Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Reexamination Certificate
2002-08-19
2004-03-30
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
C424S146100
Reexamination Certificate
active
06713058
ABSTRACT:
BACKGROUND OF THE INVENTION
The therapeutic use of antibodies is generally limited to: (a) immunotherapy, where a specific antibody directed against a discreet antigen is used to counter the effect of that antigen, e.g., 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 i.v., 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, metabolic diseases, and symptoms associated with neuropathic conditions. 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, Gamimune™ (Bayer Biological) contains 50 mg protein (immunoglobin) per mL and normal dosing can be up to 1000 mg/kg body weight. Gammar—P™ I.V. (Aventis Behring) is administered at dosages up to 400 mg/kg body weight. Bayhep B™ (Hepatitis B Immunoglobulin) (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, Imogam Rabies—HT™ (Aventis Pasteur) is 10-18% protein and is administered at a dosage of 0.133 ml/kg (240 mg/kg) body weight.
Diabetes mellitus is a metabolic disease state that is caused by a deficiency of insulin (Type I diabetes) or by the body's resistance to diabetes (Type II diabetes). The disease is characterized by chronic hyperglycemia, glycosuria, water and electrolyte loss, ketoacidosis, neuropathy, retinopathy, nephropathy, increased susceptibility to infection, and coma. Type I diabetes results from the autoimmune destruction of beta cells of the pancreas. Thus, proteins produced by beta cells have been a prime target in the study of diabetes as potential autoantigens that serve as the target for the immune response against the beta cells. One autoantigen found to correspond to the onset of Type I diabetes is glutamic acid decarboxylase (GAD) [Tisch, Roland, et al.,
Nature
366:72-75 (1993)]. Another example of a beta cell autoantigen is insulin.
Much of the research involving the autoimmune response against beta cells or the autoantigens thought to be involved in the autoimmune response has included the administration of autoantigens, immunogenic portions of autoantigens, or molecules that mimic the autoantigens. Tian, Jide, et al.,
Nat Med
2(12): 1348-53 (1996) discusses administration of GAD to alter the diverse immune response that can lead to diabetes. Ramiya, Vijayakumar K., et al.,
Autoimmunity
26:139-151 (1997) discussed administration of insulin and GAD in non-obese diabetic mouse to achieve anti-diabetic affects.
Glutamate decarboxylase (hereafter GAD) is the pyridoxal-5′-phosphate dependent enzyme that synthesizes gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in vertebrate brain (Qu et al.,
Protein Science
7:1092-1105 (1998)). Glutamic acid decarboxylase is of two types, GAD-65, which is highest in concentrations in the pancreas, and GAD-67, which is highest in concentration in the central nervous system. Each GAD is composed of two major domains: a C-terminal domain of about 500 amino acids, and a 95-100 amino acid n-terminal domain. The C-terminal domain contains the pyridoxal-P binding site and lengthy segments that have identical sequences in GAD-65 and GAD-67. The amino terminal domain of GAD targets membranes and forms heteromultimers of GAD-65 and GAD-67 (Dirkx et al.,
J. Biol. Chem.
270:2241-2246 (1995)). Phosphorylation sites have been found in GAD-65 (Namchuck et al.,
J. Biol. Chem.
272:1548-1557 (1997)). Pyridoxal-P plays a key role in the regulation of GAD activity. GAD is unusual, if not unique, among pyridoxal-P-dependent enzymes in the brain because it is present mainly in an inactive apoenzyme (GAD without bound pyridoxal-P) (Martin et al.,
J. Neuroscience
11:2725-2731 (1991)). This apoGAD serves as a reservoir of inactive enzymes that can be converted to active holoGAD when additional GABA synethesis is required (Porter et al.,
Biochem. J.
231:705-712 (1985)). The invention disclosed herein found treatment with GAD-65 antibody was most effective but not limited to treating patients suffering from diabetes while treatment with GAD-67 antibody was most effective but not limited to treating patients suffering from CNS disorders such as but not limited to multiple sclerosis, autism, Parkinson's disease, and pain related neuropathy.
Of interest to the present application is the disclosure of co-owned U.S. Pat. No. 6,187,309, which is directed to the administration of anti-rubella 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 demonstrated the efficacy of treating the symptoms of those disease states with dosages of from 0.1 mg to 1 mg of anti-rubella antibody per dose.
Autism is a complex developmental disorder that appears in the first 3 years of life. It affects the brain's normal development of social and communication skills. Autism is a spectrum that encompasses a wide continuum of behavior. Core features included impaired social interactions, impaired verbal and nonverbal communication, and restricted and repetitive patterns of behavior. The symptoms may vary from quite mild to quite severe. Autisms is a physical condition linked to abnormal biology and neurochemistry possibly linked to autoimmune disorder of type 1 diabetes and the autoantigen GAD.
The most distinctive feature of autistic children is that they appear isolated from the world around them and may appear detached, aloof, or in a dreamlike world. Autistic children often appear only vaguely aware of others in their environment, including family members, and frequently display unusual mannerisms and engage in ritualistic behavior. Appropriate play with other children or toys is uncommon and there is often a great interest in inanimate objects, especially mechanical devices and appliances. In many cases the disorder is evident during the first 30 months of life. Autistic children are normal in appearance, physically well developed and are usually boys (by a ratio of 3:1). Historically, children were frequently institutionalized by the ages of nine or ten because their parents were no longer able to control them. While, the availability and effectiveness of behavioral support services and advances in treatment and education of treatment of children with autism have reversed the trend toward institutionalization autistic children still require significant resources for their care.
There are no medical tests that can be used to determine autism. Instead, the diagnosis of autism is made when a subject displays six of 12 characteristic behaviors that match the criteria in the Diagnostic and Statistical Manual, Fourth Edition (DSM IV), published by the American Psychiatric Association. Subjects with autism, compared to other disabled persons of commensurate ability, are more difficult to teach and comparatively have significantly greater problems acquiring and using language and relating socially. Historically, about 75 percent of subjects with autism are classified as mentally retarded.
Autism was first described by Dr. Leo Kanner, a psychiatrist at John Hopkins University in the 1940′s who examined a group of 11 children who were self-absorbed and who had severe social, communication, and behavioral problems. It was originally believed that subjects with autism had good cognitive potentialities and that autistic children possessed latent genius that could be unlocked by discovery of the appropriate key for that child. Associated with that belief was the misconception that autism was caused by parent&
Henley III Raymond
Marshall & Gerstein & Borun LLP
Milkhaus Laboratory, Inc.
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