JP2002526417A - How to treat non-thyroid disease - Google Patents

Abstract

  (57) [Summary] Disclosed are methods of treating an IGF responsive, IGFBP-3 responsive, or IGF dependent non-thyroid disease. Administering a thyroid agonist and IGF to a patient suffering from an IGF-responsive non-thyroid disease to reduce the symptoms of the disease. Administering a thyroid antagonist and IGFBP-3 to a patient suffering from an IGFBP-3 responsive non-thyroid disease to reduce the symptoms of the disease. A thyroid antagonist is administered to a patient suffering from an IGF-dependent non-thyroid disease, thereby reducing the symptoms of the disease.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] TECHNICAL FIELD The present invention is broadly related to the medical field, more specifically, insulin-like growth factor (
IGF) and / or insulin-like growth factor binding protein (IGFBP).

Background The thyroid hormones triiodothyronine (T3) and tetraiodothyronine (T4) are major metabolic regulators in mammals. T4 is less active than T3 and can be converted to T3 in peripheral tissues. Administration of T4 or T3 increases metabolism, erythropoiesis, bone turnover, and muscle relaxation rates. Thyroid hormones increase the rate of protein synthesis, whereas hyperthyroidism is associated with weight loss and muscle wasting. Hypothyroidism can be accompanied by lethargy, hypopulmonary function (hypopnea), low cardiac output, and low renal output. Thyroid hormones also interact with other endocrine hormones, including growth hormones and steroid hormones.

[0003] T4 and T3 are synthesized from thyroglobulin, a protein whose tyrosine residues have been iodinated. The two iodinated tyrosine condenses to form a T4 or T3 molecule. Thyroglobulin, which is extracellularly stored in the follicular lumen of the thyroid gland, serves as a storage molecule for iodinated tyrosine residues. Iodinated tyrosine residues are released from thyroglobulin by intracellular proteolysis in thyroid cells. IGF-I has been shown to increase thyroglobulin transcription in FRTL-5 cells (rat thyroid) (Kamikubo et al., (1990) Mol. Endocrinol., 4: 2021-20.
29). However, the effect of increasing thyroglobulin mRNA levels on T4 and T3 levels is not known.

[0004] IGF-I and IGF-II are growth factors with closely related amino acid sequences and structures, and each polypeptide has a molecular weight of about 7.5 kilodaltons (Kd). IGF-I mediates the main effects of growth hormone and is therefore a major mediator of postnatal growth. IGF-I is also closely related to the actions of various other growth factors.
Treatment of cells with such growth factors increases IGF-I production. In contrast, IGF-II is thought to play a major role primarily in fetal growth. IGF-I and IGF-II both have insulin-like activity (hence the name), and also act on cells of nerve, muscle, reproductive, bone and other tissues. Mitogenic (stimulating cell division) and / or trophic (promoting recovery / survival). IGF-I also induces DNA synthesis in FRTL-5 cells, a diploid non-transformed line of rat thyroid follicle cells, and its activity has been shown to be enhanced by thyroid stimulating hormone (TSH). (Yam
amoto et al., 1996, Endocrinology 137 (5): 2036-2042). In addition, some tumors have been shown to be insulin-dependent in their continuous growth.

[0005] Unlike most growth factors, IGFs are present in significant amounts in the circulatory system,
Very little IGF is free in the circulation or other body fluids. Most circulating IGFs bind to the IGF binding protein IGFBP-3. IGF-I in serum
By measuring the abnormal growth-related diseases, such as pituitary gigantism,
Acromegaly, dwarfism, various growth hormone deficiencies and the like can be diagnosed. IG
Although FI is produced in many tissues, most circulating IGF-I is thought to be synthesized in the liver.

[0006] IGFs are characterized by at least three different cellular receptors: type 1 IGF receptor, type 2
It is known to bind to the IGF receptor and to the insulin receptor (IGF binds with much lower affinity than type 1 and type 2 receptors). Mutants of IGF-I that have altered binding to one or more of these cell receptors are described. Mutation of residue 24 (usually tyrosine) to a non-aromatic residue, or residues 28-37
Substitutions selectively affect binding to the type 1 receptor, while mutations at residues 49-51 selectively reduce binding to the type 2 receptor. Mutation at residue 60 (mutation of tyrosine to a non-aromatic residue) can alter binding to the type 1 and type 2 IGF receptors as well as to the insulin receptor (Cascieri et al. (1988)). Biochemistry 27:
3229-3233; Cascieri et al. (1989) J Biol. Chem. 264: 2199-2202; Bayne et al. (1988) J
Biol. Chem. 264: 11004-11008; Bayne et al. (1990) J. Biol. Chem. 265: 15648-15652).

[0007] Almost all IGFs are non-covalently associated, composed of IGF-I or IGF-II, IGFBP-3, and a relatively large protein subunit called the acid labile subunit (ALS). Circulates as a ternary complex. The IGF / IGFBP-3 / ALS ternary complex is composed of equimolar amounts of each of the three components. ALS is a direct I
It has no GF binding activity and appears to bind only to the IGF / IGFBP-3 binary complex. The ternary complex of IGF + IGFBP-3 + ALS has a molecular weight of about 150 Kd. This ternary complex is believed to act in the circulation `` as a reservoir and buffer for IGF-I and I to prevent rapid changes in free IGF concentration '' (Blum et al., Pp. 38
1-393, MODERN CONCEPTS IN INSULIN-LIKE GROWTH FACTORS (EM Spencer, Els
evier, New York, 1991).

[0008] Some mutant IGF-Is exhibit altered binding to IGFBP-3 and / or altered ability to form ternary complexes. For example, mutations at residues 3, 4, 8, 9, 12, 15, 16, and 24 (B domain variants) and mutations at residues 49-51 reduce the formation of binary complexes, while Mutations involving residues 55 and 56, and either IGF-I (1-62 IGF-I) in which residues 63-70 have been deleted or residues 28-37 have been replaced with a Gly4 linker. IGF-
I (1-27-Gly4-38-70 IGF-I) or IGF-I (1-27-Gly4-38-62
IGF-I), and variants thereof (eg, 1-62 IGF-I wherein residue 24 is further altered)
) Actually increased the binding to IGFBP-3. Some of these variants (especially residue 2
1-62 IGF-I, which has a mutation in 4, had a reduced ability to form a ternary complex, even though the formation of a binary complex increased (Baxter et al. (1992) J. Biol. Chem. . 267: 60-
65).

[0009] Since almost all IGF-I, I and IGFBP-3 present in the circulatory system are in the form of a complex, free IGF is hardly detectable. Furthermore, the presence of high concentrations of free IGF in the blood is not preferred. High blood levels of free IGF can cause severe hypoglycemia due to the insulin-like activity of IGF. In contrast to IGF and IGFBP-3, there is a significant pool of free ALS in plasma, which is
Ensure that the P-3 complex immediately forms a ternary complex.

[0010] While IGFBP-3 is the most abundant IGF binding protein in the circulatory system, at least five other different IGF binding proteins (IGFBPs) have been identified in various tissues and body fluids. These proteins bind to IGF but are derived from different genes and have unique amino acid sequences. Thus, a binding protein is not merely an analog or derivative of a common precursor. Unlike IGFBP-3, other IGFBPs in the circulation are not saturated with IGF. In addition, any IGFBP other than IGFBP-3
0 Kd ternary complex cannot be formed.

IGF-I and IGFBP-3 can be purified from natural sources or obtained by recombinant means. For example, purification of IGF-I from human serum is known in the art (Rinderknecht et al., (1976) Proc. Natl. Acad. Sci. USA 73: 2365-2369). The production of IGF-I by recombinant methods is disclosed in EP 0 128 733, published December 1984. IGFBP-3 is described in Baxter et al. (1986, Biochem.Biophys.Res.Comm. 139: 1256-1).
261) can be used to purify from natural sources.
Or MODERN CONCEPTS OF INSULIN-LIKE GROWTH FACTORS by Sommer et al., Pp. 71
IGFBP-3 may be synthesized recombinantly as described in 5-728 (Edited by EMSpencer, Elsevier, New York, 1991). Recombinant IGFBP-3 binds IGF-I in a 1: 1 molar ratio.

The local administration of the IGF-I / IGFBP-3 complex to wounds of rats and pigs was significantly more effective than the administration of IGF-I alone (ibid). Subcutaneous administration of the IGF-I / IGFBP-3 complex to hypophysectomized, ovariectomized, and normal rats and intravenous administration to cynomolgus monkeys resulted in "hypoglycemic effects of IGF-I administered alone. Is substantially prevented ”(supra).

IGF has been proposed as a treatment for a variety of indications. US Patent 5,434,134
Nos. 5,128,320, 4,988,675, 5,106,832, 5,534,493, 5,202,119 and 5,273,961 include cardiomyopathy and myocardial infarction, steroid-induced catabolism, II
The use of IGFs to treat type (insulin resistant) diabetes, renal disorders, pancreatic disorders, enhance humoral immune responses, and prevent acute renal failure is described, respectively. In addition, European Patent Nos.EP434625, EP436469, and EP560723,
International patent applications WO93 / 23071, WO91 / 12018, WO92 / 00754, WO93 / 02695, and WO93 / 08826 also include bone disease, type I (juvenile or insulin responsive) diabetes and gastrointestinal disorders. The use of IGF for the treatment of is described.

[0014] The use of IGF complexed with IGFBP-3 for the treatment of various diseases is also described. U.S. Pat.Nos. 5,200,509, 5,681,818, 5,187,151, 5,407,9
Nos. 13 and 5,527,776 describe IGF / IGFBP-3 for the treatment of osteoporosis, for the induction of anabolic states when given by subcutaneous bolus injection, for improving tissue repair when given systemically, and for the treatment of anemia. The use of the conjugate is described. International Patent Applications WO95 / 03817, WO95 / 08567, WO95 / 13823, WO95 / 13824 and WO96 / 02565
No. includes treatments for reproductive, immune, nervous, renal, and skeletal disorders.
The use of an IGF / IGFBP-3 complex is described.

[0015] In addition to such activity in other organ systems, IGF has trophic effects on peripheral and central nervous system cells. The trophic effects of IGF on neurons include promoting neurite outgrowth in motor neurons, as well as promoting the survival of various neuronal cell types. U.S. Patent Nos. 5,093,317, 5,420,112, 5,
068,224, and International Patent Application Nos.WO93 / 02695, WO93 / 08826 and WO95 / 13823
The article describes the use of IGF or IGF complexed with IGFBP-3 for the treatment of nervous system diseases and utilizing the trophic activity of IGF on neural tissue cells.

Other diseases include those that would benefit from reduced IGF levels. For example, the survival of some cancer cells is dependent on IGF (Resnicof
f et al., (1994) Cancer Res. 54: 2218-2222). Because IGF-dependent tumor cells undergo apoptosis, a decrease in circulating IGF levels can lead to tumor progression.
In autoimmune diseases, IGF is known to have a stimulatory effect on the immune system,
Decreased levels of GF will reduce the symptoms of autoimmune disease.

In addition to its role as a major carrier protein for IGF in serum, IGFBP-3 has recently been shown to have a number of different activities. If IGFBP-3 can inhibit the activity of exogenously added IGF-I, it may be associated with an unidentified molecule on the cell surface (Karas et al., 1997, J. Biol. Chem. .272 (26): 16514-1
6520). The binding of IGFBP-3 to the cell surface can be inhibited by heparin, but unidentified cell surface binding as the enzymatic removal of heparin glycosaminoglycans does not affect cell surface binding of IGFBP-3 The molecule may not be a heparin-like cell surface glycosaminoglycan (Yang et al., 1996, Endocrinology 137 (10): 4363-
4371). Cell surface binding molecules are described by Leal et al. (1997, J. Bio. Chem. 272 (33): 20572-205.
It is not clear whether they are identical or different from the IGFBP-3 receptor identified by 76). This IGFBP-3 receptor is identical to the type V transforming growth factor-β (TGF-β) receptor.

[0018] It was also found that IGFBP-3 promotes apoptosis. Interestingly, I
GFBP-3 has been shown to promote apoptosis in cells with and without functional type I IGF receptor (Nickerson et al., 1997, Biochem. Biophys. Res.
Comm. 237 (3): 690-693; Rajah et al., 1997, J. Biol. Chem. 272 (18): 12181-1218.
8). However, whether apoptosis is induced by full-length IGFBP-3,
Alternatively, it has been reported that it is induced by a proteolytic fragment of IGFBP-3 (Rajah et al., Ibid; Zadeh et al., 1997, Endocrinolog
y 138 (7): 3069-3072).

As with most protein-based therapies, IGF, IGFBP, and especially IGF / IGFB
P-complexes are expensive to manufacture. In addition, as with all drugs, high doses of IGF cause serious adverse effects. Thus, IGF, IGFBP, and
There is a need to enhance the effects of the IGF / IGFBP complex.

Since certain diseases are caused by or associated with excess IGF, there is a need for a compound capable of inhibiting or reducing IGF activity or a compound capable of enhancing the action of an IGF inhibitory compound Also exist in the industry.

[0021] Disclosure of the Invention The present invention by administering the compound and IGF acting on thyroid hormone system (axis), provides a method for the action of insulin-like growth factor for the non-thyroid cells (IGF) modulate I do. IGF and IGFBP, alone or in combination, can stimulate proliferation of various cell types, act as anti-apoptotic agents, or stimulate specific tissues, such as the immune and renal systems. is there. Administration of compounds that modulate the thyroid hormone system allows for exogenous and endogenous
The effect of IGF and / or IGFBP is modulated.

In certain embodiments, the present invention relates to thyroid agonists, and IGF or IGF.
Provided is a method for treating an IGF-responsive non-thyroid disease by administering GF / IGFBP. A thyroid agonist is administered with IGF to reduce or reduce the symptoms of an IGF-responsive non-thyroid disease. Alternatively, the thyroid agonist is administered with an IGF / IGFBP complex. Administration of a thyroid agonist with IGF or an IGF / IGFBP-3 complex enhances the action of IGF, thereby reducing the symptoms of an IGF-responsive non-thyroid disease.

In another embodiment, the invention provides a method of treating a non-thyroid disease responsive to IGFBP-3. IGFBP-3 and a thyroid antagonist are administered to a patient suffering from an IGFBP-3 responsive disease. When a thyroid antagonist is administered with IGFBP-3, IGFBP-3
Has enhanced antimitogenic and pro-apoptotic activity, thereby reducing the symptoms of IGFBP-3 responsive non-thyroid disease. As in the method of this embodiment, IGFBP-3 may be administered as a complex of IGFBP-3 and mutant IGF-I.

In a further embodiment, the invention provides a method of treating an IGF-dependent non-thyroid disease. A thyroid antagonist is administered to a patient suffering from an IGF-dependent non-thyroid disease. Administration of a thyroid antagonist reduces the symptoms of an IGF-dependent non-thyroid disease.

BEST MODE FOR CARRYING OUT THE INVENTION [0025] Provided herein is an improved method for treating an IGF or IGFBP-3 responsive non-thyroid disease. The symptoms of an IGF-responsive disease are alleviated by administering a thyroid agonist and IGF or an IGF / IGFBP-3 complex. The symptoms of the disease associated with excess IGF are reduced by administering a thyroid antagonist. Further, the symptoms of an IGFBP-responsive disease are alleviated by administering IGFBP and a thyroid antagonist.

Definitions As used herein, "IGF" means insulin-like growth factor from any species. IGFs include IGF-I and IGF-II which have native sequence or variant forms, including but not limited to natural allelic variants. IGFs can be from any source, natural, synthetic or recombinant.

[0027] As used herein, "IGF-I" refers to any native sequence or any variant, including, but not limited to, naturally occurring allelic variants, including bovine, ovine, porcine, and human Insulin-like growth factor I from species. IGF-I can be
It can be from any source, natural, synthetic or recombinant, as long as it binds to BP-3 and binds to and stimulates the type I IGF receptor. As used herein, mature IGF-I of the human native sequence is preferred, and those that do not include an amino-terminal methionine are preferred. More preferably, the mature IGF-I of the native sequence is produced recombinantly, for example as described in PCT publication WO 95/04076.

As used herein, the term “mutant IGF-I” refers to an IGF-I having an altered amino acid sequence at one or more sites in a molecule. Mutant IGF-I retains its ability to bind to IGFBP-3, but has altered other properties, such as binding to type I or type II IGF receptor, or binding to insulin receptor. Could be. A description of mutant IGF-I can be found in Cascieri et al., (1988) Biochemistry 27: 3229-32.
33; (1989) J. Biol. Chem. 264: 2199-2202, Bayne et al., (1990) J. Biol. Chem.
265: 15648-15652, and Baxter et al. (1992) J. Biol. Chem. 267: 60-65. As an example of a mutant IGF-I, one or more IGF-I tyrosine residues (ie, residues 24, 31, or 60) have been replaced by non-aromatic residues (ie, other than tyrosine, phenylalanine, tryptophan). Mutants and changes in amino acid residues 49, 50, 51, 53, 55, and 56 (e.g., residues 49-50 change to Thr-Ser-Ile or residues 55-56 change to Tyr-Gln ), And combinations thereof.

As used herein, “IGF-II” refers to a native sequence or a variant, including but not limited to a natural allelic variant, from any species, including bovine, ovine, porcine, and human Of insulin-like growth factor II. IGF-II, at an appropriate site, IGFBP-
As long as it binds to 3, it may be from any source, natural, synthetic or recombinant. In the present specification, mature IGF-II of a human native sequence is preferable, and one not containing an amino-terminal methionine is preferable. More preferably, mature IGF-I of the native sequence is produced recombinantly, for example, as described in PCT publication WO 95/04076.

As used herein, “IGFBP-3” refers to insulin-like growth factor binding protein 3
Say IGFBP-3 is a member of the insulin-like growth factor binding protein family. IGFBP-3 is a variant of bovine, ovine, porcine, and human, including but not limited to native sequence or naturally occurring allelic variants (eg, Ala ₅ and Gly ₅ which are variants of native human IGFBP-3). And any other species. Specific examples of preferred IGFBP-3 include native sequence human IGFBP-3 and normal NGF.
A human IGFBP-3 variant (eg, N89) in which one or more asparagine residues forming the binding glycosylation site (positions 89, 109 and 172) have been changed to aspartic acid
D; N109D; N172D; N89D, N109D; N89D, N172D;
N109D, N172D; and N89D, N109D, N172D variants), or human IGFBP-3 variants that have been changed to other amino acid residues (eg, N89X; N10
9X; N172X; N89X, N109X; N89X, N172X; N109X
, N172X; and N89X, N109X, N172X variants), and variants that have been modified to increase resistance to degradation, such as mutations at positions 116 and 135 (eg, D116E, D135E and D116E, D135E), or And mutations affecting the nuclear localization signal (NLS) of IGFBP-3 located at residues 215-232 (Radulescu, 1994, Trends Biochem Sci. 19 (7): 278). preferable
Examples of NLS mutant IGFBP-3 include K228E, R230G, K228E, R23
0G, K228X, R230X and K228X, R230X, and residue 215
, 216 and 231. Of course, a mutant of IGFBP-3 may contain two or more mutations (for example, mutant IGFBP-3 may be both an ND mutant and a degradation-resistant mutant). IGFBP-3 can form a binary complex with IGF and a ternary complex with IGF and acid labile subunit (ALS). IGFBP-3 may be from any source, natural, synthetic or recombinant, as long as it binds to IGF-I and ALS at the appropriate sites. In addition, IGFBP-3 is preferably obtained recombinantly as described in PCT application WO95 / 04076.

As used herein, the term “IGF-responsive non-thyroid disease” refers to any disease that is not thyroid disease that can be treated with IGF. IGF has a variety of effects, including but not limited to anabolic effects on the musculoskeletal system, anti-apoptotic effects on neurons, mitogenic and stimulatory effects on immune system cells, and stimulatory effects on kidney cells, Nutritional and mitogenic effects are included. Thus, IGF-responsive non-thyroid diseases are diseases other than thyroid disease that benefit from IGF activity, such as amyotrophic lateral sclerosis, Charcot-Marie-Tooth syndrome, diabetic neuropathy, and drug induction Nervous system diseases such as systemic neuropathy (eg, peripheral neuropathy induced by chemotherapeutic agents such as vincristine and cisplatin), and lung diseases such as chronic obstructive pulmonary disease, as well as glomerulonephritis, glomerulosclerosis, and interstitium Renal diseases such as inflammatory nephritis, acute tubular necrosis, diabetic nephropathy, autoimmune nephropathy, acute and chronic renal failure, as well as growth hormone deficiency, hypopituitarism, growth hormone resistance, and Laron dwarf Recovery from physical injuries, such as trauma, bruises, fractures, or surgery, as well as short bowel syndrome and pancreas Diseases such as gastrointestinal disorders, acquired immunodeficiency syndrome (AIDS), cancer cachexia, or steroid-induced catabolism (eg, asthma, autoimmune diseases, inflammatory bowel disease, immunosuppression for organ transplantation, and Catabolic reversal in patients suffering from long-term steroid treatment for diseases such as rheumatoid disease, and bone diseases such as osteoporosis, osteopetrosis, osteogenesis imperfecta, and Paget's disease, and also low gonadotropinic function Reproductive disorders, such as insufficiency, male infertility, inadequate gamete maturation, and polycystic ovarian disease, as well as anemia, plasma cell dysplasia, erythropoietin refractory disease,
And hematopoietic disorders such as deficient total hemoglobin and glucose homeostasis, including type I diabetes (IDDM), type II diabetes (NIDDM), and insulin resistant diabetes.

As used herein, the term “IGFBP-3 responsive non-thyroid disease” refers to any disease that is not thyroid disease, the symptoms of which are alleviated by treatment with IGFBP-3.
IGFBP-3 has another receptor other than the type I and type II IGF receptors, indicating that IGFBP-3 can bind to the cell surface and inhibit the action of exogenous IGF. In addition, IGFBP-3 has been shown to induce apoptosis in several cancer cell lines. Thus, an IGFBP-3 responsive disease is any disease that would benefit from the effects of IGFBP-3 administered in the absence of IGF. IGFBP-responsive diseases include, but are not limited to, cancer (including but not limited to prostate, breast, colon and lung cancer), acromegaly,
Examples include diabetic retinopathy, keloid scars, malignant exophthalmos, and other diseases known in the art.

“IGF-dependent non-thyroid disease” is a disease associated with excessive levels of IGF. IG
F is a mitogen for many cell types and also has trophic (ie, anti-apoptotic) activity. Thus, an IGF-dependent disease that is not a thyroid disease is a proliferative disease in which IGF stimulates or perpetuates the disease (eg, by preventing apoptosis in the cells causing the disease). Such diseases include cancer (including, but not limited to, prostate, breast, colon and lung cancer), proliferative diabetic retinopathy, and the like.

“Thyroid agonists” are compounds that act to increase thyroid hormone activity in a patient. The thyroid agonist can be a thyroid stimulant or a thyroid receptor agonist. The thyroid receptor agonist may be in the free acid or free base form, or may be a pharmaceutically acceptable salt of the free acid or free base. Thyroid stimulants include thyroid indirect stimulators such as thyroid stimulating hormone releasing hormone (TRH), TRH analogs, and iodinated compounds such as iodinated casein, or direct thyroid stimulators such as thyroid Stimulating hormone (TS
H) and analogs thereof. Thyroid receptor agonists include thyroid receptors such as 3,3'-5 ', 5'-L-thyroxine (T4), 3,3'-5-L-thyronine (T3), and mixtures thereof (eg, Thyroid Extract , USP or Liotrix, 4: 1 mixture of T4: T3)
Alternatively, a compound that mimics the activity of thyroid hormone or a compound that stimulates the thyroid receptor signaling pathway by interacting with the thyroid receptor or downstream signaling pathway elements.

The term “thyroid antagonist” refers to a compound that acts to reduce thyroid hormone activity in a patient. Thyroid antagonists include 6-n-propyl-2-thiouracil (propylthiouracil or PTU), methimazole, carbimazole, and reducing thyroid stimulating hormone, thyroid hormone, or thyroid receptor signaling in the art. Includes other compounds that are known.

The term “TRH analog” refers to a compound that has activity to stimulate release of thyroid hormone from the thyroid. TRH analogs generally have all or part of the structural features of the peptide L-pyroglutamyl-L-histidyl-L-prolinamide. TRH analogs for use in the methods of the present invention include those disclosed in U.S. Patent No. 4,426,378.
H analogs such as MK771 (pyro-2-aminoadipyl-histidyl-thiazolidine-4-carboxamide), histidyl-proline diketopiperazine, L-2-ketopiperidine-
6-carbonyl-L-histidyl-L-thiazolidine-4-carbonyl-B-alanineamide,
Tetrapeptide amide L-pyroglutamyl-L-histidyl-L-prolyl-B-alaninamide, L-2-oxo-oxazolidine-4-carboxylic acid, L-2-oxo-oxazolidine-4-carbonyl-L-histidyl- L-prolinamide, L-trans-5-methyl-2-oxo-oxazolidine-4-carbonyl-L-histidyl-L-prolinamide, L-2-oxothiazolidine-4-carbonyl-L-histidyl- L-prolinamide, 3-oxo-5-carboxyperhydro-1,4-thiazine-histidine-proline-NH ₂ , 3-oxo-5-carboxyperhydro-1,4-thiazine-histidine-pipecolic acid-N
H ₂ , 3-oxo-5-carboxyperhydro-1,4-thiazine-histidine-proline-NHC
H ₂ CH ₂ CH ₂ CH ₃ , 3-oxo-5-carboxyperhydro-1,4-thiazine-histidine-proline-NHCH ₂ CH ₂ C ₆ H ₅ , γ-carboxy-γ-butyrolactone-histidine-proline
-NHCH ₂ CH ₂ C ₆ H ₅ , γ-carboxy-γ-butyrolactone-histidine-proline-NH ₂ ,
γ-carboxy-γ-butyrolactone-histidine-pipecolic acid-NH ₂ , γ-carboxy-γ-butyrolactone-histidine-proline-NH-CH ₃ , γ-carboxy-γ-butyrolactone-histidine-proline-NHCH ₂ CH ₂ CH ₂ CH ₃ , γ-carboxy-γ-butyrolactone-histidine-proline-NHCH ₂ CH ₂ C ₆ H ₅ , and pharmaceutically acceptable salts thereof.

[0037] The methods disclosed herein are provided for the treatment of an IGF-responsive non-thyroid disease. According to the method of the present invention, IGF, preferably IGF-I, and a thyroid agonist are administered to a patient suffering from an IGF-responsive non-thyroid disease, thereby reducing the symptoms of the disease. In a particularly preferred embodiment, IGF-I is administered as a complex with IGFBP-3.

Further, a method for treating an IGFBP-3 responsive non-thyroid disease is disclosed. According to those methods, IGFBP-3 and a thyroid antagonist are administered to the patient, thereby reducing the symptoms of the disease. In a preferred embodiment, IGFBP-3 is administered as a complex with a mutant IGF.

[0039] Also disclosed herein are methods of treating non-thyroid disorders associated with excess IGF. According to the methods of the present invention, a thyroid antagonist is administered to a patient suffering from a non-thyroid disease associated with excess IGF, thereby reducing the symptoms of the disease.

In methods involving the administration of IGF, IGF-I is preferred, and more preferably IGF-I of the same species (ie, IGF-I from the same species as the patient to whom IGF-I is to be administered). IGF-I
Is a complex of IGF-I and IGFBP-3, more preferably the same species of IGF-I and IGFBP-3. When administering IGF-I / IGFBP-3, the complex is preferably 1: 3-3: 1 on a molar basis, more preferably 1.5: 1 to 1: 1.5, and 1: 1. Is most preferred. Preferably, IGF-I and IGFBP-
Complexation of 3 can be readily accomplished by methods well known in the art. Preferably, the complex is formed by mixing approximately equimolar amounts of IGF-I and IGFBP-3 dissolved in a physiologically compatible carrier. Physiologically compatible carriers include, for example, normal saline or phosphate buffered saline. More preferably, the concentrated solution of rhIGF-I and the concentrated solution of rhIGFBP-3 are mixed for a sufficient time to form an equimolar complex. Most preferably, the international patent application WO 96
As described in / 40736, rhIGF-I and rhIGFBP-3 are mixed during purification to form a complex.

In methods involving the administration of IGFBP-3, the IGFBP-3 is preferably of the same species. More preferably, IGFBP-3 is administered as a complex with mutant IGF-I. Also, the mutant IGF-I is preferably of the same species (ie, the main chain of IGF-I excluding the amino acid in which the mutation is present is the same as that of the wild-type IGF-I from the same species as the patient And the amino acid sequence are the same). When administering a complex of mutant IGF-I and IGFBP-3, the complex is preferably 1: 3-3: 1 on a molar basis,
It is more preferably from 1.5: 1 to 1: 1.5, most preferably 1: 1. Preferably, the mutant IGF-I and IGFBP-3 are complexed prior to administration, which can be readily accomplished by methods well known in the art. Preferably, the complex comprises approximately equimolar amounts of mutant IGF-I and IGFBP dissolved in a physiologically compatible carrier.
And -3. Physiologically compatible carriers include, for example, normal saline or phosphate buffered saline. More preferably, the concentrate of mutant rhIGF-I and the concentrate of rhIGFBP-3 are mixed for a sufficient time to form an equimolar complex. Most preferably, mutant rhIGF-I and rhIGFBP-3
Are mixed during purification to form a complex.

In a method involving administration of IGF, IGFBP-3, IGF-I / IGFBP-3 complex, or mutant IGF-I / IGFBP-3 complex, IGF, IGFBP-3, IGF-I / The IGFBP-3 complex or the mutant IGF-I / IGFBP-3 complex is preferably administered by a parenteral route. Parenteral routes include, but are not limited to, intravenous (IV), intramuscular (IM), subcutaneous (SC), intraperitoneal (IP), intranasal, and inhalant routes. IV, IM, SC, and IP administration is by bolus or infusion, and in the case of SC by a delayed release implanted device, including but not limited to pumps, delayed release formulations, and mechanical devices Is also performed.

For parenteral administration, IGF, IGFBP-3, an IGF-I / IGFBP-3 complex, or a mutant IGF-I / IGFBP-3 complex may be a semi-solid such as a solution, a suspension, etc. It can be a formulation or a liquid formulation. IGF, IGFBP-3, IGF-I / IGFBP-3 complex, or mutant IGF-I
The / IGFBP-3 complex is formulated for administration as a liquid formulation comprising additional components such as physiologically compatible carriers and / or pharmaceutically acceptable excipients known in the art. Is preferred. Acceptable additional components include salts, buffers, antibacterial agents, buffers, bulking agents, osmolyte, antioxidants, detergents, surfactants, and the like. Preferably, the IGF, IGFBP-3, IGF-I / IGFBP-3 complex, or mutant IGF-I / IGFBP-3 complex for parenteral administration is prepared according to U.S. Patent Application Serial No. 09/08.
IGF, IGFBP-3, IGF-I / IGFBP-3 complex, or mutant IGF-I in an isotonic solution of mannitol and sucrose (3: 2 molar ratio) as disclosed in US Pat. / IGFBP-
3 complex.

For methods requiring administration of a thyroid agonist, the dose of the thyroid agonist must usually be adapted to each patient, as is well known in the art. Inducing overt hyperthyroidism is usually not required and should be avoided for some indications. For example, if the symptoms of hyperthyroidism do not disrupt or reduce the therapeutic effect, induction of hyperthyroidism may be acceptable (eg, in the treatment of renal indications). Conversely, as those skilled in the art will appreciate, if the symptoms of hyperthyroidism disrupt or reduce the therapeutic effect,
In general, induction of hyperthyroidism should be avoided (eg, in the treatment of catabolic disease). It is well known in the art that treatment of a patient is usually started at a low to moderate dose and hyperthyroidism occurs, but patients with a history of catabolic disease generally start at a lower dose. is there. Hyperthyroidism can be identified by its well-known symptoms, including nervousness, affective disorders, insomnia, tremors, excessive sweating, heat intolerance, weight loss, decreased endurance. If symptoms of hyperthyroidism appear and induction of hyperthyroidism is to be avoided, the dose of thyroid agonists must be reduced and the patient should be monitored more continuously for symptoms of hyperthyroidism It is. If the symptoms of hyperthyroidism do not resolve, the dose of the thyroid agonist must be further reduced until the symptoms of hyperthyroidism resolve.

[0045] Thyroid agonists can be used in various formulations including parenteral and oral dosage forms. Oral formulations are preferred, but parenteral formulations may be acceptable, which may be rather convenient for wearing on hospital patients. As is known in the art, the dose of a thyroid agonist must also be adjusted according to what thyroid agonist is administered with IGF, IGF-I of the IGF-I / IGFBP-3 complex. For example, if the thyroid agonist is T4, the daily dose will be about 25-250 μg / day, more preferably 50-2
00 μg / day. As is known in the art, administration of T4 can result in higher "load" doses (50-
500 μg / day). When the thyroid agonist is T3, the dose is normally lower than 100 μg / day, more preferably about 10-100 μg / day. When the thyroid agonist is casein iodide, it is preferably administered orally at 50-1000 mg / day. For TRH and TRH analogs, the dose is approximately 1 μg / kg body weight.
Preferably it is in the range of 2020 mg. Similarly, it is well known in the art that in methods requiring administration of a thyroid antagonist, the dose of the thyroid antagonist is routinely determined for each patient. The induction of overt hypothyroidism is not required, but it may be advantageous for proper practice of the invention. Similar to the method for thyroid agonists, thyroid antagonists were administered at medium doses and patients were observed to have hypothyroidism. Hypothyroidism is a common symptom (in adults, lethargy, constipation, cold intolerance, menorrhagia in women of reproductive age, decreased intellectual and motor activity, dry hair, dry skin, Muscle pain, loss of hearing clarity, low and faint voice). In extreme cases, heavy mucosal edema appears, which is suggested by dull, expressionless faces, poor hair, periorbital swelling, enlarged tongues, rough and sagging pale and cold skin. If severe mucosal edema appears, the dose of the thyroid antagonist should be reduced to avoid the possibility of causing a severe and often life-threatening condition of myxedema coma. When signs of hypothyroidism appear just before severe mucosal edema, the dose of thyroid antagonist may be reduced until the symptoms of hypothyroidism resolve, which is understood by those skilled in the art. It will be.

[0046] Thyroid agonists can be manufactured as various preparations including parenteral and oral dosage forms. Oral formulations are preferred, but parenteral formulations may be acceptable, which may be rather convenient for wearing on hospital patients. As is known in the art, the dose of thyroid agonist is also adjusted by IGF, what thyroid agonist is administered with IGF-I of the IGF-I / IGFBP-3 complex, its formulation, and route of administration. Must-have. If the thyroid antagonist is propiothiouracil, the dose of propiothiouracil is 1 to 400 mg / day. Patients usually start with 50-400 mg / day, typically taking this in three equal doses, then 50-100 mg / day
Maintain the condition of taking two or three times a day in equal doses. Typically, the patient
Start at 5-50 mg / day and maintain at 1-5 mg / day.

[0047] Thyroid agonists and antagonists can be formulated by any method known in the art. Formulations for parenteral administration are generally formulated as solutions, but may be formulated in gels or solid storage forms. Formulations for oral administration are generally in the form of tablets or capsules, but syrups and solutions are also acceptable. Formulations of thyroid agonists and antagonists generally include excipients such as salts, buffers, bulking agents, detergents, binders, surfactants, stabilizers, preservatives, antioxidants, lubricants, coatings. Agents and other pharmaceutically acceptable excipients known in the art.

(A) Thyroid agonist and IGF, or (b) Thyroid antagonist and IGFBP-3
As for the method of administration of the drug, as long as the patient is exposed to the two compounds simultaneously,
The administration of the two compounds may be simultaneous, overlapping or temporally separate. When the two compounds are formulated for the same route of administration and schedule, the administration is preferably simultaneous or nearly simultaneous (eg, parallel or sequential infusion). However, in some embodiments, different routes of administration and different schedules of administration of the two compounds preclude continuous administration. If patients are exposed to both compounds simultaneously systemically, regardless of the time the compound was administered, either (a) a thyroid agonist and IGF, or (b) a thyroid antagonist and IGFBP-3 It is thought that it did.

[0049] Patents, patent applications, and publications cited throughout this disclosure are hereby incorporated by reference in their entirety.

The present invention has been described in both direct and detailed description. Equivalents and modifications of the present invention will be apparent to those skilled in the art and are within the scope of the invention.

[Brief description of the drawings]

FIG. 1 shows the amino acid sequence of native human IGF-I.

FIG. 2 shows the amino acid sequence of the naturally occurring Ala ₅ allele of native human IGFBP-3.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI Theme coat ゛ (Reference) A61K 38/04 A61P 5/16 38/22 5/50 45/00 43/00 111 A61P 5/14 A61K 37 / 36 5/16 37/32 5/50 37/43 43/00 111 37/02 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), AU, CA, JP PF terms (reference) 4C084 AA02 AA17 BA44 CA62 DB08 DB24 DB58 DC50 MA02 NA05 NA14 ZC022 ZC032 ZC062 4C086 AA01 BC38 BC42 MA01 MA02 MA04 NA05 NA14 ZC02 ZC06 4C206 AA01 FA53 MA01 MA04 NA05 NA14 ZC02 ZC06

Claims (18)

[Claims] 1. A method for alleviating the symptoms of an insulin-like growth factor (IGF) responsive non-thyroid disease, comprising administering an effective amount of IGF to a patient suffering from the disease, Administering an effective amount of a thyroid agonist, thereby reducing the symptoms of the disease. 2. The method according to claim 1, wherein the IGF is IGF-I. 3. The method according to claim 2, wherein the IGF-I is human IGF-I. 4. IGF-I is insulin-like growth factor binding protein 3 (IGFBP-3)
4. The method of claim 3, wherein said method forms a complex with said compound. 5. The method according to claim 4, wherein the IGFBP-3 is human IGFBP-3. 6. The method according to claim 5, wherein the IGFBP-3 is a natural human IGFBP-3. 7. IGF-I is insulin-like growth factor binding protein 3 (IGFBP-3)
3. The method of claim 2, wherein said method forms a complex with said compound. 8. The method according to claim 8, wherein IGFBP-3 is human IGFBP-3. 9. The method according to claim 9, wherein the IGFBP-3 is a natural human IGFBP-3. 10. The thyroid agonist is L-thyroxine (T4), L-thyronine (T3), thyroid stimulating hormone (TSH), thyroid stimulating hormone releasing hormone (TRH).
2. The method of claim 1, wherein the method is selected from the group consisting of, and a TRH analog. 11. A method for reducing the symptoms of a non-thyroid disease responsive to insulin-like growth factor binding protein (IGFBP-3), comprising administering to a patient suffering from the disease an effective amount of IGFBP-3. And administering an effective amount of a thyroid antagonist, thereby alleviating the symptoms of the disease. 12. The method according to claim 11, wherein IGFBP-3 is human IGFBP-3. 13. The method of claim 12, wherein the human IGFBP-3 is a natural human IGFBP-3. 14. The method of claim 11, wherein IGFBP-3 forms a complex with mutant IGF-I. 15. The method of claim 1, wherein the mutant IGF-I is a human mutant IGF-I.
3. The method according to 2. 16. The mutant IGF-I may have any of the following amino acid sequences: 24, 31, 49, 50, 5
13. The method of claim 12, wherein the method has a change in a position selected from the group consisting of 1, 53, 55, 56, and 60. 17. A method for alleviating the symptoms of an insulin-like growth factor (IGF) -dependent disease that is not a thyroid disease, comprising administering to a patient suffering from the disease an effective amount of a thyroid antagonist, thereby reducing the disease. Such a method, comprising alleviating the symptoms. 18. The method of claim 17, wherein the thyroid antagonist is selected from the group consisting of propylthiouracil, methimazole, and carbimazole.