Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...
Reexamination Certificate
2000-07-06
2004-07-13
Swartz, Rodney P (Department: 1609)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
C424S009100, C424S009200, C424S130100, C424S139100, C424S141100, C424S150100, C424S164100, C424S184100, C424S185100, C435S007100, C530S300000, C530S350000
Reexamination Certificate
active
06761891
ABSTRACT:
DESCRIPTION
The invention concerns a pharmaceutical composition for treating Lyme disease and a vaccine against Lyme disease and it also concerns a process for obtaining an active agent for treating Lyme disease and a process for obtaining a vaccine against Lyme disease.
Lyme borreliosis is an infectious disease transmitted by ticks and is caused by the spirochete
Borrelia burgdorferi
. The disease is a chronic, progressive infection which attacks many organs, such as the skin, the central and peripheral nervous system, the heart, the liver, the kidneys, the musculoskeletal system and joints. Various symptoms such as acute arthritis and neuroborreliosis can disappear spontaneously but usually reoccur episodically. Spirochetes have been repeatedly isolated from untreated patients and there are numerous indications for persistent infections even after treatment with antibiotics. Since a dependable treatment of this disease by therapy with antibiotics is difficult, great efforts are being made to investigate the pathogen itself and the immune response of the host to infection with
B. burgdorferi
. Although a high titre of antibodies against
B. burgdorferi
is usually found during infection in persons afflicted by Lyme disease, this does not protect against the infection.
It was found that the outer surface lipoprotein A (OspA) of
B. burgdorferi
could be an effective vaccine for the prevention of Lyme disease (EP 0 418 827). Laboratory investigations on mice have shown that a substantial protection against the disease and infection can be obtained by OspA-specific antibodies (Schaible et al., Proc. Natl. Acad. Sci. USA 87 (1990), 3768-3772).
However, these antibodies are only effective if they are present when the pathogen is transmitted. A reason for this may be that OspA is mainly expressed on spirochetes in ticks but is no longer expressed after transmission to a mammalian host. Consequently it is indeed possible to use OspA-specific antibodies to prevent transmission of the disease but they are ineffective and thus unsuitable for therapeutic applications to treat the manifest disease. Recent investigations have shown that mice can be protected against a tick-transmitted infection after active immunization with recombinant OspC (Preac-Mursic et al., Infection 20 (1992), 342-349; R. D. Gilmore et al., Infect. Immun. 64 (1996), 2234-2239). However, the immunization protocol used in these investigations does not lead to an elimination of infectious spirochetes from the vector as was shown for the OspA-specific antibodies.
Hence the object of the invention was to provide a pharmaceutical preparation for treating Lyme disease.
This object is achieved according to the invention by a pharmaceutical composition for treating Lyme disease which is characterized in that it comprises an antibody as an active agent which is specific for the 24 kDa antigen (OspC) of
B. burgdorferi
. It was surprisingly found that high titres of OspC-specific antibodies resulted in a spontaneous disappearance of the disease and/or elimination of spirochetes in various species of mice. The pharmaceutical composition for treating Lyme disease preferably contains an antibody as the active agent which is specific for the 24 kDa antigen (OspC) of
B. burgdorferi
having the sequence shown in SEQ ID NO.2.
It surprisingly turned out that the passive transfer of polyclonal OspC-reactive immune serum into
B. burgdorferi
-infected scid mice leads to a complete disappearance of chronic arthritis and carditis and to elimination of the pathogen. A critical threshold of OspC-specific antibodies which is between 3 and 10 &mgr;g anti-OspC antibody appears to be important to effectively treat an infection. This means that spirochetes express OspC in the mammalian host and are sensitive to protective antibodies in the affected tissue during infection. Thus an attack on OspC is relevant for a successful therapeutic treatment of Lyme disease.
Earlier investigations have shown that immune sera from
B. burgdorferi
-infected mice only ensure a complete protection against disease and infection when they have been administered before but not after inoculation with the pathogen. In the present invention it is shown that antibodies against OspC can lead to a spontaneous disappearance of the infection and inactivation of the spirochetes in the vertebrate. Furthermore it was found that it is possible to eliminate arthritis and carditis with polyclonal OspC-specific immune sera and to heal existing spirochete infections in C.B.-17 scid mice irrespective of whether the antibodies were administered before the disease occurred (e.g. 10 days before infection) or alternatively at a time when the disease had completely broken out (on day 19 after infection) or whether it was a chronic disease (day 60 after infection). The complete disappearance of the disease and elimination of the pathogen were dose-dependent and were achieved with 1 &mgr;g to 10 mg anti OspC antibody/mouse, preferably 5 &mgr;g to 20 &mgr;g anti OspC antibody/mouse.
Inflammatory lesions of the joints or in the heart of
B. burgdorferi
-inoculated scid mice were completely eliminated by polyclonal immune sera against OspC even when they were administered at a time when a chronic disease was present i.e. on the 60th day p.i.
REFERENCES:
patent: 94 25596 (1994-11-01), None
Bockenstedt, L.K., et al., “Borrelia burgdorferi strain-specific osp C-mediated immunity in mice.” Infection and Immunity, vol. 65, No. 11, pp. 4661-4667, Nov., 1997.*
Barthold et al., “Protective and arthritis-resolving activity in sera of mice infected with Borrelia burgdorferi”, Clinical Infectious Diseases, vol. 25, No. 1 suppl, Jul. 1997, pp. s9-s17.
Edelman et al, “The seventh international congress on lyme borreliosis: progress on the development of Lyme disease vaccines”, Vaccine, vol. 15, No. 5, Apr. 1997, pp. 463-464.
Gilmore et al., “Outer surface protein C (OspC), but not p39, is a protective immunogen against a tick-transmitted Borrelia burgdorferi challenge . . . ” Infection and Immunity, vol. 64, No. 6, Jun. 1996, pp. 2234-2239.
Zhong et al., “Therapeutic passive vaccination against chronic Lyme disease in mice”, PNAS, vol. 94, No. 23, Nov. 11, 1997, pp. 12533-12538.
Kramer Michael D.
Simon Markus M.
Wallich Reinhard
Zhong Weimin
Max-Planck-Gesellschaft zur Forderung der Wissenschaften E.V.
Rothwell Figg Ernst & Manbeck P.C.
Swartz Rodney P
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