Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
2000-11-28
2004-06-15
Kunz, Gary (Department: 1647)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C530S300000, C530S350000, C424S130100
Reexamination Certificate
active
06750324
ABSTRACT:
TECHNICAL FIELD
The invention resides in the technical fields of immunology and medicine.
BACKGROUND OF THE INVENTION
Alzheimer's disease (AD) is a progressive disease resulting in senile dementia See generally Selkoe, TINS 16, 403-409 (1993); Hardy et al., WO 92/13069; Selkoe,
J. Neuropathol. Exp. Neurol
. 53, 438-447 (1994); Duff et al.,
Nature
373, 476-477 (1995); Games et al.,
Nature
373, 523 (1995). Broadly speaking, the disease falls into two categories: late onset, which occurs in old age (65+ years) and early onset, which develops well before the senile period, i.e., between 35 and 60 years. In both types of disease, the pathology is the same but the abnormalities tend to be more severe and widespread in cases beginning at an earlier age. The disease is characterized by at least two types of lesions in the brain, senile plaques and neurofibrillary tangles. Senile plaques are areas of disorganized neuropil up to 150 &mgr;m across with extracellular amyloid deposits at the center visible by microscopic analysis of sections of brain tissue. Neurofibrillary tangles are intracellular deposits of microtubule associated tau protein consisting of two filaments twisted about each other in pairs.
The principal constituent of the plaques is a peptide termed A&bgr; or &bgr;-amyloid peptide. A&bgr; peptide is an internal fragment of 39-43 amino acids of a precursor protein termed amyloid precursor protein (APP). Several mutations within the APP protein have been correlated with the presence of Alzheimer's disease. See, e.g., Goate et al.,
Nature
349, 704) (1991) (valine
717
to isoleucine); Chartier Harlan et al.
Nature
353, 844 (1991)) (valine
717
to glycine); Murrell et al.,
Science
254, 97 (1991) (valine
717
to phenylalanine); Mullan et al.,
Nature Genet
. 1, 345 (1992) (a double mutation changing lysine
595
-methionine
596
to asparagine
595
-leucine
596
). Such mutations are thought to cause Alzheimer's disease by increased or altered processing of APP to A&bgr;, particularly processing of APP to increased amounts of the long form of A&bgr; (i.e., A&bgr;1-42 and A&bgr;1-43). Mutations in other genes, such as the presenilin genes, PS1 and PS2, are thought indirectly to affect processing of APP to generate increased amounts of long form A&bgr; (see Hardy, TINS 20, 154 (1997)). These observations indicate that A&bgr;, and particularly its long form, is a causative element in Alzheimer's disease.
McMichael, EP 526,511, proposes administration of homeopathic dosages (less than or equal to 10
−2
mg/day) of A&bgr; to patients with preestablished AD. In a typical human with about 5 liters of plasma, even the upper limit of this dosage would be expected to generate a concentration of no more than 2 pg/ml. The normal concentration of A&bgr; in human plasma is typically in the range of 50-200 pg/ml (Seubert et al.,
Nature
359, 325-327 (1992)). Because EP 526,511's proposed dosage would barely alter the level of endogenous circulating A&bgr; and because EP 526,511 does not recommend use of an adjuvant, as an immunostimulant, it seems implausible that any therapeutic benefit would result.
By contrast, the present invention is directed inter alia to treatment of Alzheimer's and other amyloidogenic diseases by administration of fragments of A&bgr;, or antibody to certain epitopes within A&bgr; to a patient under conditions that generate a beneficial immune response in the patient The invention thus fulfills a longstanding need for therapeutic regimes for preventing or ameliorating the neuropathology and, in some patients, the cognitive impairment associated with Alzheimer's disease.
This application is related to International Application No. PCT/US00/14810 filed May 26, 2000, Publication No. WO 00/72880; and, International Application No. PCT/US98/25386, filed Nov. 30, 1998, Publication No. WO 99/27944; both of which are incorporated by reference in their entirely for all purposes.
SUMMARY OF THE CLAIMED INVENTION
In one aspect, the invention provides methods of preventing or treating a disease associated with amyloid deposits of A&bgr; in the brain of a patient. Such diseases include Alzheimer's disease, Down's syndrome and cognitive impairment. The latter can occur with or without other characteristics of an amyloidogenic disease. Some methods of the invention entail administering an effective dosage of an antibody that specifically binds to a component of an amyloid deposit to the patient. Such methods are particularly useful for preventing or treating Alzheimer's disease in human patients. Some methods entail administering an effective dosage of an antibody that binds to A&bgr;. Some methods entail administering an effective dosage of an antibody that specifically binds to an epitope within residues 1-10 of A&bgr;. In some methods, the antibody specifically binds to an epitope within residues 1-6 of A&bgr;. In some methods, the antibody specifically binds to an epitope within residues 1-5 of A&bgr;. In some methods, the antibody specifically binds to an epitope within residues 1-7 of A&bgr;. In some methods, the antibody specifically binds to an epitope within residues 3-7 of A&bgr;. In some methods, the antibody specifically binds to an epitope within residues 1-3 of A&bgr;. In some methods, the antibody specifically binds to an epitope within residues 1-4 of A&bgr;. In some methods, the antibody binds to an epitope comprising a free N-terminal residue of A&bgr;. In some methods, the antibody binds to an epitope within residues of 1-10 of A&bgr; wherein residue 1 and/or residue 7 of A&bgr; is aspartic acid. In some methods, the antibody specifically binds to A&bgr; peptide without binding to full-length amyloid precursor protein (APP). In some methods, the isotype of the antibody is human IgG1.
In some methods, the antibody binds to an amyloid deposit in the patient and induces a clearing response against the amyloid deposit. For example, such a clearing response can be effected by Fc receptor mediated phagocytosis.
The methods can be used on both asymptomatic patients and those currently showing symptoms of disease. The antibody used in such methods can be a human, humanized, chimeric or nonhuman antibody and can be monoclonal or polyclonal. In some methods, the antibody is prepared from a human immunized with A&bgr; peptide, which human can be the patient to be treated with antibody.
In some methods, the antibody is administered with a pharmaceutical carrier as a pharmaceutical composition. In some methods, antibody is administered at a dosage of 0.0001 to 100 mg/kg, preferably, at least 1 mg/kg body weight antibody. In some methods, the antibody is administered in multiple dosages over a prolonged period, for example, of at least six months. In some methods, the antibody is administered as a sustained release composition. The antibody can be administered, for example, intraperitoneally, orally, subcutaneously, intracranially, intramuscularly, topically, intranasally or intravenously.
In some methods, the antibody is administered by administering a polynucleotide encoding at least one antibody chain to the patient. The polynucleotide is expressed to produce the antibody chain in the patient. Optionally, the polynucleotide encodes heavy and light chains of the antibody. The polynucleotide is expressed to produce the heavy and light chains in the patient In some methods, the patient is monitored for level of administered antibody in the blood of the patient.
In another aspect, the invention provides methods of preventing or treating a disease associated with amyloid deposits of A&bgr; in the brain of patient. For example, the methods can be used to treat Alzheimer's disease or Down's syndrome or cognitive impairment. Such methods entail administering fragments of A&bgr; or analogs thereof eliciting an immunogenic response against certain epitopes within A&bgr;. Some methods entail administering to a patient an effective dosage of a polypeptide comprising an N-terminal segment of at least residues 1
Bard Frederique
Schenk Dale B.
Yednock Theodore
Kunz Gary
Neuralab Limited
Nichols Christopher James
Townsend and Townsend / and Crew LLP
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