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Humanized antibodies that recognize beta amyloid peptideRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Immunoglobulin, Antiserum, Antibody, Or Antibody Fragment, Except Conjugate Or Complex Of The Same With Nonimmunoglobulin Material, Monoclonal Antibody Or Fragment Thereof (i.e., Produced By Any Cloning Technology), Binds Hormone Or Other Secreted Growth Regulatory Factor, Differentiation Factor, Or Intercellular Mediator (e.g., Cytokine, Etc.); Or Binds Serum Protein, Plasma Protein (e.g., Tpa, Etc.), Or FibrinHumanized antibodies that recognize beta amyloid peptide description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060280743, Humanized antibodies that recognize beta amyloid peptide. Brief Patent Description - Full Patent Description - Patent Application Claims
BACKGROUND OF THE INVENTION [0001] Alzheimer's disease (AD) is a progressive disease resulting in senile dementia. See generally Selkoe, TINS 16:403 (1993); Hardy et al., WO 92/13069; Selkoe, J Neuropathol. Exp. Neurol. 53:438 (1994); Duff et al., Nature 373:476 (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, neurofibrillary tangles and senile plaques. Neurofibrillary tangles are intracellular deposits of microtubule associated tau protein consisting of two filaments twisted about each other in pairs. Senile plaques (i.e., amyloid plaques) are areas of disorganized neuropil up to 150 .mu.m across with extracellular amyloid deposits at the center which are visible by microscopic analysis of sections of brain tissue. The accumulation of amyloid plaques within the brain is also associated with Down's syndrome and other cognitive disorders. [0002] The principal constituent of the plaques is a peptide termed A.beta. or .beta.-amyloid peptide. A.beta. peptide is a 4-kDa internal fragment of 39-43 amino acids of a larger transmembrane glycoprotein named protein termed amyloid precursor protein (APP). As a result of proteolytic processing of APP by different secretase enzymes, A.beta. is primarily found in both a short form, 40 amino acids in length, and a long form, ranging from 42-43 amino acids in length. Part of the hydrophobic transmembrane domain of APP is found at the carboxy end of A.beta., and may account for the ability of A.beta. to aggregate into plaques, particularly in the case of the long form. Accumulation of amyloid plaques in the brain eventually leads to neuronal cell death. The physical symptoms associated with this type of neural deterioration characterize Alzheimer's disease. [0003] 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.sup.717 to isoleucine); Chartier Harlan et al. Nature 353:844 (1991)) (valine.sup.717 to glycine); Murrell et al., Science 254:97 (1991) (valine.sup.717 to phenylalanine); Mullan et al., Nature Genet. 1:345 (1992) (a double mutation changing lysine.sup.595-methionine.sup.596 to asparagine.sup.595-leucine 96). Such mutations are thought to cause Alzheimer's disease by increased or altered processing of APP to A.beta., particularly processing of APP to increased amounts of the long form of A.beta. (i.e., A.beta.1-42 and A.beta.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.beta. (see Hardy, TINS 20: 154 (1997)). [0004] Mouse models have been used successfully to determine the significance of amyloid plaques in Alzheimer's (Games et al., supra, Johnson-Wood et al., Proc. Natl. Acad. Sci. USA 94:1550 (1997)). In particular, when PDAPP transgenic mice, (which express a mutant form of human APP and develop Alzheimer's disease at a young age), are injected with the long form of A.beta., they display both a decrease in the progression of Alzheimer's and an increase in antibody titers to the A.beta. peptide (Schenk et al., Nature 400, 173 (1999)). The observations discussed above indicate that A.beta., particularly in its long form, is a causative element in Alzheimer's disease. [0005] McMichael, EP 526,511, proposes administration of homeopathic dosages (less than or equal to 10.sup.-2 mg/day) of A.beta. 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.beta. in human plasma is typically in the range of 50-200 pg/ml (Seubert et al., Nature 359:325 (1992)). Because EP 526,511's proposed dosage would barely alter the level of endogenous circulating A.beta. and because EP 526,511 does not recommend use of an adjuvant, as an immunostimulant, it seems implausible that any therapeutic benefit would result. [0006] Accordingly, there exists the need for new therapies and reagents for the treatment of Alzheimer's disease, in particular, therapies and reagents capable of effecting a therapeutic benefit at physiologic (e.g., non-toxic) doses. SUMMARY OF THE INVENTION [0007] The present invention features new immunological reagents, in particular, therapeutic antibody reagents for the prevention and treatment of amyloidogenic disease (e.g., Alzheimer's disease). The invention is based, at least in part, on the identification and characterization of two monoclonal antibodies that specifically bind to A.beta. peptide and are effective at reducing plaque burden and/or reducing the neuritic dystrophy associated with amyloidogenic disorders. Structural and functional analysis of these antibodies leads to the design of various humanized antibodies for prophylactic and/or therapeutic use. In particular, the invention features humanization of the variable regions of these antibodies and, accordingly provides for humanized immunoglobulin or antibody chains, intact humanized immunoglobulins or antibodies, and functional immunoglobulin or antibody fragments, in particular, antigen binding fragments, of the featured antibodies. [0008] Polypeptides comprising the complementarity determining regions of the featured monoclonal antibodies are also disclosed, as are polynucleotide reagents, vectors and host suitable for encoding said polypeptides. [0009] Methods of treatment of amyloidogenic diseases or disorders (e.g., Alzheimer's disease) are disclosed, as are pharmaceutical compositions and kits for use in such applications. [0010] Also featured are methods of identifying residues within the featured monoclonal antibodies which are important for proper immunologic function and for identifying residues which are amenable to substitution in the design of humanized antibodies having improved binding affinities and/or reduced immunogenicity, when used as therapeutic reagents. [0011] Also featured are antibodies (e.g., humanized antibodies) having altered effector functions, and therapeutic uses thereof. BRIEF DESCRIPTION OF THE DRAWINGS [0012] FIG. 1 depicts an alignment of the amino acid sequences of the light chain of mouse 3D6, humanized 3D6, Kabat ID 109230 and germline A19 antibodies. CDR regions are indicated by arrows. Bold italics indicate rare murine residues. Bold indicates packing (VH+VL) residues. Solid fill indicates canonical/CDR interacting residues. Asterisks indicate residues selected for backmutation in humanized 3D6, version 1. [0013] FIG. 2 depicts an alignment of the amino acid sequences of the heavy chain of mouse 3D6, humanized 3D6, Kabat ID 045919 and germline VH3-23 antibodies. Annotation is the same as for FIG. 1. [0014] FIG. 3 graphically depicts the A.beta. binding properties of 3D6, chimeric 3D6 and 10D5. FIG. 3A is a graph depicting binding of A.beta. to chimeric 3D6 (PK1614) as compared to murine 3D6. FIG. 3B is a graph depicting competition of biotinylated 3D6 versus unlabeled 3D6, PK1614 and 10D5 for binding to A.beta.. [0015] FIG. 4 depicts a homology model of 3D6 VH and VL, showing .alpha.-carbon backbone trace. VH is shown in as a stippled line, and VL is shown as a solid line. CDR regions are indicated in ribbon form. [0016] FIG. 5 graphically depicts the A.beta. binding properties of chimeric 3D6 and humanized 3D6. FIG. 5A depicts ELISA results measuring the binding of humanized 3D6v1 and chimeric 3D6 to aggregated A.beta.. FIG. 5B depicts ELISA results measuring the binding of humanized 3D6v1 and humanized 3D6v2 to aggregated A.beta.. [0017] FIG. 6 is a graph quantitating the binding of humanized 3D6 and chimeric 3D6 to A.beta. plaques from brain sections of PDAPP mice. [0018] FIG. 7 is a graph showing results of a competitive binding assay testing the ability of humanized 3D6 versions 1 and 2, chimeric 3D6, murine 3D6, and 10D5 to compete with murine 3D6 for binding to A.beta.. [0019] FIG. 8 graphically depicts of an ex vivo phagocytosis assay testing the ability of humanized 3D6v2, chimeric 3D6, and human IgG to mediate the uptake of A.beta. by microglial cells. [0020] FIG. 9 depicts an alignment of the 10D5 VL and 3D6 VL amino acid sequences. Bold indicates residues that match 10D5 exactly. [0021] FIG. 10 depicts an alignment of the 10D5 VH and 3D6 VH amino acid sequences. Bold indicates residues that match 10D5 exactly. 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