Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Animal cell – per se – expressing immunoglobulin – antibody – or...
Reexamination Certificate
2001-09-19
2004-08-10
Park, Hankyel T. (Department: 1648)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Animal cell, per se, expressing immunoglobulin, antibody, or...
C435S334000, C530S388300, C530S388500
Reexamination Certificate
active
06773916
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates, in general, to treatment and diagnosis of ocular disorders. More particularly, the invention is concerned with methods of treating and diagnosing ocular disorders using sub-immunoglobulin antigen-binding molecules.
BACKGROUND OF THE INVENTION
Various ocular disorders are known but for many of these, there are less than optimal methods of treatment or diagnosis available. For example, acute anterior uveitis, an inflammation of the iris and ciliary body, is a common condition with a lifetime cumulative incidence of 0.4% in the general population (Rothova et al, 1987,
Am. J. Opthalmol.
103: 137-145). Disease tends to start in childhood or young adulthood, is frequently bilateral and is generally recurrent. Acute anterior uveitis is painful, is almost always associated with some morbidity, and can be blinding. This disease is an antigen driven, delayed-type hypersensitivity response controlled by T lymphocytes (Smith et al, 1998,
Immunol. Cell Biol.
76:497-512). Topical corticosteroids are used to control inflammation but are themselves associated with significant complications including cataract, steroid-induced glaucoma and infection.
Corneal graft rejection is another ocular disorder that suffers from a paucity of efficacious treatments. The success rate for corneal transplantation in Australia is 62% at 10 years (Williams et al, 1993,
Aust. NZ. J. Opthalmol.
21: 1-48). Irreversible rejection is the major cause of corneal graft failure, accounting for at least 30-50% of all cases, and occurs despite universal use of topical glucocorticosteroids (Williams et al, 1993,
Aust. NZ. J. Opthalmol.
21: 1-48). Adjunctive treatment with systemic immunosuppressants such as cyclosporin A is used occasionally, but probably confers little benefit on graft survival and can be associated with serious morbidity (Williams et al, 1993,
Transplantation Reviews.
7: 44-64).
Herpetic keratitis is caused by herpes simplex virus infection of the trigeminal ganglia (Streilein et. al. 1997,
Immunol. Today.
18: 443-9, Hendricks, R. L. 1997,
Cornea.
16: 503-6). Herpetic eye disease is the most common infectious cause of blindness in developed countries (Streilein et. al. 1997,
Immunol. Today
18: 443-9) and serious sequelae including pain, iritis, bacterial superinfection, corneal perforation and blindness occur in 3% of affected individuals. Epithelial herpetic disease (e.g. dendritic ulceration) is readily diagnosed by polymerase chain reaction (PCR)-based tests, amongst others, and can be treated reasonably successfully with antiviral agents. Diagnosis and treatment are far more difficult for disciform endotheliitis, or for the stromal disease (e.g. disciform keratitis, irregular stromal keratitis, kerato-uveitus) that occurs in one fifth of patients with ocular herpes. It is unusual to find virus particles in stromal biopsy specimens, and very difficult to culture virus from them. Diagnosis is usually made on clinical grounds and by exclusion. Topical acyclovir is the treatment of choice for herpetic keratitis (although emergence of drug-resistant strains is causing concern) and long-term oral prophylaxis halves the incidence of recurrences (Herpetic Eye Disease Study Group. 1998,
N. Engl. J. Med.
339: 300-6). However, corneal damage is not prevented by acyclovir. The pathogenesis of epithelial disease results from productive, lytic infection of corneal epithelial cells. In contrast, the pathogenesis of stromal or endothelial cell herpetic disease results from an immune reaction to viral antigen expressed on corneal cells or released into the stroma (Streilein et. al. 1997,
Immunol. Today
18: 443-9, Hendricks, R. L. 1997
Cornea
16: 503-6).
Reference also may be made to acanthamoeba keratitis, a very serious, painful disease that can result in loss of vision in the affected eye. The condition, caused by a common, free-living, soil and freshwater amoeba (Acanthamoeba), was once thought to be rare, but there has been an exponential increase in the number of reported cases over the past 5-10 years. Over 90% of cases have occurred in contact lens-wearers who have not adhered to recommended lens cleaning and disinfection procedures. Of critical importance in achieving a good visual outcome is early diagnosis. In the early stages of infection, amoebae are found in the corneal epithelium where they can be removed by debridement, often without the need for antimicrobial agents (Brooks et al. 1994,
Cornea
13:186-189). Unfortunately, the diagnosis is often delayed, as the clinical picture can resemble other forms of infectious keratitis, particularly herpetic keratitis. This allows the organisms to invade the corneal stoma where they attack keratocytes (Badenoch et al. 1995,
Int. J. Parasitol.
25: 229-239) and cause irreversible tissue damage. In this situation, attempting to achieve a laboratory diagnosis by corneal scrapings is usually unsuccessful and deep biopsy, itself damaging, is unreliable.
Immunoglobulins have gained widespread diagnostic and therapeutic application in various medicinal fields. For example, whole monoclonal and/or polyclonal antibodies have been used to suppress transplant rejection, to modulate different autoimmune diseases, to treat neoplasias, and to prevent and treat infectious diseases. Typically, systemic administration of antibodies is required for these purposes, which may cause serious systemic side effects. These side effects have prevented the systemic application of antibodies for treating diseases affecting non-vital organs like the eye. However, there are many ocular diseases such as those described above, where antibody treatment would have advantages.
In view of the above, Whitcup et al (WO 93/06865) disclose the use of monoclonal antibodies against cell adhesion molecules to treat ocular inflammation. In particular, Whitcup et al contemplate administration of such antibodies to the eye by intravenous injection, by intracameral or periocular injection, by surgical implantation of a depot, and by topical administration using eye drops or ophthalmic ointment. Whitcup et al provide enabled methods for parenteral administration of anti-cell adhesion molecule antibodies in an animal model. However, they do not provide any enabled methods for topical administration of such antibodies and are wholly silent on any data establishing the utility of the claimed methods. In fact, the present inventors have found that conventional whole antibodies alone cannot penetrate the cornea or the sclera via topical routes.
Various anatomical barriers relating to the eye may underlie the poor intraocular penetrance of whole antibodies. In this regard, the cornea is the principal barrier to entry of foreign substances. It has two distinct penetration barriers, the corneal epithelium and the corneal stroma (Burstein and Anderson, 1985,
J. Ocul. Pharmacol.
1(3): 309-26; Maurice D M, 1980,
Int. Ophthalmol. Clin.
20(3):7-20; and Mishima S, 1981,
Invest. Ophthalmol. Vis. Sci.,
21(4): 504-41). The corneal epithelium is a major barrier for hydrophilic substances. Hydrophilic molecules less than 350 Da can enter via a paracellular route, but larger hydrophilic molecules are essentially barred. This barrier function can be modulated to an extent by the use of penetration enhancers. The second barrier, the corneal stroma, interferes with penetration of lipophilic drugs and large hydrophilic drugs. The corneal stroma is regularly quoted as being “transparent” to hydrophilic molecules of up to 500 kDa (Bartlett and Jaanus in
Clinical Ocular Pharmacology
). This figure however is contradicted by studies of Olsen et al (1995,
Inv. Ophihal. Vis. Sci
36(9): 1893-1903) who showed in vitro that human scleral permeability decreased linearly with increasing molecular weight of hydrophilic compounds up to about 40 kDa after which permeability decreased sharply. Comparative studies with bovine and rabbit stroma and sclera suggest that stroma is similar though slightly more transparent (Maurice and Polgar, 1977,
Exp. Eye Res.
25:
Coster Douglas John
Thiel Michael Alexander
Williams Keryn Anne
Zola Heddy
Burrous Beth A.
Foley & Lardner LLP
Park Hankyel T.
The Flinders University of South Australia
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