WO2003093446A2 - Anticorps permettant d'ameliorer l'excroissance des neurites - Google Patents

Anticorps permettant d'ameliorer l'excroissance des neurites Download PDF

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Publication number
WO2003093446A2
WO2003093446A2 PCT/US2003/014157 US0314157W WO03093446A2 WO 2003093446 A2 WO2003093446 A2 WO 2003093446A2 US 0314157 W US0314157 W US 0314157W WO 03093446 A2 WO03093446 A2 WO 03093446A2
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WO
WIPO (PCT)
Prior art keywords
antibodies
fragments
injury
nervous system
central nervous
Prior art date
Application number
PCT/US2003/014157
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English (en)
Other versions
WO2003093446A3 (fr
Inventor
Elliott A. Gruskin
J. F. Iaci
A. M. Vecchione
S. J. Hogan
T. J. Neuberger
Original Assignee
Acorda Therapeutics, Inc.
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 Acorda Therapeutics, Inc. filed Critical Acorda Therapeutics, Inc.
Priority to AU2003228885A priority Critical patent/AU2003228885A1/en
Publication of WO2003093446A2 publication Critical patent/WO2003093446A2/fr
Publication of WO2003093446A3 publication Critical patent/WO2003093446A3/fr

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • Antibodies which are reactive to inhibitory molecules can enhance neurite outgrowth and generation in injured central nervous system sites. DESCRIPTION OF RELATED ART
  • a neurite is a process growing from a neuron, or nerve cell, in culture and generically applies to both dendrites and axons.
  • the extension of neurons is also required to regenerate or re-establish neuronal connections which may have been lost as a result of injury or disease.
  • a number of molecules have been identified that inhibit the regeneration of injured neurites in the adult mammalian central nervous system. These molecules are expressed in adult mammalian central nervous system (“CNS”), for the most part, on oligodendrocytes and myelin, and on the glial scars of injured CNS tissue.
  • CNS central nervous system
  • CSPGs chondroitin sulfate proteoglycans
  • Proteoglycans contain long carbohydrate side-chains of glycosaminoglycans, which are covalently attached to a core protein by a glycosidic linkage.
  • the glycosaminoglycans consist of repeating disaccharide units, all bearing negatively charged groups, usually sulfate or carbohydrate groups.
  • the proteoglycan core protein is typically biologically inactive and the glycosaminoglycan chains account for inhibitory activity. (Nieto-Sampedro, M., Neurite outgrowth inhibitors in gliotic tissue. Adv. Exp. Med. Biol. 468: 207-24 (1999).
  • glycosaminoglycans most notably chondroitin sulfate (CS) and dermatan sulfate (DS), are important components of CSPG. They are inhibitory molecules that contribute to the lack of regeneration of the CNS in adult mammals, by hindering axonal and neuritic growth. (However, CSPGs are important in neuronal guidance and patterning during development, rather than inhibition).
  • the chondroitin sulfate family includes seven sub-types designated unsulfated chondroitin sulfate, oversulfated chondroitin sulfate, and chondroitin sulfates A-E, which vary in the number and position of their sulfate functional groups.
  • Dermatan sulfate is also referred to as chondroitin sulfate B, and it differs in that iduronic acid is the predominant residue in the alternative hexuronic acid position.
  • Glycosaminoglycans are unbranched polysaccharides consisting of alternating hexosamine and hexuronic residues which carry sulfate groups in different positions.
  • the GAGs are typically divided into three families according to the composition of the disaccharide backbone. These are: heparin/heparan sulfate [HexA-GlcNAc(SO.sub.4)]; chondroitin sulfate [HexA-GalNAc]; and keratan sulfate [Gal-GlcNAc].
  • CNS- reactive antibodies have been identified that can neutralize and overcome these inhibitory molecules. By reacting with CNS tissues, the antibodies enhance neurite outgrowth and overcome substrates inhibitory to neurite growth.
  • This disclosure relates to a method of treating an injury to the central nervous system.
  • Such a treatment involves administering antibodies that neutralize the inhibitory molecules expressed in a CNS injury, typically a glial scarring area.
  • This disclosure relates to a method of administering antibodies to neutralize the inhibitory molecules often associated with diseased or injured CNS tissues.
  • the neutralizing antibodies enhance the outgrowth of neurites in the CNS by providing a positive growth environment.
  • the outgrowth of neurites will allow the regeneration of the injured or diseased neuronal tissues, thereby avoiding or reversing the motor function disabilities associated with such insults to CNS tissues.
  • a nerve is severed, the distal neurites become separated from the nerve cell body and degenerate. Neurite death and degeneration leaves only the empty nerve sheath, which will also eventually degenerate. In addition, some degeneration of the proximal stump occurs.
  • neurons can regenerate by re-extension of the severed axons. This regeneration is more likely if it occurs at a sufficient distance from the nerve cell body.
  • the newly regenerating neurites, or "nerve sprouts” grow distally toward the sheath of the distal portion of the severed nerve. If the neurites successfully enter the sheath, they will often grow down its length toward their synaptic target cells, and function may be restored. Regeneration and regrowth of the neurites is impeded or prevented by scar formation, which can be stimulated by trauma or disease.
  • the scar tissue is composed of extra cellular molecules, primarily chondroitin sulfate proteoglycans ("CSPGs").
  • CSPGs extra cellular matrix molecules
  • These regulator molecules can be secreted or immobilized on the surface of the cell which produces them.
  • the binding of the regulator molecule to a receptor on the neuronal cell surface causes a signal which regulates the intracellular molecules.
  • Many types of molecules which regulate neuronal outgrowth are known. Some stimulate neurite growth (e.g., neurotrophic molecules, neurotransmitters, extracellular matrix molecules and cell adhesion molecules) while others function as inhibitors or negative regulators.
  • Antibodies have been isolated and identified which are suitable for overcoming neurite-inhibitory substrates.
  • the antibodies are selected on the basis of their reactivity with CNS tissues.
  • the antibodies are screened in a series of in vitro assays to determine their ability to neutralize inhibitory substrates, including CSPGs and white matter areas of brain sections, thereby promoting neurite outgrowth.
  • Certain antibodies have been shown to promote and improve neurite outgrowths over inhibitory CSPGs and white matter tracts on unfixed brain sections.
  • Identified antibodies have also been shown to enhance neurite outgrowth of the hippocampal and cortical neurons, when used as a substrate.
  • the antibodies are monoclonal.
  • the antibodies are human and monoclonal.
  • Suitable antibodies can be directed to CSPGs, cell adhesion molecules, and antibodies obtained from a spinal cord homogenate- immunized mammal.
  • Suitable antibodies include those described in U.S. Patent 5,591 ,629 and U.S. pending patent applications 08/692,084 filed August 6, 1996; 08/779,784 filed January 7,1997; 09/322,862 filed May 28, 1999; 09/580,787 filed May 30, 2000; and 10/010,729 filed November 13, 2001. The disclosures of each application and the patent are incorporated herein in their entirety.
  • the antibody, or fragments, or combination of antibodies, herein may be administered to a patient with a CNS injury or disease.
  • the antibody, or fragments thereof, or combination of antibodies can be administered to the patient on a daily, weekly, bi-weekly or monthly basis, as medically determined by the condition of the patient and the severity of the injury.
  • the antibodies or fragments can be typically administered in a composition comprising a pharmaceutical carrier.
  • a pharmaceutical carrier can be any compatible, non-toxic substance suitable for delivery of the monoclonal antibodies to the patient, sterile water, alcohol, fats, waxes, and inert solids may be included in the carrier.
  • Pharmaceutically acceptable adjuvants may also be incorporated into the pharmaceutical composition.
  • compositions for parental administration may include a solution of the antibody, antibody fragment or a cocktail thereof dissolved in an acceptable carrier, preferably an aqueous carrier.
  • an acceptable carrier preferably an aqueous carrier.
  • aqueous carriers can be used, e.g., water, buffered water, 0.4% saline, 0.3% glycine and the like. These solutions are sterile and generally free of particulate matter.
  • the compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents and the like, for example sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc.
  • the concentration of antibody or antibody fragment in these formulations can vary widely, e.g., from less than about 0.5%, usually at or at least about 1% to as much as 15 or 20% by weight and will be selected primarily based on fluid volumes, viscosities, etc., in accordance with the particular mode of administration selected.

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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)

Abstract

L'invention concerne un procédé consistant à administrer un anticorps neutralisant ou des fragments de celui-ci, ou une combinaison d'anticorps afin d'obtenir l'excroissance neurale dans le système nerveux central. Ce procédé permet de neutraliser les molécules inhibitrices qui inhibent ou contribuent à l'inhibition de la régénération de tissu nerveux.
PCT/US2003/014157 2002-05-04 2003-05-05 Anticorps permettant d'ameliorer l'excroissance des neurites WO2003093446A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003228885A AU2003228885A1 (en) 2002-05-04 2003-05-05 Antibodies for enhancing neurite outgrowth

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US37767502P 2002-05-04 2002-05-04
US60/377,675 2002-05-04

Publications (2)

Publication Number Publication Date
WO2003093446A2 true WO2003093446A2 (fr) 2003-11-13
WO2003093446A3 WO2003093446A3 (fr) 2004-06-17

Family

ID=29401547

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2003/014157 WO2003093446A2 (fr) 2002-05-04 2003-05-05 Anticorps permettant d'ameliorer l'excroissance des neurites

Country Status (2)

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AU (1) AU2003228885A1 (fr)
WO (1) WO2003093446A2 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0411893A2 (fr) * 1989-07-31 1991-02-06 Eli Lilly And Company Anticorps chimériques dirigés contre un antigène glycoprotéique humain

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0411893A2 (fr) * 1989-07-31 1991-02-06 Eli Lilly And Company Anticorps chimériques dirigés contre un antigène glycoprotéique humain

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MOON L.D.F. ET AL.: 'Regeneration of CNS axons back to their target following treatment of adult rat brain with chondroitinase ABC' NATURE NEUROSCIENCE vol. 4, no. 5, May 2001, pages 465 - 466, XP008018581 *
SOMASEKHAR T. ET AL.: 'Selective early innervation of a subset of epidermal cells in Xenopus may be mediated by chondroitin sulfate proteoglycans' DEVELOPMENTAL BRAIN RESEARCH vol. 99, 1997, pages 208 - 215, XP002975727 *

Also Published As

Publication number Publication date
AU2003228885A8 (en) 2003-11-17
WO2003093446A3 (fr) 2004-06-17
AU2003228885A1 (en) 2003-11-17

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