage of Sca-1+ cells following treatment with P-Gal (control), thyroid stimulating hormone receptor (TSHR), or TSHR and linsitinib. FIG. 2B shows the levels of SDF-1 protein following treatment with P-Gal (control), TSHR, or TSHR and linsitinib.

[0010] FIG. 3 A shows the levels of CCL5 protein following treatment with P-Gal (control), TSHR, or TSHR and linsitinib. FIG. 3B shows the levels of osteopontin protein following treatment with P-Gal (control), TSHR, or TSHR and linsitinib. FIG. 3C shows the levels of IL-6 protein following treatment.

[0011] FIG. 4A shows the levels of IL-10 protein following treatment with P-Gal (control), TSHR, or TSHR and linsitinib. FIG. 4B shows the levels of PGE2 protein following treatment P-Gal (control), TSHR, or TSHR and linsitinib.

[0012] FIG. 5A shows the levels of arginase following treatment with P-Gal (control), TSHR, or TSHR and linsitinib. FIG. 5B shows the levels of arginine following treatment.

[0013] FIG. 6 is a series of images showing arginase-l+ cells that were visualized with FITC-anti-arginase-1 staining following immunization of mice with P-Gal (control), TSHR, or TSHR and linsitinib.

[0014] FIG. 7A shows the levels of arginase expression in the presence or absence of linsitinib. FIG. 7B shows the levels of arginine in the presence or absence of linsitinib.

[0015] FIG. 8A shows the levels of IL-10 protein in bone marrow cells in the presence or absence of linsitinib and / or arginine at differing levels. FIG. 8B shows the levels of IL- 10 protein in spleen in the presence or absence of linsitinib and / or arginine at differing levels.

[0016] FIG. 9 shows the levels of PGE2 protein in bone marrow cells in the presence or absence of linsitinib and / or arginine.DETAILED DESCRIPTION OF THE INVENTION

[0017] The headings provided herein are not limitations of the various embodiments of the disclosure, which can be defined by reference to the specification as a whole. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.I. Definitions

[0018] So that the present disclosure can be more readily understood, certain terms are first defined. As used in this application, except as otherwise expressly provided herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout the application.

[0019] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0020] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The terms "a" (or "an"), as well as the terms "one or more," and "at least one" can be used interchangeably herein. In certain aspects, the term "a" or "an" means "single." In other aspects, the term "a" or "an" includes "two or more" or "multiple."

[0021] Furthermore, "and / or" where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term "and / or" as used in a phrase such as "A and / or B" herein is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Likewise, the term "and / or" as used in a phrase such as "A, B, and / or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0022] The term “about” is used herein to mean approximately, roughly, around, or in the regions of. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” can modify a numerical value above and below the stated value by a variance of, e.g., 10 percent, up or down (higher or lower).

[0023] Units, prefixes, and symbols are denoted in their Systeme International de Unites (SI) accepted form.

[0024] Numeric ranges are inclusive of the numbers defining the range. Where a range of values is recited, it is to be understood that each intervening integer value, and each fraction thereof, between the recited upper and lower limits of that range is also specifically disclosed, along with each subrange between such values.

[0025] The upper and lower limits of any range can independently be included in or excluded from the range, and each range where either, neither or both limits are included is also encompassed within the disclosure. Thus, ranges recited herein are understood to be shorthand for all of the values within the range, inclusive of the recited endpoints. For example, a range of 1 to 10 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0026] Any numerical value inherently contains certain errors necessarily resulting from the standard deviation found in their respective measurements. Additionally, all ranges disclosed herein are to be understood to encompass any and all subranges subsumed therein. For example, a stated range "1 to 10" should be considered to include any and allsubranges between (and inclusive of) the minimum value of 1 and the maximum value of 10; that is, all subranges beginning with a minimum value of 1 or more, such as 1 to 6.1, and ending with a maximum value of 10 or less, such as 5.5 to 10.

[0027] Where a value is explicitly recited, it is to be understood that values, which are about the same quantity or amount as the recited value are also within the scope of the disclosure. Where a combination is disclosed, each sub-combination of the elements of that combination is also specifically disclosed and is within the scope of the disclosure. Conversely, where different elements or groups of elements are individually disclosed, combinations thereof are also disclosed. Where any element of a disclosure is disclosed as having a plurality of alternatives, examples of that disclosure in which each alternative is excluded singly or in any combination with the other alternatives are also hereby disclosed; more than one element of a disclosure can have such exclusions, and all combinations of elements having such exclusions are hereby disclosed.

[0028] A “pharmaceutical composition” comprises an IGF-1R inhibitor (e.g., linsitinib), or a pharmaceutically acceptable salt thereof, having a desired degree of purity in a physiologically acceptable carrier, excipient or stabilizer. Pharmaceutically acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed and include without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0029] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refer to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. In one aspect, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press andthe American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004 (incorporated herein by reference).

[0030] The term "pharmaceutically-acceptable salts" refers to the relatively non-toxic, inorganic and organic acid addition salts of an IGF-1R inhibitor (e.g., linsitinib). These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19).

[0031] The pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids. For example, such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.

[0032] The term “subject” refers to an animal, including, but not limited to, a primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject.

[0033] As used herein, the terms "treat," "treated," and "treating" mean both therapeutic treatment and prophylactic or preventative measures wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder, or disease, or obtain beneficial or desired clinical results. Thus, those in need of treatment include those already diagnosed with or suspected of having the disorder. Beneficial or desired clinicalresults include, but are not limited to, alleviation of symptoms; diminishment of the extent of a condition, disorder, or disease; stabilized (i.e., not worsening) state of condition, disorder, or disease; delay in onset or slowing of condition, disorder, or disease progression; amelioration of the condition, disorder, or disease state or remission (whether partial or total), whether detectable or undetectable; an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. The term "administering," as used herein, refers to any mode of transferring, delivering, introducing, or transporting a therapeutic agent to a subject in need of treatment with such an agent. Such modes of administration include, but are not limited to, oral, topical, intravenous, intraperitoneal, intramuscular, intradermal, intranasal, and subcutaneous, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, transtracheal, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrastemal injections and infusions.

[0034] The term “therapeutically effective amount” refer to an amount of an agent (e.g., linsitinib) that provides beneficial or desired therapeutic and / or prophylactic results. For prophylactic use, beneficial or desired results can include, for example, one or more results such as eliminating or reducing the risk, lessening the severity, or delaying the onset of the disease, including biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, beneficial or desired results can include, for example, one or more clinical results such as decreasing one or more symptoms and pathological conditions resulting from or associated with the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing the effect of other medication such as via targeting, delaying the progression of the disease, and / or prolonging survival. An effective amount can be, for example, an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As it is understood in the clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an effective amount may be considered in the contextof administering one or more therapeutic agents. An effective amount can be administered in one dosage or can be divided into multiple dosages, the total of such dosages being the effective amount. For example, an effective amount can be provided in two separate administrations over a period of time, that in aggregate, provide the effective amount of the formulation.

[0035] In the case of multiple sclerosis, the effective amount of the IGF-1R inhibitor (e.g., linsitinib), or pharmaceutically acceptable salt thereof, is the amount clinically proven to treat the symptoms.IL Methods of Treatment

[0036] The present disclosure provides methods of treating a subject having multiple sclerosis comprising administering to the subject, in need thereof, a therapeutically effective amount of one or more compounds that inhibits insulin-like growth factor receptor- 1 (IGF-1R). In some aspects, the rheumatoid arthritis is one resulting from inflammation.

[0037] In some aspects, the one or more compounds that inhibit IGF-1R is an antibody, or an antigen binding fragment thereof, or a small molecule or a salt or polymorph thereof. The one or more compounds that inhibit IGF-1R can be selected from the group consisting of teprotumumab, ganitumab, figitumumab, MEDI-573, cixutumumab, dalotuzumab, robatumumab, AVE1642, BIIB022, xentuzumab, istiratumab, lonigutamab, dalotuzamab, linsitinib, ceritinib, osimertinib, luminespib, brigatinib, picropodophyllin, ginsenoside, IDR-E804, nordihydroguaiaretic acid, BMS-754807, BMS-536924, BMS- 554417, GSK1838705A, GSK1904529A, NVP-AEW541, NVP-ADW742, GTx-134, AG1024, KW-2450, PL-2258, INSM-18, AZD3463, AZD9362, BI885578, BI893923, TT-100, XL-228, VRDN-001, AG-1024, AZ12253801, TAE 226, AZ7550, PQ401, NBI- 31772, AG 538, NT157, and A-928605, or a salt or polymorph of any of the foregoing.

[0038] In some aspects, the one or more compounds that inhibit IGF-1R can be an antibody, or an antigen binding fragment thereof e.g., teprotumumab and VRDN-001). In some aspects, the one or more compounds can be a human, chimeric human, or humanized monoclonal antibody, or an antigen binding fragment thereof, suitable for human therapy. In some aspects, the one or more compounds that inhibit IGF-1R that is an antibody, or an antigen binding fragment thereof, e.g., teprotumumab and VRDN-001 is administered one or more times per month. For example, in some aspects, the one ormore compounds that inhibit IGF-1R that is an antibody, or an antigen binding fragment thereof, e.g., teprotumumab and VRDN-001 is administered once, twice, three times, or four times per month.

[0039] In some aspects, the one or more compounds that inhibit IGF-1R can be a small molecule. In some aspects, the small molecule that inhibits IGF-1R is linsitinib, or a pharmaceutically acceptable salt thereof.

[0040] In some aspects, the one or more compounds that inhibit IGF-1R that is a small molecule (e.g., linsitinib) is administered one or more times per day. For example, in some aspects, the one or more compounds that inhibit IGF-1R that is a small molecule (e.g., linsitinib) is administered four times per day, three times per day, twice per day or once per day.

[0041] In some aspects, the one or more compounds that inhibit IGF-1R (e.g., linsitinib), is administered orally. In some aspects, the one or more compounds that inhibit IGF-1R (e.g., linsitinib, teprotumumab and VRDN-001) is administered intravenously, intraperitoneally, subcutaneously, and / or intramuscular.

[0042] In some aspects, the one or more compounds that inhibit IGFR-1R (e.g., linsitinib, teprotumumab and VRDN-001), is administered with an additional therapy that includes any therapy used to treat multiple sclerosis.

[0043] In some aspects, the methods comprise administering to the subject a therapeutically effect amount of one or more compounds that inhibit IGF-1R (e.g., linsitinib, teprotumumab and VRDN-001). In some aspects, the methods comprise administering to the subject a therapeutically effective amount of a compound that inhibits IGF-1R that is linsitinib, or a pharmaceutically acceptable salt thereof.

[0044] The dosage of the one or more compounds that inhibit the IGF-1R receptor may further vary between patients, based on different factors such as the age, gender, race, and body weight of each patient. In some aspects, the dosage varies by body weight of the patient. The dosage could range from about 1 mg of the antibody, or an antigen binding fragment thereof, per kilogram of body weight to about 100 mg of the antibody, or an antigen binding fragment thereof, per kilogram of body weight. The dosage of a small molecule compound (e.g., linsitinib) can be administered at a dose of from 0.01 to 500 mg / kg per day and / or from 0.1 mg to 5 g per day. The dose range for adult humans of a small molecule compound (e.g., linsitinib) is generally from 5 mg to 2 g per day. Tablets or other forms of presentation provided in discrete units may conveniently contain anamount of the one or more compounds which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, for example around 10 mg to 200 mg.III. Pharmaceutical Compositions

[0045] In some aspects, the one or more compounds that inhibit IGF-1R (e.g., linsitinib, teprotumumab, and VRDN-001) can be formulated as compositions for oral, intravenously, intraperitoneal, subcutaneous, and / or intramuscular administration.

[0046] The compositions intended for oral use (e.g., linsitinib) can be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.

[0047] In some aspects, the one or more compounds that inhibit IGF-1R (e.g., linsitinib, teprotumumab, and VRDN-001) can be formulated by combining the components with, e.g., pharmaceutically acceptable carriers or excipients. In some aspects, the one or more compounds that inhibit IGF-1R (e.g., linsitinib, teprotumumab, and VRDN-001) can be formulated in oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, and the like.

[0048] In some aspects, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with the compound and / or additional therapeutic agent described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.IV. Kits

[0049] In some aspects, the present disclosure relates to a kit comprising a pharmaceutical composition comprising the one or more compounds that inhibit IGF-1R (e.g., linsitinib, teprotumumab, and VRDN-001) packaged in a manner that facilitates its use to practice methods of the present disclosure.

[0050] In some aspects, the kit further comprises instructions for administering the pharmaceutical composition comprising the one or more compounds that inhibit IGF-1R (e.g., linsitinib, teprotumumab, and VRDN-001) to treat multiple sclerosis.

[0051] All of the references cited herein are incorporated herein by reference in their entireties.

[0052] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, aspects, claims, and examples described herein. Such equivalents were considered to be within the scope of this invention and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including but not limited to reaction times, reaction size / volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing / oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.EXAMPLES

[0053] The examples presented below are provided for the purpose of illustration only and the embodiments described herein should in no way be construed as being limited to the examples below. Rather, the embodiments should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.Example 1: Linsitinib inhibited TSHR-induced CD4+ T Cell infiltration in vivo

[0054] Mice were immunized with thyroid stimulating hormone receptor (TSHR), [3-Gal (control), or TSHR+linsitinib. CD4+ T cells were measured, and the results are shown in FIG. 1. An increase in CD4+ cells in the bone marrow of TSHR-immunized mice was observed, indicating activation of bone marrow. Mice immunized with a combination of TSHR and linsitinib had decreased CD4+ cells, almost normalized to levels of -Gal control mice.Example 2: Linsitinib inhibited TSHR-induced autoimmune-mediated stimulating of bone marrow stem cells in vivo

[0055] Mice were immunized with P-Gal (control), thyroid stimulating hormone receptor (TSHR), or TSHR+linsitinib. Stem cell antigen-1 (Sca-1)+ cells were measured, and theresults are shown in FIG. 2A. An increase in Sca-1+ cells in the bone marrow of TSHR- immunized mice was observed, indicating increased hematopoiesis. Mice immunized with a combination of TSHR and linsitinib had decreased Sca-1+ cells down to levels of P-Gal control mice.

[0056] Additionally, levels of stromal cell-derived factor-1 (SDF-1) were measured and the results are shown in FIG. 2B. An increase in SDF-1 in the bone marrow of TSHR- immunized mice was observed, indicating mobilization of bone marrow stem cells and initiation of inflammatory processes. Mice immunized with a combination of TSHR and linsitinib had decreased SDF-1 levels down to levels of P-Gal control mice.Example 3: Linsitinib inhibited TSHR-induced upregulation of pro-inflammatory cytokines in vivo

[0057] Mice were immunized with -Gal (control), thyroid stimulating hormone receptor (TSHR), or TSHR+linsitinib. Levels of CCL5, Osteopontin, and IL-6 were measured, and the results are shown in FIG. 3 A-C, respectively. TSHR increased the amount of CCL5, osteopontin, and IL-6 in the bone marrow of immunized mice, indicating stimulation of pro-inflammatory processes. These increases were reversed in mice immunized with both TSHR and linsitinib, compared to P-Gal control mice.Example 4: Linsitinib inhibited TSHR-induced downregulation of anti-inflammatory cytokines in vivo.

[0058] Mice were immunized with P-Gal (control), thyroid stimulating hormone receptor (TSHR), or TSHR+linsitinib. Levels of IL-10 and PGE2 were measured, and the results are shown in FIG. 4A-B, respectively. TSHR decreased the amount of IL- 10 and PGE2 in the bone marrow of immunized mice, indicating silencing of anti-inflammatory processes. These decreases were reversed in mice immunized with both TSHR and linsitinib, compared to P-Gal control mice.Example 5: Linsitinib inhibits TSHR-induced T cell activation and immune response in vivo via arginase-1 and arginine levels

[0059] Mice were immunized with P-Gal (control), thyroid stimulating hormone receptor (TSHR), or TSHR+linsitinib. Arginase-1 and arginine levels were measured, and the results are shown in FIG. 5A-B, respectively. Arginase- 1 expression in bone marrow wassignificantly decreased in TSHR-immunized mice, with a concomitant increase in arginine concentrations. Mice immunized with both TSHR and linsitinib had normalized levels of arginase-1 and arginine compared to -Gal control mice. T cell proliferation and activation is dependent on arginine levels, thus TSHR-induced increases in arginine stimulate T cell activation and autoimmune response.

[0060] Additionally, arginase-l+ cells were visualized with FITC-anti-arginase-1 staining, and the results are shown in FIG. 6. TSHR-immunized mice showed significantly lower numbers of arginase-l+ cells in the bone marrow. These decreases were reverse in mice immunized with both TSHR and linsitinib, compared to P-Gal control mice.

[0061] To further investigate the effect of linsitinib on arginase- 1, mice were treated for 2.5 days with l.p. injections (10 mg / kg) of linsitinib, twice daily. Control mice were injected with solvent. Levels of arginase- 1 and arginine were measured, and results are shown in FIG. 7A-B, respectively. Linsitinib induced the expression of arginase- 1 in the bone marrow of mice, and concomitantly reduced the levels of arginine.

[0062] These data suggest that linsitinib induces an immunosuppressive effect via arginine levels.Example 6: Linsitinib induces an increase in IL-10 in vitro and in vivo

[0063] Bone marrow cells were treated with linsitinib and arginine in varying concentrations. IL-10 protein levels were measured, and the results are shown in FIG. 8A. Cells treated without linsitinib and supplemented with arginine showed low levels of IL- 10 protein. Cells treated with linsitinib had significantly elevated levels of IL- 10 protein, compared to untreated control, and treatment with arginine reduced these effects.

[0064] In mice treated with varying concentrations of linsitinib and arginine, IL-10 levels in the spleen were measured. Results are shown in FIG. 8B. In mice treated with linsitinib, there was a significant increase in IL-10 levels compared to untreated control, and supplementation with arginine reversed these increases.

[0065] Together, these data indicated that linsitinib induced expression of antiinflammatory cytokine IL- 10 in bone marrow and in mouse spleen, which was inhibited by supplementation with arginine, a mimic for arginase- 1 activity.Example 7: Linsitinib induces an increase in PGE2 in vitro

[0066] Bone marrow cells were treated with linsitinib and arginine in varying concentrations. PGE2 protein levels were measured, and the results are shown in FIG. 9A. Cells treated without linsitinib and supplemented with arginine showed low levels of PGE2 protein. Cells treated with linsitinib had significantly elevated levels of PGE2 protein, compared to untreated control, and treatment with arginine reduced these effects.Example 8

[0067] A patient having multiple sclerosis will be administered a therapeutically effective amount of a compound that inhibits IGF-1R (e.g., linsitinib). The patient’s response will be monitored and the amount of the compound that inhibits IGF-1R (e.g., linsitinib) will be adjusted as necessary.

Claims

WHAT IS CLAIMED IS:

1. A method of treating a subject having multiple sclerosis, comprising administering to the subject, in need thereof, a therapeutically effective amount of one or more compounds that inhibits insulin-like growth factor receptor-1 (IGF-1R).

2. The method of claim 1, wherein the one or more compounds is an antibody, or an antigen binding fragment thereof, or a small molecule or a salt or polymorph thereof.

3. The method of claim 2, wherein the one or more compounds is selected from the group consisting of teprotumumab, ganitumab, figitumumab, MEDL573, cixutumumab, dalotuzumab, robatumumab, AVE1642, BIIB022, xentuzumab, istiratumab, lonigutamab, dalotuzumab, linsitinib, ceritinib, osimertinib, luminespib, brigatinib, picropodophyllin, ginsenoside, IDR-E804, nordihydroguaiaretic acid, BMS-754807, B MS-536924, BMS- 554417, GSK1838705A, GSK1904529A, NVP-AEW541, NVP-ADW742, GTx-134, AG1024, KW-2450, PL-2258, INSM-18, AZD3463, AZD9362, BI885578, BI893923, TT-100, XL-228, VRDN-001, AG-1024, AZ12253801, TAE 226, AZ7550, PQ401, NBI- 31772, AG 538, NT157, and A-928605, or a salt or polymorph of any of the foregoing.

4. The method of claim 3, wherein the one or more compounds is an antibody, or an antigen binding fragment thereof.

5. The method of claim 4, wherein the one or more compounds is a human, chimeric human, or humanized monoclonal antibody, or an antigen binding fragment thereof, suitable for human therapy.

6. The method of claim 3, wherein the one or more compounds is a small molecule.

7. The method of any one of claims 1-6, wherein the one or more compounds is administered orally, intradermally, subcutaneously (SC), intravenously (IV), or by inhalation.

8. The method of any one of claims 1-7, wherein the one or more compounds that inhibit IGF-1R is administered one or more times per month.

9. The method of any one of claims 1-7, wherein the one or more compounds that inhibit IGF-1R is administered orally four times per day, three times per day, twice per day or once per day.

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