WO1994028412A1 - Composition et procede d'imagerie in vivo de depots d'amyloide - Google Patents

Composition et procede d'imagerie in vivo de depots d'amyloide Download PDF

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WO1994028412A1
WO1994028412A1 PCT/US1994/005809 US9405809W WO9428412A1 WO 1994028412 A1 WO1994028412 A1 WO 1994028412A1 US 9405809 W US9405809 W US 9405809W WO 9428412 A1 WO9428412 A1 WO 9428412A1
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Charles A. Marotta
Ronald E. Majocha
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The Miriam Hospital
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • the present invention relates to the identification of compositions which are suitable for use in in vivo imaging of amyloid deposits and methods related thereto. More specifically, the present invention relates to a method of diagnosing Alzheimer's Disease.
  • AD Alzheimer's Disease
  • the condition is characterized by impairments in memory, cognition, language and mobility, and these impairments progress over time.
  • amyloid is composed of fibrils of 4-8 nm in diameter that form the core of senile plaques. Mertz et al . , Acta Neuropathol . , 60: 113-124 (1983).
  • the amyloid is readily demonstrated by application of thioflavin S or Congo red to brain sections. In the latter case, polarized light causes amyloid to appear with a characteristic yellow-green color.
  • the staining property reflects the presence of twisted beta-pleated sheet fibrils, as noted above.
  • a detailed discussion of the biochemistry and histochemistry of amyloid can be found in Glenner, N. Engl . J. Med. , 302: 1333-1343 (1980).
  • vascular amyloidosis referred to as congophilic angiopathy
  • congophilic angiopathy has been recognized since the early part of this century as a significant aspect of the microscopic pathology of Alzheimer's Disease. Vinters, et al . Stroke , 18: 311-324 (1987). Over 90% of Alzheimer cases have congophilic angiopathy. Glenner, et al . , Ann . Pathol . , 1: 120-129 (1981). Similar to parenchymal amyloid deposits, vascular amyloid is demonstrated by characteristic thioflavin S and Congo red staining reactions. The parieto-occipital cortex is usually more affected than that in the frontal and temporal lobes. Tomlinson et al . , supra (1984).
  • amyloidosis In vascular amyloidosis, the amyloid appears to infiltrate the micro-vasculature, and affected vessels often pass from the leptomeninges into the cortex. Small cerebral vessels with arterioles that appear as thickened tubes are observed. The changes include the small pial and intracortical arterioles, the leptomeningeal vessels and the intracortical capillaries.
  • Tomlinson et al . , supra (1984) Immunocytochemical and electron microscopic studies have indicated that the amyloid component of senile plaques are often observed in close proximity to affected microvessels. Allsop, et al . Neurosci . Lett . , 68: 252-256 (1986). However, the angiopathy may occur without senile plaques. Montjoy, et al . , J . Neurol . Sci . , 57: 89-103 (1982).
  • the 0/A4 peptide (residues 596-638 or 639) is either 42 or 43 amino acids in length and partly includes the putative transmembrane domain (amino acids 625-648) .
  • the C-terminal region of the APP is relatively small, consisting of 57 residues.
  • lysine residues are present (residues 649-651) which, according to Kang et al . supra (1987), could interact with phospholipid head groups in the membrane. This feature has been described for the junction between membrane and cytoplasmic domains of cell-surface receptors.
  • One site is a potential glycosylation sequence.
  • Glenner et al . teach the use of the ⁇ /A4 peptide, or fragments thereof, for the production of antibodies which recognize the antigenic determinants of the polypeptide or homologues thereof.
  • Glenner et al . further teach the use of the disclosed polypeptide for the production of nucleic acid probes which hybridize with the gene encoding the polypeptide.
  • polypeptide has the following amino acid sequence (SEQ ID N0:1) : H 2 N-Asp-Ala-Glu-Phe-Arg-His-Asp-Ser-Gly-Tyr-Gln- Val-His-His-Gln-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Val-Gly- Ser-Asn-Lys-COOH.
  • the diagnostic methods taught in this patent are characterized as non-invasive.
  • ⁇ /A4 has been considered for use in in vitro diagnostic methods, this polypeptide has never been described in connection with in vivo diagnostic imaging methods. Therefore, a need exists for a diagnostic in vivo imaging method that exploits the self-aggregation properties of amyloid proteins such as ⁇ /A4.
  • One object of the present invention is to provide an amyloid binding composition for in vivo imaging of amyloid deposits comprising a labeled amyloid protein which binds to amyloid deposits in vivo and a pharmaceutically acceptable carrier.
  • Another object of the present invention is to provide an in vivo method for detecting amyloid deposits in a subject comprising the steps of administering to a subject a detectable quantity of an amyloid binding composition comprising a labeled amyloid binding protein and a pharmaceutically acceptable carrier and detecting the binding of the labeled protein to the amyloid deposit.
  • Another object of the present invention is to provide a method of diagnosing an amyloidosis-associated disease, such as Alzheimer's Disease and Down Syndrome, by applying the above method to the detection of amyloid deposits in subjects suspected of having an amyloidosis- associated disease.
  • amyloid binding protein of the present invention includes all variants of the amyloid protein which bind to amyloid deposits in vivo.
  • Figure l shows a chart setting forth chemically documented amyloidosis with protein types.
  • Figure 2 depicts a PAGE-SDS gel of the A4-0 synthetic amyloid peptide.
  • the amyloid polypeptide of 28 residues corresponding to the previously reported sequence of Masters et al . , Proc . Natl . Acad . Sci . USA 82: 4245-4249 (1985) was synthesized on a Biosearch SAM2 synthesizer using the general procedure of Merrifield, J. Am . Chem . Soc , 85: 2149-2154 (1963). Purification was achieved with a 3 X 65 cm column of Sephadex G50 (10-40 ⁇ ) . The peptide (10 ⁇ g) was suspended in sample buffer containing 2% SDS (Brown, et al., J. Neurochem .
  • Electrophoresis was carried out on a uniform 10% gel containing 0.1% SDS.
  • A Molecular weight markers: phosphorylase B (94 kd) , bovine serum albumin (68 kd) , ovalbumin (43 kd) , carbonic anhydrase (29 kd) , trypsin inhibitor (22 kd) , lysozyme (14.5 kd) .
  • B The synthetic amyloid peptide ran as a sharp band at the front of the gel and as an aggregated form of higher molecular weight.
  • Figure 3 depicts gel electrophoresis of the synthetic peptides A4-0 and P2 (APP amino acids 413-429) .
  • Lanes 1-3 containing A4-0 (10 ug) were incubated with 2% SDS and 5% 2-ME at 95°C for 5 minutes (Lane 1) , 30 min (Lane 2) and 60 minutes (Lane 3) .
  • Lane 4 contained P2 (lOug) .
  • Gels were stained with Coomassie Brilliant blue R-250. Molecular weights are shown on the right (Kd) .
  • Figure 4 shows slot blots of immunostained A4-0 after addition of itself or a second A4 homologue.
  • This assay depicts the increase staining intensity after A4 homologues are added to one another. This reflects the ability of homologues to self-aggregate and thus increase the staining intensity.
  • the slot contained 1 ug of A4 peptide.
  • the blots were then immunostained (see descriptions of Figures 5, 6 and 7) .
  • Figure 5 shows immunoblots with and without exogenous A4-0 peptide. Density values of the immunoreaction products of A4-0 with and without exogenous peptides after reaction with 10H3. The values of the bars correspond to the density of blots shown in Figure 4. The description of Figure 4 indicates the condition of each blot with regard to the exogenous peptide that was added to the blotted peptide prior to addition of 10H3. The height of the bars above the black bar (no peptide addition) is a measure of the extent to which the exogenous peptide bound to the attached peptide on the filter paper and increased the density of immunostaining of the complex.
  • A4-0 was added to the A4-0 that was already present at a concentration of 1 ug.
  • the blot was then immunostained to develop the colored reaction product.
  • the data were derived from scanning Figure 4.
  • Figure 6 shows immunoblots with and without exogenous A4-H peptide. At the three indicated concentrations (2.5, 5.0 and 10.0 ug/ml) A4-H as added to the A4-0 that was already present at a concentration of 1 ug. The blot was then immunostained to develop the colored reaction product. The data were derived from scanning Figure 4. See description of Figure 5 for more details.
  • Figure 7 shows immunoblots with and without exogenous Opl peptide. At the three indicated concentrations (2.5, 5.0 and 10.0 ug/ml) Opl as added to the A4-0 that was already present at a concentration of 1 ug. The blot was then immunostained to develop the colored reaction product. The data were derived from scanning Figure 4. See description of Figure 5 for more details.
  • Figure 8 shows the reactivity of 10H3 towards A4-0 (upper panel) .
  • Figure 9 is the nucleotide sequence and predicted amino acid sequence of cDNA encoding the precursor protein (APP) of the /3/A4 with the 0/A4 region boxed, as set forth in Kang et al . , supra , (1987) .
  • APP precursor protein
  • an amyloid binding composition comprising a labeled amyloid protein may be used in vivo for detecting the presence and location of amyloid deposits.
  • the amyloid binding composition of the present invention comprises a labeled amyloid protein and a pharmaceutically acceptable carrier.
  • This protein is any natural or synthetic protein which binds to amyloid deposits in vivo.
  • the protein is the ⁇ -amyloid polypeptide ( ⁇ /A4 peptide) , which in its longest form has 42 to 43 amino acid residues, as shown in Figure 9. See Masters, et al. , Proc . Nat . Acad . Sci . , USA . , 82: 4245-4249 (1985) .
  • amyloid deposit includes amorphous, eosinophilic materials that are associated with amyloidosis, a disease complex including over 20 different clinically defined syndromes, as discussed above.
  • amyloid deposits are proteinaceous, and their chemical compositions are unique for each of the clinical syndromes with which they are associated, as set forth in Figure 1.
  • the amyloid deposit of the present invention is that found in the brain of Alzheimer's Disease patients.
  • amyloid deposits are found in senile plaques in selected areas of the AD brain and are composed of fibrils of 4-8 nm diameter. These plaques are detected by application of thioflavin S or Congo red to brain sections and in the latter case, appear yellow-green under polarized light. They have twisted beta-pleated sheet fibrils and are further characterized by Glenner, N . Eng. J. Med . , 302: 1333-1343 (1980).
  • the amyloid deposit of the present invention is that which is associated with vascular amyloidosis, as described in Vinters, Stroke , 18: 311-324 (1987). Vascular amyloid deposits infiltrate the cerebral micro- vasculature.
  • amyloidosis-associated disease includes any disease characterized by local or systemic amyloid deposits. (See Figure 1)
  • the amyloidosis-associated disease of the present invention is Alzheimer's Disease or Down Syndrome.
  • amyloid protein of the present invention includes recombinant and synthetic amyloid protein and variants of the naturally occurring, recombinant and synthetic protein.
  • the amyloid protein of the invention comprises the 0-amyloid polypeptide and variants thereof.
  • the category of "variants" includes, for example, a fragment of the ⁇ - amyloid polypeptide or any homologous amino acid sequence or amino acid addition, wherein the resulting polypeptide has the same or similar function as the natural occurring polypeptide in that it binds to amyloid deposits in vivo .
  • the amyloid protein of the present invention is comprised of the 0-amyloid polypeptide or variant thereof and amino acids from the APP protein which are from regions of the APP protein which are either adjacent or non-adjacent to the 0-amyloid polypeptide.
  • the amyloid protein of the present invention comprises:
  • X and Y are one or more APP amino acids which are not ajacent to 0/A4 in the nature;
  • fragment includes a linear amino acid subsequence of the ⁇ -amyloid polypeptide, wherein such fragment binds amyloid deposits in vivo .
  • a variant which contains an amino acid sequence variation or substitution is a homologous sequence. "Homology" between two sequences connotes a likeness short of identity indicative of a derivation of the first sequence from the second.
  • a polypeptide is "homologous" to ⁇ - amyloid polypeptide if it contains an amino acid sequence similar enough to the natural sequence so as to confer the same or similar amyloid binding property as the natural ⁇ -amyloid polypeptide.
  • Such a sequence may be only a few amino acids long and may be a single linear sequence or one or more linear sequences which confer binding activity to the polypeptide when amino acids from separated portions of a linear sequence are spatially juxtaposed after protein folding.
  • the variants encompassed by this invention can be ascertained, for example, by the in vitro quantitative assays describe below in Examples 3-7.
  • Protein which qualifies as "amyloid protein” according to the above criteria can be produced by methods known and emerging in the art, including conventional reverse genetic techniques, i.e., by designing a genetic sequence based upon an amino acid sequence or by conventional genetic splicing techniques.
  • ⁇ -amyloid polypeptide variants can be produced by techniques which involve site-directed mutagenesis or oligonucleotide-directed mutagenesis. See, for example, "Mutagenesis of Cloned DNA,” in CURRENT PROTOCOLS IN MOLECULAR BIOLOGY 8.0.3 et seq. (Ausubel, et al . eds. 1989) ("Ausubel”).
  • amyloid protein variants within the present invention are molecules that correspond to a portion of the ⁇ -amyloid polypeptide, but are not coincident with the natural molecule, and display the binding activity of the natural molecule when presented alone or, alternatively, when linked to a carrier or biologically active signal sequence that permits proteins to pass through membranes. See von Heijne, G., J. Mol . Biol . , 184: 99-105 (1985).
  • An amyloid protein variant of this type could represent an actual fragment, as discussed above, or could be a polypeptide synthesized de novo or recombinantly.
  • a polynucleotide molecule encoding such a molecule would preferably comprise a nucleotide sequence, corresponding to the desired amino acid sequence, that is optimized for the host of choice in terms of codon usage, initiation of translation, and expression of commercially useful amounts of, for instance, ⁇ -amyloid polypeptide or fl ⁇ amyloid polypeptide variant.
  • the vector selected for transforming the chosen host organism with such a polynucleotide molecule should allow for efficient maintenance and transcription of the sequence encoding the polypeptide.
  • the encoding polynucleotide molecule may code for a chimeric protein; that is, it can have a nucleotide sequence encoding a biologically active part of the ⁇ -amyloid molecule operably linked to a coding sequence for a non- ⁇ -amyloid moiety, such as a signal peptide for the host cell.
  • a non- ⁇ -amyloid moiety such as a signal peptide for the host cell.
  • total DNA from cerebrovascular tissue can be prepared according to published methods. See, for example, Maniatis, et al . , MOLECULAR CLONING: A LABORATORY MANUAL (Cold Spring Harbor Laboratories, NY 1982); Baess, Acta Pathol .
  • the DNA thus obtained can be partially digested with a restriction enzyme to provide an assortment of genomic fragments.
  • An enzyme with a tetranucleotide recognition site such as Sau3A (MJbol) , is suitable for this purpose.
  • the fragments from such a partial digestion then can be size-fractionated, for example, by sucrose gradient centrifugation (see Maniatis, supra) or by pulsed field gel electrophoresis (See Anad, Trends in Genetics, November 1986, at pages 278-83), to provide fragments of a length commensurate with that of DNA encoding the ⁇ - amyloid molecule.
  • amyloid cDNA derived drom mRNA of the Alzheimer brain and the expression thereof is described in detail in Zain et al . , Proc. Natl . Acad . Sci . USA. , 85: 929-933 (1988) and Marotta et al . , Proc. Natl . Acad . Sci . USA. , 86: 337-341 (1989) , respectively, both of which are herein incorporated by reference.
  • the selected fragments can be cloned into a suitable cloning vector.
  • a DNA sequence thus obtained could be inserted, for example, at the BamHl site of the pUCl ⁇ cloning vector which is transfected into appropriate host cells such as E. coli or a mammalian cell.
  • a variety of screening mechanisms known in the art of the invention can then be used to identify clones containing the ⁇ -amyloid gene.
  • amyloid protein of the present invention is purified from tissue samples.
  • tissue samples For example, brains from Alzheimer's Disease post-mortum patients are histologically sectioned and stained with Congo Red dye. Upon visualization with a polarizing microscope, amyloid deposits can be identified by their green color. Brains exhibiting extensive cerebrovascular amyloidosis are used as source for purified amyloid protein. After removal of contaminants from the amyloid containing vessels of the meninges, the meningeal tissues are homogenized and centrifuged to yield a brownish layer rich in amyloid fibrils. This layer is then digested with collagenase, solubilized in 6M guanidine HCl, pH 8.0 and centrifuged.
  • the supernatant containing the solubilized protein is desalted by dialysis and gel exclusion column chromatography and high performance liquid chromatography is used to purify the polypeptide.
  • the amino acids for the purified protein e.g., ⁇ -amyloid polypeptide
  • an automated amino acid sequencer such as a Beckman 890 C spinning cup sequencer
  • high performance liquid chromatography in order to determine the amino acid sequence of the amyloid protein. See Glenner & Wong, Biochem . Biophys . Chem . Res . Commun . , 120: 885 (1984).
  • amyloid protein and variants thereof can be produced in accordance with published methods. For instance, Kirschner et al . , Proc. Natl . Acad. Sci . USA, 84: 6953-57 (1987) used an ABI
  • Synthesizer model 380 B (Applied Biosystems, Foster City, CA) to synthesize synthetic ⁇ -amyloid peptides consisting of residues 1-28 and homologues thereof.
  • General methods for peptide synthesis can be found in Clark Lewis et al . , Science , 231: 134 (1986). See also, Hilbich et al . , J. Mol . Biol . , 218: 149-163 (1991); Majocha et al . , Proc. Natl . Acad. Sci . USA, 85: 6182-6186 (1988); and U.S. Patent application No. 105,751 by Marotta et al .
  • in vivo imaging refers to any method that permits the detection of a labeled amyloid protein which binds to amyloid deposits located in a subject's body.
  • a "subject” is a mammal, preferably a human. Often, particularly when the composition and method of the invention is directed to the diagnosis of Alzheimer's Disease or Down Syndrome, the subject will manifest clinical symptoms of the suspected amyloidosis. These clinical symptoms are well-known to the practitioner of this invention and include loss of memory, and other impairments described above.
  • the amyloid binding composition of the present invention must be of a "detectable quantity.” A detectable quantity is that which is sufficient to enable detection of the site of amyloid deposit location when compared to a background signal.
  • the dosage of the amyloid binding composition will vary depending upon such considerations as age, condition, sex, extent of disease in the patient, counterindications, and other variables, to be adjusted by the individual physician. Dosage can vary from 0.01 mg/kg to 2,0000 mg/kg, preferably 0.1 mg/kg to 1,000 mg/kg.
  • amyloid protein may be labeled by any of several techniques known to the art. See, e . g. , Wagner et al . , J. Nucl . Med . , 20: 428 (1979); Sundberg et al., J. Med. Chem . , 17: 1340 (1974) and Saha et al . , J. Nucl . Med. , 6: 542 (1976).
  • the label is chosen based upon the type of detection instrument employed. For instance, a chosen radionucleotide must have a type of decay which is detectable for a given type of instrument. Another consideration relates to the half-life of the isotope. The half-life should be long enough so that it is still detectable at the time of maximum uptake by the target, but short enough so that the host does not sustain deleterious radiation.
  • the chosen label will lack a particulate emission, but will produce a large number of photons in a 140-200 keV range, which may be readily detected by, for instance, conventional gamma camera.
  • Suitable radioisotopes for purposes of this invention include, gamma-emitters, position-emitters, x- ray emitters and fluorescence-emitters. These radioisotopes include Iodine-131, Iodine-123, Iodine-126, Iodine-133, Bromine- 77, Indium-Ill, Indium-113m, Gallium-67, Gallium-68, Ruthenium-95, Rutheium-97, Ruthenium-103, Ruthenium-105, Mercury-107, Mercury-203, Rhenium-99m, Rhenium-105, Rhenium 101, Tellurium-121m, Tellurium-122m, Tellurium-125m, Thulium-165, Thulium-167, Thulium-168, Technetium-99m and Fluorine-18.
  • the preferred radiolabel is Technetium-99m.
  • Suitable paramagnetic isotopes for use in Magnetic Resonance Imaging (MRI) include 157 Gd, 5S Mn, ,62 Dy, 52 Cr, and ⁇ Fe.
  • Administration to the subject may be accomplished intraventricularly, intravenously, intraarterially, via the spinal fluid or the like. Administration may also be intradermal or intracavitary, depending upon the body site under examination. After a sufficient time has lapsed for the labeled amyloid protein to bind with amyloid deposits, for example 30 minutes to 48 hours, the area of the subject under diagnosis is examined by routine imaging techniques such as MRI, SPECT and planar scintillation imaging. The exact protocol will necessarily vary depending upon factors specific to the patient, as noted above, and depending upon the body site under examination, method of administration and type of label used; the determination of specific procedures would be routine to the skilled artisan. The distribution of the bound radioactive isotope and its decrease with time is then monitored and recorded. By comparing the results with data obtained from studies of clinically normal individuals, the presence and location of amyloid deposits can be determined.
  • the methods of the present invention is used to diagnoses an amyloidosis-associated disease.
  • the site of examination is the brain
  • the in vivo detection of amyloid deposits according to the methods of the present invention signifies a diagnosis of Alzheimer's Disease.
  • the detection of amyloid deposits in the brain of patients manifesting clinical symptoms of Down Syndrome signifies a diagnosis of Down Syndrome.
  • the gene for APP located on chromosome 21, is over-represented in Down Syndrome individuals (Serra et al . , Araer. J. Med. Gen . Supp. , 7: 11-19 (1990).
  • amyloid-binding compositions of the present invention are advantageously administered in the form of injectable compositions.
  • a typical composition for such purpose comprises a pharmaceutically acceptable carrier.
  • the composition may contain about 10 mg of human serum albumin and from about 20 to 200 micrograms of the labeled amyloid protein per milliliter of phosphate buffer containing NaCl.
  • Other pharmaceutically acceptable carriers include aqueous solutions, non-toxic excipients, including salts, preservatives, buffers and the like, as described in REMINGTON'S PHARMACEUTICAL SCIENCES, 15th Ed. Easton: Mack Publishing Co. pp 1405- 1412 and 1461-1487 (1975) and THE NATIONAL FORMULARY XIV., 14th Ed.
  • non-aqueous solvents examples include propylene glycol, polyethylene glycol, vegetable oil and injectable organic esters such as ethyloleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, saline solutions, parenteral vehicles such as sodium chloride. Ringer's dextrose, etc.
  • Intravenous vehicles include fluid and nutrient replenishers. Preservatives include antimicrobials, anti-oxidants, chelating agents and inert gases. The pH and exact concentration of the various components of the binding composition are adjusted according to routine skills in the art.
  • amyloid binding compositions of the present invention are those that, in addition to binding to amyloid deposits in in vivo, are also non- toxic at appropriate dosage levels, have a satisfactory duration of effect, and display an adequate ability to cross the blood-brain barrier.
  • United States Patent No. 4,540,564 discloses an approach for enhancing blood-brain barrier-penetrating ability by attaching a centrally acting drug species to a reduced. biooxidizable, lipoidal form of dihydropyridine pyridinium salt redox carrier.
  • the composition of the present invention includes such a blood-brain barrier crossing enhancer carrier.
  • In vivo animal testing provides yet a further basis for determining dosage ranges, efficacy of transfer through the blood barrier and binding ability.
  • Particularly preferred for this purpose is the "senile animal" model for cerebral amyloidosis — animals such as aged dogs or monkeys, which are known to develop variable numbers of Alzheimer-type cerebral senile plaques, see Wisniewski, et al . , J. Neuropathol . & Exp. Neurol . , 32: 566 (1973), Selkoe, et al . , Science 235: 873 (1987) are tested for binding and detection efficacy.
  • This in vivo assay requires control-biopsy monitoring to confirm and quantify the presence of amyloid deposits.
  • PC12 cells transfected with the 0- amyloid polypeptide C-terminal region of the APP were implanted into the suprachiasmatic nuclei ("SCN") of rats; the SCN is a primary circadian oscillator in mammals. Animals receiving a yloidotic cell grafts, but not animals receiving control cell grafts, exhibited disrupted activity rhythms, although temperature rhythms were unaffected. The specificity of the disruption was similar to circadian dysfunction seen in AD patients. The data supported an association between a defined behavioral disruption and amyloid overexpression either directly or through the release of cellular factors as a consequence of amyloid overproduction.
  • A4 is intended to be the same as 0/A4, throughout the examples.
  • the peptides used in the following Examples have the following structures: A4-0 (peptides 1-28), SEQ ID NO:7:
  • the A4-0(l-28) polypeptide that was reported in Masters, et al . Proc. Nat ' l . Acad. Sci . U.S.A. , 82 : 4245- 4249 (1985) is the first 28 amino acids of the 4.2 Kd peptide derived from senile plaque cores of an AD brain. Masters, et al . have also shown that the naturally occurring peptide aggregates even in denaturing gels.
  • the A4-0(l-28) sequence of this invention was synthesized by Biosearch in San Rafael, CA. The underlined amino acids differ from A4-P(l-28) , as shown below.
  • A4-H (peptides 1-28) The underlined amino acids differ from A4-P(l-28) , as shown below.
  • the A4-H peptide is the same as A4-0(l-28) except that it was synthesized by the Harvard Microchemistry Laboratory.
  • A4-P (peptides 1-28), SEQ ID NO:8:
  • A4-B (peptides 1-28), SEQ ID NO:9:
  • A4(l-10) consists of the first 10 amino acids of the amyloid peptide derived from any source and is described in U.S. Patent No. 4,666,829 by Glenner et al . Thus far, this sequence appears conserved in all reports on amyloid that is derived from non-Familial AD cases.
  • the A4-(l- 10) antigen used in the present studies was synthesized by the Harvard Microchemistry Laboratory. Summary of sequence variations: dashed line indicates sequence conservation among the peptides shown.
  • A4-P (1-28) N Gin Asn-Lys- (Glenner)
  • A4-B (1-28) N Glu Asn-Lys- (Kang) Opl N 1
  • the synthetic ⁇ -amyloid 28-mer polypeptide, A4-0 (Masters, et al . , supra . ) was analyzed by polyacrylamide gel electrophoresis (PAGE) procedures (Brown, et al . , J. Neurochem . , 40 : 299-308 (1983)) and was noted to have unusual aggregation properties.
  • the peptide was dissolved in a PAGE sample buffer containing SDS and urea and was electrophoresed on a 10% gel containing SDS (See description of Figure 2) .
  • the peptide appeared as a broad band at approximately 23-25 kd and a narrow band that migrated at the get front during electrophoresis (See Figure 2) .
  • the higher molecular weight species appeared to be an aggregate since it was eliminated by adding urea to the separating get and, subsequently, a 3-4 kd band was obtained (not shown) .
  • Polyclonal antiserum to the 28-mer was prepared and applied to nitrocellulose blots of an overloaded gel. The latter contained a series of aggregated peptides of various apparent molecular weights, all of which reacted with the antiserum.
  • the synthetic 28-mer had aggregational properties not unlike the naturally occurring A4- ⁇ amyloid protein of 4 kd (Masters, et al . , supra) .
  • Applicants' studies demonstrating the aggregation properties of the A4-0 peptide were previously reported (Salim, et al . , "Molecular Cloning of Amyloid cDNA from Alzheimer Brain Messenger RNA" in Familial Alzheimer' s Disease, J.P. Blass et al . eds.. Marcel Dekker, NY pp 153-165 (1988).
  • peptide P2(413-429) used as a control and corresponding to an extracytoplasmic region of the B/A4 precursor protein, migrated with the bromphenol blue dye front on both SDS-PAGE and SDS/urea-PAGE systems ( Figure 3, lane 4). Since the theoretical molecular weight of the 28 amino acid peptide A4-0 is 3,178 Da the results indicate that the band of 15kDa is an aggregate. Migration of A4-0 peptide bands on both gel systems was not affected by 2-ME nor by pre-treatment with 80% formic acid (data not shown) .
  • the density of staining (the optical density of the immunoreaction product) is quantitated in Figures 5, 6 and 7.
  • the OD is a measure of the extent of the aggregation since it will be related to the antibody concentration and thus the color reaction.
  • the density values shown in Figure 5 were obtained by densitometric scanning of the reaction product on blots from which the control value (no primary antibody) was subtracted.
  • a further control was one in which the mab 10H3 was added to blots containing Opl in the absence of added exogenous peptide. This control value represents the antibody-antigen reaction without interference from added peptides.
  • Example 3 The experiment of Example 3 was repeated except that the exogenous peptide was A4-H.
  • the data are shown in Figure 6 and based upon these results, applicants concluded that A4-H bound to A4-0 at an optimal concentration of 2.5 ug/ml.
  • Example 3 The experiment of Example 3 was repeated except that the exogenous peptide was Opl.
  • the data are shown in Figure 7 and based upon these results, applicants concluded that Opl bound to A4-0 at an optimal concentration of 2.5 ug/ml.
  • CAA CCA GTG ACC ATC CAG AAC TGG TGC AAG CGG GGC CGC AAG CAG TGC 461 Gin Pro Val Thr He Gin Asn Trp Cys Lys Arg Gly Arg Lys Gin Cys S»0 95 100 105
  • GAG AAA GTG GAA TCT TTG GAA CAG GAA GCA GCC AAC GAG AGA CAG CAG 1277 Glu Lys Val Glu Ser Leu Glu Gin Glu Ala Ala Asn Glu Arg Gin Gin 365 370 375
  • GCT GCC GAC CGA GGA CTG ACC ACT CGA CCA GGT TCT GGG TTG ACA AAT 1901 Ala Ala Asp Arg Gly Leu Thr Thr Arg Pro Gly Ser Gly Leu Thr Asn 570 575 580 585
  • GCTTCTGCTA TATTTGTGAT ATAGGAATTA AGAGGATACA CACGTTTGTT TCTTCGTGCC 2841

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Abstract

L'invention se rapporte à une composition fixant l'amyloïde destinée à l'imagerie in vivo de dépôts d'amyloïde et comprenant une protéine d'amyloïde marquée ou une variante de celle-ci qui se fixe aux dépôts d'amyloïde in vivo et à un excipient pharmaceutiquement acceptable. L'invention se rapporte également à des procédés de détection des dépôts d'amyloïde et à des procédés de diagnostic de la maladie d'Alzheimer et du syndrome de Down.
PCT/US1994/005809 1993-05-28 1994-05-27 Composition et procede d'imagerie in vivo de depots d'amyloide WO1994028412A1 (fr)

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AU70438/94A AU7043894A (en) 1993-05-28 1994-05-27 Composition and method for (in vivo) imaging of amyloid deposits

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US08/069,010 1993-05-28

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Cited By (37)

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WO1996028471A1 (fr) * 1995-03-14 1996-09-19 Praecis Pharmaceuticals Incorporated Modulateurs de l'agregation de substances amyloides
US5817626A (en) * 1995-03-14 1998-10-06 Praecis Pharmaceuticals Incorporated Modulators of beta-amyloid peptide aggregation
US5854215A (en) * 1995-03-14 1998-12-29 Praecis Pharmaceuticals Incorporated Modulators of β-amyloid peptide aggregation
US5985242A (en) * 1995-10-27 1999-11-16 Praecis Pharmaceuticals, Inc. Modulators of β-amyloid peptide aggregation comprising D-amino acids
US6001331A (en) * 1996-01-24 1999-12-14 Warner-Lambert Company Method of imaging amyloid deposits
WO2000034511A2 (fr) * 1998-12-07 2000-06-15 Aventis Pharma Deutschland Gmbh ANALYSE SELECTIVE DE Aβ-PEPTIDE
FR2796952A1 (fr) * 1999-07-30 2001-02-02 Centre Nat Rech Scient Nouvelles applications de peptides issus du domaine cytoplasmique du precurseur de la proteine amyloide
US6277826B1 (en) 1996-08-27 2001-08-21 Praecis Pharmaceuticals, Inc. Modulators of β-amyloid peptide aggregation comprising D-amino acids
US6303567B1 (en) 1995-03-14 2001-10-16 Praecis Pharmaceuticals, Inc . Modulators of β-amyloid peptide aggregation comprising D-amino acids
US6589504B1 (en) 2000-09-22 2003-07-08 Pharmacia & Upjohn Company Compounds and methods for diagnosing and treating amyloid-related conditions
US6610658B1 (en) 1999-03-04 2003-08-26 Praecis Pharmaceuticals Inc. Modulators of μ-amyloid peptide aggregation
US6710226B1 (en) 1997-12-02 2004-03-23 Neuralab Limited Transgenic mouse assay to determine the effect of Aβ antibodies and Aβ Fragments on alzheimer's disease characteristics
US6743427B1 (en) 1997-12-02 2004-06-01 Neuralab Limited Prevention and treatment of amyloidogenic disease
US6750324B1 (en) 1997-12-02 2004-06-15 Neuralab Limited Humanized and chimeric N-terminal amyloid beta-antibodies
US6761888B1 (en) 2000-05-26 2004-07-13 Neuralab Limited Passive immunization treatment of Alzheimer's disease
US6770448B2 (en) 1997-08-14 2004-08-03 The Regents Of The University Of California Fluorescent amyloid Aβ peptides and uses thereof
US6787637B1 (en) 1999-05-28 2004-09-07 Neuralab Limited N-Terminal amyloid-β antibodies
US6787143B1 (en) 1997-12-02 2004-09-07 Neuralab Limited Prevention and treatment of amyloidogenic disease
US6808712B2 (en) 1997-12-02 2004-10-26 Neuralab Limited Prevention and treatment of amyloidogenic disease
WO2002096350A3 (fr) * 2001-05-25 2004-11-11 United Biomedical Inc Composition de peptide immunogene pour la prevention et le traitement de la maladie d'alzheimer
JP2007300856A (ja) * 2006-05-11 2007-11-22 Hiroshi Mori アミロイドタンパク質模倣物
US7569660B1 (en) 1999-06-09 2009-08-04 The University Of Chicago Recombinant prion-like proteins and materials comprising same
US7700751B2 (en) 2000-12-06 2010-04-20 Janssen Alzheimer Immunotherapy Humanized antibodies that recognize β-amyloid peptide
US7790856B2 (en) 1998-04-07 2010-09-07 Janssen Alzheimer Immunotherapy Humanized antibodies that recognize beta amyloid peptide
US7871615B2 (en) 2003-05-30 2011-01-18 Janssen Alzheimer Immunotherapy Humanized antibodies that recognize beta amyloid peptide
US7893214B2 (en) 1997-12-02 2011-02-22 Janssen Alzheimer Immunotherapy Humanized antibodies that recognize beta amyloid peptide
US7964192B1 (en) 1997-12-02 2011-06-21 Janssen Alzheimer Immunotherapy Prevention and treatment of amyloidgenic disease
US7977316B2 (en) 1999-06-01 2011-07-12 Elan Pharmaceuticals, Inc. Prevention and treatment of amyloidogenic diseases
US8003097B2 (en) 2007-04-18 2011-08-23 Janssen Alzheimer Immunotherapy Treatment of cerebral amyloid angiopathy
US8105594B2 (en) 1998-05-21 2012-01-31 Alan Solomon Methods for amyloid removal using anti-amyloid antibodies
US8128928B2 (en) 2002-03-12 2012-03-06 Wyeth Llc Humanized antibodies that recognize beta amyloid peptide
US8613920B2 (en) 2007-07-27 2013-12-24 Janssen Alzheimer Immunotherapy Treatment of amyloidogenic diseases
US8784810B2 (en) 2006-04-18 2014-07-22 Janssen Alzheimer Immunotherapy Treatment of amyloidogenic diseases
US8916165B2 (en) 2004-12-15 2014-12-23 Janssen Alzheimer Immunotherapy Humanized Aβ antibodies for use in improving cognition
US9067981B1 (en) 2008-10-30 2015-06-30 Janssen Sciences Ireland Uc Hybrid amyloid-beta antibodies
US9102752B2 (en) 2013-03-15 2015-08-11 United Biomedical, Inc. Peptide vaccine for prevention and immunotherapy of dementia of the Alzheimer's type
US9644025B2 (en) 2007-10-17 2017-05-09 Wyeth Llc Immunotherapy regimes dependent on ApoE status

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WO1996028471A1 (fr) * 1995-03-14 1996-09-19 Praecis Pharmaceuticals Incorporated Modulateurs de l'agregation de substances amyloides
US5817626A (en) * 1995-03-14 1998-10-06 Praecis Pharmaceuticals Incorporated Modulators of beta-amyloid peptide aggregation
US5854215A (en) * 1995-03-14 1998-12-29 Praecis Pharmaceuticals Incorporated Modulators of β-amyloid peptide aggregation
US5854204A (en) * 1995-03-14 1998-12-29 Praecis Pharmaceuticals, Inc. Aβ peptides that modulate β-amyloid aggregation
US7658917B2 (en) 1995-03-14 2010-02-09 Praecis Pharmaceuticals, Inc. Modulators of amyloid aggregation
US6303567B1 (en) 1995-03-14 2001-10-16 Praecis Pharmaceuticals, Inc . Modulators of β-amyloid peptide aggregation comprising D-amino acids
US6319498B1 (en) 1995-03-14 2001-11-20 Praecis Pharmaceuticals Incorporated Modulators of amyloid aggregation
US5985242A (en) * 1995-10-27 1999-11-16 Praecis Pharmaceuticals, Inc. Modulators of β-amyloid peptide aggregation comprising D-amino acids
US6689752B2 (en) 1995-10-27 2004-02-10 Praecis Pharmaceuticals, Incorporated Modulators of β-amyloid peptide aggregation comprising D-amino acids
US7175828B2 (en) 1995-10-27 2007-02-13 Praecis Pharmaceuticals, Inc. Modulators of β-amyloid peptide aggregation comprising D-amino acids
US6001331A (en) * 1996-01-24 1999-12-14 Warner-Lambert Company Method of imaging amyloid deposits
US6277826B1 (en) 1996-08-27 2001-08-21 Praecis Pharmaceuticals, Inc. Modulators of β-amyloid peptide aggregation comprising D-amino acids
US6770448B2 (en) 1997-08-14 2004-08-03 The Regents Of The University Of California Fluorescent amyloid Aβ peptides and uses thereof
US6710226B1 (en) 1997-12-02 2004-03-23 Neuralab Limited Transgenic mouse assay to determine the effect of Aβ antibodies and Aβ Fragments on alzheimer's disease characteristics
US6787138B1 (en) 1997-12-02 2004-09-07 Neuralab Limited Prevention and treatment of amyloidogenic disease
US8034339B2 (en) 1997-12-02 2011-10-11 Janssen Alzheimer Immunotherapy Prevention and treatment of amyloidogenic disease
US9051363B2 (en) 1997-12-02 2015-06-09 Janssen Sciences Ireland Uc Humanized antibodies that recognize beta amyloid peptide
US6743427B1 (en) 1997-12-02 2004-06-01 Neuralab Limited Prevention and treatment of amyloidogenic disease
US6750324B1 (en) 1997-12-02 2004-06-15 Neuralab Limited Humanized and chimeric N-terminal amyloid beta-antibodies
US7964192B1 (en) 1997-12-02 2011-06-21 Janssen Alzheimer Immunotherapy Prevention and treatment of amyloidgenic disease
US8535673B2 (en) 1997-12-02 2013-09-17 Janssen Alzheimer Immunotherapy Prevention and treatment of amyloidogenic disease
US7893214B2 (en) 1997-12-02 2011-02-22 Janssen Alzheimer Immunotherapy Humanized antibodies that recognize beta amyloid peptide
US6787143B1 (en) 1997-12-02 2004-09-07 Neuralab Limited Prevention and treatment of amyloidogenic disease
US6787523B1 (en) 1997-12-02 2004-09-07 Neuralab Limited Prevention and treatment of amyloidogenic disease
US8034348B2 (en) 1997-12-02 2011-10-11 Janssen Alzheimer Immunotherapy Prevention and treatment of amyloidogenic disease
US6787144B1 (en) 1997-12-02 2004-09-07 Neuralab Limited Prevention and treatment of amyloidogenic disease
US6787139B1 (en) 1997-12-02 2004-09-07 Neuralab Limited Prevention and treatment of amyloidogenic disease
US6787140B1 (en) 1997-12-02 2004-09-07 Neuralab Limited Prevention and treatment of amyloidogenic disease
US6808712B2 (en) 1997-12-02 2004-10-26 Neuralab Limited Prevention and treatment of amyloidogenic disease
US6982084B2 (en) 1997-12-02 2006-01-03 Neuralab Limited Prevention and treatment of amyloidogenic disease
US6818218B2 (en) 1997-12-02 2004-11-16 Neuralab Limited Prevention and treatment of amyloidogenic disease
US8642044B2 (en) 1997-12-02 2014-02-04 Janssen Alzheimer Immunotherapy Prevention and treatment of amyloidogenic disease
US7790856B2 (en) 1998-04-07 2010-09-07 Janssen Alzheimer Immunotherapy Humanized antibodies that recognize beta amyloid peptide
US8105594B2 (en) 1998-05-21 2012-01-31 Alan Solomon Methods for amyloid removal using anti-amyloid antibodies
US7109027B2 (en) 1998-12-07 2006-09-19 Sanofi-Aventis Deutschland Gmbh Aβ-Peptide screening assay
WO2000034511A3 (fr) * 1998-12-07 2000-11-16 Aventis Pharma Gmbh ANALYSE SELECTIVE DE Aβ-PEPTIDE
WO2000034511A2 (fr) * 1998-12-07 2000-06-15 Aventis Pharma Deutschland Gmbh ANALYSE SELECTIVE DE Aβ-PEPTIDE
US6610658B1 (en) 1999-03-04 2003-08-26 Praecis Pharmaceuticals Inc. Modulators of μ-amyloid peptide aggregation
US7803774B2 (en) 1999-03-04 2010-09-28 Praecis Pharmaceuticals, Inc. Modulators of β-amyloid peptide aggregation
US6787637B1 (en) 1999-05-28 2004-09-07 Neuralab Limited N-Terminal amyloid-β antibodies
US7977316B2 (en) 1999-06-01 2011-07-12 Elan Pharmaceuticals, Inc. Prevention and treatment of amyloidogenic diseases
US8124081B2 (en) 1999-06-01 2012-02-28 Crimagua Limited Prevention and treatment of amyloidogenic diseases
US7569660B1 (en) 1999-06-09 2009-08-04 The University Of Chicago Recombinant prion-like proteins and materials comprising same
US7115380B2 (en) 1999-07-30 2006-10-03 Centre National De La Recherche Scientifique Applications of peptides derived from the cytoplasmic domain of amyloid precursor protein (APP)
WO2001009170A1 (fr) * 1999-07-30 2001-02-08 Centre National De La Recherche Scientifique-Cnrs Applications de peptides issus du domaine cytoplasmique du precurseur de la proteine amyloide (app)
US6905832B1 (en) 1999-07-30 2005-06-14 Centre National De La Recherche Scientifique (Cnrs) Uses of peptides derived from the cytoplasmic domain of the amyloid protein precursor (APP)
FR2796952A1 (fr) * 1999-07-30 2001-02-02 Centre Nat Rech Scient Nouvelles applications de peptides issus du domaine cytoplasmique du precurseur de la proteine amyloide
US6761888B1 (en) 2000-05-26 2004-07-13 Neuralab Limited Passive immunization treatment of Alzheimer's disease
US6589504B1 (en) 2000-09-22 2003-07-08 Pharmacia & Upjohn Company Compounds and methods for diagnosing and treating amyloid-related conditions
US7700751B2 (en) 2000-12-06 2010-04-20 Janssen Alzheimer Immunotherapy Humanized antibodies that recognize β-amyloid peptide
AU2002303211B2 (en) * 2001-05-25 2008-02-28 United Biomedical, Inc. Immunogenic peptide composition for the prevention and treatment of alzheimer's disease
US7951909B2 (en) 2001-05-25 2011-05-31 United Biomedical, Inc. Immunogenic peptide composition comprising a promiscuous helper T cell epitope and an N-terminal fragment of Aβ1-42 peptide
WO2002096350A3 (fr) * 2001-05-25 2004-11-11 United Biomedical Inc Composition de peptide immunogene pour la prevention et le traitement de la maladie d'alzheimer
US8232373B2 (en) 2001-05-25 2012-07-31 United Biomedical, Inc. Immunogenic peptide composition for the prevention and treatment of alzheimer's disease
US8128928B2 (en) 2002-03-12 2012-03-06 Wyeth Llc Humanized antibodies that recognize beta amyloid peptide
US7871615B2 (en) 2003-05-30 2011-01-18 Janssen Alzheimer Immunotherapy Humanized antibodies that recognize beta amyloid peptide
US8916165B2 (en) 2004-12-15 2014-12-23 Janssen Alzheimer Immunotherapy Humanized Aβ antibodies for use in improving cognition
US8784810B2 (en) 2006-04-18 2014-07-22 Janssen Alzheimer Immunotherapy Treatment of amyloidogenic diseases
JP2007300856A (ja) * 2006-05-11 2007-11-22 Hiroshi Mori アミロイドタンパク質模倣物
US8003097B2 (en) 2007-04-18 2011-08-23 Janssen Alzheimer Immunotherapy Treatment of cerebral amyloid angiopathy
US8613920B2 (en) 2007-07-27 2013-12-24 Janssen Alzheimer Immunotherapy Treatment of amyloidogenic diseases
US9644025B2 (en) 2007-10-17 2017-05-09 Wyeth Llc Immunotherapy regimes dependent on ApoE status
US9067981B1 (en) 2008-10-30 2015-06-30 Janssen Sciences Ireland Uc Hybrid amyloid-beta antibodies
US9102752B2 (en) 2013-03-15 2015-08-11 United Biomedical, Inc. Peptide vaccine for prevention and immunotherapy of dementia of the Alzheimer's type

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