Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,...
Patent
1994-06-22
2000-09-19
Chin, Christopher L.
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
4241331, 4241371, 4241541, 435 696, 5303873, 5303875, 5303882, 53038873, 53038875, 530395, 536 2353, A61K 39395
Patent
active
061207667
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a method of treatment of certain auto-immune conditions in a human or animal subject.
The cells and molecules in an animal body do not normally stimulate an adaptive immune response in that body as a result of a number of mechanisms which ensure a state referred to as "self-tolerance". However, in certain circumstances these mechanisms may fail to prevent the stimulation of such an immune response and this condition is referred to as "auto-immunity". A number of diseases in humans and animals are now thought to result from auto-immunity.
Multiple sclerosis is a demyelinating disease of the central nervous system the onset of which generally occurs within the age range from about 15 to 45. Myelin is a fatty substance which forms a sheath around certain nerve fibres and which conducts nervous impulses at a rate which enables muscles to make precise and delicate movements. The disease is characterised by induration of the sheath substance leading to the formation of plaques of varying size and location which interfere with the impulses normally conducted by the sheath. The course of the disease can be highly variable in individual patients and may be subject to periods of spontaneous remission. However, the disease generally results in progressive deterioration of the control of muscle function with ultimate paralysis in many cases. The precise cause of multiple sclerosis is unknown and it may result form a complex interaction of a number of different factors. However, it is now generally recognised that there is at least an autoimmune component in the causation of the disease.
The CDw52 antigen (a 23 kDa glycoprotein also referred to as CAMPATH-1) is strongly expressed on the surface of all human lymphocytes and most monocytes but is absent from other blood cells including stem cells. A number of antibodies have been developed directed against CDw52 which is an unusually good target for complement-mediated attack. Antibodies against CDw52 bind to all lymphocytes and monocytes but lyse only lymphocytes (T and B) in vivo. Antigens similar to CDw52 are expressed in other mammalian species.
Antibodies which have been developed against CDw52 and which have been used in therapy include the following:
CAMPATH-1M is a rat IgM monoclonal antibody which has been used extensively in vitro for purging bone marrow harvests in order to deplete the T cell population prior to bone marrow transplanation. Marked reduction in the incidence and severity of graft-versus-host disease has been seen with this therapy.
CAMPATH-1G is a rat IgG2b class-switch variant of an IgG2a antibody recognising the CDw52 antigen which has been used in vivo to achieve immunosupression in more than 100 patients undergoing organ and bone marrow transplantation, management of organ rejection and treatment of haematologic malignancies with a high level of success. However, the rapid development of an anti-rat immunoglobulin response, including the possibility of anaphylaxis, is likely to limit the use of rat monoclonal antibodies against the CDw52 antigen in humans in vivo.
CAMPATH-1H is a genetically manipulated IgG antibody obtained by grafting the complementarity determining regions from CAMPATH-1G into human framework regions. The resulting "humanized" antibody is highly effective in vitro being equivalent to the rat monoclonal antibody at complement lysis and two to four times better in cell-mediated lysis of human lymphocytes. No limiting anti-globulin response is anticipated with this humanized antibody.
Expression of CAMPATH-1H was achieved initially in rat myeloma cells by placing DNA encoding the engineered antibody chains in genomic context under control of the immunoglobulin promoter/enhancer. CAMPATH-1H has recently been expressed to high levels in Chinese hamster ovary (CHO) cells.
It has now surprisingly been found that antibodies against the CDw52 antigen may be effective in the treatment of multiple sclerosis.
The present invention provides a method of treatment of a human subject suffering from multip
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Hale Geoffrey
Waldmann Herman
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