Multicellular living organisms and unmodified parts thereof and – Nonhuman animal – The nonhuman animal is a model for human disease
Reexamination Certificate
2000-11-27
2004-03-23
Crouch, Deborah (Department: 1632)
Multicellular living organisms and unmodified parts thereof and
Nonhuman animal
The nonhuman animal is a model for human disease
C800S003000, C800S018000
Reexamination Certificate
active
06710226
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 observation s 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 A&bgr;, other active immunogen or antibody to 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.
SUMMARY OF THE CLAIMED INVENTION
In one aspect, the invention provides methods of preventing or treating a disease characterized by amyloid deposit in a patient. Such methods entail administering an effective dosage of an antibody that specifically binds to the amyloid deposit or a component thereof to the patient. Such methods are particularly useful for preventing or treating Alzheimer's disease in which case the amyloid deposit is A&bgr;. 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 used binds to an epitope within residues 1-28 of A&bgr;. In some methods the antibody binds to an epitope within residues 1-10, and in some methods within residues 1-5. In some methods, the antibody specifically binds to A&bgr; peptide without binding to full-length amyloid precursor protein (APP).
In some methods antibody is administered at a dosage of at least 1 mg/kg body weight antibody. In some methods, the antibody is administered in multiple dosages over a period 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 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 Alzheimer's disease. These methods entail administering an effective dosage of a polypeptide comprising an active fragment of AD that induces an immune response to A&bgr; in the patient. In some methods, the fragment comprises an epitope within amino acids 1-12 of A&bgr;. In some method, the fragment comprises an epitope within amino acids 1-16 of A&bgr;. In some methods, the fragment comprises an epitope within amino acids 13-28 of A&bgr;. In some methods, the fragment is free of at least the 5 C-terminal amino acids in A&bgr;43. In some methods, the fragment comprises up to 20 contiguous amino acids from A&bgr;. Fragments are typically administered at greater than 10 micrograms per dose per patient.
In some methods, the fragment is administered with an adjuvant that enhances the immune response to the A&bgr; peptide. The adjuvant and fragment can be administered in either order of together as a composition. The adjuvant can be, for example, alum, MPL, QS-21 or incomplete Freund's adjuvant.
The invention further provides pharmaceutical compositions comprising active fragments of A&bgr;, such as described above, and an adjuvant.
The invention further provides methods of screening an antibody to A&bgr; or an active fragment of A&bgr; for use in treatment of Alzheimer's disease. Such methods entail administering an antibody that specifically binds to A&bgr; or a fragment of A&bgr; to a transgenic animal disposed to develop characteristics of Alzheimer's disease. One then detects a reduction in the extent or rate of development of the characteristics relative to a control transgenic animal as a measure of the efficacy of the antibody or fragment. Optionally, antibodies can also be screened for capacity to bind an epitope within amino acids 1-28 or other epitope of A&bgr;.
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patent: 5004697 (1991-04-01), Pardridge
patent: 5057540 (1991-10-01), Kensil et al.
patent: 5187153 (1993-02-01), Cordell et al.
patent: 5192753 (1993-03-01), McGeer et al.
patent: 5208036 (1993-05-01), Eppstein et al.
patent: 5220013 (1993-06-01), Ponte et al.
patent: 5231000 (1993-07-01), Majocha et al.
patent: 5231170 (1993-07-01), Averback
patent: 5270165 (1993-12-01), Van Nostrand et al.
patent: 5387742 (199
Crouch Deborah
Neuralab Limited
Townsend and Townsend / and Crew LLP
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