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Title:  Interleukin antagonists for the treatment of neurological, retinal and muscular disorders

United States Patent:  6,623,736

Issued:  September 23, 2003

Inventors:  Tobinick; Edward L. (100 UCLA Medical Plaza, Los Angeles, CA 90024-6903)

Appl. No.:  152477

Filed:  May 23, 2002

Abstract

Interleukin (IL) antagonists are provided for the treatment in humans of neurological disorders, trauma, injuries or compression; neurodegenerative disorders including Alzheimer's Disease; demyelinating neurological disorders including multiple sclerosis; retinal disorders; and muscular disorders. The IL antagonists are used to treat these disorders by inhibiting the action of IL in the human body. The administration of these IL antagonists is performed by intrathecal administration; intracerebroventricular administration; intranasal administration; by inhalation; or by alternative routes of administration.

SUMMARY OF THE INVENTION

The present invention provides a method for inhibiting the action of IL for treating neurological, retinal, and muscular disorders in a human by administering to the human therapeutically effective doses of IL antagonists for reducing the inflammation of neuronal, retinal, or muscular tissue of the human and/or preventing immune system damage to neuronal, retinal, or muscular tissue. The preferred forms of administration are intrathecal and intracerebroventricular administration into the cerebrospinal fluid (CSF).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

IL antagonist regimens to be used for neurological disorders are designed in two general ways: 1) acute regimens, designed to achieve rapid blood levels and rapid action, wherein IL blockade is desired for hours to days; and 2) chronic regimens, wherein IL blockade is desired for days, weeks, or months. Currently investigational IL-1 antagonists which are suitable for these regimens are IL1-R type II (interleukin 1 receptor type II) from Immunex Corporation and IL1-RA (interleukin 1 receptor antagonist) from Amgen Corporation.

Trauma, injury, compression and other neurological disorders can affect individual nerves, nerve roots, the spinal cord, or the brain. The disorders which are of most concern here are the following:

Alzheimer's Disease

Parkinson's Disease

Postherpetic Neuralgia

Pick's Disease

Huntington's Disease

Neurodegenerative Diseases

AIDS Dementia Complex

Inflammatory Diseases of the Brain, Spinal Cord, or Retina

Autoimmune Diseases of the Brain, Spinal Cord, or Retina

Multiple Sclerosis

Spinal Cord Injury

Spinal Cord Compression

Herniated Disc

Guillain-Barre Syndrome

Traumatic Brain Injury

Muscular Dystrophy

Polymyositis--Dermatomyositis

Intrathecal administration of IL antagonists is the preferred way to treat neurologic trauma, injury, compression and neurological disorders in comparison with steroids. Experimental evidence has shown that excessive levels of IL are released by injury to neuronal tissue. Accordingly, the use of IL antagonists will result in amelioration of these neurological conditions. Because of the profoundly powerful action of the new IL antagonists, they can prevent neurologic injury in a unique way, filling an urgent clinical need for more effective therapy. Also, these antagonists have an extremely safe side effect profile. Importantly, the IL antagonists lack the adverse effects of steroids as previously described. Lastly, steroids are only partially effective or completely ineffective. Intrathecal administration of IL antagonists is also the preferred way to treat retinal disorders.

Types of IL-1 Inhibitors

Antibodies (immunoglobulins) are proteins produced by one class of lymphocytes (B cells) in response to specific exogenous foreign molecules (antigens). Monoclonal antibodies (mAB), identical immunoglobulin copies which recognize a single antigen, are derived from clones (identical copies) of a single B cell. This technology enables large quantities of an immunoglobulin with a specific target to be mass produced.

Monoclonal antibodies with a high affinity for a specific cytokine will tend to reduce the biologic activity of that cytokine. Substances which reduce the biologic effect of a cytokine can be described in any of the following ways: as a cytokine blocker; as a cytokine inhibitor; or as a cytokine antagonist. In this patent we will use the terms blocker, inhibitor, and antagonist interchangeably with respect to interleukin.

Cytokine antagonists can take several forms. They may be monoclonal antibodies (defined above). They may take the form of a soluble receptor to that cytokine. Soluble receptors freely circulate in the body. When they encounter their target cytokine they bind to it, effectively inactivating the cytokine, since the cytokine is then no longer able to bind with its biologic target in the body. An even more potent antagonist consists of two soluble receptors fused together to a specific portion of an immunoglobulin molecule (Fc fragment). This produces a dimer composed of two soluble receptors which have a high affinity for the target, and a prolonged half-life.

Interleukin-1 (IL-1) is a proinflammatory cytokine which has been implicated in the inflammatory response occurring in the brain, spinal cord, retina, muscle, and elsewhere in the body. There are two naturally occurring inhibitors of IL-1 in the body: IL-1 receptor antagonist (IL-1 RA) and IL-1 receptor type II (IL-1 R type II). Additional inhibitors of IL-1 for the purpose of this patent are soluble IL-1 receptors: fusion proteins consisting of two IL-1 receptors attached to the Fc portion of a human IgG molecule (IL-1 R-FP); and monoclonal antibodies with a high affinity for IL-1.

A Detailed discussion of each of the clinical conditions follows:

1) Acute Spinal Cord Injury

About 10,000 cases occur per year in the U.S., with a current population of over 200,000 patients with residual neurologic damage, many of whom are paralyzed (quadriplegia or paraplegia). Current treatment for the acute injury is inadequate. In the early 1990's it was shown that early (within 8 hours of injury) treatment with high doses of steroids (methyl prednisolone) was beneficial for some of these patients. Surgical stabilization and spinal decompression is often necessary because of excessive swelling (edema) which can itself cause further severe injury to the cord due to further compression of the cord against its bony spinal canal. The etiology of most of these cases are motor vehicle accidents, with the remainder being sports injuries, falls, and other accidents. The window of opportunity for treatment is small, since massive swelling can occur within minutes.

The treatment regimen used here would be the acute regimen. This would involve the use of IL antagonists. A preferred regimen for acute spinal cord injury involves intrathecal administration. This acute regimen is a unique delivery method and is uniquely necessary for clinical neurologic conditions requiring rapid blockade of IL.

2) Demyelinating Disease, such as Multiple Sclerosis

Demyelinating neurological diseases, the most important being multiple sclerosis, are inadequately treated by currently available therapies, and continue to produce progressive, severe, neurologic impairment in a large population of patients in the United States and worldwide. There is experimental evidence which documents the role of IL in multiple sclerosis. There is a wide body of work which documents the role of both cellular and humoral immunity in multiple sclerosis. Using IL antagonists represents a novel approach to the treatment of these important disorders.

Several novel approaches are suggested. For acute demyelinating disease, it is paramount to use therapy which is rapidly effective to prevent permanent neurological damage. In this case, novel routes of administration of the IL antagonists may be used. These novel routes include intrathecal administration. These novel regimens are designed as such because of the mechanisms of action and low toxicity of these biopharmaceutical agents.

3) Neurodegenerative Diseases

Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Pick's Disease, Creutzfeld-Jakob Disease, and AIDS Dementia Complex are all chronic, progressive, incurable disorders which lack satisfactory treatment. They all have important components of inflammation in which interleukins are implicated as contributing to neuronal damage. Chronic administration of the interleukin antagonists discussed here will help reduce the inflammatory response and the immune response affecting the brain tissue in these disorders. Amelioration of disease progression will occur, resulting in improvement in the patient's clinical condition. For all of these central nervous system conditions chronic administration of interleukin antagonists directly into the cerebrospinal fluid, either at the level of the spinal cord or into the cerebroventricular system, is the preferred method.

4) Herniated Nucleus Pulposus (Herniated Disc)

Low back pain affects 70% of the population during their lifetime, with 25% of this group having pain in the sciatic distribution. Current pharmacologic treatment is inadequate, consisting of analgesics and anti-inflammatory medications, such as nonsteroidal antiinflammatories (NSAIDS), such as ibuprofen (Motrin, etc.) and epidural steroid injections (generally regarded as having limited usefulness. Many of these patients eventually have surgery. Complications of lumbar disc herniation include permanent damage to the sciatic nerve, causing muscle weakness and atrophy in the lower extremity. Acute herniation with rapid onset of pain and sciatic nerve symptoms could be treated with the above acute regimen, with or without addition of the chronic regimen (described below), if symptoms continued. An alternative acute regimen for sciatica involves the subcutaneous bolus injection of an IL antagonist into the subcutaneous tissue directly overlying the area of sciatica involvement. This produces an enhanced therapeutic level of the mediation at the target site due to direct local absorption. Treatment could also be reserved for patients not responding to conventional therapy. The acute treatment regimen, as outlined above, could be used for patients in whom rapid control of symptoms was desired. Herniated cervical discs would be treated the same way as herniated lumbar discs with the need for careful evaluation by a neurologist, neurosurgeon, and/or orthopedic surgeon for signs of neurologic compromise kept in mind.

5) Spinal Cord Compression Due to Metastatic Cancer

Cord compression due to metastatic cancer is a catastrophic event leading to rapid paralysis if not quickly diagnosed and treated. It is most common with cancers of the breast, colon, lung and prostate, but can be a complication of metastatic disease from a wide variety of malignancies, including melanoma and multiple myeloma. Current treatment regimens include high dose steroids, emergency radiation treatment, and/or emergent surgical decompression. Paralysis can occur within hours, so treatment must be initiated within this time period to avoid permanent sequelae. The mechanism of action IL blockade here would be similar to that above. In addition, it is possible that IL blockade could be directly tumoricidal or tumoristatic with certain malignancies. Impending cord compression could be treated with the chronic regimen. However, as explained above, most patients would need to be emergently treated with the acute regimen, as outlined above.

6) Primary or Metastatic Brain Tumors

Primary brain tumors can be either benign (most commonly meningioma) or malignant (usually gliomas). Metastatic brain tumors can be from any source, most commonly lung cancer, breast cancer, or other malignancies such as melanoma. Treatment for these tumors is primarily surgery or radiation, with generally poor response to chemotherapy. Many of these tumors cause surrounding edema which can cause further neurologic deterioration. IL blockade, either the acute or chronic treatment regimen, would be beneficial while these patients are awaiting surgery. Additionally, IL blockade, as discussed above, would have direct tumor inhibiting properties.

7) Chronic Pain Syndromes Due to Metastatic Tumor

Pain due to metastatic cancer is inadequately treated by currently used agents. It is probable that the mechanism of action of this pain is mediated in part by the overproduction of IL. IL blockade would be beneficial for selected tumors, particularly bone metastases where compression is involved. The chronic treatment regimens would be used. One general note of caution when treating malignancies is necessary: While IL blockade is likely to have an antitumor effect with certain malignancies, it is also possible that IL blockade could increase growth rates with certain malignancies.

8) Inflammatory CNS Diseases, Such As Subacute Sclerosing Panencephalitis

Subacute sclerosing panencephalitis is a rare inflammatory disease of the brain, secondary to infection with a measles virus.

9) Huntington's Disease

Huntington's disease (Huntington's chorea) is a rare, progressive, fatal neurological disorder for which there is currently no effective treatment. It is often hereditary, and is characterized by a movement disorder (chorea), as well as progressive dementia.

10) Creutzfeld-Jakob Disease

Creutzfeld-Jakob disease, as well as New Variant Creuzfeld-Jakob disease, is one of the transmissible spongioform encephalopathies, along with Kuru and Scrapie and "Mad Cow Disease (Bovine spongioform encephalopathy)". These diseases are caused by infection with a new class of biologic agent called prions. These diseases are progressive, fatal, and can be contracted by ingesting tissue of an infected animal. There is no known treatment.

11) Parkinson's Disease

Parkinson's disease is a common neurologic disorder characterized by tremor, gait disorder, and dementia, for which there is no known cure.

12) Myasthenia Gravis

Myasthenia gravis is an autoimmune disorder of the neuromuscular junction, characterized by muscle weakness and easy fatiguability. There is no known cure. Corticosteroids are one of the mainstays of treatment.

13) Guillain-Barre Syndrome

Guillain-Barre syndrome is characterized by the rapid onset of weakness, usually in an ascending distribution, and often culminating in difficulty breathing. It often follows a preceding viral infection.

14) Bell's Palsy

Bell's palsy is characterized by the sudden onset of hemifacial paralysis, caused by acute mononeuropathy of the seventh cranial nerve, the facial nerve. It can follow viral infection, vaccination, or may be idiopathic. The mainstay of treatment is large doses of corticosteroids.

15) Diabetic Neuropathy

Diabetic neuropathy consists of a variety of clinical syndromes of neurologic damage occurring in patients with either juvenile onset or adult onset diabetes mellitus. Diabetic peripheral neuropathy causes sensory deficits, numbness, tingling, and painful paresthesias in the extremities. Diabetic autonomic neuropathy causes disorders of the autonomic nervous system, including diabetic gastropathy.

16) Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis is a progressive fatal, neurologic disease causing progressive weakness and cranial nerve palsies, causing difficulty with speech, eye movements, and such. There is no known cure.

17) Optic Neuritis

Optic neuritis is characterized by acute inflammation affecting the optic nerve, causing visual field defects. It is often part of Multiple Sclerosis, for which it may be the presenting symptom. Attacks can be intermittent and repeated.

18) Macular Degeneration

Macular degeneration is a leading cause of blindness, affecting predominantly the older population, for which there is no known cure.

19) Retinitis Pigmentosa

Retinitis pigmentosa is a hereditary retinal disease, resulting in blindness, for which there is no known cure.

20) Diabetic Retinopathy

Diabetic Retinopathy includes a spectrum of retinal disorders, including hemorrhage and exudates, which occur in patients with diabetes mellitus. Part of the retinopathy is due to a vascular damage caused by diabetes.

21) Muscular Dystrophy

Muscular dystrophy is a group of related diseases of muscle, many of which are hereditary, characterized by progressive muscular weakness. The cause and cure are unknown.

22) Polymyositis--Dermatomyositis

Polymyositis is an autoimmune inflammatory disease of muscle, characterized by progressive proximal muscle weakness and muscle wasting. Pathology shows an intense inflammatory infiltrate in the muscle. Treatment includes immunosuppressive drugs, corticosteroids, and respiratory support for more advanced cases. Dermatomyositis is polymyositis with a characteristic accompanying skin rash.

Combination Therapy

Treatment of neurologic, retinal, and muscular disorders may be accomplished by use of these Interleukin Antagonists singly; in combination with each other; or in combination with other medications.

For treatment of inflammatory and autoimmune disorders it may be useful to combine any of the agents described herein (interleukin antagonists) with other anti-inflammatory or immunosuppressive agents, or with other biologic agents. In particular, the combination of any of the agents described herein as IL Blockers with any of the following drugs offer advantages in terms of improved efficacy:

etanercept

TNF antagonists other than etanercept including, but not limited to D2 E7, infliximab, TNF alpha converting enzyme inhibitor (TACE inhibitor), and thalidomide

methotrexate

mitoxantrone

leflunomide

For example, certain patients with Alzheimer's Disease may show only a partial response to IL-1 antagonists. The addition of intrathecal TNF antagonists will further inhibit the inflammatory cascade, thereby further reducing neuronal damage, and causing greater clinical benefit. One preferred combination is intrathecal IL-1 RA with intrathecal etanercept for the treatment of Alzheimer's Disease.

Combination therapy will provide synergistic effects. Careful monitoring for adverse effects will be necessary because of the greater possibility of this occurring with drug combinations.

Dosages

General guidelines: substances administered by peripheral routes will require a higher dosage than those delivered by the intrathecal route. Peripheral routes of administration are defined herein as those which do not involve administration into the cerebrospinal fluid (CSF), for example, intranasal administration.

For example, IL-1 R-FP when administered subcutaneously will generally be effective at a dosage level of between 10 mg and 250 mg (mean dose of 50 mg); when given intrathecally doses of between 0.5 mg and 25 mg (mean dose of 10 mg) will generally be used.

Monoclonal antibodies will generally be used at somewhat higher dosages, usually 0.5-25 mg/kg when administered peripherally, and 0.1-1.0 mg/kg when given intrathecally.

IL-1 RA and IL-1 R type II dosages will be similar and will approximate 0.02 to 3.0 mg/kg when given daily by subcutaneous bolus injection, and 0.01 to 0.5 mg/kg when administered intrathecally.

Routes of Administration

For the muscular disorders listed above, the peripheral routes of administration may be employed. These include subcutaneous, intravenous, intramuscular, intranasal, oral, transepidermal, parenteral, mucosal, intrarectal, or by inhalation.

For the retinal disorders listed above, the peripheral routes of administration may be employed, or CSF administration may be employed.

For the neurological disorders listed above, the peripheral routes of administration may be employed, but CSF administration is the preferred route.

Administering the IL Blocker into the cerebrospinal fluid is performed by implanting in the scalp of the patient a subcutaneous reservoir for receiving the IL Blocker. The reservoir has an attached catheter to communicate with the cerebroventricular system of the patient. The reservoir is accessed by needle injection from the outside through the scalp, thereby allowing the introduction of the IL Blocker directly into the reservoir and the catheter in order to communicate and supply the IL Blocker into the cerebroventricular system.

Alternatively, the IL Blocker may be administered into the cerebrospinal fluid by implanting in the abdomen of the patient a subcutaneous reservoir for receiving the IL Blocker. The reservoir has an attached catheter to communicate with the intrathecal space of the patient, and the catheter is placed into the intrathecal space. The reservoir is accessed by needle injection from the outside through the skin, thereby allowing the introduction of the IL Blocker directly into the reservoir and the catheter in order to communicate and supply the IL Blocker into the cerebrospinal fluid.

Advantages of the Present Invention

Accordingly, an advantage of the present invention is that it provides for IL antagonists as a new pharmacologic treatment of neurological disorders, trauma, injuries and compression affecting the nervous system of the human body; demyelinating neurologic disease; neurodegenerative diseases; retinal diseases; and muscular diseases; such that the use of these IL antagonists will result in the amelioration of these conditions.

Another advantage of the present invention is that it provides for IL antagonists for providing suppression and inhibition of the action of IL in a human to treat neurological injury, trauma or compression; demyelinating neurologic disease; neurodegenerative diseases; retinal diseases; and muscular diseases.

Another advantage of the present invention is that it provides for IL antagonists that reduce inflammation by inhibiting the action of IL in the human body for the immediate, short term (acute conditions) and long term (chronic conditions), such that this reduction in inflammation will produce clinical improvement in the patient and will give the patient a better opportunity to heal, slow disease progression, prevent neurological damage, prevent retinal and muscular damage, or otherwise improves the patient's health.

Another advantage of the present invention is that it provides for IL antagonists, using intrathecal administration as the preferred form of administration, that offer acute and chronic treatment regimens for neurological conditions caused by neurological trauma, compression, injury and/or disease, such conditions including acute spinal cord injury, herniated nucleus pulposus (herniated disc), spinal cord compression due to metastatic cancer, primary or metastatic brain tumors, chronic pain syndromes due to metastatic tumor, increased intracranial pressure, demyelinating diseases such as multiple sclerosis, inflammatory CNS diseases, such as subacute sclerosing panencephalitis, other related neurological disorders and diseases, retinal disorders, and muscular disorders.

A latitude of modification, change, and substitution is intended in the foregoing disclosure, and in some instances, some features of the invention will be employed without a corresponding use of other features. Accordingly, it is appropriate that the appended claims be construed broadly and in a manner consistent with the spirit and scope of the invention herein.

Claim 1 of 17 Claims

What is claimed is:

1. A method for inhibiting the action of IL for treating disorders of the optic nerve or retina in a human by administering an IL Blocker for reducing the inflammation of the optic nerve or retina of said human, or for modulating the immune response affecting the optic nerve or retina of said human, comprising the step of:

administering a therapeutically effective dosage level to said human of said IL Blocker for reducing the inflammation of the optic nerve or retina of said human, or for modulating the immune response affecting the optic nerve or retina of said human.




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