Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form
Reexamination Certificate
2000-12-27
2002-07-23
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
C424S422000, C424S434000, C424S427000, C424S134100, C514S898000, C514S885000, C514S913000, C514S914000
Reexamination Certificate
active
06423321
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to specific cytokine antagonists, including TNF antagonists and IL-1 antagonists, for the treatment of hearing loss, including sensorineural hearing loss and presbycusis. The invention also includes methods of administration for these antagonists.
BACKGROUND OF THE INVENTION
Hearing loss occurs in humans in many forms. Hearing is essential to the normal conduct of one's daily activities and people with impaired hearing have many difficulties. Hearing loss can date from birth; it can be acquired later in life; or it can be the result of trauma, accident, disease, or a toxic effect of a medication. It can be genetic, either as a solitary disorder or as part of a complex syndrome. Hearing loss is one of the most common chronic neurological impairments, estimated to affect about 4 percent of those under 45 in the United States, and about 29 percent of those 65 years or older.
As defined herein, the auditory apparatus includes the cochlea, the auditory division of the eighth cranial nerve, and the central auditory pathways. Sensorineural hearing loss is one particular category of hearing loss and is caused by lesions of the cochlea and/or the auditory division of the eighth cranial nerve. Prior to this invention, treatment of this condition was primarily limited to the use of hearing aids.
The pathogenetic mechanism of most forms of hearing loss has yet to be fully defined. Hearing loss can be due to conductive problems, which is not the subject of this patent; central hearing loss due to lesions of the central auditory pathway; or sensorineural hearing loss.
Humans react to sounds that are transduced into neurally conducted impulses through the action of neuroepithelial cells (hair cells) and spiral ganglion cells (neurons) in the inner ear. These impulses are transmitted along the cochlear division of the eighth cranial nerve into the brainstem and the central auditory pathways.
Presbycusis, or age-related hearing loss, is a type of sensorineural deafness which affects one-third of the population over the age of 75. The exact mechanism of presbycusis is unknown, and has long been thought to be multifactorial. Inflammation has not previously been thought to be a significant factor in the pathogenesis of presbycusis. Yet a previous study did suggest that genes encoded by the major histocompatibility complex (MHC) had a role in certain hearing disorders. (Bernstein, Acta Otolaryngol 1996 Sep; 116(5):666-71). The MHC is known to be central to the immune response and inflammation.
As will be discussed below there is now clinical evidence that inflammation has a role in the pathogenesis of various types of sensorineural hearing loss, including presbycusis. This opens up a new avenue of treatment of these disorders utilizing cytokine antagonists.
Monoclonal antibodies with a high affinity for a specific cytokine 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, the terms blocker, inhibitor, and antagonist are used interchangeably with respect to interleukin-1 and tumor necrosis factor (TNF).
Cytokine antagonists can take several forms. They may be monoclonal antibodies (defined above); or in 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.
Cytokine antagonists of the kind discussed in this patent play a central role in the inflammatory response and in immune injury. TNF is formed by the cleavage of a precursor transmembrane protein, forming soluble molecules, which aggregate to form trimolecular complexes. These complexes then bind to receptors found on a variety of cells. Binding produces an array of proinflammatory effects, including release of other pro-inflammatory cytokines, including interleukin (IL)-6, IL-8, and IL-1; release of matrix metalloproteinases; and up-regulation of the expression of endothelial adhesion molecules, further amplifying the inflammatory and immune cascade by attracting leukocytes into extravascular tissues. TNF is now well established as key in the pathogenesis of rheumatoid arthritis(RA) and Crohn's Disease, and new evidence of its involvement in other non-neurologic disorders and in other non-neurologic organ systems, such as the heart, is rapidly accumulating.
Tumor necrosis factor (TNF) is intimately involved in the nervous system. It is central to the response to injury, either virally induced, or occurring as a result of mechanical trauma. TNF is also central to neuronal apoptosis, a process important in many neurological disorders.
Specific inhibitors of TNF, only recently commercially available, now provide the possibility of therapeutic intervention in TNF mediated disorders. These antagonists, mainly developed to treat rheumatoid arthritis, include: 1) etanercept (Enbrel® sold by the Immunex Corporation), which is a recombinant fusion protein consisting of two soluble TNF receptors joined by the Fc fragment of a human IgGI molecule, for treating RA, Juvenile Rheumatoid Arthritis and Psoriatic Arthritis; 2) infliximab (Remicade® sold by Johnson and Johnson); and 3) D2E7, a human anti-TNF monoclonal antibody (sold by Knoll Pharmaceuticals). Other specific anti-TNF agents are under development, including CDP 571 (a chimeric, but 95% humanized, anti-TNF mAb), and a pegylated soluble TNF type 1 receptor.
Few effective therapeutic agents are available for the treatment of neurological disorders. The nervous system has only a limited capacity for repair. Neurological injury is therefore often permanent, irreversible, and clinically devastating. There is an urgent need for effective treatments of a wide variety of neurological conditions, many of which are chronic, progressive, and incurable. TNF modulation with these new agents offers a new modality of treatment for many of these disorders. 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). Interleukin-1 antagonists are in the process of being developed for clinical use in arthritis. The two specific agents which are of most relevance here are IL-1 RA (Anakinra, being developed by Amgen), and IL-1 R type II (Immunex).
The use of TNF antagonists and Interleukin antagonists for the treatment of neurological, retinal, optic nerve, and muscular disorders are the subject of pending patent applications by the author. The present invention covers using these agents to treat sensorineural hearing loss, and other forms of neurologically-mediated hearing loss.
There are various mechanisms whereby these cytokine antagonists may favorably influence the degree of hearing loss and the course and natural history of these disorders. The most direct mechanism is, of course, through their profound anti-inflammatory action. Inflammation can occur at any anatomic site in the auditory pathway, from the cochlea to the eighth cranial nerve to the brainstem or may even involve the higher auditory pathways of the brain. Additionally these agents may exert their beneficial effect through other mechanisms, such as through anti-apoptotic pathways. The exact locations at which these medications exert their beneficial effects for the treatment of hearing loss will undoutedly vary depending upon
Channavajjala Lakshmi
Page Thurman K.
Sutton Ezra
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