Autoimmune diseases, such as systemic lupus erythematosus (SLE), myasthenia gravis (MG) and idiopathic thrombocytopenic purpura (ITP), among others, remain clinically important diseases in humans. As the name implies, autoimmune diseases wreak their havoc through the body""s own immune system. While the pathological mechanisms differ between individual types of autoimmune diseases, one general mechanism involves the binding of certain antibodies (referred to herein as self-reactive antibodies or autoantibodies) present in the sera of patients to self nuclear or cellular antigens.
SLE has an incidence of about 1 in 700 women between the ages of 20 and 60. SLE can affect any organ system and can cause severe tissue damage. Numerous autoantibodies of differing specificity are present in SLE. SLE patients often produce autoantibodies having anti-DNA, anti-Ro, and anti-platelet specificity and which are capable of initiating clinical features of the disease, such as glomerulonephritis, arthritis, serositis, complete heart block in newborns, and hematologic abnormalities. These autoantibodies are also possibly related to central nervous system disturbances. Kidney damage, measured by the amount of proteinuria in the urine, is one of the most acute areas of damage associated with pathogenicity in SLE, and accounts for at least 50% of the mortality and morbidity of the disease. The presence of antibodies immunoreactive with double-stranded native DNA is used as a diagnostic marker for SLE.
Antibodies are composed of heavy and light polypeptide chains which are joined by disulfide bridges. Antibodies are divided into different classes according to their heavy chain structure; antibodies belonging to the same class are referred to as isotypes of each other. In addition, antibodies of a given isotype can be divided into subtypes. Antigenic determinants on antibodies that differ among animals that have inherited different alleles are referred to as allotopes; antibodies that share an allotope are referred to as members of the same allotype. Another type of antigenic determinant present on antibody molecules are those found primarily in the hypervariable region of the antigen binding site of the antibody. These determinants are referred to as idiotopes; antibodies that share an idiotope are referred to as members of the same idiotype. Idiotypic determinants are controlled by both genetic and antigenic influences. Antibodies having common or shared idiotypes generally exhibit the same antigenic specificity. However, antibodies from genetically different individuals which share a common antigenic specificity may exhibit idiotypic heterogeneity but, in some instances, show a major cross-reactive antigenic determinant. Thus, antibodies which bind the same antigen may have distinct idiotypic determinants, but also may share cross-reacting properties.
Currently, there are no really curative treatments for patients that have been diagnosed with SLE. From a practical standpoint, physicians generally employ a number of powerful immunosuppressive drugs such as high-dose corticosteroids, azathioprine or cyclophosphamidexe2x80x94many of which have potentially harmful side effects to the patients being treated. In addition, these immunosuppressive drugs interfere with the person""s ability to produce all antibodies, not just the self-reactive anti-DNA antibodies. Immunosuppressants also weaken the body""s defense against other potential pathogens thereby making the patient extremely susceptible to infection and other potentially fatal diseases, such as cancer. In some of these instances, the side effects of current treatment modalities can be fatal.
One method of treatment for SLE, described in Diamond et al. (U.S. Pat No. 4,690,905), consists of generating monoclonal antibodies against anti-DNA antibodies (the monoclonal antibodies being referred to therein as anti-idiotypic antibodies) and then using these anti-idiotypic antibodies to remove the pathogenic anti-DNA antibodies from the patient""s system. However, there are several drawbacks to this approach. For example, the removal of large quantities of blood for treatment can be a dangerous, complicated process. Essentially, blood is removed from a patient, treated to remove the anti-DNA antibodies, and then the treated blood returned to the patient. Such a removal technique would be similar to that used for hemodialysis, i.e., via an arterial passage. This type of treatment would be inconvenient (a qualified professional would be required to conduct treatment regularly), expensive, painful, and in some instances might subject the patient to a risk of infection and/or hemorrhaging, as well as depletion of effective blood volume inducing circulatory collapse, acute left ventricular failure or acute renal failure. One treatment session may take hours to complete. It also could present certain other risks: heart failure caused by the rapid transfer of blood, blood loss, acute kidney failure due to temporary major depletion of effective circulating plasma volume, and/or the possible spreading of dangerous diseases such as HIV, hepatitis B, and hepatitis C. The therapeutic method of the present invention avoids these problems. It merely requires an injection, or other equivalent mode of administration, of an antibody composition to the patient.
High dose intravenous immune globulin (IVIG) infusions have also been used in treating certain autoimmune diseases. Previous studies have indicated that IVIG may contain anti-idiotype activity against anti-DNA antibodies, as well as many other autoantibodies (Jordan, S. C., 1989; Silvestris et al., 1994; Mouthon et al., 1996; Silvestris et al., 1996). The effects of IVIG infusions are apparently related to changes in the repertoire of autoantibodies expressed in the patient. This modulation of pathogenic Id antibodies is thought to depend on their specific interaction with the regulatory anti-idiotype molecules that occur naturally in healthy donors. Production of anti-idiotypic antibodies inhibiting the potentially harmful autoimmune repertoire may result from activation of the Id network committed to controlling the secretion of natural autoantibodies by CD5-positive B cells.
Up until the present time, treatment of SLE with IVIG has provided mixed results, including both resolution of lupus nephritis (Akashi et al., 1990), and in a few instances, exacerbation of proteinuria and kidney damage (Jordan et al., 1989). The cause of this increase is not clear but it is believed that there is increased glomerular deposition of immune-complexed, polyreactive, non-Id-specific IgG antibodies.
As can be understood from the above, although there are several treatments for autoimmune disease such as systemic lupus erythematosus, all possess serious disadvantages. Thus, persons afflicted with SLE who show clinical evidence for SLE nephritis need a cost-efficient and safe treatment that will help prevent or ameliorate the tissue damage that leads ultimately to kidney failure and the need for chronic hemodialysis and/or renal transplantation caused by their condition.
The subject invention concerns novel compositions and methods for the treatment of antibody-based autoimmune diseases, and in particular, SLE. One aspect of the present invention concerns a therapeutic method for treating patients suffering from, or predisposed to, autoimmune disorders such as SLE nephritis. The method comprises administering an anti-idiotypic antibody composition to a patient afflicted with an autoimmune disease, wherein the anti-idiotypic antibodies selectively immunoreact with autoantibodies bearing the appropriate idiotype, thereby inhibiting the autoantibodies and their destructive autoimmune responses without inducing generalized immunosuppression. The novel anti-idiotypic antibody compositions, prepared in accordance with the procedures of the subject invention, comprise anti-idiotypic antibodies having specificity for pathogenic self-reactive antibodies in a patient""s body, thereby modulating the potential of the self-reactive antibodies to form immune complexes with self antigens and cause harm to normal cells and tissues, particularly within the patient""s kidney filtering systems. One embodiment of the present invention is a method for treating SLE using anti-DNA anti-idiotypic antibody compositions prepared from pooled human intravenous gamma globulin (IVIG). The potential risks and negative side effects associated with other current autoimmune disease therapies are avoided with the present method.
Another aspect of the subject invention concerns novel compositions comprising purified human anti-idiotypic antibodies which have binding specificity for self-reactive antibodies that are associated with clinical pathogenesis of certain autoimmune diseases. The antibody compositions are capable of modulating the deleterious effect of the self-reactive autoantibodies on cells and tissues of the affected patient. Specifically exemplified in the present invention is a purified anti-DNA anti-idiotypic antibody composition that can be used to treat patients afflicted with SLE nephritis.
In a further aspect, the subject invention is directed toward a method of producing the novel anti-idiotypic antibody compositions which can be used in the therapeutic method of the present invention. The subject antibodies can be produced by adsorbing pooled normal human gamma globulin with a solid phase substrate having antibody molecules attached thereto that selectively bind with anti-idiotypic antibodies present in the human gamma globulin, whereby an antibody/anti-id antibody complex is formed on the solid phase. The anti-idiotypic antibodies from the intravenous gamma globulin preparations are then eluted from the solid phase substrate. The procedure allows for the isolation and enrichment of anti-idiotypic antibodies from the other antibodies present in the pooled gamma globulin preparation.