Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,...
Reexamination Certificate
1999-11-16
2002-09-10
Ulm, John (Department: 1646)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
C424S143100, C424S152100, C514S002600, C514S008200, C514S012200, C514S013800, C514S014800, C514S015800, C514S016700, C514S017400, C514S018700, C530S300000, C530S350000, C530S387100, C530S388100, C530S388220
Reexamination Certificate
active
06447775
ABSTRACT:
FIELD OF THE INVENTION
The present invention broadly relates to the treatment, diagnosis, and prophylactic prevention of Alzheimer's disease. More specifically, the present invention relates to methods and compositions for preventing the endocytosis and cellular internalization of integral membrane amyloid &bgr;-precursor protein (APP) and its subsequent catabolism by blocking or interfering with the association or binding of APP with members of the low density lipoprotein receptor family.
BACKGROUND OF THE INVENTION
Alzheimer's disease (AD) is a late onset neurodegenerative disorder characterized by the extracellular deposition of insoluble aggregates composed of the 40 to 42 amino acid A&bgr; peptide in the brain (Glenner and Wong,
Biochem. Biophys. Res. Commun
. 120:885-890 (1984); Masters et al.,
EMBO J
. 4:2757-2763 (1985)). A&bgr; peptide is derived from an integral membrane protein termed amyloid &bgr;-protein precursor protein (APP) (Tanzi et al.,
Science
235:880 (1987); Kang et al.,
Nature
325:733-736 (1987)). The function and metabolism of APP have been the subject of intensive study due to the fact that mutations in APP are associated with an autosomal dominant form of AD, (Goate et al., Nature 349:704-707 (1991)) and over-production of APP is the presumptive cause of AD in trisomy 21 (Tanzi et al.,
Science
235:880 (1987); Hyman et al.,
Proc. Natl. Acad. Sci. USA
92:3586-3590 (1995)). Multiple APP isoforms can be generated by alternatively splicing of mRNAs. The major isoforms in brain are APP695, APP751, and APP770 containing 695, 751 and 770 amino acids, respectively. These isoforms are transmembranous proteins having large extracellular regions, with hydrophobic membrane spanning domains and short cytoplasmic segments. APP is also a member of an evolutionary conserved family of proteins which include the APP-like proteins, APLP1 and APLP2 (Wasco et al.,
Proc. Natl. Acad. Sci. USA
89:10758-10762 (1992); Wasco et al.,
Nature Genet
. 5:95-100 (1993); Slunt et al.,
J. Biol Chem
. 269:2637-2644 (1994)).
Secreted forms of APP are generated by proteolytic cleavages within their extracellular domain close to the transmembrane region. The extracellular regions of APP751, APP770, and APLP2 each contain a Kunitz protease inhibitor (KPI) domain encoded by an alternatively-transcribed exon (Kitaguchi et al.,
Nature
331:530-532 (1988); Tanzi et al.,
Nature
331:528-530 (1988); Wasco et al.,
Nature Genet
. 5:95-100 (1993); Slunt et al.,
J. Biol. Chem
. 269:2637-2644 (1994)). Secreted forms of APP having the KPI domain correspond to a protease inhibitor that has been identified separately and named protease nexin II (APP/PN-2) (Van Nostrand and Cunningham,
J. Biol. Chem
. 262:8508-8514 (1987); Oltersdorf et al.,
Nature
341:144-147 (1989); Van Nostrand et al.,
Nature
341:546-549 (1989)), a potent inhibitor of the blood coagulation factors IXa (Schmaier et al.,
J. Clin. Invest
. 92:2540-2545 (1993)) and XIa (Van Nostrand et al.,
J. Biol. Chem
. 265:9591-9594 (1990)). APP/PN-2 binds with high affinity to cultured fibroblasts (Johnson-Wood et al.,
Biochem. Biophys. Res. Commun
. 200:1685-1692 (1994)), and APP/PN-2:proteinase complexes are internalized and degraded by cultured cells (Knauer and Cunningham,
Proc. Natl. Acad. Sc. USA
79:2310-2314 (1982); Knauer et al.,
J. Cell. Physiol
. 117:385-396 (1983)) although the mechanism for this process is unknown. Recent studies have identified the low density lipoprotein receptor-related protein (LRP) as the receptor responsible for the catabolism of another Kunitz-type inhibitor, tissue factor pathway inhibitor (TFPI) (Warshawsky et al.,
Proc. Natl. Acad. Sci. USA
91:6664-6668 (1994)).
LRP is a large multiligand receptor (Krieger and Herz,
Annu. Rev. Biochem
. 63:601-637 (1994)) that is a member of the LDL receptor family, which also includes the LDL receptor (Yamamoto et al.,
Cell
39:27-38 (1984)), the VLDL receptor (Takahashi et al.,
Proc. Natl. Acad. Sci. USA
89:9252-9256 (1992)), and glycoprotein 330 (Saito et al.,
Proc. Natl. Acad. Sci. USA
91:9725-9729 (1994)). A 39 kDa protein, termed the receptor associated protein (RAP) (Strickland et al.,
J. Biol. Chem
. 266:13364-13369 (1991)) binds to members of the LDL receptor family (Williams et al.,
J. Biol. Chem
. 267:9035-9040 (1992); Kounnas et al.,
J. Biol. Chem
. 267:21162-21166 (1992); Battey et al.,
J. Biol. Chem
. 269:23268-23273 (1994)) and blocks their ligand binding capacity. LRP mediates the cellular uptake and subsequent degradation of proteinases, such as tissue-type plasminogen activator (Bu et al.,
Proc. Natl. Acad. Sci. USA
89:7427-7431 (1992)) and urokinase-type plasminogen activator (Kounnas et al.,
J. Biol. Chem
. 268:21862-21867 (1993)), proteinase-inhibitor complexes, such as &agr;
2
-macroglobulin-proteinase complexes (Ashcom et al.,
J. Cell Biol
. 110: 1041-1048 (1990); Moestrup and Gliemann,
J. Biol. Chem
. 264:15574-15577 (1989)), serpin-proteinase complexes (Orth et al.,
Proc. Natl. Acad. Sci. USA
89:7422-7426 (1992); Nykjaer et al.,
J. Bio. Chem
. 267:14543-14546 (1992); Poller et al.,
J. Biol. Chem
. 270:2841-2845 (1995)), matrix proteins, such as thrombospondin (Mikhailenko et al.,
J. Biol. Chem
. 270:9543-9549 (1995)), apolipoprotein E (apoE)-enriched lipoproteins (Kowal et al.,
J. Biol. Chem
. 265:10771-10779 (1990); Beisiegel et al.,
Nature
341:162-164 (1989)), hepatic lipase (Kounnas et al.,
J. Biol. Chem
. 270:9307-9312 (1995)) and lipoprotein lipase (Chappell et al.,
J. Biol. Chem
. 268:14168-14175 (1993)).
LRP is expressed in many tissues and is a major apoe receptor in the central nervous system (Rebeck et al.,
Neuron
11:575-580 (1993)). Genetic data implicate inheritance of the &egr;4 allele of apoe as a risk factor in AD (Strittmatter et al.,
Proc. Natl. Acad. Sci. USA
90:1977-1981 (1993); Rebeck et al.,
Neuron
11:575-580 (1993); Poirier et al.,
Lancet
342:697-699 (1993); Saunders et al.,
Neurology
43:1467-1472 (1993)). A possible involvement of LRP in AD is suggested in part by the observation that LRP, as well as apoE and other LRP ligands, decorate senile plaques (Rebeck et al.,
Ann. Neurol
. 37:211-217 (1995)).
The ability of LRP to mediate the cellular catabolism of TFPI, a KPI-containing protein, led to the investigation of the role of LRP in the catabolism of APP
s
770. The present inventors have found that LRP is capable of binding and mediating the internalization and degradation of APP
s
770 as well as its complexes with proteinases.
Because catabolism of APP has been shown to generate the A&bgr; peptide, which is believed to be the causative agent of Alzheimer's Disease, there is a need for compositions and methods which reduce the interaction, cellular internalization and subsequent catabolism of APP.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide agents which bind to APP or LDL-receptor family members and reduce the interaction, cellular internalization, and subsequent catabolism of APP. Other objects, features and advantages of the present invention will be set forth in the detailed description of preferred embodiments that follows, and in part will be apparent from the description or may be learned by practice of the invention. These objects and advantages of the invention will be realized and attained by the compositions methods particularly pointed out in the written description and claims hereof.
A first embodiment of the present invention therefore relates to agents which bind to the APP-binding site on the LRP particle (Group I agents) and agents which bind to the LRP-binding site found on APP (Group II agents).
An additional embodiment of the present invention relates to DNA molecules which encode peptides and antibodies that are Group I agents and/or Group II agents and to host organisms that have been transformed with the DNA molecules of the present invention.
The present invention also relates to processes for preparing DNA molecules which encode a functional derivative or a fragment of LRP, RAP or AP
Hyman Bradley T.
Kounnas Maria Z.
Moir Robert D.
Rebeck G. William
Strickland Dudley K.
Chernyshev Olga N.
Sterne Kessler Goldstein & Fox P.L.L.C.
The General Hospital Corporation
Ulm John
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