Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Reexamination Certificate
2001-01-31
2001-09-25
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
Reexamination Certificate
active
06294171
ABSTRACT:
BACKGROUND OF THE INVENTION
The therapeutic use of antibodies is generally limited to: (a) imimunotherapy where a specific antibody directed against a discreet antigen is used to counter the effect of that antigen. Examples include using an antitoxin administered to neutralize a toxin, or antibody against an infectious agent to interrupt the pathophysiological process induced by that target organism; (b) the administration, often iv, of high levels of antibody (gamma globulin therapy) to compensate for transient or permanent immune deficiency; and (c) monoclonal antibody therapy to combat cancer, certain autoimmune disorders and metabolic diseases. In all these cases, antibody is provided in relatively high concentrations for the purpose of having that antibody combine directly with its target antigen to render that antigen inoperable, non-infectious or neutralized. For example, Gamnimune™ (Bayer Biological) contains 50 mg protein (immunoglobin) per mL and normal dosing can be up to 1000 mg/kg body weight. Ganunar—P™ I.V. (Aventis Behring) is administered at dosages up to 400 mg/kg body weight. Bayhep B™ (Hepatitis B knunoglobulin) (Bayer Biological) is 15-18% protein [immunoglobulin] is administered at dosages of up to 0.6 ml/kg body weight=0.01 g/kg =100 mg/kg. Further, hnogam Rabies—HT™ (Aventis Pasteur) is 10-18% protein and is administered at a dosage of 0.133 ml/kg (240 mg/kg) body weight.
Of interest to the present application is the disclosure of co-owned, allowed U.S. patent application Ser. No. 09/514,993 which is directed to the administration of anti-ruibeola antibodies for the treatment of symptoms of various central nervous system diseases including autism, multiple sclerosis, attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD). Examples therein emonstrated the efficacy of treating the symptoms of those disease states with dosages of from 0.1 mg to 1 mg of anti-rubeola antibody per dose.
While the administration of larger quantities of immunoglobulins is effective in the treatment of many disease states there remains a dosire in the art for alternative methods for treatment of disease states.
SUMMARY OF THE INVENTION
The present invention is directed to the discovery that the symptoms of disease states associated with the presence of a toxin or infectious agent may be effectively treated by administration of very low levels of antibodies specific for the toxin or infectious agent. The levels of antibodies admninistered are substantially lower than those traditionally administered to directly neutralize target antigens and for example are typically less than 0.1 mg of antibody per day. Specifically, the antibodies may be administered in one or in multiple dosages but the sum of antibodies administered in any 24 hour period is less than 0.1 mg.
While the antibody may be monoclonal or polyclonal, it is preferably monoclonal according to one aspect of the invention. The antibody may be admninistered by a variety of manners but is preferably administered enterically and most preferably orally. Suitable methods of oral administration include oral drench and sublingual administration. According to another preferred aspect of the invention the antibody is administered in an enterically protected form. In addition, the antibodies of the invention may be administered by injection such as by subcutaneous injection.
The symptoms of various disease states can be treated according to the invention including those of various central nervous disorders including autism, multiple sclerosis, attention deficit disorder (ADD), and attention deficit hyperactivity disorder (ADHD), all of which can be treated by administration of very low levels of anti-rubeola antibody. Dosages of antibodies administered according to the invention including anti-rubeola antibodies range from 1×10
−10
to a 1×10
−1
mg/dosage with dosages of from 1×10
−5
to 1×10
−4
mg (e.g. 8×10
−5
mg) and dosages of from 2×10
−5
to 2×10
−3
mg being preferred.
The invention also provides treatment of the symptoms of pulmonary infection by administering an effective amount of anti-Mycoplasma pneumonia antibody with daily dosages of less than 0.1 mg being preferred and daily dosages ranging from 1×10
−5
to 1×10
−3
mg/day being particularly preferred.
The invention also provides treatment of symptoms of Alzheimer's Disease by administering an effective amount of anti-amyloid beta antibodies with daily dosages of less than 0.1 mg being preferred and daily dosages ranging from 1×10
−5
to 1×10
31 3
being particularly preferred.
According to a further aspect of the invention it has been discovered that administration of anti-rubeola antibodies can be effective in the treatment of symptoms of Crohn's Disease. Accordingly, the invention provides a method of treating the symptoms of Crohn's Disease comprising administering an effective amount of anti-rubeola antibody. Preferred dosages are less than 0.1 mg antibody daily with daily dosages ranging from 2×10
−5
to 2×10
−3
mg being particularly preferred.
According to a further aspect of the invention it has been discovered that the administration of anti-Klebsiella pneumnonia antibodies can be useful for the treatment of rheumatoid arthritis and specifically for juvenile rheumatoid arthritis. Preferred dosages are less than 0.1 mg of anti-Klebsiella pneumonia antibody daily with daily dosages ranging from 1×10
−4
to 1×10
−3
mg/day (e.g. 4×10
−4
mg/day) being particularly preferred.
The invention also provides methods for treating the symptoms of diabetes comprising the method of administering an effective amount of antibody directed against glutamnic acid decarboxylase. Preferred dosages are less than 0.1 mg of anti-glutamic acid decarboxylase antibody daily with daily dosages ranging from 1×10
−4
to 1×10
−3
mg/day (e.g. 4×10
−4
mg/day) being particularly preferred.
The invention also provides pharmaceutical compositions for administration to subjects for treatment of the symptoms of disease states comprising antibody specific for a toxin or infectious agent associated with the disease state in a dosage unit of less than 0.1 mg antibody.
DETAILED DESCRIPTION
Without intending to be bound by any particular theory of the invention, it is believed that the invention described herein utilizes antibodies in remarkably low concentrations as molecular signals to induce a response similar or even superior to that seen with the traditional approach of introducing antibody at concentrations several logs greater than that associated with this invention. However, even though the concentrations of antibody are significantly different between traditional use and this invention, the specificity of the reaction remains intact. That is, low level of antibody directed against target A will react with target A but not B, unless B is antigenically closely related to A.
The similarity in responses between traditional gammaglobulin therapy and the invention, and the disparity of concentrations of antibody to induce the desired result, recalls the relationship in concentrations of antigen, or antigenic extract, used by allergists employing the maximum tolerated dose approach to hypersensitivity therapy and those using the neutralization method.
In the case of the present invention results similar to those obtained by traditional gamma globulin therapy are reached by an apparently different pathway. The traditional approach of using specific antibody in high concentration to treat or counter a specific antigen is well understood in that the antibody makes direct contact with its antigen target, combines with it, and alones or in the presence of other factors, such as the complement system, the antigen is destroyed or neutralized. The mechanism of action of the present invention whereby antigens are
Henley III Raymond
Marshall Gerstein & Borun
Milkhaus Laboratory, Inc.
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