Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
2000-04-21
2003-07-15
Swartz, Rodney P (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Bacterium or component thereof or substance produced by said...
C424S009200, C424S093400, C424S184100, C435S174000
Reexamination Certificate
active
06592875
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates generally to the treatment of Lyme Disease and compositions for use therein.
Lyme Disease is a tick-bourne multisystem inflammatory disorder caused by the spirochete
Borrelia burgdorferi
. The disorder was first recognized in 1975 because of a clustering of cases in Lyme Connecticut. In the United States, the white-footed mouse and deer are the preferred hosts for the immature and adult ticks (
I. dammini
), respectively.
The disease is divided into early disease (stages 1 and 2) and late disease (stage 3). Stage 1 is characterized by the presence of a distinctive skin lesion, erythema migrans. Stage 2 is a disseminated phase of the infection, with manifestations in the skin, CNS, musculoskeletal system and heart. Late disease, or stage 3 reflects persistent infection that is clinically manifest for more that one year after onset. Common clinical features include carditis, neurologic abnormalities and arthritis.
Treatment of active Lyme disease consists of administration of appropriate antibiotics although treatment of acute disease is reported to be more successful than treatment of chronic disease. Early studies indicated that oral tetracycline treatment of early localized Lyme disease reduces the likelihood of later neurologic, cardiac and rheumatic complications. Doxcycline is currently the drug of choice for this early stage. Administration of ceftriaxone is recommended for treatment of the cardiac, neurologic, and rheumatologic manifestations of disseminated and persistent Lyme disease.
The most practical means of preventing Lyme disease is to minimize exposure to ticks by wearing protective clothing, using acaricides and avoiding the habitat of the host vectors. Recently, a vaccine comprising a recombinant
B. burgdorferi
outer-surface lipoproteins (Osp A) has been tested in animals and in humans. This Lyme disease vaccine (LYMErix™, SmithKline Beecham Biologicals) has been shown to serve as a protective antigen in animals and as a safe immunogen in humans. The LYMEriX™ vaccine is administered at a dosage of 30 micrograms of recombinant Osp A lipoprotein at 0, 1 and 12 months with all three doses required to achieve optimal protection.
B. burgdoiferi
expresses OspA while residing in the midgut of the infected tick, but OspA is down regulated after tick attachment and is usually undetectable or absent when
B. Burgdorferi
is inoculated into the human host. Schwan et al. Proc. Natt. Acad. Sci. (USA) 92/;2909-2913 (1995). Therefore, a novel hypothesis has been proposed to explain the effectiveness of lipoprotein OspA vaccination. When infected ticks bite humans who have been vaccinated with recombinant OspA, the vaccine-induced antibodies are taken up by the tick and interact with the
B. Burgdorferi
in the midgut of the tick, thereby preventing transmission of the organism to the host. This mechanism has been suggested by a pre-clinical study in which
B. Burgdorferi
were detected by immunofluorescence assay in none of the ticks that fed on OspA-immunized mice, compared with 72% of ticks that fed on control-immunized mice. Fikrig et al. Proc. Natl. Acad. Sci. (USA) 89:5418-5421 (1992).
Despite such advances in prevention of Lyme disease there still remains a need for improved methods of treatment for the disease.
SUMMARY OF THE INVENTION
The invention provides methods for treating a patient suffering from Lyme disease comprising the step of: administering a composition comprising a
Borrelia burgdorferi
antigen at a sub-vaccine level effective to alleviate symptoms of Lyme disease. Suitable antigens for use according to the invention include outer surface lipoproteins of
Borrelia burgdorferi
such as the outer surface lipoproteins OspA, OspB, OspC and the antigen LFA-a. A preferred antigen for use according to the invention is lysed
Borrelia burgdorferi
produced by treatment of the organism in phenol followed by multiple freeze/thaw cycles. Borrelia burgdorferi for use according to the invention is publically available as ATCC deposit 35210.
The
Borrelia burgdorferi
antigens are administered at sub-vaccine levels. Sub-vaccine levels are defined as levels less than those sufficient to induce an effective humoral immune response as exemplified by the determination of a positive wheal upon subcutaneous injection. According to one aspect of the invention, the composition comprises from about 0.5×10
−6
g to about 0.02×10
−6
g of the outer surface lipoprotein per dose and from one to four doses are administered daily. More preferably, the composition is administered at a dosage of about 0.1×10
−6
g of the outer surface lipoprotein. The compositions of the invention may be administered to patients by a variety of suitable methods with means selected from the group consisting of sublingual, subcutaneous, intravenous, intramuscular, and intrathecal administration being preferred. Particularly preferred methods of administration are sublingual and subcutaneous methods of administration. When the composition is administered sublingually, it is preferred that four doses be administered daily. When the composition is administered by injection such as subcutaneously, it is preferred that it be administered in a single daily dose.
According to one preferred method the composition is administered to a patient in a single dose of about 0.05 cc in a pharmaceutically acceptable carrier. Such pharmaceutically-acceptable carriers include water, saline, albumin, and dextrose and combinations thereof.
Compositions of the invention for treatment of the symptoms of Lyme disease comprise
Borrelia burgdorferi
antigens at a sub-vaccine level effective to alleviate symptoms of Lyme disease in a pharmaceutically acceptable carrier. Preferred are compositions which comprise from about 0.5×10
−6
g to about 0.02×10
−6
g of the
Borrelia burgdorferi
per dose with those comprising about 0.1×10
−6
g of the
Borrelia burgdorferi
per dose being most preferred.
Additional aspects and advantages of the invention will become apparent upon consideration of the following detailed description thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the discovery that the administration of
Borrelia burgdorferi
antigens at a sub-vaccine levels is effective to alleviate symptoms of Lyme disease. While not wishing to be bound by a particular theory of invention, it is believed that many of the symptoms of Lyme Disease result as a consequence of a hypersensitivity reaction to
Borrelia burgdorferi
that becomes an auto-immune disorder. The therapy of the invention functions to interrupt the hypersensitivity reaction by inducing suppressor T cells that shut down effector cells (helper T cells, mast cells and killer T cells) that promote the auto-immune response.
REFERENCES:
patent: 5178859 (1993-01-01), Simon et al.
patent: 5582829 (1996-12-01), Alliger et al.
patent: 5688512 (1997-11-01), Bergstrom et al.
patent: 5807685 (1998-09-01), Flavell et al.
Marshall Gerstein & Borun
Milkhaus Laboratory, Inc.
Swartz Rodney P
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