WO2014006105A1 - Régime posologique optimal d'un anticorps anti-nogo-a dans le traitement de la sclérose latérale amyotrophique - Google Patents

Régime posologique optimal d'un anticorps anti-nogo-a dans le traitement de la sclérose latérale amyotrophique Download PDF

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WO2014006105A1
WO2014006105A1 PCT/EP2013/064063 EP2013064063W WO2014006105A1 WO 2014006105 A1 WO2014006105 A1 WO 2014006105A1 EP 2013064063 W EP2013064063 W EP 2013064063W WO 2014006105 A1 WO2014006105 A1 WO 2014006105A1
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nogo
antibody
localisation
days
dosage
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PCT/EP2013/064063
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Jonathan BULLMAN
David KRULL
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Glaxo Group Limited
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Priority to IN2952KON2014 priority Critical patent/IN2014KN02952A/en
Priority to CN201380035806.8A priority patent/CN104395343A/zh
Priority to JP2015519214A priority patent/JP2015521992A/ja
Priority to CA2876284A priority patent/CA2876284A1/fr
Priority to KR20157003097A priority patent/KR20150036398A/ko
Priority to AU2013285493A priority patent/AU2013285493A1/en
Priority to EP13732986.8A priority patent/EP2870177A1/fr
Priority to BR112014032987A priority patent/BR112014032987A2/pt
Priority to RU2014150265A priority patent/RU2014150265A/ru
Publication of WO2014006105A1 publication Critical patent/WO2014006105A1/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
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • 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
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered

Definitions

  • the invention relates to a method of treatment or prophylaxis of a neurological disorder, in particular but not exclusively amyotrophic lateral sclerosis (ALS), comprising administration of an anti-Nogo-A antibody.
  • a neurological disorder in particular but not exclusively amyotrophic lateral sclerosis (ALS)
  • ALS amyotrophic lateral sclerosis
  • ALS Amyotrophic lateral sclerosis
  • Lou Gehrig's Disease or Maladie de Charcot is the most common adult-onset motor neuron disease.
  • the primary disease hallmark is the progressive degeneration of the upper and lower motor neurons in the corticospinal tracts.
  • Dysfunction of lower motor neurons in the brainstem and spinal cord) triggers generalized weakness, muscle atrophy and paralysis. Failure of the respiratory muscles is generally the fatal event, occurring within 1-5 years of onset.
  • ALS is the most common motor neuron disease in adults affecting approximately 30,000 people in the United States and 5,000 in the United Kingdom each year (Leigh & Swash, 1991). The typical age of onset is between 50 and 70 years, although sometimes occurring at a younger age. Most cases (90-95%) are classified as sporadic ALS (sALS) and the remainder are inherited and referred to as familial ALS (fALS). Sporadic and familial forms are clinically and pathologically similar, suggesting a common pathogenesis (Bruijn et al, 2004). However, the precise cause for most cases is still unknown, and there is no effective remedy to stop the course of the disease.
  • Nogo also known as Reticulon-4 or Neurite outgrowth inhibitor, is a protein that in humans is encoded by the RTN4 gene that has been identified as an inhibitor of neurite outgrowth specific to the central nervous system.
  • Nogo-A having 1192 amino acid residues (GenBank accession no. AJ251383); Nogo-B, a splice variant which lacks residues 186 to 1004 in the putative extracellular domain (GenBank accession no. AJ251384) and a shorter splice variant, Nogo-C, which also lacks residues 186 to 1004 and also has smaller, alternative amino terminal domain (GenBank accession no. AJ251385) (Prinjha R et al (2000) Nature 403, 383- 384).
  • Inhibition of the CNS inhibitory proteins such as Nogo may provide a therapeutic means to ameliorate neuronal damage and promote neuronal repair and growth thereby potentially assisting recovery from neuronal injury such as that sustained in stroke.
  • Examples of such Nogo inhibitors may include small molecules, peptides and antibodies.
  • IN-1 Fab fragment or humanised IN-1 enhanced recovery in rats that have undergone spinal cord transection (Fiedler, M et al (2002) Protein Eng 15 931-941; Brosamle, C et al (2000) J. Neuroscience 20 8061-8068).
  • WO 2004/052932 discloses a murine antibody 11C7 which binds to certain forms of human Nogo with high affinity.
  • WO 2005/061544 also discloses high affinity monoclonal antibodies, including a murine monoclonal antibody 2A10, and generally discloses humanised variants thereof, for example H I Ll l (the sequences for the HI and Ll l are provided in SEQ ID NOs. 33 and 34 respectively (VH or VL sequences only)).
  • the antibodies disclosed bind to human Nogo-A with high affinity.
  • WO 2007/068750 discloses a number of high affinity humanised monoclonal anti-Nogo antibodies, including H28L16 (the sequences for the H28 and L16 are provided in SEQ ID NOs. 49 and 14, respectively (VH or VL sequences only)).
  • the antibodies disclosed were indicated to be useful in the treatment of neurological diseases.
  • it remains a highly desirable goal to optimize the therapeutic regime for such disorders.
  • a method of treatment or prophylaxis of a neurological disorder in a patient which comprises administering to said patient an anti-Nogo-A antibody, or a functional fragment thereof, at a dosage to achieve and maintain a level of co-localisation of said antibody with human Nogo-A on the cell membrane in said patient of greater than 90%.
  • an anti-Nogo-A antibody for use in the treatment or prophylaxis of a neurological disorder in a patient which comprises administering said anti-Nogo-A antibody, or a functional fragment thereof, at a dosage to achieve and maintain a level of co-localisation of said antibody with human Nogo-A on the cell membrane in said patient of greater than 90%.
  • a pharmaceutical composition comprising an anti-Nogo-A antibody, or a functional fragment thereof, for use in the treatment or prophylaxis of a neurological disorder in a patient which comprises administering said anti-Nogo-A antibody, or a functional fragment thereof, at a dosage to achieve and maintain a level of co-localisation of said antibody with human Nogo-A on the cell membrane in said patient of greater than 90%.
  • FIG. 1 Laser scanning cytometry (LSC) well scan to identify the tissue section (grey image) and four regions (cyan boxes) were placed in each section. High-resolution field scans produced images of the location of the three dyes. Individual proteins are colored blue (gamma sarcoglycan), red (Nogo A) and green (H28L16).
  • Figure 2 Gating of Event Populations (pre dose biopsy). Scatter plots were created to separate the pixels of dye for features based on fluorescence intensity.
  • FIG. 3 Gating of Event Populations (pre dose biopsy). This figure is a field image showing the process of "back gating" which is used to show the gated events on the tissue section.
  • Figure 4 Gating of Event Populations (post dose biopsy). Scatter plots were created as in Figure 2 however following dosing with 15 mg/kg H28L16.
  • Figure 5 Gating of Event Populations (post dose biopsy). Back gating was performed as with Figure 3 however following dosing with 15 mg/kg H28L16.
  • FIG. 6 NogoA/H28L16 Expression (gamma sarcoglycan channel not displayed). The individual fluorescent channels are shown. The top row shows target only (Nogo A), second row shows H28L16 only and third row shows Nogo A and H28L16.
  • Figure 7 Percent of Nogo A on the membrane co-localised with H28L16. Shows the percentage of Nogo A on the muscle fibre membrane that is co-localised with H28L16. The box highlighted "15mg/kg” shows the greatest amount of co-localisation was achieved post-dosing with 15 mg/kg H28L16. Each bar represents one section.
  • Figure 8 Median Percent Membrane Nogo-A Co-localised with H28L16. Data from 2.5 mg/kg repeat-dose (left panel), 15 mg/kg repeat-dose (central 3 panels) and 15 mg/kg single dose (right panel). Median of triplicate sections from biopsies from repeat-dose cohorts, with a single section from biopsies from single dose cohorts.
  • Figure 9 Model Estimated Relationship (Emax) between Plasma H28L16 Concentrations and percentage of Membrane Nogo-A Co-Localised with H28L16.
  • Figure 10 Predicted Median (5 th and 95 th Percentile) H28L16 Plasma
  • Figure 11 Predicted Median (5 th and 95 th Percentile) H28L16 Plasma Concentration Time Profiles for 15mg/kg H28L16 administered every 2 weeks.
  • Figure 12 Variable heavy and variable light chain regions of the H28L16 antibody.
  • a method of treatment or prophylaxis of a neurological disorder in a patient which comprises administering to said patient an anti-Nogo-A antibody, or a functional fragment thereof, at a dosage to achieve and maintain a level of co-localisation of said antibody with human Nogo-A on the cell membrane in said patient of greater than 90%.
  • references herein to "co-localisation” refer to the proportion of membrane bound Nogo-A being localized, associated with or bound to the anti-Nogo-A antibody. For example, a value of 100% co-localisation equates to all membrane Nogo-A being co-localised with anti-Nogo-A antibody.
  • co-localisation does not equate to target occupancy, however, it does provide an extremely useful measure of likely pharmacodynamic effect in order to ascertain an optimal dosage regime.
  • Data is presented herein which demonstrates that co-localisation of Nogo-A on the cell membrane with anti-Nogo-A antibody at a level of greater than 90% achieved the maximum pharmacodynamic effect.
  • anti-Nogo-A antibody refers to any antibody or variant form thereof, including but not limited to, antibody fragment, domain antibody or single chain antibody capable of binding to Nogo-A.
  • An anti-Nogo-A antibody may be a neutralising anti-Nogo-A antibody.
  • An anti-Nogo-A may be murine, chimeric, humanized, or fully human antibody or fragment thereof.
  • Neutralising and grammatical variations thereof refers to inhibition, either total or partial, of any Nogo function, and more particularly, any Nogo-A function.
  • references to "Treatment” as used herein refer to the reduction or elimination of disease symptoms associated with and/or causes of amyotrophic lateral sclerosis, including the reduction in or elimination of the progressive degeneration of the neurons in the corticospinal tracts, the denervation of muscle fibres, and/or muscle weakness and/or spasticity.
  • References to "Prophylaxis” as used herein refer to the retardation, prevention or minimization of disease symptoms associated with amyotrophic lateral sclerosis, including the retardation, prevention or minimization of the progressive degeneration of the neurons in the corticospinal tracts, the denervation of muscle fibres, and/or muscle weakness and/or spasticity. It will be appreciated that the amount and frequency of anti-Nogo-A antibody to be administered will be chosen to ensure that co-localisation with Nogo-A on the cell membrane of greater than 90% is achieved and maintained.
  • WO 2010/004031 discloses that a suitable dosage amount of an anti-Nogo-A antibody for treating ALS or other neurological diseases in a human will be in the range of 0.1 mg/kg to 300 mg/kg, usually from about 2 mg/kg to about 40 mg/kg .
  • the dosage of anti-Nogo-A antibody is between 0.1 mg/kg and 300 mg/kg.
  • the dosage of anti-Nogo-A antibody is between 2 mg/kg and 40 mg/kg .
  • WO 2007/068750 discloses that a suitable dosage amount of an anti-Nogo-A antibody for treating stroke and other neurological diseases in a human will be in the range of 700 mg to 3500 mg per 70 kg body weight.
  • the dosage of anti-Nogo-A antibody is between 10 mg/kg and 50 mg/kg .
  • the dosage of anti-Nogo-A antibody is 15 mg/kg .
  • Data is presented herein which surprisingly shows beneficial results for a dosage amount of 15 mg/kg .
  • this dosage amount is particularly amenable to convenient frequency of dosage to achieve the greater than the threshold of the invention of 90% co-localisation with Nogo- A on the cell membrane.
  • a suitable dosage interval to maintain greater than 90% co-localisation is between 8 and 22 days.
  • a suitable dosage interval to maintain greater than 90% co-localisation is between 10 and 18 days.
  • a suitable dosage interval to maintain greater than 90% co-localisation is 14 days. It will be appreciated that slight variation of the dosage interval of 14 days will be acceptable and dosing could occur at 14 days +/- up to 3 days either before or after the optimum 14 day dosage interval . Thus, in one embodiment, when the dosage is 15 mg/kg, a suitable dosage interval to maintain greater than 90% co-localisation is between 11 and 17 days (i.e. 3 days either before or after the optimum 14 day dosage interval). In an alternative embodiment, when the dosage is 15 mg/kg, a suitable dosage interval to maintain greater than 90% co- localisation is between 12 and 16 days (i.e. 2 days either before or after the optimum 14 day dosage interval).
  • a suitable dosage interval to maintain greater than 90% co- localisation is between 13 and 15 days (i.e. 1 day either before or after the optimum 14 day dosage interval).
  • a method of treatment or prophylaxis of a neurological disorder in a patient which comprises administering to said patient an anti-Nogo-A antibody at a dosage of 15 mg/kg every 14 days (+/- 3 days).
  • anti-Nogo-A antibodies which may be used in accordance with the invention are described in WO 2004/052932, WO 2005/028508, WO 2005/061544 and WO 2007/068750, the anti-Nogo-A antibodies of which are herein incorporated by reference.
  • the anti-Nogo-A antibody is a monoclonal antibody.
  • the anti-Nogo-A antibody is a humanised antibody.
  • Humanized antibody refers to a type of engineered antibody having its CDRs derived from a non-human donor immunoglobulin, the remaining immunoglobulin-derived parts of the molecule being derived from one (or more) human immunoglobulin(s).
  • framework support residues may be altered to preserve binding affinity (see, e.g ., Queen et al., Proc. Natl Acad Sci USA, 86: 10029-10032 (1989), Hodgson et al., Bio/Technology, 9 :421 (1991 )).
  • a suitable human acceptor antibody may be one selected from a conventional database, e.g ., the KABAT® database, Los Alamos database, and Swiss Protein database, by homology to the nucleotide and amino acid sequences of the donor antibody (in this case the murine donor antibody 2A10).
  • a human antibody characterized by a homology to the framework regions of the donor antibody (on an amino acid basis) may be suitable to provide a heavy chain constant region and/or a heavy chain variable framework region for insertion of the donor CDRs.
  • a suitable acceptor antibody capable of donating light chain constant or variable framework regions may be selected in a similar manner. It should be noted that the acceptor antibody heavy and light chains are not required to originate from the same acceptor antibody.
  • EP-A-0239400 and EP-A-054951 describe several ways of producing such humanised antibodies.
  • the term "donor antibody” refers to a non-human antibody which contributes the amino acid sequences of its variable regions, CDRs, or other functional fragments or analogs thereof to the humanised antibody, and thereby provide the humanised antibody with the antigenic specificity and neutralizing activity characteristic of the donor antibody.
  • acceptor antibody refers to an antibody heterologous to the donor antibody, which provides the amino acid sequences of its heavy and/or light chain framework regions and/or its heavy and/or light chain constant regions to the humanised antibody.
  • the acceptor antibody may be derived from any mammal provided that it is non-immunogenic in humans.
  • the acceptor antibody is a human antibody.
  • humanisation may be achieved by a process of "veneering".
  • a statistical analysis of unique human and murine immunoglobulin heavy and light chain variable regions revealed that the precise patterns of exposed residues are different in human and murine antibodies, and most individual surface positions have a strong preference for a small number of different residues (see Padlan E.A. et a/; (1991 ) Mol.
  • CDRs are defined as the complementarity determining region amino acid sequences of an antibody which are the hypervariable regions of immunoglobulin heavy and light chains. See, e.g ., Kabat et al., Sequences of Proteins of Immunological Interest, 4th Ed ., U.S. Department of Health and Human Services, National Institutes of Health (1987). There are three heavy chain and three light chain CDRs (or CDR regions) in the variable portion of an immunoglobulin. Thus, “CDRs” as used herein refers to all three heavy chain CDRs, or all three light chain CDRs (or both all heavy and all light chain CDRs, if appropriate).
  • the structure and protein folding of the antibody may mean that other residues are considered part of the antigen binding region and would be understood to be so by a skilled person. See for example Chothia et a/., (1989) Conformations of immunoglobulin hypervariable regions; Nature 342, p877-883.
  • the anti-Nogo-A antibody is a neutralizing anti-Nogo-A antibody or a fragment thereof such as murine antibodies 2A10, 15C3 and 2C4 (as described in WO 2005/016544, the content of which are incorporated herein by reference it its entirety).
  • the anti-Nogo-A antibody is any of the antibodies described in WO 2004/052932 (the content of which are incorporated herein by reference it its entirety).
  • Examples of antibodies disclosed in WO 2004/052932 are 11C7, including humanised variants thereof.
  • the anti-Nogo-A antibody is any of the human anti-Nogo-A antibodies as described in WO 2005/028508 and WO 2009/056509 (the content of which are incorporated herein by reference it its entirety). In a further embodiment, the anti-Nogo-A antibody is human anti-Nogo-A antibody 6A3 as described in WO 2009/056509.
  • the anti-Nogo-A antibody comprises an anti-Nogo-A antibody described in WO 2007/068750.
  • the anti- Nogo-A antibody comprises a humanised antibody such as a humanised variant of 2A10, for example, H20L16, H28L16, H28L13 and H27L16 (as described in WO 2007/068750, the content of which are incorporated herein by reference it its entirety), a human antibody, or a fragment thereof.
  • the anti-Nogo-A antibody comprises H27L16 (SEQ ID NO: 48 and SEQ ID NO: 14 of WO 2007/068750), H28L13 (SEQ ID NO: 49 and SEQ ID NO: 13 of WO 2007/068750) or H28L16 (SEQ ID NO: 49 and SEQ ID NO: 14 of WO 2007/068750).
  • the anti-Nogo-A antibody comprises H28L16 (SEQ ID NO: 49 and SEQ ID NO: 14 of WO 2007/068750, respectively, SEQ ID NO: l and SEQ ID NO: 2 herein).
  • the anti-Nogo-A antibody comprises H27FL L16FL (SEQ ID NO: 54 and SEQ ID NO: 18 of WO 2007/068750), H28FL L13FL (SEQ ID NO: 55 and SEQ ID NO: 17 of WO 2007/068750) or H28FL L16FL (SEQ ID NO: 55 and SEQ ID NO: 18 of WO 2007/068750).
  • the anti-Nogo-A antibody comprises H28FL L16FL (SEQ ID NO: 55 and SEQ ID NO: 18 of WO 2007/068750).
  • the anti-Nogo-A antibody comprises H28L16 (SEQ ID NO: 49 and SEQ ID NO: 14 of WO 2007/068750) or H28FL L16FL (SEQ ID NO: 55 and SEQ ID NO: 18 of WO 2007/068750). In a yet further embodiment, the anti-Nogo-A antibody comprises H28L16 (SEQ ID NO: 49 and SEQ ID NO: 14 of WO 2007/068750).
  • the anti-Nogo-A antibody or fragment thereof comprises one or more, optionally six, of the CDRs of 2A10, H28L16 or 6A3.
  • the anti-Nogo-A antibody or fragment thereof is an antibody that binds to the same human Nogo-A epitope as H28L16 (human Nogo-A 610-621aa, which includes SEQ ID NO: 6 from WO 2010/004031) or competes with the binding of H28L16 to human Nogo-A.
  • Examples of neurological disorders which may be treated in accordance with the dosage regime of the invention are selected from : stroke (ischemic or haemorrhagic), traumatic brain injury, spinal cord injury, Alzheimer's disease, fronto-temporal dementias (tauopathies), peripheral neuropathy, Parkinson's disease, Creutzfeldt-Jakob disease (CJD), Schizophrenia, amyotrophic lateral sclerosis (ALS), multiple sclerosis, Huntington's disease, multiple sclerosis, inclusion body myositis, polymyositis, dermatomyositis, morphologically nonspecific myopathies, congestive heart failure and neuropathic pain .
  • stroke ischemic or haemorrhagic
  • traumatic brain injury traumatic brain injury
  • spinal cord injury Alzheimer's disease
  • tauopathies fronto-temporal dementias
  • peripheral neuropathy Parkinson's disease
  • Creutzfeldt-Jakob disease CJD
  • Schizophrenia amyotrophic lateral s
  • the neurological disorder is amyotrophic lateral sclerosis (ALS).
  • ALS amyotrophic lateral sclerosis
  • the mode of administration of the anti-Nogo-A antibody or fragment thereof of the invention may be any suitable route which delivers the agent to the host.
  • the antibodies, and pharmaceutical compositions of the invention are particularly useful for parenteral administration, i.e., subcutaneously (s.c), intrathecal ⁇ , intraperitoneally (i.p.), intramuscularly (i.m.), intravenously (i.v.), or intranasally (i.n.).
  • the anti-Nogo-A antibody or fragment thereof is administered intravenously.
  • the anti- Nogo-A antibody or fragment thereof is administered subcutaneously.
  • an anti-Nogo-A antibody for use in the treatment or prophylaxis of a neurological disorder in a patient which comprises administering said anti-Nogo-A antibody, or a functional fragment thereof, at a dosage to achieve and maintain a level of co-localisation of said antibody with human Nogo-A on the cell membrane in said patient of greater than 90%.
  • a pharmaceutical composition comprising an anti-Nogo-A antibody, or a functional fragment thereof, for use in the treatment or prophylaxis of a neurological disorder in a patient which comprises administering said anti-Nogo-A antibody, or a functional fragment thereof, at a dosage to achieve and maintain a level of co-localisation of said antibody with human Nogo-A on the cell membrane in said patient of greater than 90%.
  • the pharmaceutical composition of the invention typically contains an effective amount of the antibody of the invention as an active ingredient in a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier typically an aqueous carrier.
  • aqueous carriers may be employed, e.g ., 0.9% saline, 0.3% glycine, and the like. These solutions are sterile and generally free of particulate matter.
  • compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, etc.
  • concentration of the antibody of the invention in such pharmaceutical formulation can vary widely, i.e., 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., according to the particular mode of administration selected.
  • a pharmaceutical composition of the invention for intramuscular injection could be prepared to contain 1 ml_ sterile buffered water, and between about 1 ng to about 100 mg, e.g . about 50 ng to about 30 mg or more, such as, about 5 mg to about 25 mg, of an antibody of the invention.
  • a pharmaceutical composition of the invention for intravenous infusion could be made up to contain about 250 ml of 0.9% normal saline (sodium chloride) solution, and about 1 to about 30 and typically 5 mg to about 25 mg of an engineered antibody of the invention per ml of 0.9% normal saline (sodium chloride) solution.
  • parenterally administrable compositions are well known or will be apparent to those skilled in the art and are described in more detail in, for example, Remington's Pharmaceutical Science, 15th ed., Mack Publishing Company, Easton, Pennsylvania.
  • intravenously administrable antibody formulations of the invention see Lasmar U and Parkins D "The formulation of Biopharmaceutical products", Pharma. Sci.Tech. today, page 129-137, Vol .3 (3 rd April 2000), Wang, W “Instability, stabilisation and formulation of liquid protein pharmaceuticals", Int. J. Pharm 185 (1999) 129- 188, Stability of Protein Pharmaceuticals Part A and B ed Ahem T.J., Manning M .
  • the antibodies described herein can be lyophilized for storage and reconstituted in a suitable carrier prior to use. This technique has been shown to be effective with conventional immunoglobulins and art-known lyophilization and reconstitution techniques can be employed .
  • the anti-Nogo-A antibody is administered in combination with a further therapeutic agent.
  • the further therapeutic agent is an agent having efficacy against amyotrophic lateral sclerosis (ALS).
  • the agent having efficacy against amyotrophic lateral sclerosis is dexpramipexole.
  • Dexpramipexole KNS- 760704; ( «)-/V 6 -propyl-4,5,6,7-tetrahydrobenzo[c/]thiazole-2,6-diamine
  • KNS- 760704 ( «)-/V 6 -propyl-4,5,6,7-tetrahydrobenzo[c/]thiazole-2,6-diamine
  • the anti-Nogo-A antibody is administered with a compound having anti-glutamate activity.
  • the compound having anti-glutamate activity is riluzole.
  • the compound having anti-glutamate activity is an antagonist of an AMPA receptor, such as a 2,3- benzodiazepine compound, in particular, talampanel .
  • the compound having anti-glutamate activity is TRO 19622 or ceftriaxone.
  • the anti-Nogo-A antibody and the compound having anti-glutamate activity may be administered to the patient simultaneously, sequentially or separately.
  • the compound having anti-glutamate activity is riluzole
  • about 50mg to about 150 or 200mg riluzole may be administered to the patient daily, typically lOOmg riluzole is administered to the patient daily.
  • Riluzole is typically orally administered .
  • Talampanel is administered, typically orally, at about lOmg to about 250mg, from once to five times per day. In one embodiment, Talampanel is administered at a dosage of 25mg or 50mg, from once to five times per day, optionally three times per day.
  • Laser Scanning Cytometry uses lasers to excite fluorescent dyes to produce an image of the dye's location in cells and tissue sections which enables the measurement of expression at the location.
  • the dyes are attached to antibodies that bind to targeted proteins.
  • a commercial anti-Nogo A antibody attached to Alexa 647 dye was used to identify the target of H28L16.
  • the use of the commercial Nogo A antibody allowed the measurement of the target in the tissue sections. It was also desired to know how much of the target (Nogo A) was located on the muscle fibre membrane. This was performed by staining sections with antibodies to the muscle fibre membrane protein anti-gamma sarcoglycan attached to an Alexa 488 dye.
  • FIG. 1 shows an LSC region image in which colours were assigned to each channel.
  • the individual proteins are colored blue (gamma sarcoglycan), red (Nogo A) and green (H28L16).
  • the rectangular boxes outlined in white are the individual field images that make up the region image.
  • Each region image contained 10 field images.
  • Scatter plots were created to separate the pixels of dye for features based on fluorescence intensity.
  • the pixels were threshold (background noise was separated from specific signal) using a process known as "gating".
  • the gating is displayed as colored lines on the scatter plots and the gate is labeled Rl, R2, and R3...etc, according to the order that the gate was created ( Figure 2).
  • the scatter plots of Figure 2 were created by plotting two channels against each other. Membrane and non-membrane areas of the tissue were separated by plotting the "green maxpixel” against the "green intensity”.
  • the brightest pixels in Rl are on the membrane that was labelled with the gamma sarcoglycan antibody.
  • the dimmer pixels in R5 are the unlabelled fibres.
  • the groups of pixels within a gated population can be displayed on the image as a colored box. This process is known as "back gating". It is a quality control task to verify the most accurate placement of the gates (Figure 3).
  • the gated populations in the scatter plots in Figure 2 are displayed in the image in Figure 3. It should be noted from Figure 3 that these data are from a patient dosed with vehicle only, so there is minimal background staining with the anti-idiotype antibody against H28L16 and little evidence of co-localisation with Nogo-A (red boxes).
  • Figure 6 shows the individual fluorescent channels.
  • the pre-dose biopsy is red and there is no orange/yellow fluorescence compared to the post-dose biopsy that shows co-localisation of H28L16 with Nogo A and excess H28L16 that is not co-localised with Nogo A. High co-localisation occurred along the fibre
  • Figure 7 is a graph that shows the percentage of Nogo A on the muscle fibre membrane that is co-localised with H28L16. Three sections were cut and evaluated for each patient biopsy (pre and post dosing with either drug or placebo). Some low level of co-localisation was seen in biopsies from undosed subjects (either pre-dose or placebo dosed) representing non-specific
  • Frozen biopsies of sufficient quality to support immunohistochemical analysis were stained with antibodies against Nogo-A, anti-idiotype antibodies against H28L16 and anti-gamma sarcoglycan (to define muscle membrane). Expression was visualised using fluorescently labelled secondary antibodies, and quantified using Laser Scanning Cytometry (LSC). Using this approach, the expression of Nogo-A on muscle membrane could be assessed and was distinguished from intra-cellular Nogo-A expression by co-location with gamma sarcoglycan. In addition, an estimate of the level of H28L16 in muscle was measured and an estimate of the degree of co-localisation of Nogo-A with H28L16 on the muscle membrane was derived .
  • LSC Laser Scanning Cytometry
  • Figure 8 displays the median percentage of Nogo-A co-localised with H28L16 at the muscle cell membrane in post-dose biopsies taken from the 2.5 mg/kg and 15 mg/kg cohorts (where 100% would equate to all membrane Nogo-A co-localised with H28L16).
  • Predicted plasma H28L16 concentration time profiles for 15 mg/kg administered every 2 and 4 weeks are displayed below in Figure 10 and Figure 11, respectively.
  • Predicted plasma exposure of H28L16 (C max and AUQo-tau)) with regard to the proposed dosing regimen of 15 mg/kg every 2 weeks is displayed in Table 1.
  • the monkey-to-human margins of exposure to H28L16 over the predicted human plasma exposure at steady state in the proposed Phase 2 study, based on a dose of 15 mg/kg administered every 2 weeks are (i) 33-fold based on dose ratio, (ii) 10-fold based on steady state AUC ratio, (iii) 27-fold based on steady state C max ratio.
  • the optimal dose for H28L16 appears to be 15 mg/kg once every 2 weeks. This dose, although expected to exceed exposure levels so far achieved in clinical studies, is well supported by non-clinical safety data and maximises the opportunity of delivering efficacy in ALS patients.

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Abstract

L'invention concerne une méthode de traitement ou de prophylaxie d'un trouble neurologique, en particulier, mais sans y être limité, la sclérose latérale amyotrophique (ALS), comprenant l'administration d'un anticorps anti-Nogo-A.
PCT/EP2013/064063 2012-07-05 2013-07-03 Régime posologique optimal d'un anticorps anti-nogo-a dans le traitement de la sclérose latérale amyotrophique WO2014006105A1 (fr)

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IN2952KON2014 IN2014KN02952A (fr) 2012-07-05 2013-07-03
CN201380035806.8A CN104395343A (zh) 2012-07-05 2013-07-03 抗Nogo-A抗体在肌萎缩侧索硬化治疗中的最佳剂量方案
JP2015519214A JP2015521992A (ja) 2012-07-05 2013-07-03 筋萎縮性側索硬化症の治療における抗Ｎｏｇｏ−Ａ抗体の最適投与レジメン
CA2876284A CA2876284A1 (fr) 2012-07-05 2013-07-03 Regime posologique optimal d'un anticorps anti-nogo-a dans le traitement de la sclerose laterale amyotrophique
KR20157003097A KR20150036398A (ko) 2012-07-05 2013-07-03 근육위축가쪽경화증의 치료에서의 항­ｎｏｇｏ­ａ 항체의 최적 투여 섭생
AU2013285493A AU2013285493A1 (en) 2012-07-05 2013-07-03 Optimum dose regime of an anti-Nogo-A antibody in the treatment of amyotrophic lateral sclerosis
EP13732986.8A EP2870177A1 (fr) 2012-07-05 2013-07-03 Régime posologique optimal d'un anticorps anti-nogo-a dans le traitement de la sclérose latérale amyotrophique
BR112014032987A BR112014032987A2 (pt) 2012-07-05 2013-07-03 método de tratamento ou profilaxia de um distúrbio neurológico
RU2014150265A RU2014150265A (ru) 2012-07-05 2013-07-03 Оптимальный дозовый режим антитела против nogo-a в лечении бокового амиотрофического склероза

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KR102279751B1 (ko) * 2019-06-28 2021-07-21 경북대학교 산학협력단 근원성 인자 또는 nogo-a 측정 제제를 포함하는 근육병 진단용 조성물과 이를 이용한 근육병 진단 방법
KR102409771B1 (ko) * 2020-06-17 2022-06-16 경북대학교 산학협력단 Nogo-A 및 필라민-C의 상호 결합을 이용한 근육질환의 치료제 스크리닝 방법

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0054951A1 (fr) 1980-12-24 1982-06-30 Chugai Seiyaku Kabushiki Kaisha Dibenzo(b,f)(1,4)oxazépines, leur procédé de préparation et les compositions pharmaceutiques les contenant
EP0239400A2 (fr) 1986-03-27 1987-09-30 Medical Research Council Anticorps recombinants et leurs procédés de production
WO2004006955A1 (fr) 2001-07-12 2004-01-22 Jefferson Foote Anticorps super humanises
WO2004052932A2 (fr) 2002-12-10 2004-06-24 Novartis Ag Molecules de liaison a nogo a et leur utilisation pharmaceutique
WO2005016544A1 (fr) 2003-08-08 2005-02-24 Westfalia Separator Ag Centrifugeuse a vis a paroi pleine comprenant un disque d'ecorçage
WO2005028508A2 (fr) 2003-09-19 2005-03-31 Novartis Ag Molecules se liant a nogo-a et utilisation pharmaceutique de celles-ci
WO2005061544A2 (fr) 2003-12-22 2005-07-07 Glaxo Group Limited Immunoglobulines
WO2007068750A2 (fr) 2005-12-16 2007-06-21 Glaxo Group Limited Immunoglobulines
WO2009056509A1 (fr) 2007-11-02 2009-05-07 Novartis Ag Molécules améliorées de liaison à nogo-a et utilisation pharmaceutique de celles-ci
WO2010004031A2 (fr) 2008-07-11 2010-01-14 Glaxo Group Limited Traitement inédit

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0054951A1 (fr) 1980-12-24 1982-06-30 Chugai Seiyaku Kabushiki Kaisha Dibenzo(b,f)(1,4)oxazépines, leur procédé de préparation et les compositions pharmaceutiques les contenant
EP0239400A2 (fr) 1986-03-27 1987-09-30 Medical Research Council Anticorps recombinants et leurs procédés de production
WO2004006955A1 (fr) 2001-07-12 2004-01-22 Jefferson Foote Anticorps super humanises
WO2004052932A2 (fr) 2002-12-10 2004-06-24 Novartis Ag Molecules de liaison a nogo a et leur utilisation pharmaceutique
WO2005016544A1 (fr) 2003-08-08 2005-02-24 Westfalia Separator Ag Centrifugeuse a vis a paroi pleine comprenant un disque d'ecorçage
WO2005028508A2 (fr) 2003-09-19 2005-03-31 Novartis Ag Molecules se liant a nogo-a et utilisation pharmaceutique de celles-ci
WO2005061544A2 (fr) 2003-12-22 2005-07-07 Glaxo Group Limited Immunoglobulines
WO2007068750A2 (fr) 2005-12-16 2007-06-21 Glaxo Group Limited Immunoglobulines
WO2009056509A1 (fr) 2007-11-02 2009-05-07 Novartis Ag Molécules améliorées de liaison à nogo-a et utilisation pharmaceutique de celles-ci
WO2010004031A2 (fr) 2008-07-11 2010-01-14 Glaxo Group Limited Traitement inédit

Non-Patent Citations (25)

* Cited by examiner, † Cited by third party
Title
"Pharma. Sci.Tech.today", vol. 3, 3 April 2000, article "The formulation of Biopharmaceutical products", pages: 129 - 137
"Remington's Pharmaceutical Science", MACK PUBLISHING COMPANY
"Stability of Protein Pharmaceuticals Part A and B", 1992, PLENUM PRESS
AKERS.M.J.: "Excipient-Drug interactions in Parenteral Formulations", J.PHARM SCI, vol. 91, 2002, pages 2283 - 2300
BREGMAN, BS ET AL., NATURE, vol. 378, 1995, pages 498 - 501
BROSAMLE, C ET AL., J. NEUROSCIENCE, vol. 20, 2000, pages 8061 - 8068
CARONI, P; SCHWAB, ME, NEURON, vol. 1, 1988, pages 85 - 96
CHEN ET AL., NATURE, vol. 403, 2000, pages 434 - 439
CHOTHIA ET AL.: "Conformations of immunoglobulin hypervariable regions", NATURE, vol. 342, 1989, pages 877 - 883
FIEDLER, M ET AL., PROTEIN ENG, vol. 15, 2002, pages 931 - 941
GLAXOSMITHKLINE GROUP OF COMPANIES: "A Single and Repeat Dose Escalation Study of the Safety,Pharmacokinetics and Pharmacodynamics of GSK1223249 inPatients with ALS", 10 December 2010 (2010-12-10), XP002712128, Retrieved from the Internet <URL:http://download.gsk-clinicalstudyregister.com/files/af650dad-99d2-48f6-ad9b-37f6701ac466> [retrieved on 20130902] *
HA, E; WANG W; WANG YJ: "Peroxide formation in polysorbate 80 and protein stability", J. PHARM SCI, vol. 91, 2002, pages 2252 - 2264
HODGSON ET AL., BIO/TECHNOLOGY, vol. 9, 1991, pages 421
IMAMURA, K ET AL.: "Effects of types of sugar on stabilization of Protein in the dried state", J PHARM SCI, vol. 92, 2003, pages 266 - 274
IZUTSU; KKOJIMA, S., J PHARM. PHARMACOL, vol. 54, 2002, pages 1033 - 1039
JOHNSON, R: "Mannitol-sucrose mixtures-versatile formulations for protein lyophilization", J. PHARM. SCI, vol. 91, 2002, pages 914 - 922
KABAT ET AL.: "Sequences of Proteins of Immunological Interest", 1987, NATIONAL INSTITUTES OF HEALTH
MARK G. E. ET AL.: "Handbook of Experimental Pharmacology", vol. 113, 1994, SPRINGER- VERLAG, pages: 105 - 134
PADLAN E.A. ET AL., MOL.LMMUNOL., vol. 28, 1991, pages 489 - 498
PEDERSEN J.T. ET AL., J. MOL. BIOL., vol. 235, 1994, pages 959 - 973
PRINJHA R ET AL., NATURE, vol. 403, 2000, pages 383 - 384
QUEEN ET AL., PROC. NATL ACAD SCI USA, vol. 86, 1989, pages 10029 - 10032
SCHNELL, L; SCHWAB, ME, NATURE, vol. 343, 1990, pages 269 - 272
THALLMAIR, M ET AL., NATURE NEUROSCIENCE, vol. 1, 1998, pages 124 - 131
WANG, W: "Instability, stabilisation and formulation of liquid protein pharmaceuticals", INT. J. PHARM, vol. 185, 1999, pages 129 - 188

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