WO2005023193A2

WO2005023193A2 - Methods of treating endometriosis

Info

Publication number: WO2005023193A2
Application number: PCT/US2004/028770
Authority: WO
Inventors: Paul Martha
Original assignee: Interleukin Genetics, Inc.
Priority date: 2003-09-04
Filing date: 2004-09-03
Publication date: 2005-03-17
Also published as: WO2005023193A3

Abstract

The invention provides a method of alleviating a sign or symptom of endometriois in a subject, by administering to the subject a composition containing a compound which inhibits angiogenisis, inflammation or matrix metalloproteinase expression or activity.

Description

Attorney Docket No. 24299-527

METHODS OF TREATING ENDOMETRIOSIS

FIELD OF THE INVENTION The invention relates to the treatment of endometriosis.

BACKGROUND OF THE INVENTION Endometriosis is one of the most commonly encountered gynecologic diseases requiring medical and/or surgical therapy. It is a leading cause of hysterectomy in the united states and has significant associated morbidity. Endometriosis is a significant public health issue because of the large number of women it affects and the significant morbidity associated with this disease. SUMMARY OF THE INVENTION The invention features methods of preventing or alleviating a sign or symptom of endometriosis. The endometriosis is pelvic endometriosis. Alternatively, the endometriosis is non-pelvic endometriosis. Endometriosis is prevented or treated by identifying a subject suffering from or at risk of developing endometriosis and administering to the subject a composition containing an endometriosis inhibitor compound. An endometriosis inhibitor compound is an anti-angiogenic compound, an anti-inflammatory compound or a matrix metalloproteinase (MMP) inhibitor (e.g., MMP-3 or MMP 7) The subject is a mammal such as human, or a non-human primate. The subject is suffering from or at risk of developing endometriosis. A subject suffering from or at risk of developing endometriosis is identified by methods known in the art, e.g., pelvic exam. Signs and symptoms of endometriosis include for example, dysmenorrhea, dyspareunia, or chronic pelvic pain. Endometriosis inhibitors are administered systemically. Alternatively endometriosis inhibitors are administered locally (e.g., directly to endometrial tissue). For example, endometriosis inhibitors are administers orally, intravenously,' intraperitoneally, nasally, intrauterine or patch delivery. Endometriosis inhibitors are administered alone or in combination with another anti-inflammatory compound, anti-angiogenic compound, MPP inhibitor or therapeutic drugs used to treat endometriosis. An anti-angiogenic compound includes for example an IL-8 antibody, a IL-8 antagonist, a VEGF antagonist, a soluble fit- 1 receptor, a VEGF antibody or a VEGF receptor polypeptide. An anti-inflammatory compound is a pro-inflammatory cytokine inhibitor, a complement inhibitor, a complementarity determining (CD) region antagonist; a phosphodiesterase inhibitor, a cox-1 inhibitor or a cox-2 inhibitor. A pro-inflammatory cytokine inhibitor is for example, doxycycline, pentoxifylline, an IL-8 inhibitor compound, an IL-1 inhibitor compound, a tumor necrosis factor α inhibitor compound, an IL-10 agonist, a compound which increases IL-10 expression or activity, an 1L-15 inhibitor compound, NFKB inhibitor compound, P38 Kinase inhibitor compound or an

IL-6 inhibitor compound. An IL-1 inhibitor compound is for example an IL-1 receptor antagonist, an IL-1 receptor polypeptide, an IL-lβ converting enzyme inhibitor or an IL-1 antibody. A tumor necrosis factor α inhibitor is for example a tumor necrosis factor α receptor antagonist, a tumor necrosis factor α receptor polypeptide, or a tumor necrosis factor α antibody. An IL-8 inhibitor compound is for example an IL-8 receptor antagonist, an I L-

8 receptor polypeptide, or an IL-8 antibody. An IL-6 inhibitor is for example an IL-6 receptor antagonist, an IL-6 receptor polypeptide, or an IL-6 antibody. An IL-15 inhibitor compound is for example an IL-15 receptor antagonist; an IL-15 receptor polypeptide, or an IL- 15 antibody. A complement inhibitor is a C5 or C5a inhibitor such as a C5a antibody or fragment thereof. A complementarity determining region antagonist is for example a CD3 antibody, a CD25 antibody, a leukocyte function associated antigen polypeptide or a CD1 la antibody. A phosphodiesterase inhibitor is for example pentoxifylline, vinopecetine, propentofyllin, cilostazol, vesnarinine, amrinone, rolipram, dippridamole, or SelCIDs. A matrix metalloproteinase inhibitor is for example doxycycline, COL-3, marimastat, batimastat, MM1270, ABT-518 or retinoic acid. Also included in the invention is a method of screening for an endometriosis inhibitor. Endometriosis inhibitors are screened by injecting into the peritoneum of a non- human mammal a population of endometrial cells and administering to the mammal a test compound. An endometriotic lesion in the peritoneum of the mammal if present is detected. The absence or a decrease of the lesion in the presence of the test compound compared to the absence of the test compound indicates the test compound is a endometriosis inhibitor compound. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. n addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Other features and advantages of the invention will be apparent from the following detailed description and from the claims.

DETAILED DESCRIPTION Endometriosis is one of the most common gynecogic disorders. It effects about 10% of the female population of child-bearing years, or about 6 million women in the United

States and millions more worldwide. Endometriosis is defined by the presence of viable endometrial tissue (i.e, glandular and stromal elements) outside the uterine cavity, usually in the abdomen on the ovaries, fallopian tubes, and ligaments that support the uterus; the area between the vagina and rectum; the outer surface of the uterus; and the lining of the pelvic cavity. However, other sites for these endometrial growths include the bladder, bowel, vagina, cervix, vulva, in abdominal surgical scars, in the lung, arm, thigh, and other locations. The extrauterine endometrial tissue develops into growths or lesions which respond to the menstrual cycle in the same way that the tissue of the uterine lining. This results in internal bleeding, breakdown of the blood and tissue from the lesions, and inflammation which cause pain, infertility, scar tissue formation, adhesions, and bowel problems. A panel of compounds that includes both FDA approved drugs and drug candidate compounds that have been administered to humans in clinical trials are screened in a murine endometriosis model, and drugs, which prevent or alleviate a sign or symptom of endometriosis, are identified and are collectively refered to herein as endometriosis inhibitor compound. Endometriosis inhibitor compounds are classified in one or more of the following categories: angiogenic inhibitors, inflammation inhibitors or metalloproteinase (MPP) inhibitors. Accordingly, the invention provides a method of inhibiting the extrauterine endometrial cell growth by administering to a tissue an endometriosis inhibitor compound.

The tissue is endometriotic tissue. Tissues are directly contacted with an inhibitor. Alternatively, the inhibitor is administered systemically. The methods are useful to alleviate the signs or symptoms of endometriosis. Endometriosis is pelvic endometriosis or non-pelvic endometriosis. Pelvic endometriosis is defined as endometriotic lesions within the pelvis, and includes the ovaries, pouch of

Douglas and the uterosacral ligaments. Non-pelvic endometriosis is defined as endometriotic lesions outside the pelvis and includes the cervix, vagina, vulva, intestinal tract, urinary tract, abdominal wall, thoracic cage, lung, extremities, and the central nervous system. The methods described herein lead to a reduction in the severity or the alleviation of one or more signs or symptoms of an endometriosis. Endometriosis disorders are diagnosed and or monitored, typically by a physician using standard methodologies e.g., pelvic exam, laparoscopy, serum CA-125 levels, ultrasound or MRI. Signs and symptoms of endometriosis include for example, dysmenorrhea, dyspareunia, chronic pelvic pain, infertility, constipation, sciatica, pain with bowel movements, elevated CA-125 levels. Efficaciousness of treatment is determined in association with any known method for diagnosing or treating endometriosis. Alleviation of one or more signs or symptoms of the endometriosis indicates that the compound confers a clinical benefit. EXEMPLARY ENDOMETRIOSIS INHIBITOR COMPOUNDS Endometriosis inhibitor compounds include compounds that inhibit angiogenesis, inflammation and/or metalloproteinase expression or activity. Endometriosis inhibitor compounds include for example the compounds listed in Table 1. Table 1

PDEi= Phosphodiesterase inhibitors; AI=Anti-inflammatory compounds; Angio= Angiogenesis inhibitors; PICi=Pro-inflammatory cytokine inhibitors; MMPi=Matrix metalloproteinase inhibitors; IL-li=lnterleukin-l inhibitors; IL-6i=Interleukin-6 inhibitors; IL-8i=Interleukin-8 inhibitors; TNFi=TNF-alpha inhibitors; Compi =Complement inhibitors; CDRa=Complementarity Determing Region (CDR) antagonists; ICAM=Intracellular Adhesion Molecules; V-protectant= Vascular protectant compound

An angiogenic inhibitor is a compound that decreases angiogenesis. Angiogenic inhibitors are known in the art or are identified using methods described herein. A decrease in angiogenesis defined by a reduction blood vessel formation or endothelial cell migration. For example, angiogenesis is measured in vitro by determining endothelial cell proliferation, or endothelial cell migration using a Boyden chamber. A decrease in proliferation or migration in the presence of the compound compared to the level in the absence or the compound indicates a decrease in angiogenesis. Exemplary angiogenic inhibitor compounds include an IL-8 antibody, a IL-8 antagonist, a soluble flt-1 receptor, a VEGF antagonist, a VEGF antibody or a VEGF receptor polypeptide. An inflammation inhibitor is a compound that decreases inflammation. Inflammation inhibitors are known in the art or are identified using methods described herein. A decrease in inflammation is characterized by a reduction of redness, pain and swelling of the treated tissue compared to a tissue that has not been contacted with a inflammation inhibitor. Alternatively, an inflammatory response is evaluated by measuring c-reactive protein, or IL-1 in the tissue or in the serum or plasma. Cytokine production is measured by methods known in the art. For example, cytokine production is determined using an immunoassay specific for the cytokine. A decrease in production of the cytokine in the presence of the compound compared to the level in the absence of the compound indicates a decrease in cytokine production. A decrease in white blood count also indicates a decrease in inflammation. A inflammation inhibitor compound is for example a pro-inflammatory cytokine inhibitor, a phosphodiesterase inhibitor, a complement inhibitor, a complementarity determining (CD) region antagonist, a cox-1 inhibitor, or a cox-2 inhibitor. A matrix metalloproteinase inhibitor is a compound that decreases matrix metalloproteinase expression or activity. Metalloproteinase inhibitors are known in the art or are identified using methods described herein. A decrease in metalloproteinase expression or activity is defined by a reduction of extracellular matrix turnover (i.e., degradation and remodeling) or a reduction in he expression of MMP or MMP mRNA levels. Matrix metalloproteinase activity is measured for example by using a readily available commercial kit such as the MT-MMP Activity Assay Kit (CHEMICON). Matrix metalloproteinase expression is determined for example by measuring the level polypeptide using e.g., immunoassays based on antibodies to MPP proteins. Alternatively, matrix metalloproteinase expression is determined by measuring the level of MPP mRNAs in, e.g., northern blot hybridization analyses or MPP nucleic acids in, e.g., amplification-based detection methods such as reverse-transcription based polymerase chain reaction. Pentoxiflline Pentoxiflline is an analogue of Xanthine, that inhibits phosphodiesterase activity. It increases the deformability of RBC, thereby allowing the RBC to migrate through the capillaries more easily, improving the circulation through the blood vessels. Pentoxiflline is used orally to treat peripheral vascular diseases evident as intermittent claudication, trophic leg ulcers, cerebrovascular disease, retinal vascular disorders, diabetic vascular disorders, and ischaemic heart disease. Standard dosage of pentoxiflline is 400 mg 2 or 3 times a day. Doxycycline Doxycycline is a tetracycline derivative that inhibits MMPs and has uses similar to those of tetracycline such as treating periodontitis, bacterial infection, malaria or syphilis.

Doxycycline is normally administered by mouth as doxycycline or its various derivatives. The standard dose is 200 mg of doxycycline on the first day (as a single dose or 100 mg repeated after 12 hours), followed by 100 mg daily. Kineret Kineret is indicated for the reduction in signs and symptoms of moderately to severely active rheumatoid arthritis. The standard dose of Kineret for the treatment of patients with rheumatoid arthritis is 100 mg/day administered daily by subcutaneous injection. IL-1 Trap The IL-1 Trap is a highly potent blocker of interleukin- 1 for the reduction in signs and symptoms rheumatoid arthritis. Standard dose is 200, 400 or 800 micrograms/kilogram. Soluble IL-1 receptor Soluble IL-1 receptor constitutes the extracellular portion of either the type I or type II IL-1 receptor. When administered therapeuticallyit inhibits IL-1 (and downstream inflammatory) activity by binding to IL-1 alpha and beta thereby blocking their ability to bind and activate IL-1 receptors. Standard doses for soluble IL-1 receptor range from 0.02 mg/kg to 3 mg/kg per day. Anti-IL-1 beta receptor Fab CDP484 is an example of an Fab molecule being tested in humans for its ability to block IL-1 beta activation of its receptors. Standards doses are those being tested in phase I clinical trials. Enbrel Enbrel is a fusion protein that binds to TNF-alpha and blocks its biologic activity. Enbrel is indicated for reduction in signs and symptoms of moderately to severely active rheumatoid arthritis. The standard dose of Enbrel for adult patients is 25 mg given twice weekly as a subquetaneous injectioa Remicade Remicade (Infliximab), is a TNF-alpha inhibiting monoclonal antibody used to treat rheumatoid arthritis and Crohn's disease. The standard does of Infliximab is 5 mg kg given as a single intravenous infusion for treatment of moderately to severely active Crohn's disease in patients. In patients with fistulizing disease, an initial 5 mg/kg dose is followed with additional 5 mg kg doses at 2 and 6 weeks after the first infusion. Humira Humira (adalimumab) is indicated for reducing signs and symptoms and inhibiting the progression of structural damage in adult patients with moderately to severely active rheumatoid arthritis. Adalimumab binds specifically to TNF-alpha and blocks its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface TNF expressing cells in vitro in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (T F-beta). Adalimumab also modulates biological responses that are induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and ICAM-1 with an IC₅o of 1 -2 X 10^"10M). The standard dose of adalimumab for adult patients with rheumatoid arthritis is 40 mg administered every other week as a subcutaneous injection. The maximum serum concentration (C_max) and the time to reach the maximum concentration (T_max) are 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three studies following a single 40 mg subcutaneous dose was 64%. The pharmacokinetics of adalimumab were linear over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. The single dose pharmacokinetics of adalimumab were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The distribution volume (V_ss) ranged from 4.7 to 6.0 L. The systemic clearance of adalimumab is approximately 12 mL/hr. The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. Adalimumab concentrations in the synovial fluid from five rheumatoid arthritis patients ranged from 31- 96% of those in serum. Onercept Onercept is a recombinant, unmodified, fully human soluble type I TNF receptor

(p55), which acts as an anti TNF agent. Onercept (r-hTBP-1) is indicated for reducing signs and symptoms in both psoriasis and psoriatic arthritis. Standard dose for treating psoriasis is of 150mg, subcutaneously, three times a week for a period of 12 weeks. Standard dose for treating psoriatic arthritis, is 50mg or lOOmg subcutaneously three times a week for a period of 12 weeks. Vinpocetine Vinpocetine is a derivative of vincamine, which is an extract of the periwinkle.

Vinpocetine attenuates cognitive deficits, reduces ischaemia-induced hippocampal cell loss and increases cerebral blood flow and glucose utilization. Vinpocetine is used for the treatment of cerebral circulatory disorders such as memory problems, acute stroke, aphasia (loss of the power of expression), apraxia (inability to coordinate movements), motor disorders, dizziness and other cerebro-vestibular (inner-ear) problems, and headache.

Vinpocetine is also used to treat acute or chronic ophthalmological diseases and in the treatment of sensorineural hearing impairment. Standard first dose is 15-30mg with a maintenance dose of 10-15 mg per day. Propentofyllin Propentofylline increases the average ratio of blood flow per unit glucose utilization and is capable of increasing cerebral blood flow in excess of metabolic demand. Standard dose of propentofyllin is 0.5-1.5 mg/kg/min i.v. Cilostazol

Cilostazol, a type III phosphodiesterase inhibitor, which enhances vasodilation and reduces platelet aggregation. Cilostazol is used to reduce the symptoms of intermittent claudication. Standard dosage for cilostazol is 50 -100 mg taken twice daily taken at least 30 minutes before or two hours after a meal. A dose of 50 mg twice daily should be considered in patients who are concomitantly receiving medications that inhibit cytochrome P-450 enzymes. Vesnarinone Vesnarinone is a phosphodiesterase Type III inhibitor with demonstrated efficacy in reducing the morbidity and mortaility associated with heart failure. The standard dose of vesnarinone is 60 mg per day with doses up to 120 mg per day also studied in clinical trials. Amrinone Amrinone is used to reduce the signs and symptoms of hypertension and CHF. Standard dose for amrinone is 0.75mg/kg IVB over 2-3 minutes, followed by 5-15 ug/kg/min IVPB.

Rolipram Rolipram is a phosphodiesterase (PDE) type 4 inhibitor used as an antidepressant, and has immunomodulatory properties useful in treating multiple sclerosis.

Selective Cytokine Inhibitory Drugs CselCIDs™) Selective Cytokine Inhibitory Drugs, (SelCIDs™ ) have an inhibitory effect on phosphodiesterase type 4 enzyme (PDE-4). SelCIDs™ currently in phase II trials for

Crohn's disease. IL-6 receptor antagonist Interleukin-6 (IL-6) - is a prototypic pleiotrophic cytokine with numerous biological functions. It has been described as both a pro-inflammatory and anti-inflammatory molecule, and levels of circulating IL-6 are elevated in several inflammatory diseases, including rheumatoid arthritis. IL-6 functions are mediated through a receptor system comprised of two molecules on the cell surface: a signal transducer and a binding molecule, IL-6 receptor. The humanized anti-IL-6 receptor monoclonal antibody (MRA) is used in the treatment of rheumatoid arthritis. Standard dose of MRA is 4-8 mg/kg IL-8 Antibody ABX-IL8 is an IL-8 fully human monoclonal antibody. ABX-IL8 targets Interleukin- 8 which is a cytokine that can cause unwanted inflammation by first enabling immune cells, including neutrophils, to migrate to inflammatory sites and subsequently activating them. IL- 8 contributes to a number of inflammatory diseases, including psoriasis, rheumatoid arthritis, and inflammatory bowel disease. Standard dose is 3.0 mg/kg, administered once every three weeks for four consecutive doses Retinoids Retinoids are a class of compounds consisting of four isoprenoid units joined in a head-to-tail manner. All retinoids may be formally derived from a monocyclic parent compound containing five carbon-carbon double bonds and a functional group at the terminus of the acyclic portion. Retinoids are synthetic derivatives of Vitamin A. Retinoids include Accutane (isotretinoin), Soriatane (acetretin) and Vesanoid (tretinoin) and are administered orally. Accutane is a prescription oral medication used to treat severe acne. Standard dose of Accutane is 0.5 to 2 mg/kg given in 2 divided doses daily for 15 to 20 weeks. Soriatane (actiretin) is used to treat severe psoriasis, a chronic disfiguring skin disease. Vesanoid (tretinoin) is used to treat a form of leukemia (acute promyelocytic leukemia). Topical versions of tretinoin (Retin-A and Renova) and another retinoid called adapalene (Differen) also are used to treat acne and sun-damaged skin. Matrix Metalloproteinase Inhibitors The matrix metalloproteinase (MPP) family consists of 1 1 enzymes. MPPs contain a zinc atom in a highly conserved active site and are responsible for the turnover and remodeling of extracellular matrix proteins. Substrates for the enzymes include the fibrillar collagens of bone, interstitia, and skin, as well as proteins such as type IV collagen and laminin which make up the basal lamina that separate tissues. Once activated, matrix metalloproteinases may be inhibited by general protease inhibitors, such as alpha2- macroglobulin, or by one of a group of specific inhibitors known as tissue inhibitors of metalloproteinases (TIMPs). Avastin Avastin is an investigational recombinant humanized antibody to vascular endothelial cell growth factor (rhuMAb-VEGF). Avastin, binds to and inhibit Vascular Endothelial Growth Factor (VEGF), a protein that plays a critical role in tumor angiogenesis (the formation of new blood vessels to the tumor) and maintenance of established tumor blood vessels. Standard does of avastin is 7.5 mg kg every 21 days, IV. Flt-1 soluble receptor Flt-1 is a receptor for vascular endothelial growth factor (VEGF). It is also sometimes called VEGFRl . The soluble portion of the receptor can be used therapeutically by administering to a human to bind VEGF and thereby block VEGF's angiogenic activity. Standard doses are approximately 25-100 micrograms per day. NF Kappa B Inhibitors NF-kappa B is a transcription factor that consists of 2 subunits: a 50 kilodalton subunit (p50) and a 65 kilodalton subunit (p65, also known as RelA). Weak Inhibitors of

NF-kappa B include for example, N-acetyl-L-cysteine, curcumin, and strong antioxidants. Moderately Strong Inhibitors of NF-kappa B include for example, Selenium, Se, Aspirin, ASA, Asacol, 5-ASA, Tepoxaline, Sulindac, and Clinoril. Strong Inhibitors of NF-kappa B include for example, Sulindac sulfide and Sulfasalazine. P38 Kinase Inhibitors The p38 MAP kinase is activated in response to cellular stress, such as stimulation by

LPS. A series of compounds, known as pyridinyl-imidazoles, can inhibit the p38-mediated production of pro-inflammatory cytokines (TNF and IL-1) in response to LPS stimulation. These compounds are highly specific against the p38 MAP kinase. The pyridinylimidazole compounds, exemplified by SB 203580, were originally prepared as inflammatory cytokine synthesis inhibitors that subsequently were found to be selective inhibitors of p38 MAP kinase. SB 203580 inhibits the catalytic activity of p38 MAP kinase by competitive binding in the ATP pocket. The p38 MAP kinase inhibitors are efficacious in several disease, including inflammation, arthritis and other joint diseases, septic shock, and myocardial injury. p38 MAP kinase inhibitors include SCIO-469, SCIO-323 and VX-745. Preclinical data have demonstrated that oral SCIO-469 and SCIO-323 lead to suppression of induced

TNF-alpha levels over a wide range of doses. C5 Inhibitors Complement activation results in a unidirectional sequence of enzymatic and biochemical reactions known as the complement cascade. In this cascade, a specific complement protein, C5, forms two highly active, inflammatory byproducts, C5a and C5b-9, which jointly activate white blood cells. This in turn evokes a number of other inflammatory byproducts, including injurious cytokines, inflammatory enzymes, and cell adhesion molecules. Together, these byproducts can lead to the destruction of tissue seen in many inflammatory diseases. C5 and C5a inhibitor therapy reduces complement activation and inflammation. C5 inhibitors include pexelizumab and eculizumab. Standards dosage of C5 inhibitors is a a single dose of 8 mg/kg. A C5a inhibitor includes NGD 2000-1, an orally active drug that blocks the activity of the C5a protein at its receptor Visilizumab Visilizumab is a humanized monoclonal antibody that binds to receptors on T cells. These cells are involved in inflammatory processes in ulcerative colitis. Standard dose of visilizuman is 1-3 mg/m . Daclizumab Daclizumab is an immunosuppressive agent used to prevent kidney transplant rejection. Standard dose for adults or children is 1 milligram (mg) per kilogram (kg).

Leukocyte Function Associated Antigen-3 Fusion Protein Amevive® (alefacept) is an immunosuppressive dimeric fusion protein that consists of the extracellular CD2-binding portion of the human leukocyte function antigen-3 (LFA-3) linked to the Fc (hinge, CH2 and CH3 domains) portion of human IgGl used in the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy.. The standard dose is 7.5 mg given once weekly as an I.V. bolus or 15 mg given once weekly as an intramuscular (IM) injection with a recommended regimen of 12 weekly injections Anti-CD4 monoclonal antibody A humanized monoclonal antibody to CD4 (HuMax-CD4) has been studied in clinical trials for treatment of psoriasis. It blocks the biologic activity of CD4. Standard doses range is from 35 to 160 mg per day. Interleukin-1 beta (IL-1 beta) convertins enzyme Inhibitor Interleukin-1 beta (IL-1 beta) converting enzyme inhibitors include for example Pralnacasan. Pralnacasan is an orally available inhibitor of interleukin-1 beta (IL-1 beta) converting enzyme (also known as ICE or caspase-1). A standard doses is 100 mg, pralnacasan thrice daily. Vascular Protectants Vascular protectants include for example AGI-1067, AGI-4207 and AGI-1096. AGI-1067 dosed orally, blocks VCAM-1 expression, prevents atherosclerosis and has potent anti-oxidant activity. AGIX-4207 is used to treat rheumatoid arthritis (RA). Unlike currently marketed biological TNF-alpha (tumor necrosis factor-alpha) inhibitors, AGIX-4207 is a selective modulator of TNF-alpha induced redox-sensitive inflammatory genes. By targeting a specific subset of TNF-alpha activity, AGIX-4207 decreases chronic inflammation in rheumatoid arthritis AGI-1096 is a novel anti-oxidant and selective anti-inflammatory agent. AGI-1096 inhibits the expression of certain inflammatory proteins, including VCAM-1, in endothelial cells lining the inside surfaces of blood vessel walls. AGI-1096 prevents transplant rejection by diminishing the transplant response to inflammation, and by protecting the blood vessels to the transplanted organ through its v-protectant activity. Antegren Antegren, a humanized monoclonal antibody, that inhibits alpha 4 integrin and prevents migration of inflammatory cells from blood vessels to sites of inflammation. A standard does is 3-6mg/kg. Natalizumab Natalizumab is a recombinant immunoglobulin-4 (IgG4) monoclonal antibody directed against alpha(4) integrin, used in the treatment of Crohn's disease multiple sclerosis.. A standard dose for Crohns's disease is two intravenous infusions of 3 milligrams/kilogram (mg/kg), separated by 4 weeks, have been effective in Crohn's disease. A standard dose for multiple sclerosis is 3-mg/kg infusion every 28 days. CDlla Inhibitors Raptiva™ (efalizumab), is a humanized anti-CD 1 la monoclonal antibody, for the treatment of moderate-to-severe plaque psoriasis, psoriatic arthritis and other indications. Raptiva™ is administered as a subcutaneous (under the skin) injection at 1 mg/kg for up to 24 weeks Anti- alpha 5-beta-l intesrin An Fab portion of a monoclonal antibody that directly binds alpha 5-beta-l integrin is under study for the treatment of human macular degeneration. IL-15 Inhibitors Interleukin IL-15 Cytokine Receptor Blocker (CRB-15) is used as a treatment for Rheumatoid Arthritis (RA) and Transplantation Intercellular Adhesion Molecule(ICAM) Inhibitors Anti-sense oligonucleotide therapy is being used at up to 2 mg/kg per dose for the inhibition of intracellular adhesion molecule activity. THERAPEUTIC ADMINISTRATION The invention includes administering to a subject a composition containing an endometriosis inhibitor compound (referred to herein as an "therapeutic compound"). An effective amount of a therapeutic compound is an amount less than a standard dose. Alternatively, an effective amount of a therapeutic compound is an amount greater than a standard dose. A standard dose is the amount typically administered to a subject treat (i.e., alleviate a sign or symptom) the therapeutics' common indication, (i.e., a non- endometriotic indication). Effective doses vary, as recognized by those skilled in the art, depending on route of administration, excipient usage, and coadministration with other therapeutic treatments including use of other anti-inflammatory agents, anti-angiogenic, metalloproteinase inhibitor or therapeutic agents for treating, preventing or alleviating a sign or symptom of a endometriosis. A therapeutic regimen is carried out by identifying a mammal, e.g., a human patient suffering from (or at risk of developing) endometriosis, using standard methods. The pharmaceutical compound is administered to such an individual using methods known in the art. Preferably, the compound is administered orally, rectally, vaginally, intrauterine, nasally, topically or parenterally, e.g., subcutaneously, intraperitoneally, intramuscularly, and intravenously. The compound is administered prophylactically, or after the detection of endometriosis. The compound is optionally formulated as a component of a cocktail of therapeutic drugs to treat endometriosis. Examples of formulations suitable for parenteral administration include aqueous solutions of the active agent in an isotonic saline solution, a 5% glucose solution, or another standard pharmaceutically acceptable excipient.

Standard solubilizing agents such as PVP or cyclodextrins are also utilized as pharmaceutical excipients for delivery of the therapeutic compounds. The therapeutic compounds described herein are formulated into compositions for other routes of administration utilizing conventional methods. For example, an endometriosis inhibitor is formulated in a capsule or a tablet for oral administration.

Capsules may contain any standard pharmaceutically acceptable materials such as gelatin or cellulose. Tablets may be formulated in accordance with conventional procedures by compressing mixtures of a therapeutic compound with a solid carrier and a lubricant. Examples of solid carriers include starch and sugar bentonite. The compound is administered in the form of a hard shell tablet or a capsule containing a binder, e.g., lactose or mannitol, a conventional filler, and a tableting agent. Other formulations include an ointment, suppository, paste, spray, patch, cream, gel, resorbable sponge, or foam. Such formulations are produced using methods well known in the art. Endometriosis inhibitor compounds are effective upon direct contact of the compound with the affected tissue. Accordingly, the compound is administered topically.

Alternatively, endometriosis inhibitors are administered systemically. Additionally, compounds are administered by implanting (either directly into an organ, or subcutaneously) a solid or resorbable matrix which slowly releases the compound into adjacent and surrounding tissues of the subject.

EVALUATION OF ANTI-EN DOMETRIOSIS ACTIVITY Anti-endometriosis activity of a compound is identified by injecting into the peritoneum of a non-human mammal a population of endometrial cell and measuring endometriotic lesion formation. A decrease or absence of endometriotic lesion in the presence of the test compound compared to the level in the absence of the test compound indicates that the compound inhibits endometriosis. Endometriotic lesions are measured for example, histologically. Other embodiments are within the following claims.

Claims

What is claimed is:

1. Use of an anti-angiogenic compound in the manufacture of a medicament for the alleviation of a sign or symptom of endometriosis in a subject wherein thesubject is suffering from or predisposed to developing endometriosis.

2. The use according to claim 1 , wherein the anti-angiogenic compound is selected from the group consisting of a IL-8 antibody, a IL-8 antagonist, a flt-1 soluble receptor, a VEGF antagonist; a VEGF antibody and a VEGF receptor polypeptide.

3. Use of an an anti-inflammatory compound in the manufacture of a medicament for the alleviation of a sign or symptom of endometriosis in a subject wherein thesubject is suffering from or predisposed to developing endometriosis.

4. The use according to claim 3, wherein the anti-inflammatory compound is selected from the group consisting of a pro-inflammatory cytokine inhibitor, a complement inhibitor, a complementarity determining (CD) region antagonist; a phosphodiesterase inhibitor a cox-1 inhibitor and a cox-2 inhibitor.

5. The use according to claim 4, wherein the pro-inflammatory cytokine inhibitor is selected from the group consisting of doxycycline, pentoxifylline, an IL-8 inhibitor compound, an IL-1 inhibitor compound, a tumor necrosis factor inhibitor compound, an IL-10 agonist, a compound that increase the expression or activity of IL-10, an IL-15 inhibitor compound, NFKB inhibitor compound, P38 Kinase inhibitor compound, and an IL-6 inhibitor compound.

6. The use according to claim 5, wherein the IL-1 inhibitor compound is selected from the group consisting of an IL-1 receptor antagonist, an IL-1 receptor polypeptide, an IL-lβ converting enzyme inhibitor (ICE), and an IL-1 antibody.

7. The use according to claim 5, wherein the tumor necrosis factor α inhibitor compound is selected from the group consisting of a tumor necrosis factor α receptor antagonist, a tumor necrosis factor α receptor polypeptide, and a tumor necrosis factor α antibody.

8. The use according to claim 5, wherein the IL-8 inhibitor compound is selected from the group consisting of an IL-8 receptor antagonist, an IL- 8 receptor polypeptide, and an IL-8 antibody.

9. The use according to claim 5, wherein the IL-6 inhibitor compound is selected from the group consisting of an IL-6 receptor antagonist, an IL-6 receptor polypeptide, and an IL-6 antibody.

10. The use according to claim 5, wherein the IL-10 agonist or compound increases the expression or activity of IL-10 is selected from the group consisting of an IL-10 receptor agonist; an IL-10 receptor polypeptide, and an IL-10 antibody.

1 1. The use according to claim 5, wherein the IL-15 inhibitor compound is selected from the group consisting of an IL-15 receptor antagonist; an IL-15 receptor polypeptide, and an IL-15 antibody.

12. The use according to claim 4, wherein the complement inhibitor is a C5a inhibitor.

13. The use according to claim 12, wherein the C5a inhibitor is a C5a antibody or fragment thereof.

14. The use according to claim 4, wherein the complementarity determining region antagonist is selected from the group consisting of CD3 antibody, a CD4 antibody, a CD25 antibody, a leukocyte function associated antigen polypeptide and a CD1 1 a antibody.

15. The use according to claim 5,wherein the phosphodiesterase inhibitor is selected from the group consisting of pentoxifylline, vinopecetine, propentofyllin, cilostazol, vesnarinine, amrinone, rolipram, dippridamole, and SelCIDs.

16. Use of a matrix metalloproteinase (MMP) inhibitor in the manufacture of a medicament for the alleviation of a sign or symptom of endometriosis in a subject wherein thesubject is suffering from or predisposed to developing endometriosis.

17. The use according to claim 16, wherein the matrix metalloproteinase inhibitor is selected form the group consisting of doxycycline COL-3, marimastat, batimastat, MM1270, ABT-518, prinomastat and retinoic acid.

18. The use according to claim 16, wherein the metallproteinase is MMP-2, MMP -3, MMP-7 or MMP-9.

19. The use according to any one of claims 1-18, wherein the compound is administered by the administration route selected from the group consisting of oral, intravenous, intraperitoneal, nasal, intrauterine and patch delivery.

20. The use according to any one of claims 1-18, wherein the compound is administered systemically.

21. The use according to any one of claims 1-18, wherein the compound is administered locally.

22. The use according to any one of claims 1-18, wherein the compound is administered directly to endometrial tissue.

23. The use according to any one of claims 1-18, wherein the endometriosis is pelvic endometriosis or non-pelvic endometriosis.

24. A method of alleviating a sign or symptom of endometriosis, comprising administering to a subject suffering from or predisposed to developing endometriosis a composition comprising an anti-angiogenic compound.

25. The method of claim 24, wherein the anti-angiogenic compound is selected from the group consisting of a IL-8 antibody, a IL-8 antagonist, a flt-1 soluble receptor, a VEGF antagonist; a VEGF antibody and a VEGF receptor polypeptide.

26. The method of claim 24, wherein the composition is administered by the administration route selected from the group consisting of oral, intravenous, intraperitoneal, nasal, intrauterine and patch delivery.

27. The method of claim 24, wherein the composition is administered systemically.

28. The method of claim 24, wherein the composition is administered locally.

29. The method of claim 28, wherein the composition is administered directly to endometrial tissue.

30. The method of claim 24, wherein the endometriosis is pelvic endometriosis or non- pelvic endometriosis.

31. A method of alleviating a sign or symptom of endometriosis, comprising administering to a subject suffering from or predisposed to developing endometriosis a composition comprising an anti-inflammatory compound.

32. The method of claim 31, wherein the anti-inflammatory compound is selected from the group consisting of a pro-inflammatory cytokine inhibitor, a complement inhibitor, a complementarity determining (CD) region antagonist; a phosphodiesterase inhibitor a cox-1 inhibitor and a cox-2 inhibitor.

33. The method of claim 32, wherein the pro-inflammatory cytokine inhibitor is selected from the group consisting of doxycycline, pentoxifylline, an IL-8 inhibitor compound, an IL-1 inhibitor compound, a tumor necrosis factor α inhibitor compound, an IL-10 agonist, a compound that increase the expression or activity of IL-10, an IL-15 inhibitor compound, NFKB inhibitor compound, P38 Kinase inhibitor compound, and an IL-6 inhibitor compound.

34. The method of claim 32, wherein the IL-1 inhibitor compound is selected from the group consisting of an IL-1 receptor antagonist, an IL-1 receptor polypeptide, an IL- 1 β converting enzyme inhibitor (ICE), and an IL-1 antibody.

35. The method of claim 32, wherein the tumor necrosis factor α inhibitor compound is selected from the group consisting of a tumor necrosis factor α receptor antagonist, a tumor necrosis factor α receptor polypeptide, and a tumor necrosis factor α antibody.

36. The method of claim 32, wherein the IL-8 inhibitor compound is selected from the group consisting of an IL-8 receptor antagonist, an IL- 8 receptor polypeptide, and an IL-8 antibody.

37. The method of claim 32, wherein the IL-6 inhibitor compound is selected from the group consisting of an IL-6 receptor antagonist, an IL-6 receptor polypeptide, and an IL-6 antibody.

38. The method of claim 32, wherein the IL-10 agonist or compound increases the expression or activity of IL-10 is selected from the group consisting of an IL-10 receptor agonist; an IL-10 receptor polypeptide, and an IL-10 antibody.

39. The method of claim 32, wherein the IL-15 inhibitor compound is selected from the group consisting of an IL-15 receptor antagonist; an IL-15 receptor polypeptide, and an IL-15 antibody.

40. The method of claim 31, wherein the complement inhibitor is a C5a inhibitor.

41. The method of claim 40, wherein the C5a inhibitor is a C5a antibody or fragment thereof.

42. The method of claim 31, wherein the complementarity determining region antagonist is selected from the group consisting of CD3 antibody, a CD4 antibody, a CD25 antibody, a leukocyte function associated antigen polypeptide and a CD1 la antibody.

43. The method of claim 31, wherein the phosphodiesterase inhibitor is selected from the group consisting of pentoxifylline, vinopecetine, propentofyllin, cilostazol, vesnarinine, amrinone, rolipram, dippridamole, and SelCIDs.

44. The method of claim 31 , wherein the composition is administered by the administration route selected from the group consisting of oral, intravenous, intraperitoneal, nasal, intrauterine and patch delivery.

45. The method of claim 31, wherein the composition is administered systemically.

46. The method of claim 31, wherein the composition is administered locally.

47. The method of claim 46, wherein the composition is administered directly to endometrial tissue.

48. The method of claim 31 , wherein the endometriosis is pelvic endometriosis or non- pelvic endometriosis.

49. A method of alleviating a sign or symptom of endometriosis, comprising administering to a subject suffering from or predisposed to developing endometriosis a composition comprising a matrix metalloproteinase (MMP) inhibitor.

50. The method of claim 49, wherein the matrix metalloproteinase inhibitor is selected form the group consisting of doxycycline COL-3, marimastat, batimastat, MM 1270, ABT-518, prinomastat and retinoic acid.

51. The method of claim 50, wherein the metallproteinase is MMP-2, MMP-3, MMP-7 or MMP-9.

52. The method of claim 50, wherein the composition is administered by the administration route selected from the group consisting of oral, intravenous, intraperitoneal, nasal, intrauterine and patch delivery.

53. The method of claim 50, wherein the composition is administered systemically.

54. The method of claim 50, wherein the composition is administered locally.

55. The method of claim 50, wherein the composition is administered directly to endometrial tissue.

56. The method of claim 50, wherein the endometriosis is pelvic endometriosis or non- pelvic endometriosis.