WO1995022344A1 - Utilisation therapeutique de glycoproteines associees a la myeline (gam) - Google Patents

Utilisation therapeutique de glycoproteines associees a la myeline (gam) Download PDF

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WO1995022344A1
WO1995022344A1 PCT/CA1995/000089 CA9500089W WO9522344A1 WO 1995022344 A1 WO1995022344 A1 WO 1995022344A1 CA 9500089 W CA9500089 W CA 9500089W WO 9522344 A1 WO9522344 A1 WO 9522344A1
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mag
growth
neurons
myelin
inhibition
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PCT/CA1995/000089
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Lisa Joan Mckerracher
Samuel David
Peter Erich Braun
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Mcgill University
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Priority to AU17035/95A priority Critical patent/AU1703595A/en
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Priority to SE9703032A priority patent/SE9703032D0/xx

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4711—Alzheimer's disease; Amyloid plaque core protein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to the use of a myelin associated glycoprotein (MAG) for the regulation of growth of neurons in peripheral nervous system (PNS) or central nervous system (CNS).
  • MAG myelin associated glycoprotein
  • CNS central nervous system
  • a major barrier to axonal regeneration in the CNS of mammals is the presence of growth inhibitory molecules. It is not known whether there is one or several inhibitory pro ⁇ teins present in myelin membranes, and the primary sequence has not yet been identified for any myelin associated protein inhibitor. The axon growth inhibi ⁇ tory property of CNS myelin has been well established, but the inhibitory proteins remain unknown. It is well documented that myelin in the CNS of adult mam- mals inhibits the growth of neurons in vi tro (P. Caroni, M.E. Schwab, (1988) Neuron, 1:85-96; M.E. Schwab, P.
  • Inhibitory activity can be extracted from SDS gels with proteins of approximately 250 and 35 kDa. Further, many in vivo experiments suggest that myelin- derived inhibitors block regeneration in vivo (Schnell and Schwab, (1990) Nature, 243:268; Schnell et al., (1994) Nature, 367:170).
  • tenascin molecules secreted by oligodendro- cytes, that have growth inhibitory properties, have been identified as 160 and 180 kDa homologues of tenascin (Peshiva et al., (1989) JOB, 109:1765-1788; Fuss et al., (1993) JCB, 120:1237-1249; Lochter et al., (1991) JCB, 113:1159-1171).
  • the tenascin-like proteins are secreted and, therefore, are not expected to be present in myelin.
  • myelin-derived inhibitory protein It would be highly desirable to be provided with such a myelin-derived inhibitory protein to be able to find reagents to overcome growth inhibition which would allow regenerative regrowth of damaged axons in the mammalian CNS.
  • myelin asso ⁇ ciated glycoprotein (MAG) as one of the major molecu- lar components involved in contact-mediated growth inhibition on myelin.
  • the growth inhibitory property of MAG was determined by: 1) demonstrating that MAG chromatographed with partially purified myelin-derived inhibitory activity; 2) testing the ability of recom- binant MAG to inhibit neurite growth.
  • MAG myelin associated glycopro ⁇ tein
  • a method to suppress the inhibition of neuron growth comprising the steps of delivering, to the nerve growth environ- ment, a myelin-associated glycoprotein antagonist in an amount effective to reverse said inhibition.
  • an assay method useful to identify MAG antagonist agents that suppress inhibition of neuron growth comprising the steps of: a) culturing neurons on a growth permissive substrate that incorporates a growth-inhibiting amount of MAG; and b) exposing the cultured neurons of step a) to a candidate MAG antagonist agent in an amount and for a period sufficient prospectively to permit growth of the neurons; thereby identifying as MAG antagonists the can ⁇ didates of step b) which elicit neurite outgrowth from the cultured neurons of step a) .
  • a method for inhibiting neuron growth comprising the steps of introducing into the growth environment of the neurons a growth inhibiting amount of MAG or a MAG agonist.
  • Antist refers to a pharmaceutical agent having myelin associated glycoprotein biological activity of inhibiting the neurite outgrowth of neu ⁇ rons cultured on a permissive substrate or inhibiting the regeneration of damaged neurons. It would be desirable to inhibit neuron growth in cases of epilepsy, neuroblastoma, and neuromas, a disease state in a mammal which includes neurite outgrowth or other neural growth of an abnormal sort which causes pain at the end of an amputated limb.
  • Agonists which may be used in accordance with the present invention include without limitation a MAG fragment, an analog of MAG or of the MAG fragment, a derivative of either MAG, the MAG fragment or said analog, an anti-idiotypic MAG antibody or a binding fragment thereof, MAG ectodo- main, and a pharmaceutical agent.
  • Antagonist refers to a pharmaceutical agent which in accordance with the present invention which inhibits at least one biological activity normally associated with MAG, that is blocking or suppressing the inhibition of neuron growth.
  • Antagonists which may be used in accordance with the present invention include without limitation a MAG antibody or a binding fragment of said antibody, a MAG fragment, a deriva ⁇ tive of MAG or of a MAG fragment, an analog of MAG or of a MAG fragment or of said derivative, and a pharma ⁇ ceutical agent, and is further characterized by the property of suppressing MAG-mediated inhibition of neurite outgrowth.
  • the agonist or antagonist of MAG in accordance with the present invention is not limited to MAG or its derivatives, but also includes the therapeutic application of all agents, referred herein as pharma ⁇ ceutical agents, which alter the biological activity of the neuronal receptor for MAG such that growth of neurons or their axons is suppressed.
  • the receptor can be identified with known technologies by those skilled in the art (Mason, (1994) Curr. Biol . , 4:1158- 1161) and its association with MAG or fragments thereof can be determined.
  • the neuronal receptor for MAG may or may not be the same as cell surface mole ⁇ cules that recognize and bind MAG in an adhesion assay (Kelm et al., (1994) Curr. Biol .
  • an effective amount or “growth-inhibit ⁇ ing amount” refers to the amount of pharmaceutical agent required to produce a desired agonist or antago ⁇ nist effect of the MAG biological activity.
  • the pre ⁇ cise effective amount will vary with the nature of pharmaceutical agent used and may be determined by one of ordinary skill in the art with only routine experi ⁇ mentation.
  • MAG biological activity refers to cellular events triggered by MAG, being of either biochemical or biophysical nature.
  • the following list is provided, without limitation, which discloses some of the known activities associ ⁇ ated with MAG: contact-mediated growth inhibition on myelin, inhibition of neuron growth, inhibition of neurite outgrowth, adhesion to neuronal cells, and promotion of neurite outgrowth from newborn dorsal root ganglion neurons.
  • Fig. 1 illustrates the neurite outgrowth from Dil-labeled NG108-15 cells on myelin and MAG substrates X 160;
  • Fig. 2 illustrates a quantitative analysis of neurite outgrowth from NG108-15 cells on different substrates
  • Fig. 3 is the analysis of growth inhibition after separation of myelin proteins by DEAE anion exchange chromatography.
  • the strategy pursued was the purification of myelin inhibitors by non-denaturing extraction and column chromatography. This approach has allowed the identi ⁇ fication of a known protein of unknown function as a major myelin-derived growth inhibitor.
  • the myelin-associated glycoprotein was identified as a major inhibitory molecules present in myelin.
  • the primary sequence of the protein has previously been reported (Arquint et al., (1987) PNAS, 84:600-604; Salzer et al. , (1987) JOB, 104:957-965).
  • This protein is present in both peripheral nervous system (PNS) and CNS myelin, an observation consistent with findings that PNS myelin also has inhibitory properties (Fig. 2).
  • Myelin-derived inhibitory activity was assessed by bioassays performed in tissue culture.
  • Cells grow neurites on "permissive" substrates such as a polylys- ine or laminin substrate (Fig. 1A) .
  • Purified bovine CNS myelin used as a tissue culture substrate permit ⁇ ted cell attachment, but inhibited cAMP-induced neu ⁇ rite outgrowth from NG108-15 cells (Fig. IB).
  • Cells grown on 4 ⁇ g of myelin were rounded and did not grow neurites (Fig. IB).
  • When cells were grown on recombi- nant MAG they did not spread or differentiate neurites Fig. 1C; Attia S. et al. , (1993) J. Neurochem.
  • Bovine corpus callosum or sciatic nerve was homogenized with a DounceTM homogenizer, and myelin was purified as described by W.T. Norton et al. ((1973) J. Neurochem. , 21:749-757) .
  • Myelin with 4 ⁇ g or 8 ⁇ g protein was added to polylysine-coated 96 well plates, dried and washed with PBS before plating the cells.
  • NG108 cells readily accessible to those skilled in the art, a cell line that extends neurites in response to cAMP (D.G.
  • cAMP primed NG108 cells were labeled with the lipophilic dye Di-I(1, 1 '-dioctadecyl-3, 3, 3 * , 3 ' -tetra- methylindocarbocyanine perchlorate) by incubating the cultures with 1% solution of the dye in culture medium for 2 hr. The cells were then rinsed and maintained in culture for 3 hr. prior to using them for the neu ⁇ rite outgrowth assay. Dil-labeled NG108 cells were added to the wells at a density of 1000 cells/well, and cultured for 24 hr.
  • DMEM Dulbecco's minimal essen- tial medium
  • the cultures were then fixed with 4% paraformaldehyde and 0.1% glutaraldehyde in 0.1 M phosphate buffer for 30 min., washed and stored in buffer, the percentage of NG108 cells extending neu- rites longer than 1 cell body diameter was estimated with a Zeiss AxiomatTM inverted microscope equipped with fluorescence optics.
  • myelin-derived inhibitory activity was solubilized in octylglucoside and chroma- tographed on a DEAE anion exchange column.
  • Bovine brain myelin was extracted for 2 hr. at 20°C with 1% octylglucoside (1 ml per mg of protein) in 0.2 M phosphate buffer (pH 6.8) containing 0.1 M Na2S ⁇ 4, 1 mM EDTA, 1 mM dithiothreitol and a cocktail of protease inhibitors.
  • the extract was clarified by centrifugation at 400,000 g.min. and applied to a col ⁇ umn of DEAE-SepharoseTM (Pharmacia; 1.3 cm X 10 cm).
  • Fig. 3 A profile of growth inhibition present in the column fractions is shown in Fig. 3. Percent inhibition was calculated as (C - E/C x 100) where C was the average number of cells with neurites on polylysine substrates, and E was the average number of cells with neurites on the test substrate.
  • Western blots of the inhibitory frac ⁇ tions with anti-MAG antibody (GenS3; Nobile-Orazio et al., (1984) Neurology, 34:1336-1342) showed that the inhibitory peaks that eluted in low salt corresponded to the elution profile for MAG (Fig. 3).
  • FIG. 3 is a Western blots of column fractions probed with anti-MAG antibody.
  • the inhibitory activity eluted at the highest salt concentrations (Fig. 3, fractions 23-26) was not enriched in MAG, and likely represents a different inhibitory protein activity, possibly the one reported by Schwab (M.E. Schwab, (1993) Annu . Rev. Neurosci . , 16:565).
  • MAG may be an inhibi ⁇ tor of axon growth.
  • Direct evidence for this role was obtained by showing that recombinant MAG was a potent inhibitor of neurite outgrowth from NG108 cells (Fig 1C; Fig. 2). Heating recombinant MAG at 80°C for 1 hr. abolished this activity (Fig. ID; Fig. 2).
  • Comparison of cells grown on polylysine, CNS myelin, peripheral nerve myelin, recombinant MAG (MAG), dena- tured MAG (denat. MAG), and bovine serum albumin (BSA) demonstrate the potent growth inhibition of PNS and CNS, myelin and MAG.
  • Results are the mean of 3 experiments done in triplicate; 2 experiments for denatured MAG (Fig. 2). In these experiments, no cells extended neurites when plated on MAG compared to 73%+ 4 on denatured MAG, or to 69% ⁇ 4 on BSA, used as a control. Because MAG is a component of myelin pro ⁇ pokerd by both Schwann cells and CNS glial cells, neu ⁇ rite growth inhibition present in peripheral nerve and CNS myelin were compared. Purified bovine CNS and peripheral nerve myelin plated at 4 ⁇ g protein/well inhibited neurite outgrowth equally (Fig. 2).
  • MAG is reported here as having potent neurite growth-inhibitory activity, its sequence homology with adhesion molecules of the immunoglobulin family has led others to investigate a possible role for MAG in cell adhesion (M. Arquint et al. , (1987) Proc . Natl . Acad. Sci . U. S. A. , 84:600; M. Poltorak et al., (1987) J. Cell Biol . , 105:1893; J.L. Salzer et al., (1987) J. Cell Biol . , 104:957; Kelm, S. et al. , (1994) Current Biology, 4:965-972; Schachner et al. , (1994) Curr. Opinion Neurobiol . , 4:726-734; Doherty et ⁇ al., (1994) Curr. Opinion Neurobiol . , 4:49-55).
  • the results of the present invention were cor- related as follows with the growth inhibitory proper ⁇ ties of MAG with experimental evidence that the MAG extracellular domain may mediate adhesion to axons.
  • the finding that recombinant MAG lacking the L2/HNK-1 carbohydrate epitope is a potent neurite out- growth inhibitor suggests that there may be functional differences among carbohydrate variants of MAG.
  • observations that MAG-containing liposomes bind to neurons specifically suggests a receptor- mediated interaction between neurons and MAG.
  • such experiments do not reveal how MAG binding may affect growth cone dynamics.
  • adhesive prop ⁇ erties of MAG have been examined when it was expressed in heterologous, living cells. In these experiments, cell adhesion molecules or extracellular matrix compo- nents that are known to override the growth inhibition on myelin may be present.
  • MAG growth inhibitory properties
  • myelin debris in the CNS is not removed very quickly after injury (G. Stoll et al., (1989) J. Neurosci . , 9:2327- 2335).
  • peripheral nerve myelin is asso ⁇ ciated with molecules such as laminin that can over ⁇ ride the inhibitory effects of myelin.
  • CNS neurons will regenerate in a peripheral nerve environment, they show little capacity to elon ⁇ gate in the CNS.
  • Growth inhibition by MAG which is a prominent glycoprotein component of the total myelin protein (R.H. Quarles, D.R. Coleman, J.L.
  • MAG is a major growth inhibitory protein in myelin
  • agents and therapies that suppress MAG-medi ⁇ ated inhibition of nerve growth.
  • the invention provides an assay method adapted to identify MAG antagonist, that is agents that block or suppress the growth-inhibiting action of MAG.
  • the assay is a tissue culture assay that measures neurite out ⁇ growth as a convenient end-point, and accordingly uses nerve cells that extend neurites when grown on a per- missive substrate.
  • Nerve cells suitable in this regard include neuroblastoma cells of the NG108 line ⁇ age, such as NG108-15, as well as other neuronal cell lines such as PC12 cells (American Type Culture Collection, 12301 Parklawn Drive, Rockville, MD 20852 USA, ATCC accession No.
  • CRL 1721 human neuroblastoma cells, and primary cultures of CNS or PNS neurons taken from embryonic, postnatal or adult animals.
  • the nerve cells for instance about 10 ⁇ cells-microwell or equivalent, are cultured on a growth permissive sub- strate, such as polylysine or laminin, that is over- layed with a growth-inhibiting amount of MAG.
  • the MAG incorporated in the culture is suitably myelin- extracted MAG, although forms of MAG -other than endogenous forms can be used provided they exhibit the MAG property of inhibiting neuron growth when added to a substrate that is otherwise growth permissive.
  • Suitable MAG alternatives include, for example, the MAG ectodomain reported by Salzer et al. ((1989) Develop. Neurosci . , 11:377-390) and by Attia et al. ((1993) J. Neurochem. , 61:718-726), and other growth- inhibiting MAG fragments.
  • candidate MAG antagonists i.e., compounds that block the growth-inhibiting effect of MAG
  • candidate MAG antagonists are added to the MAG-containing tissue culture preferably in amounts sufficient to neutralize the MAG growth-inhibiting activity, that is between 1.5 and 15 ⁇ g of MAG antagonists per well containing a density of 1000 NG108-15 cells/well cultured for 24 hr. in Dulbecco's minimal essential medium. After culturing for a period sufficient for neurite outgrowth, e.g. 3- 7 days, the culture is evaluated for neurite outgrowth, and MAG antagonists are thereby revealed as those candidates which elicit neurite outgrowth.
  • candidates selected as MAG antagonists are those which elicit neurite outgrowth to a statisti ⁇ cally significant extent, e.g., in at least 50%, more desirably at least 60%, e.g. 70%, per 1,000 cultured neurons.
  • assay tests include without limitation the following: 1) The growth cone collapse assay that is used to assess growth inhibi ⁇ tory activity of collapsin (Raper, J.A., and Kapfhammer, J.P., (1990) Neuron, 2:21-29; Luo et al. , (1993) Cell , 75:217-227) and of various other inhibi- tory molecules (Igarashi, M. et al. , (1993) Science, 259:77-79) whereby the test substance is added to the culture medium and a loss of elaborate growth cone morphology is scored. 2) The use of patterned sub ⁇ strates to assess substrate preference (Walter, J.
  • Useful MAG antagonists include antibodies to MAG and the binding fragments of those antibodies. Antibodies which are either monoclonal or polyclonal can be produced which recognize MAG and its various epitopes using now routine procedures. For the rais ⁇ ing of antibody, various host animals can be immunized by injection with MAG or fragment thereof, including but not limited to rabbits, mice, rats, etc.
  • adjuvants may be used to increase the immunological response, depending on the host species, and including but not limited to Freund's (complete and incomplete), mineral gels such as aluminum hydroxide, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanins, dinmitrophenol, and potentially useful human adjuvants such as BCG (Bacille Calmette- Guerin) .
  • a monoclonal antibody to an epitope of MAG can be prepared by using any technique which provides for the production of antibody molecules by continuous cell lines in culture.
  • the monoclonal antibodies for therapeutic use may be human monoclonal antibodies or chimeric human- mouse (or other species) monoclonal antibodies.
  • Human monoclonal antibodies may be made by any of numerous techniques known in the art (e.g. Teng et al. , (1983) Proc . Natl . Acad. Sci . U. S. A. , 80:7308-7312; Kozbor et al., (1983) Immunology Today, 4:72-79; Olsson et al., (1982) Meth . Enzymol . , 92:3-16).
  • Chimeric antibody molecules may be prepared containing a mouse antigen- binding domain with human contact regions (Morrision et al., (1984) Proc . Natl . Acad. Sci . U. S. A. , 81:6851; Takeda et al., (1985) Nature, 314:452).
  • a molecular clone of an antibody to a MAG epi ⁇ tope can be prepared by known techniques. Recombinant DNA methodology may be used to construct nucleic acid sequences which encode a monoclonal antibody molecule, or antigen binding region thereof (see e.g., Maniatis et al., (1982) In Molecular Cloning, A Laboratory Manual , Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.).
  • MAG antibody molecules may be purified by known techniques, such as immunoabsorption or immu- noaffinity chromatography, chromatographic methods such as HPLC (high performance liquid chromatography), or a combination thereof, etc.
  • MAG antibody fragments which contain the idio- type of the molecule can be generated by known tech ⁇ niques.
  • fragments include but are not limited to: the F (ab' )2 fragment which can be produced by pepsin digestion of the antibody molecule; the Fab, fragments which can be generated by reducing the disulfide bridges of the F(ab'>2 fragment, and the two Fab or Fab fragments which can be generated by treating the antibody molecule with papain and a reducing agent.
  • Monoclonal antibodies known to react with human MAG may be tested for their usefulness to serve as MAG antagonists (Nobile-Orazio et al. , (1984) Neurology, 34:1336-1342; Doberson et al., (1985) Neurochem. Res . , 10:499-513).
  • MAG antagonist candidates for evaluation in the assay are fragments, analogs and derivatives of MAG. Such candidates may interfere with MAG-mediated growth inhibition as competitive but non-functional mimics of endogenous MAG. From the reported amino acid sequence of MAG and from the cloned DNA coding for it, it will be appreciated that MAG fragments can be produced either by peptide syn ⁇ thesis or by recombinant DNA expression of either a truncated MAG, such as the 67kD ectodomain described by Attia S. et al. ((1993) J. Neurochem.
  • MAG or MAG fragments can be gener- ated also by recombinant DNA techniques or by peptide synthesis, and will incorporate one or more, e.g. 1-5, L- or D-amino acid substitutions.
  • Derivatives of MAG, MAG fragments and MAG analogs can be generated by chemical reaction of the parent substance to incorpo ⁇ rate the desired derivatizing group, such as N-termi- nal, C-terminal and intra-residue modifying groups that have the effect of masking or stabilizing the substance or target amino acids within it.
  • candidate MAG antagonists include those that are derived from a determination of the functionally active region(s) of MAG contained within, but not exclusively limited to, the known immunoglobulin-like domains.
  • any oth ⁇ ers to be prepared against epitopes in the ectodomain when found to be function-blocking in in vi tro assays, can be used to map the active regions of the polypep- tide as has been reported (Fahrig et al., (1993) Europ. , J. Neurosci . , 5:1118-1126; Tropak et al. , (1994) J. Neurochem. , 62:854-862).
  • it can be determined which of the five immunoglobulin-like domains of MAG is/are recognized by neuronal receptors and/or are involved in inhibition of neurite out- growth.
  • synthetic peptides can be prepared to be assayed as candidate antagonists of the MAG effect.
  • Derivatives of these can be prepared, including those with selected amino acid substitutions to provide desirable properties to enhance their effectiveness as antagonists of the MAG candidate functional regions of MAG can also be determined by the preparation of altered forms of the MAG ectodomain using recombinant DNA technologies to produce deletion or insertion mutants that can be expressed in various cell types as chimaeric proteins that contain the Fc portion of immunoglobulin G (Kelm et al., (1994) Curr. Biol . , 4:965-972).
  • candidate mutant forms of MAG can be expressed on cell surfaces by transfection of various cultured cell types.
  • the MAG antagonist is formulated as a pharmaceutical composition which contains the MAG antagonist in an amount effective to suppress MAG-mediated inhibition of nerve growth, in combination with a suitable phar ⁇ maceutical carrier.
  • Such compositions are useful, in accordance with another aspect of the invention, to suppress MAG-inhibited nerve growth in patients diag ⁇ nosed with a variety of neurological disorders, condi- tions and ailments of the PNS and the CNS where treat ⁇ ment to increase neurite extension, growth, or regen ⁇ eration is desired, e.g., in patients with nervous system damage.
  • MAG antagonists can be treated with such MAG antagonists.
  • disorders include but are not limited to Strokes, Alzheimer's disease, Down's syndrome, Creutzfeldt-Jacob disease, kuru, Gerstman-Straussler syndrome, scrapie, transmissible mink encephalopathy, Huntington's disease, Riley-Day familial dysautonomia, multiple system atrophy, amyotropic lateral sclerosis or Lou Gehrig's disease, progressive supranuclear palsy, Parkinson's disease and the like.
  • the MAG antagonists may be used to promote the regeneration of CNS pathways, fiber systems and tracts.
  • MAG antagonists are used to promote the regen ⁇ eration of nerve fibers over long distances following spinal cord damage.
  • MAG and related compounds that retain the MAG property of inhibiting neuron growth are used therapeutically to treat conditions in which suppression of undesired neuronal growth is desired. These include for example the treatment of tumors of nerve tissue and of conditions resulting from uncontrolled nerve sprouting such as is associated with epilepsy and in the spinal cord after nerve injury.
  • patients with neuro- blastoma, and particularly with neuropathies associ ⁇ ated with circulating MAG antibody can be treated with MAG or MAG agonist.
  • Useful for nerve growth suppression are pharma ⁇ ceutical compositions that contain, in an amount effective to suppress nerve growth, either MAG or a MAG agonist in combination with an acceptable carrier.
  • MAG can be obtained either by extraction from myelin as described above or, more practically, by recombi ⁇ nant DNA expression of MAG-encoding DNA in the manner reported by Attia S. et al. ((1993) J. Neurochem. , 61:718-726).
  • Useful MAG agonists are those compounds which, when added to the permissive substrate described above, suppress the growth of neuronal cells.
  • MAG agonists are those compounds which cause a statistically significant reduction in the number of neuronal cells that extend neurites, relative to control cells not exposed to the agonist.
  • Candidate MAG agonists include fragments of MAG that incorporate the ectodomain, including the ectodomain per se and other N- and/or C-terminally truncated fragments of MAG or the ectodomain, as well as analogs thereof in which amino acids, e.g. from 1 to 10 residues, are substituted, particularly conser ⁇ vatively, and derivatives of MAG or MAG fragments in which the N- and/or C-terminal residues are derivat- ized by chemical stabilizing groups.
  • Such MAG ago ⁇ nists can also include anti-idiotypes of MAG antibod ⁇ ies and their binding fragments.
  • can- didate MAG agonists include specific regions of the MAG ectodomain, and analogs or derivatives of these. These can be identified by using the same technologies described above for identification of MAG regions that serve as inhibitors of neurite outgrowth.
  • the MAG-related derivatives, analogs, and frag ⁇ ments of the invention can be produced by various methods known in the art. The manipulations which result in their production can occur at the gene of protein level. For example, MAG-encoding DNA can be modified by any of numerous strategies known in the art (Maniatis et al.
  • the MAG-encoding gene can be mutated in vi tro or in vivo, for instance in the man- ner applied for production of the ectodomain, to create and/or destroy translation, initiation, and/or termination sequences, or to create variations in coding regions and/or form new restriction endonucle- ase sites or destroy preexisting ones, to facilitate further in vitro modification.
  • Any technique for mut- agenesis known in the art can be used, including but not limited to, in vi tro site-directed mutagenesi ⁇ (Hutchinson, et al., (1978) J. Biol . Che . , 253:6551), use of TABTM linkers (Pharmacia), etc.
  • MAG MAG agonist
  • MAG antagonist various known delivery systems can be used, such as encapsulation in liposomes or semiperme- able membranes, expression by suitably transformed or transfected glial cells, oligodendroglial cells, fibroblasts, etc. according to the procedure knownto those skilled in the art (Lindvall et al. , (1994) Curr. Opinion Neurobiol . , 4:752-757).
  • Linkage to ligands such as antibodies can be used to target delivery to myelin and to other therapeutically rele- vant sites in vivo .
  • Methods of introduction include but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, oral, and
  • cells secreting MAG antago ⁇ nist activity for example, and not by way of limita ⁇ tion
  • hybridoma cells, excapsulated in a suitable bio ⁇ logical membrane may be implanted in a patient so as to provide a continuous source of MAG inhibitor.

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Abstract

L'invention se rapporte à l'utilisation d'une glycoprotéine associée à la myéline (GAM) pour la régulation de la croissance des neurones dans le système nerveux périphérique (SNP) ou dans le système nerveux central (SNC). Cette invention se rapporte à des agonistes de GAM, destinés à inhiber la croissance des neurones, ainsi qu'à des antagonistes de GAM destinés à supprimer l'inhibition de la croissance des neurones. Cette invention se rapporte également à un procédé de dosage servant à identifier les agents antagonistes de GAM qui suppriment l'inhibition de la croissance des neurones, ce procédé consistant: (a) à cultiver des neurones sur un substrat permettant la croissance, dans lequel est incorporée une quantité de GAM inhibant la croissance et (b) à exposer les neurones cultivés à l'étape (a) à un agent antagoniste de GAM candidat, selon une quantité et pendant une période suffisantes pour permettre avec le temps la croissance de ces neurones; pour pouvoir identifier comme antagoniste de GAM les candidtats de l'étape (b) qui déclenchent la formation après coup de neurites à partir des neurones cultivés à l'étape (a).
PCT/CA1995/000089 1994-02-21 1995-02-17 Utilisation therapeutique de glycoproteines associees a la myeline (gam) WO1995022344A1 (fr)

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AU17035/95A AU1703595A (en) 1994-02-21 1995-02-17 Therapeutic use of myelin-associated glycoprotein (mag)
SE9703032A SE9703032D0 (sv) 1994-02-21 1997-08-21 Terapeutisk användning av myelinassocierad glykoportein

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GB9403250.5 1994-02-21
GB9403250A GB9403250D0 (en) 1994-02-21 1994-02-21 Therapeutic use of myelin-associated glycoprotein (mag)

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WO1997001352A1 (fr) * 1995-06-27 1997-01-16 Research Foundation Of Cuny, Hunter College Compositions et procedes utilisant la glycoproteine associee a la myeline (mag) et ses inhibiteurs
WO1998022499A2 (fr) * 1996-11-15 1998-05-28 Lisa Joan Mckerracher Systeme de regulation de la croissance tumorale neuronale et neurale, anticorps destines a cet effet et utilisations de ceux-ci
WO1999053945A1 (fr) * 1998-04-16 1999-10-28 Samuel David Molecules inhibant la croissance neuronale ou leurs derives utilises pour immuniser des mammiferes et ainsi favoriser la regeneration de l'axone
WO1999060021A2 (fr) * 1998-05-19 1999-11-25 Yeda Research And Development Co. Ltd. Lymphocytes t actives, antigenes specifiques du systeme nerveux et leur utilisation
WO2002014537A2 (fr) * 2000-08-14 2002-02-21 Fallon Joan M Diagnostic et traitement de la dysautonomie et autres états de dysautonomie
WO2002062383A2 (fr) * 2001-02-08 2002-08-15 Smithkline Beecham P.L.C. Nouvelle methode de traitement
WO2004014953A2 (fr) 2002-08-06 2004-02-19 Glaxo Group Limited Anticorps
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US5932542A (en) * 1995-06-27 1999-08-03 Research Foundation Of Cuny, Hunter College Composition and methods using myelin-associated glycoprotein (MAG) and inhibitors thereof
US6203792B1 (en) 1995-06-27 2001-03-20 Research Foundation Of Cuny, Hunter College Composition and methods using myelin-associated glycoprotein (MAG) and inhibitors thereof
WO1997001352A1 (fr) * 1995-06-27 1997-01-16 Research Foundation Of Cuny, Hunter College Compositions et procedes utilisant la glycoproteine associee a la myeline (mag) et ses inhibiteurs
WO1998022499A2 (fr) * 1996-11-15 1998-05-28 Lisa Joan Mckerracher Systeme de regulation de la croissance tumorale neuronale et neurale, anticorps destines a cet effet et utilisations de ceux-ci
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WO1999053945A1 (fr) * 1998-04-16 1999-10-28 Samuel David Molecules inhibant la croissance neuronale ou leurs derives utilises pour immuniser des mammiferes et ainsi favoriser la regeneration de l'axone
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CA2183630A1 (fr) 1995-08-24
GB9403250D0 (en) 1994-04-13
SE9703032D0 (sv) 1997-08-21
AU1703595A (en) 1995-09-04

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