Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
2001-09-05
2004-04-20
Mertz, Prema (Department: 1646)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C530S387100, C530S387300, C530S388220, C536S023400, C536S023500
Reexamination Certificate
active
06723538
ABSTRACT:
TECHNICAL FIELD
This invention relates generally to cell biology, virology and medicine. In particular, the invention is directed to chimeric polypeptides, e.g., bispecific antibodies, comprising a chemokine receptor binding domain and a T cell surface polypeptide, a cell toxin, or a cell toxin binding domain, nucleic acids that encode them, and methods of making and using them. The chimeric polypeptides of the invention can include, be bound to, or attached to, a cell toxin. The invention is also directed to making and using pharmaceutical compositions, for example, for the treatment of immunological (e.g., autoimmune) disorders and for the targeted elimination of cells, e.g., T lymphocytes and other cells latently infected with a primate immunodeficiency virus, such as a human immunodeficiency virus, e.g., HIV-1. The pharmaceutical compositions and methods of the invention can be used for the treatment, prevention and/or alleviation of inflammatory joint and renal diseases, inflammatory bowel diseases, multiple sclerosis, skin diseases, diabetes or transplant rejection.
BACKGROUND
Immunological diseases/disorders, like autoimmune diseases, inflammation disorders as well as infectious diseases are not only increasing but represent substantial threats to global health. For example, in Germany, about 1% of the population suffer from the autoimmune disease rheumatoid arthritis. In addition, there is a number of other joint diseases also leading to arthritis. Currently, three groups of drugs-non-steroidal anti-rheumatics, cortisone preparations and second-line agents- and TNF&agr; blocking agents are used for treating inflammatory joint diseases. Up to now, the therapy has focused on the local injection of cortisone preparations in combination with a systemic administration of anti-phlogistics or second-line agents.
Non-steroidal anti-rheumatics have a mild analgetic and anti-inflammatory effect, but they have many side effects when applied frequently (e.g. gastric ulcers, nephroses). In high dosages, cortisone preparations have a strong decongestant and analgetic effect, however, leading to a quick relapse after discontinuation of the therapy. Moreover, cortisone preparations cannot stop the destruction process of the joint disease. A long-term therapy with cortisone usually entails severe side effects, such as infections, Cushing's phenomenon, osteoporosis, parchment-like skin, metabolic and hormonal disorders. The local injection of cortisone also has the essential disadvantage that the activity of the migrated white blood cells is only reduced. As the infiltrating cells are not destroyed, a quick relapse occurs after discontinuation of the therapy. As mentioned above, the same applies to the systemic application. Rarely, inflammation due to the irritative effect of cortisone crystals is aggravated after injection of cortisone. The duration of effect of a cortisone injection varies tremendously and ranges from primary ineffectiveness to a duration of effect of several weeks.
In rheumatology, second-line agents are used to achieve a long-term suppression of the inflammation and a reduction in cortisone preparations. Due to the considerable toxicity (e.g., allergies, infections, malignant diseases, renal insufficiency, blood pressure crises, pulmonary diseases) it is necessary for medical specialists to attend closely to the patients. After beginning treatment, no therapeutic effect may be apparent for the first three months. Currently, there are 4 or 5 of such second-line agents at disposal, which are used individually at first or are combined if the therapy is not effective. Mostly, there is hardly anything known about the mode of action of second-line agents. It is not yet entirely clear whether the application of second-line agents can diminish the destruction of the joint.
In recent years, a new group of substances has been introduced into the treatment of rheumatoid arthritis, which is based on the blocking of cell signal substances, particularly TNF&agr;, by means of monoclonal antibodies or soluble receptor constructs.
In addition, there are patients that do not respond to currently available therapies. In other cases, the conventional therapy has to be stopped due to intolerable side effects.
A similar situation exists for many other inflammatory and autoimmune diseases like inflammatory renal diseases, inflammatory bowel diseases, multiple sclerosis and transplant rejection, where current treatments have many limitations. For example, agents used in inflammatory and autoimmune diseases include anti-inflammatory and immunosuppressive agents like azathioprine, cyclophosphamide, glucocorticoids like prednisone; immunosuppressants like cyclosporin A, Tacrolimus (FK506), Sirolimus (Rapamycin); and protein drugs like calcineurin, beta-interferon, anti-TNF alpha monoclonal antibodies (remicade). These agents show general immunomodulating effects and therefore efficacy and side effects profiles can pose severe limitations for the treatment options; see, e.g., Harrison's Principles of Internal Medicine, eds. Fauci et al., 14
th
edition, McGraw-Hill publisher.
Inflammatory bowel diseases, such as Crohn's disease, ulcerative colitis, are treated with the anti-inflammatory agents sulfazsalazine (Azulfidine) and glucocorticoids, like prednisone and, in selected cases, with TNF-&agr; blocking agents. In ulcerative colitis immunosuppressive therapy with drugs such as azathioprine is well established, in severely ill patients the potent immunosuppressive agent cyclosporine is used (see, e.g., Harrison's Principles of Internal Medicine, eds. Fauci et al., 14
th
edition, McGraw-Hill publisher). In many cases no sufficient reduction of disease activity is achieved with current drugs, such that even surgical intervention is sometimes necessary.
Inflammatory renal diseases (nephritis) are treated with e.g. glucocorticoids, alkylating agents and/or plasmapheresis. Additional diseases with similar treatment options include systemic lupus erythematosus (SLE), Sjogren's syndrome, polymyositis, dermatomyositis, mixed connective tissue disease, anti-phospholipid-antibody syndrome.
For some of these diseases, few therapeutic options have been available up to now. All these diseases share an inflammatory component. However, the inflammatory component cannot be sufficiently suppressed by the currently available drugs. For some drugs, e.g. alkylating agents a maximal lifetime dose per patient cannot be exceeded.
Transplant rejection is treated using immunosuppressive agents including azathioprine, mycophenolate mofetil, glucocorticoids, cyclosporine, Tacrolimus (FK506), Sirolimus (Rapamycin). A combination of steroids and a low dose of mouse monoclonal antibody OKT3 binding to CD3 on T-cells is used to anergize and deplete T-cells. Therapy is continued using immunosuppressants like cyclosporine. Mouse anti-human antibodies (MAHAs) have common side effects and limit the use of OKT3 (Fauci et al., supra, pp. 2374-2381).
Approaches to treat multiple sclerosis include treatments which effect the overall immune system like anti-inflammatory agents including azathioprine, cyclophosphamide, prednisone, corticosteroids, cyclosporin A, calcineurin, Rapamycin, beta-interferon (see, e.g., Fauci et al., supra, pp. 2415-2419; Wang (2000) J. Immunol. 165:548-557). In addition, a number of non-specific treatments are administered that may improve the quality of life including physical therapy and psycho-pharmacological agents. None of the treatment options mentioned above has a curative effect. Even the most promising compound, &bgr;-interferon, leads only to a slower disease progression, while exhibiting significant side effects.
Furthermore, human immunodeficiency virus-type 1 (HIV-1), the most common cause of AIDS, has infected more than 50 million individuals (including those who have died), and the rate of new infections is estimated at nearly 6 million per year (AIDS Epidemic Update: December 1999 (UNAIDS, Geneva, 1999), www.unaids.org). Equally disturbing are the uncertainties of
Mack Matthias
Schlondorff Detlef
Spring Michael
Fish & Richardson P.C.
Mertz Prema
Micromet AG
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