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WO1992008483A1 - REDUCTION DE LA DEGENERESCENCE NEURONALE LIEE A LA PROTEINE β-AMYLOIDE PAR UN EFFET ANTAGONISTE SUR L'ACTIVITE NEURONALE PROVOQUEE PAR LE NGF - Google Patents

REDUCTION DE LA DEGENERESCENCE NEURONALE LIEE A LA PROTEINE β-AMYLOIDE PAR UN EFFET ANTAGONISTE SUR L'ACTIVITE NEURONALE PROVOQUEE PAR LE NGF Download PDF

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Publication number
WO1992008483A1
WO1992008483A1 PCT/US1991/008476 US9108476W WO9208483A1 WO 1992008483 A1 WO1992008483 A1 WO 1992008483A1 US 9108476 W US9108476 W US 9108476W WO 9208483 A1 WO9208483 A1 WO 9208483A1
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WO
WIPO (PCT)
Prior art keywords
ngf
neurons
amyloid
ability
neuronal
Prior art date
Application number
PCT/US1991/008476
Other languages
English (en)
Inventor
Bruce A. Yankner
Original Assignee
The Children's Medical Center Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Children's Medical Center Corporation filed Critical The Children's Medical Center Corporation
Publication of WO1992008483A1 publication Critical patent/WO1992008483A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention is in the general field of therapeutics for diseases characterized by pathological accumulation of neuronal plaques comprising 0-amyloid protein.
  • j3-amyloid protein is the primary constituent of senile plaques and cerebrovascular deposits in Alzheimer disease (AD) and in aged Down syndrome. Giaccone er al., Neurosci . Lett . 97:232-238 (1989) report that accumulation of ⁇ amyloid is one of the earliest detectable pathologic changes in the brains of patients with Down syndrome destined to develop Alzheimer-type dementia. In AD, the extent of cortical amyloid plaque development correlates with disease severity as reported by captivating et al., Br. J. Psychiatry 114:797-811 (1968).
  • one aspect of the invention features methods of treating patients at risk for ⁇ - amyloid related neurodegeneration by administering an antagonist of NGF-neuronal interaction.
  • Preferred embodiments of the invention feature administering NGF antagonists (particularly anti-NGF antibody or NGF-binding fragments of such antibodies) to the patient's neurons.
  • therapeutics which block the neuronal NGF receptor can be administered.
  • the invention features screening candidate compounds for the ability to treat ⁇ - amyloid related neurodegenerative disease by subjecting cultured neurons to NGF in combination with candidate compounds, and determining the ability of the candidate to antagonize NGF-induced effect on the neurons.
  • Such determination may be direct, e.g. , by determining the ability of the candidate to antagonize an NGF-induced neuronal function such as growth; alternatively, the determination may be indirect, e.g. , by determining the ability of candidates to antagonize NGF potentiation of / 9-amyloid related neurotoxicity.
  • NGF nerve growth factor
  • NGF receptor is reported by Radeke et al.. Nature 325:593-597 (1987); Chao et al.,
  • NGF and NGF receptor from other mammalian sources can be obtained using standard techniques involving the use of nucleic acid probes from known mammalian NGF or NGF receptor genes, described above to recover cDNA from neuronal mRNA preparations
  • a mammal particularly a rodent or » a primate
  • a mammal is used to test a candidate compound in vivo.
  • ⁇ ⁇ A neurotoxic 0-amyloid peptide e.g. APP or a fragment
  • BDNF brain-derived neurotrophic factor
  • NT3 neurotrophin-3
  • BDNF is reported to be functionally cross-reactive with NGF.
  • BDNF and NT-3 are reported by Barde et al., EMBO J. 1:549 (1982); Davies, Trends Neurosci 11:243 (1988); Barde,
  • Antibodies to nerve growth factors useful in the invention can be obtained by techniques well known to those in the field. For example, a mammal can be challenged with one of the above-described nerve growth factors, and standard techniques can be used for generating hybridomas, and for screening the hybridomas to identify hybridomas producing anti-nerve growth factor antibody. Standard immunopurification techniques can then be applied to hybridoma supernatant to obtain purified anti-NGF antibody.
  • Other therapeutics useful in the invention are derived from anti-NGF antibodies by standard techniques.
  • the genome of the above-described hybridoma can be probed by known techniques to clone nucleic acid encoding the variable portion of the monoclonal antibody for attachment to a carrier suitable for therapeutic use. See, e.g., Huse et al. Science, 246:12751281 (1989), hereby incorporated by reference.
  • Other methods of producing NGF-binding molecules from anti-NGF antibodies can also be used.
  • Genex, U. S. Patent 4,946,778 discloses a method for forming single-chain antibodies; Capon et al., Nature, 337:529 et seq. (1989) discloses another method for forming antigen-binding molecules based on an antibody to the antigen.
  • Anti-NGF antibody (or NGF-binding fragments of it) or other antagonist can be formulated in an appropriate buffered saline vehicle and administered to patients at risk for ⁇ -amyloid associated neurodegeneration, for example patients exhibiting symptoms that are characteristic of Alzheimer's disease.
  • the antagonist can be administered directly to the central nervous system.
  • the antagonist can be administered using in-dwelling catheters implanted surgically in the ventricals of the head or in a region with access to the cerebrospinal fluid (CSF) of the spinal chord.
  • CSF cerebrospinal fluid
  • peripherally antagonists that cross the blood-brain barrier (or that can be adapted to do so) .
  • drug carriers sold by Pharmatec, Inc., Alachua, Florida which can be used to facilitate transport to the central nervous system of peripherally administrated drugs [ADD PATENTS] .
  • Candidates for use in the invention may be screened for their ability to antagonize NGF potentiation of the neurotoxicity of the first 40 a ino acids of / 3-amyloid to cultured neurons (primary rat hippocampal cultures) , as described in the following example.
  • the advantages of this culture system are that is enriched in neurons, and neurons can be cultured at low density to facilitate quantification. Neurons can be identified readily morpoholgically and by immunohistochemical markers, as described below.
  • Culture System Primary rat embryonic hippocampal cultures were established by a modification of the protocol previously described Banker et al.. Brain Res . 126:397-425 (1977); and Banker et al., J. Comp. Neurol .
  • the hippocampus was dissected from the brains of embryonic day 18 rat embryos, incubated in 0.5% trypsin (30 min at 37°C) , dissociated by gentle trituration, and cultured at a density of 2 x 10 4 cells per 16-mm polylysine-coated tissue culture well (Costar) in
  • Dulbecco's modified Eagle's medium supplemented with 10% (vol/vol) iron-supplemented calf serum (Hyclone) , 5% (wt/vol) Ham's F-12 nutrient mixture, 2 mM glutamine, 1 m sodium pyruvate, 2.5% (wt/vol) Hepes, penicillin (100 units/ml) , and streptomycin (100 ⁇ g/ml) .
  • NGF potentiation of j8-amyloid associated toxicity is demonstrated as follows. Addition of /3-(l-40) at 20 ⁇ M resulted in a 40-50% decrease in the number of viable pyramidal neurons relative to untreated control cultures
  • various growth factors (acidic and basic FGF, insulin, EGF, PDGF, and IGF-10 had no 35 significant ability to potentiate / 3-amyloid associated neurotoxicity at sub-toxic dosages of the latter, even when the growth factors were administered at much higher concentrations than NGF.
  • a monoclonal antibody against NGF i.e., a monoclonal antibody against mouse 2.5S NGF clone 27/21, described by Korsching et al. , Proc. Natl . Acad. Sci . USA 80:3513-3516 (1983)
  • was added final concentration 0.5 ⁇ g/ml
  • Korsching, et al, Proc Nat'l Acad. Sci. USA 80:3513-3516 (1983) was added (final concentration 0.5 ⁇ g/ml), see Korsching, et al, Proc Nat'l Acad. Sci. USA 80:3513-3516 (1983), to the cultures with j8-(l-40), at the lower non-toxic dose, together with a potentiating dosage of NGF.
  • Fig.l the survival of 4-day-old hippocampal neurons with the designated treatments were compared to untreated controls (Bar #1) . Survival was determined 24 hours after treatment.
  • NGF potentiates the ⁇ amyloid associated toxicity (Bar #'s 2-5), particularly at non-toxic dosages of the latter.
  • NGF and anti-NGF are not toxic (Bar #'s 7 and 8).
  • NGF concentration dependent as shown in Fig. 2.
  • NGF was active at 0.1-1 ng/ml, with a half-maximal potentiating concentration of 0.2-0.3 ng/ml ( «1 x 10 "11 M) , which is similar to the concentration range reported to be required for the neurite outgrowth response to NGF and for occupancy of the high-affinity NGF receptor. More specifically.
  • in vivo animal screening can be used in which the candidates are co-administered with ⁇ - amyloid protein or a toxic fragment thereof to create a lesion that can be visualized using cell stain techniques (e.g., immunohistological strains) directed to appropriate markers such as Tau protein or other appropriate cytoskeletal proteins (e.g., using anti MAP- 2 antibody or Ala -50 antibody available from Abbot Laboratories in Chicago, IL) .
  • cell stain techniques e.g., immunohistological strains
  • appropriate markers such as Tau protein or other appropriate cytoskeletal proteins (e.g., using anti MAP- 2 antibody or Ala -50 antibody available from Abbot Laboratories in Chicago, IL) .
  • NGF-responsive neurons may be a neurotoxic interaction of / 8-amyloid with NGF.
  • j8-amyloid alone is reported to exhibit neurotoxic effects in culture at the 10 ⁇ 8 -10 ⁇ 7 M concentration range, in the presence of physiological levels of NGF, subpicomolar concentrations of / 3-amyloid become neurotoxic.
  • ,3-amyloid deposits may cause induction of the NGF receptor in neuronal cell types typically unresponsive to NGF. Such an induction may be difficult to detect if it is transient or results in the degeneration of affected cells.
  • neurons degenerated in response to ⁇ -(l-40) possess NGF receptors, as demonstrated by immunohistochemical analysis performed with a monoclonal antibody to the rat NGF receptor (clone 192) . See, Chandler et al., J. Biol . Chem . 259:6882-6889 (1984); and Taniuchi et al., J. Cell Biol . 101:1100-1106 (1985).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Procédés thérapeutiques permettant d'obtenir un effet antagoniste sur la dégénérescence neuronale liée à la protéine β et aggravée par le NGF ou par les facteurs de croissances apparentés. On décrit des thérapies fondées sur l'utilisation d'antagonistes de NGF et d'antagonistes de l'interaction du NGF avec le récepteur de NGF.
PCT/US1991/008476 1990-11-13 1991-11-13 REDUCTION DE LA DEGENERESCENCE NEURONALE LIEE A LA PROTEINE β-AMYLOIDE PAR UN EFFET ANTAGONISTE SUR L'ACTIVITE NEURONALE PROVOQUEE PAR LE NGF WO1992008483A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US612,329 1984-05-21
US61232990A 1990-11-13 1990-11-13

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU674864B2 (en) * 1992-07-08 1997-01-16 Applied Research Systems Ars Holding N.V. Pharmaceutical composition containing IL-6, their uses for the treatment of consumptive thrombo-hemorrhagic disorder
US6291247B1 (en) 1994-05-11 2001-09-18 Queen's University At Kingston Methods of screening for factors that disrupt neurotrophin conformation and reduce neurotrophin biological activity
FR2807660A1 (fr) * 2000-04-13 2001-10-19 Warner Lambert Co Utilisation d'antagonistes du ngf pour la prevention ou le traitement de douleurs viscerales chroniques
WO2001010203A3 (fr) * 1999-08-06 2002-09-12 S I S S A Scuola Internaz Supe Animaux transgeniques utilises dans l'etude de syndromes neurodegeneratifs
EP1500399A1 (fr) * 2003-07-24 2005-01-26 Institut Pasteur Immunisation active et passive contre neurotrophines pro-apoptotiques pour le traitement ou la prévention des maladies neurologiques
US8246956B2 (en) 2003-12-24 2012-08-21 Abbott Research B.V. Humanized anti-nerve growth factor antibodies
US8679534B2 (en) 1997-12-12 2014-03-25 Andrx Labs, Llc HMG-CoA reductase inhibitor extended release formulation
US9688749B2 (en) 2005-06-07 2017-06-27 Abbvie Inc. Molecules that are able to inhibit the binding between NGF and the TrkA receptor as analgesics with prolonged effect

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4230691A (en) * 1978-05-23 1980-10-28 The Massachusetts General Hospital Nerve growth factor antibody and process
US4474892A (en) * 1983-02-16 1984-10-02 Board Of Trustees Of The Leland Stanford Junior University Two-site immunoassays using monoclonal antibodies of different classes or subclasses and test kits for performing same
US4701407A (en) * 1982-11-24 1987-10-20 Baylor College Of Medicine Diagnosis of Alzheimer disease
US4868107A (en) * 1986-11-18 1989-09-19 The United States Of America As Represented By The Department Of Health And Human Services Method for detecting antibodies against neuropeptides and drugs in human body fluid

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4230691A (en) * 1978-05-23 1980-10-28 The Massachusetts General Hospital Nerve growth factor antibody and process
US4701407A (en) * 1982-11-24 1987-10-20 Baylor College Of Medicine Diagnosis of Alzheimer disease
US4474892A (en) * 1983-02-16 1984-10-02 Board Of Trustees Of The Leland Stanford Junior University Two-site immunoassays using monoclonal antibodies of different classes or subclasses and test kits for performing same
US4868107A (en) * 1986-11-18 1989-09-19 The United States Of America As Represented By The Department Of Health And Human Services Method for detecting antibodies against neuropeptides and drugs in human body fluid

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF BIOLOGICAL CHEMISTRY, Volume 259, No. 24, issued 25 December 1984, BERND et al., "Association of I125 Nerve Growth Factor with PC12 Pheochromocytoma Cells", pages 15509-15516. *
PROC. NAT'L ACAD. SCI., Volume 80, issued June 1983, KORSCHING et al., "Nerve Growth Factor in sympathetic ganglia and corresponding target organs of the rat: Correlation with density of sympathetic inhervation", pages 3513-3516. *
SCIENCE, Volume 243, issued 17 March 1989, WHITSON et al., "Amyloid B Protein Enhances the Survival of Hippocampal Neurons in Vitro", pages 1488-1490. *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU674864B2 (en) * 1992-07-08 1997-01-16 Applied Research Systems Ars Holding N.V. Pharmaceutical composition containing IL-6, their uses for the treatment of consumptive thrombo-hemorrhagic disorder
US6291247B1 (en) 1994-05-11 2001-09-18 Queen's University At Kingston Methods of screening for factors that disrupt neurotrophin conformation and reduce neurotrophin biological activity
US8679534B2 (en) 1997-12-12 2014-03-25 Andrx Labs, Llc HMG-CoA reductase inhibitor extended release formulation
US7273964B1 (en) 1999-08-06 2007-09-25 Scuola Internazionale Superiore Di Studi Avanzati Non-human transgenic animals for the study of neurodegenerative syndromes
WO2001010203A3 (fr) * 1999-08-06 2002-09-12 S I S S A Scuola Internaz Supe Animaux transgeniques utilises dans l'etude de syndromes neurodegeneratifs
FR2807660A1 (fr) * 2000-04-13 2001-10-19 Warner Lambert Co Utilisation d'antagonistes du ngf pour la prevention ou le traitement de douleurs viscerales chroniques
WO2001078698A3 (fr) * 2000-04-13 2002-04-25 Warner Lambert Co Utilisation des antagonistes du ngf dans la prevention et le traitement de la douleur viscerale chronique
WO2005014039A3 (fr) * 2003-07-24 2005-06-09 Pasteur Institut Immunisation active ou passive contre des neurotrophines proapoptotiques afin de traiter et/ou de prevenir des maladies neurodegeneratives
EP1500399A1 (fr) * 2003-07-24 2005-01-26 Institut Pasteur Immunisation active et passive contre neurotrophines pro-apoptotiques pour le traitement ou la prévention des maladies neurologiques
US8246956B2 (en) 2003-12-24 2012-08-21 Abbott Research B.V. Humanized anti-nerve growth factor antibodies
US8257710B2 (en) 2003-12-24 2012-09-04 Abbott Research, B.V. Method for the treatment of pain with humanized anti-nerve growth factor antibodies
US8877491B2 (en) 2003-12-24 2014-11-04 Abbvie Inc. Polynucleotides encoding humanized anti-NGF antibodies
US9688749B2 (en) 2005-06-07 2017-06-27 Abbvie Inc. Molecules that are able to inhibit the binding between NGF and the TrkA receptor as analgesics with prolonged effect

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AU9059991A (en) 1992-06-11

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