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WO1999000150A2 - Ciblage d'un medicament radiopharmaceutique peptidique utilisant in vivo la barriere hemato-encephalique d'un primate et un anticorps monoclonal dirige contre le recepteur humain de l'insuline - Google Patents

Ciblage d'un medicament radiopharmaceutique peptidique utilisant in vivo la barriere hemato-encephalique d'un primate et un anticorps monoclonal dirige contre le recepteur humain de l'insuline Download PDF

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Publication number
WO1999000150A2
WO1999000150A2 PCT/US1998/013398 US9813398W WO9900150A2 WO 1999000150 A2 WO1999000150 A2 WO 1999000150A2 US 9813398 W US9813398 W US 9813398W WO 9900150 A2 WO9900150 A2 WO 9900150A2
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brain
radiolabeled
peptide
composition
monoclonal antibody
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PCT/US1998/013398
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WO1999000150A3 (fr
WO1999000150A9 (fr
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William M. Pardridge
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Regents Of The University Of California
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Priority to AU82698/98A priority Critical patent/AU8269898A/en
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Publication of WO1999000150A3 publication Critical patent/WO1999000150A3/fr
Publication of WO1999000150A9 publication Critical patent/WO1999000150A9/fr

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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
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1093—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody conjugates with carriers being antibodies

Definitions

  • the present invention relates generally to the introduction of radiolabeled peptide pharmaceutical agents into the brain by transcytosis across the blood-brain barrier.
  • Peptide radiopharmacueticals have potential for diagnostic imaging.
  • the somatostatin receptor is overexpressed in certain neuroendocrine tumors, as well as brain tumors, such as meningiomas or gliomas and [ 125 I]- or [ m In]-labeled octreotide, a somatostatin peptide analog, has been used to image these tumors.
  • octreotide Owing to the small size of the peptide radiopharmaceutical, octreotide readily crosses the porous capillaries perfusing tumors in the periphery, or certain brain tumors, such as meningiomas, which lack a blood-brain barrier (BBB)
  • BBB blood-brain barrier
  • well- differentiated gliomas which also overexpress somatostatin receptors, have an intact BBB, and it is not possible to image these tumors with octreotide, since this peptide does not cross the BBB in vivo.
  • amyloid In addition to tumors, it should also be possible to image other medical disorders with peptide radiopharmaceuticals, such as amyloid.
  • Extracellular AD amyloid is comprised of two types' senile (neuritic) plaque and vascular amyloid
  • Both types of amyloid in AD are comprised of a 43 amino acid amyloidotic peptide, designated A ⁇ 1"43 , as well as A ⁇ 1"42 forms, which are produced from the abnormal proteolysis of a normal cellular protein, the amyloid peptide precursor.
  • the A ⁇ amyloid of tissue sections of AD autopsy brain can be identified with dyes, such as
  • a ⁇ amyloid of AD sections may also be identified in vitro by autoradiography with [ ⁇ J-A ⁇ 1" 40 , a peptide which contains the first 40 amino acids of the A ⁇ 1"42 ' 43 peptide, and which deposits with high affinity onto pre-existing A ⁇ amyloid Therefore, radiolabeled A ⁇ 1"40 is a potential peptide radiopharmaceutical that could be used for neurodiagnostic quantitation of the A ⁇ amyloid burden in AD brain of living subjects using standard external detection methodologies, such as single photon emission computed tomography (SPECT) or positron emission tomography (PET).
  • SPECT single photon emission computed tomography
  • PET positron emission tomography
  • [ ⁇ IJ-A ⁇ 1"40 does not cross the BBB in rats unless a vector mediated BBB drug delivery system is used.
  • a ⁇ amyloid does not deposit in the brain of aged rats, but A ⁇ amyloid does form in the brain of New World primates, such as the aged (15-20 years) squirrel monkey in the form of vascular amyloid, and A ⁇ amyloid is produced in the brain of Old World primates, such as the aged (27-30 years) rhesus monkey in neuritic plaque form
  • Another object of the invention is to enhance the brain uptake of a peptide radio- pharmaceutical with the use of a BBB drug targeting system
  • Radiolabeled truncated analogs of A ⁇ 1"43 conjugated to a BBB drug delivery system are enabled to enter the brain from blood to a high degree, which allows for imaging amyloid plaques in AD brain tissue following systemic (intravenous ) injection Radiolabeling can be accomplished using I25 I, m In, or 99n c, for example
  • a highly effective drug delivery system is 83-14 HIRMAb, the 83-14 monoclonal antibody to the human insulin receptor, which can be conjugated to radiolabeled truncated analogs of A ⁇ 1"43 by means of avidin-biotin technology, polyethyleneglycol, or other polymeric linking agents
  • FIG. 4 Time-course of 0 5 nM 8314-SA binding to human brain capillary preparation in the absence (closed circles) or the presence (open circles) of the 10 ⁇ g/mL 8314 MAb
  • the tracer used in this radio-receptor assay was [ 3 H]-biotin (InM), which binds to the 8314-SA conjugate with a high affinity
  • No competition of [ 3 H]- biotin/8314-SA conjugate uptake by the capillaries was observed with 10 ⁇ g/mL mouse IgG 2a , the isotype control for the 83-14 MAb
  • the capillary uptake of [ 3 H]-biotin bound to streptavidin alone was ⁇ 2%
  • Data are means of duplicates that varied ⁇ 10%
  • Figure 6 Emulsion autoradiography showing the binding of [ 125 I]-b ⁇ o-A ⁇ ' "4 ° (A) or [ 125 I]- bio- A ⁇ 1"40 ⁇ 14-SA conjugate (B) to amyloid plaques of frozen section of human
  • AD brain under b ⁇ ghtfield microscopy Magnification bar is 23 ⁇ m
  • Figure 7 Plasma profile of either unconjugated (open circles) or the
  • Figure 8 Brian volume of distribution (V D ) of either [ 1 5 I]-b ⁇ o-A ⁇ ' "4 ° or the [ 125 I]-b ⁇ o-A ⁇ ' " 40 /8314-SA conjugate at 3, 24, or 48 hours after I v injection to rhesus monkeys
  • the filled bars represent the V D values of gray matter, while the open bars represent those of white matte of the monkey brains
  • Figure 9 Phosphorimager scans for left or right cerebral hemisphere in two different rhesus monkeys
  • the images in panel A represent the brain uptake 3 hours following intravenous injection of 300 ⁇ Ci of unconjugated [ I25 I]-b ⁇ o-A ⁇ 0
  • the images in the right hand panel (B) represent the brain uptake 3 hours after intravenous injection of [' ⁇ FJ-bio-A ⁇ 1"40 conjugated to 8314/streptav ⁇ d ⁇ n Images for the left and right occip
  • FIG 11 Scheme depicting the multifunctionality and three domains of the peptide radiopharmaceutical conjugated to the blood-brain barrier (BBB) delivery system
  • the imaging agent is comprised of amyloid binding domain, a linker domain, and a
  • BBB transport domain the latter constituted by the monoclonal antibody (MAb) to the human insulin receptor (HIR)
  • MAb monoclonal antibody
  • HIR human insulin receptor
  • a typical BBB delivery system is the 83-14 monoclonal antibody (MAb) to the human insulin receptor (HIR).
  • the 83-14 HIRMAb undergoes receptor- mediated transcytosis through the BBB of Old World primates, such as rhesus moneys, but not New World primates, such as squirrel monkeys. This observation is consistent with the greater genetic similarity between humans and Old World primates, as compared to New World primates.
  • the 83-14 HIRMAb has a very high affinity for the human or Old World primate insulin receptor and is both an endocytosing antibody in isolated human brain capillaries, and a BBB transcytosing antibody in anesthetized rhesus monkeys.
  • the conjugation of [' ⁇ FJ-bio-A ⁇ 1"40 to the 83-14 HIRMAb is facilitated with the use of avidin-biotin technology applied to brain drug delivery.
  • the peptide radiopharmaceutical is monobiotinylated and, in parallel, a conjugate of streptavidin (SA) and the 83-14 HIRMAb is prepared through the formation of stable thio-ether linkage between the SA and the 83-14 MAb.
  • SA streptavidin
  • the 83-14 MAb was purified from mouse ascites using protein G-Sepharose 4 Fast Flow affinity chromatography.
  • the purified 83-14 MAb was thiolated with a 10: 1 molar ratio of Traut's reagent, and Ellman's reagent was used to demonstrate that this reaction resulted in the insertion of a single thiol group on the surface of the MAb.
  • the SA was activated with a 20: 1 molar ratio of MBS, and the thiolated 83-14 MAb and the MBS-activated SA were incubated overnight at room temperature.
  • the 8314/SA A- 280 peak ( Figure 1A) was greater than the 8314/SA 3 H-biotin binding peak ( Figure IB), which indicated unconjugated 83-14 MAb was also contained in this peak.
  • K D 0.45 nM
  • unconjugated 83-14 MAb could compete for binding to the BBB of the 8314/SA conjugate. Therefore, unconjugated 83-14 MAb was removed by iminobiotin affinity chromatography. The fractions from the Sephacryl S-300 column were concentrated with a Centricon-30 (Amicon Inc., Beverly, MA).
  • the iminobiotin gel (2 mL) was packed in a column (7 x 100 mm), and the column was activated with 10 mL of binding buffer (50 mM ammonium carbonate/0.5 M NaCl/pH 11.0).
  • the number of biotin binding sites on the 8314/SA conjugate was measured with a [ 3 H]-biotin binding assay, and was 4.0+0.2, consistent with a 1: 1 conjugation of the 83-14 MAb and SA, which has 4 biotin binding sites.
  • reaction solution was diluted with 1 mL of 90% acetonitrile/ 10% 20 mM TEAP (trimethylamine/phosphoric acid)/pH 2.8 and loaded onto the PHEA extraction cartridge, which was pre-activated with 5 mL of 90% acetonitrile as shown in Figure 2.
  • the iodinated bio-A ⁇ 1"40 had a trichloroacetic acid (TCA) precipitation of >97% as shown in Figure 2, and was injected into the rhesus monkeys on the same day as iodination occurred.
  • TCA trichloroacetic acid
  • Human brain capillaries were isolated and cryo-preserved The isolated capillaries were thawed at room temperature and resuspended in Ringer-Hepes buffer (RHB, pH 7 4) containing 141 mM NaCl, 4 mM KC1, 2 8 mM CaCl 2 10 mM Hepes and 0 1% human serum albumin (HSA).
  • RHB Ringer-Hepes buffer
  • HSA human serum albumin
  • the capillaries (100-125 ⁇ g protein) were incubated with 0 025 ⁇ Ci/ml of either [ 3 H]- biotin or [ ⁇ FJ-bio-A ⁇ 1"40 either in the presence or in the absence of 0 5nM of 8314/SA Some of the tubes were enriched with 10 ⁇ g/ml of either unconjugated 83-14 MAb or mouse IgG 2a for competition studies. The reaction volume was brought to 0 5 with the RHB/0.1% HSA The incubations were performed at room temperature for 15, 30, and 60 minutes
  • Snap frozen AD cortex was provided by the UCLA Department of Pathology/Neuropathology, and 15 ⁇ sections were cut on a Bright cryostat and thaw-mounted to gelatin-coated slides.
  • the slides were incubated with 250 ⁇ L of TBM buffer containing 0 5 ⁇ Ci/mL of either '"T-bio-A ⁇ 1"40 or '"i-bio-A ⁇ 1" 40 /8314-SA with or without 10 ⁇ M unlabeled A ⁇ 1"40 for competition
  • the slides were incubated at room temperature for 2 hours, and were washed 4 times with 2-minute washes in
  • the two monkeys were sacrificed by a lethal injection of sodium pentobarbital (100 mg/kg), and brains were removed instantly, cut into 5 coronal slabs, and frozen in powdered dry ice, and stored at -70°C for subsequent frozen sectioning and phosphorimaging. Gray and white matter of the frontal cortex were separated, and radioactivity was counted using a Beckman gamma counter.
  • the conjugate of [ 125 I]-bio-A ⁇ M0 (300 ⁇ Ci) and 8314/SA (60 ⁇ g) was injected intravenously to monkey #3 and #4 (both 15 years) after sedation with 10 mg/kg ketamine (i.m.).
  • Monkey #3 was sacrificed 24 hours post-dose
  • monkey #4 was sacrificed 48 hours post-dose for the removal of brain.
  • a ⁇ t) A ⁇ k '' + A,e- k -'
  • A(t) % injected dose (LD)/mL plasma.
  • the monkey brain was rapidly removed from the cranium and sectioned into 5 coronal slabs of approximately 4 mm Each slab was individually plunged into powdered dry ice for rapid freezing over 30 minutes Embedding medium was placed between the brain slab and circular slabs of laboratory cork (35 mm diameter, ⁇ /8 inch thickness), and this was placed back in the powdered dry ice for additional freezing over a 2 hour period These preparations were then stored at - 70°C in 35 mm petri dishes For frozen sectioning, the brain was thawed to - 20°C and the cork was mounted on a cryostat orientable object holder with additional embedding medium and placed on a universal holder, and 20 ⁇ sections were cut on a Bright cryostat at -20°C Sections were mounted on precleaned Fisher microscope slides (75 x 50 x 1 mm) and air-dried at room temperature for 60 minutes The slides were then glued to a paper g ⁇ d, which was wrapped in transparent film, and placed in a
  • EXAMPLE 8 The affinity of the 83-14 MAb for the human brain insulin receptor was unaffected by conjugation of the 50,000 Da streptavidin to the antibody, as demonstrated by the radioreceptor data shown in Figure 4
  • [ ⁇ ]-biotin was bound to the /8314-SA conjugate and incubated with human brain capillaries with or without 10 ⁇ g/mL unconjugated 83-14 MAb
  • the binding of the [ ⁇ ]-biotin/8314-SA to the isolated human brain capillaries reached 10% at 60 minutes of incubation at room temperature as shown in Figure 4, which is comparable to the binding to human brain capillaries of unconjugated [ 125 I]- labeled 83-14 MAb
  • the plasma TCA-precipitable radioactivity date was subjected to a biexponential analysis to compute the pharmacokinetic parameters shown in Table 1
  • the frontal cortex was counted for total [ 125 I] radioactivity, and the brain volume of distribution (V D ) was computed for the A ⁇ 1 40 with or without conjugation to the 83 14/DA vector
  • the gray matter BBB permeability-surface area (PS) for the free peptide or for the conjugate was computed from the brain V D and the plasma area under the concentration curve (AUC), and was ⁇ 0 25 and 1 74 ⁇ L/min g, respectively
  • the brain V D of the A ⁇ 1"40 conjugated to the 8314/SA delivery system was ? 10-fold greater than the brain V D of the unconjugated peptide as shown in Figure 8, and this difference is also seen in the images obtained with the phosphorimager shown in Figure 9 There is no discernible brain uptake when the peptide was administered without the brain delivery system (Figure 9, left panel).
  • V c , V ss refer to kg body weight
  • a peptide radiopharmaceutical may be specially formulated for BBB drug delivery, and this formulation requires (i) synthesis and purification of the 8314/SA conjugate (Figure 1), and (ii) synthesis and purification of radiolabeled monobiotinylated A ⁇ 1"40 using hydrophilic interaction liquid chromatography ( Figure 2).
  • the bifunctionality of the 8314/SA conjugate is retained as this molecule both binds [ 125 I]-bio-A ⁇ ' "4 ° ( Figure 3), and binds the human brain capillary of BBB insulin receptor ( Figures 4,5).
  • the pharmacokinetics of the peptide radiopharmaceutical demonstrate a relatively rapid decline in the plasma concentration ad metabolic stability of the conjugate
  • the brain uptake of the peptide radiopharmaceutical without conjugation to the BBB delivery system is negligible ( Figures 8 and 9), but the brain uptake of the peptide radiopharmaceutical conjugated to the 8314/SA BBB delivery system is very high ( Figures 8 and 9) and this brain uptake of radioactivity is nearly 90% cleared by 48 hours after intravenous injection ( Figures 8 and 10)
  • the synthesis and purification of the 8314/SA vector requires a two-step procedure involving Sephacryl S-300 gel filtration ( Figure 1), and iminobiotin affinity chromatography ( Figure 2).
  • the first chromatographic procedure removes unconjugated streptavidin, and the second chromatography removes unconjugated 83-14 MAb
  • the use of the iminobiotin affinity chromatography is a novel procedure that allows for elution of the 8314/SA conjugate from the iminobiotin column under relatively mild conditions. It is imperative to remove all unconjugated 83-14 MAb, because the affinity of this antibody for the BBB insulin receptor is extremely high with a K D of 0.45 ⁇ 0.10 nM 921).
  • the presence of any unconjugated 83-14 MAb in the formulation comprised of the 8314/SA complex would compete with binding of the 8314/SA conjugate to the BBB insulin receptor, and this would inhibit brain uptake of the conjugated peptide radiopharmaceutical.
  • the monobiotinylated A ⁇ 1"40 must be iodinated and purified.
  • the A ⁇ 1"40 is a relatively hydrophobic peptide, and the subsequent biotinylation and iodination further increases the hydrophobicity of this molecule, which makes it difficult to release the [' ⁇ Ij-bio-A ⁇ 1'40 from reverse phase surfaces.
  • the multi-functionality of the amyloid imaging agent is retained following conjugation of [ ⁇ IJ-bio-A ⁇ 1"40 to the 8314/SA conjugate.
  • the three domains are depicted in Figure 1 1, and include the amyloid binding domain, a linker domain, and a BBB transport domain.
  • High affinity binding of the [ 125 I]-bio-A ⁇ 1"40 /8314-SA to the BBB insulin receptor is demonstrated both in vitro with isolated brain capillaries ( Figures 4 and 5) and in vivo in rhesus monkeys ( Figure 9).
  • the biotin binding properties of the 8314/SA conjugate is contained within the linker domain (Figure 11), and is demonstrated with the HPLC experiments in Figure 3, as well as the radioreceptor assays in Figures 4 and 5.
  • the amyloid binding domain is comprised of the radio labeled A ⁇ 1"40 .
  • the retention of the amyloid binding properties of the peptide pharmaceutical following conjugation to the BBB delivery system is demonstrated with the emulsion autoradiography experiments using AD tissue sections ( Figure 6).
  • [ 125 I]-bio-A ⁇ M0 is rapidly removed from the bloodstream, and is subjected to rapid metabolic degradation as indicated by the decrease in plasma TCA precipitability ( Figure 6).
  • [ 125 I]-bio-A ⁇ 1"40 is rapidly removed from the bloodstream, and is subjected to rapid metabolic degradation as indicated by the decrease in plasma TCA precipitability ( Figure 6).
  • [ 125 I]-bio-A ⁇ 1"40 is >90% bound by human albumin, this binding is relatively weak in vivo and does not inhibit the rapid clearance of [' ⁇ Ij-bio-A ⁇ 1'40 in vivo ( Figure 7).
  • the TCA- soluble [ 125 I] radioactivity in plasma at 1-3 hours following intravenous injection of the peptide may arise from proteolysis of the peptide with release of iodotyrosine.
  • An alternative pathway is surface deiodination of the intact peptide possibly by ecto-enzymes on the endothelial surface of organ capillary beds.
  • This amyloid is on the brain side of the microvasculature and is separated from labelled A ⁇ 1"40 absorbed to the luminal surface of the brain capillary endothelium by the endothelial membranes that constitute the BBB in vivo. Since A ⁇ 1"40 does not cross the BBB, systemically infused [ 125 I]A ⁇ M0 cannot label the A ⁇ amyloid in brain unless there is BBB disruption. However, the BBB is intact in Alzheimer's disease. Recent studies performed common carotid arterial infusion of relatively high doses (80-165 ⁇ Ci/kg) of [ 125 I]A ⁇ 1"40 into aged anesthetized squirrel monkeys.
  • the avid brain uptake of the peptide pharmaceutical formulated as a conjugate with the BBB delivery system ( Figure 9) demonstrates that brain structures can be readily imaged with this approach as the quality of the image is comparable to a standard '2-deoxyglucose" image seen with PET scans in humans or quantitative autoradiography in rats.
  • the clear image of the distribution of the peptide radiopharmaceutical in brain ( Figure 9) is due to the high activity of he 83-14 MAb as a BBB delivery sector.
  • the PS product of BBB transport of the 83-14 MAb in the primate brain is nearly 10-fold greater than the PS product of BBB transport of an anti-transferrin receptor MAb in the primate brain.
  • the image in Figure 9 demonstrates it is possible to achieve a high distribution of a peptide radiopharmaceutical in brain using a BBB delivery system, whereas there is negligible brain uptake of the peptide radiopharmaceutical when no BBB delivery system is used.
  • the time course studies in Figure 10 indicate that nearly 90% of the peptide radiopharmaceutical that is initially extracted by brain is subject to metabolic transformation and clearance from brain by 48 hours after intravenous administration.
  • the imaging agent In the absence of extracellular amyloid, the imaging agent will undergo receptor-mediated endocytosis into cells in brain bearing insulin receptor on the cell membrane surface, and this endocytosis is followed by degradation within the lysosomal compartment and release of the iodide radioactivity (Figure 10).
  • the susceptibility of A ⁇ 1"40 to protease attack is greatly reduced following deposition onto pre-existing A ⁇ amyloid.
  • the formulation of the amyloid imaging agent described in Figure 11 may appear to be relatively complex from the point of view of manufacturing this agent as an amyloid imaging agent for use in human subjects suspected of having Alzheimer's disease.
  • the formulation of the amyloid imaging agent is simplified with the use of avidin-biotin technology, and the use of a '2-vial" formulation.
  • One vial contains the MAb/avidin fusion protein, and the second vial contains the radiolabeled, biotinylated A ⁇ 1"40 peptide.
  • the two vials may be mixed immediately prior to administration to the subject, which takes advantage of the rapid capture of biotin analogs by MAb/avidin fusion proteins.
  • an MAb/avidin fusion gene and fusion protein have been synthesized and expressed, and demonstrated to have optimal pharmacokinetics.
  • the immunogenicity of the MAb portion of the delivery vector may be minimized by 'humanization" of the murine framework sequences of the MAb.
  • the immunogenicity of the avidin component may be minimized owing to oral antigen tolerance, induced by the presence of egg products in the diet. Indeed, relatively large (10 mg) quantities of avidin have been administered intravenously to humans without significant immunologic sequelae.
  • peptide radiopharmaceuficals may be specially formulated to enable these molecules to undergo receptor-mediated transport through the BBB.
  • the use of this brain drug delivery approach may allow for imaging brain amyloid or other structures using specific peptide radiopharmaceuficals that are intended to image a specialized function or property of brain.
  • BBB blood-brain barrier
  • SA streptavidin
  • a ⁇ 1"40 first 40 amino acids of ⁇ - peptide of Alzheimer's disease
  • MAb monoclonal antibody
  • HLLC hydrophilic interaction liquid chromatography
  • APP amyloid peptide precursor
  • FUR human insulin receptor
  • TEAP triethylamine phosphate
  • HSA human serum albumin
  • RHB Ringer's Hepes buffer
  • LD injected dose
  • V D blood-brain barrier
  • SA streptavidin
  • a ⁇ 1"40 first 40 amino acids of ⁇ - peptide of Alzheimer's disease
  • MAb monoclonal antibody
  • HLLC hydrophilic interaction liquid chromatography
  • APP amyloid peptide precursor
  • FUR human insulin receptor
  • TEAP triethylamine phosphate
  • HSA human serum albumin
  • RHB Ringer's Hepes buffer
  • LD injected dose
  • V D injected dose

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Abstract

Selon cette invention, le peptide [125I]-Aβ1-40 a été mono-biotinylé et conjugué à un système de ciblage cérébral et d'administration d'un médicament à la barrière hémato-encéphalique (BBB), système renfermant un complexe de l'anticorps monoclonal 83-14 (MAb) dirigé contre le récepteur humain de l'insuline et marqué par la streptavidine (SA) et ce, dans le but de produire, trois heures après l'injection intraveineuse, un accroissement sensible de l'assimilation du [125I]-bio-Aβ1-40 par le cerveau du singe rhésus, par rapport à l'assimilation obtenue sans administration de médicament à la BBB.
PCT/US1998/013398 1997-06-27 1998-06-26 Ciblage d'un medicament radiopharmaceutique peptidique utilisant in vivo la barriere hemato-encephalique d'un primate et un anticorps monoclonal dirige contre le recepteur humain de l'insuline WO1999000150A2 (fr)

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AU82698/98A AU8269898A (en) 1997-06-27 1998-06-26 Drug targeting of a peptide radiopharmaceutical through the primate blood-brain barrier in vivo with a monoclonal antibody to the human insulin receptor

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WO2001044300A2 (fr) * 1999-12-13 2001-06-21 Cambridge Antibody Technology Limited Elements de liaison specifiques du cerveau
WO2002021141A2 (fr) * 2000-09-06 2002-03-14 Aventis Pharma S.A. Procedes et compositions relatifs a des maladies associees a l'amyloide
WO2002089841A2 (fr) * 2001-05-04 2002-11-14 Nymox Corporation Procede pour prevenir la mort cellulaire a l'aide d'anticorps agissant a l'encontre de proteines filamenteuses nerveuses
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
US6787140B1 (en) 1997-12-02 2004-09-07 Neuralab Limited Prevention and treatment of amyloidogenic disease
US6787637B1 (en) 1999-05-28 2004-09-07 Neuralab Limited N-Terminal amyloid-β antibodies
US6808712B2 (en) 1997-12-02 2004-10-26 Neuralab Limited Prevention and treatment of amyloidogenic disease
US6875434B1 (en) 1997-12-02 2005-04-05 Neuralab Limited Methods of treatment of Alzheimer's disease
US6923964B1 (en) 1997-12-02 2005-08-02 Neuralab Limited Active immunization of AScr for prion disorders
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