WO2023140780A1 - Method of treating inflammatory disease - Google Patents

Method of treating inflammatory disease Download PDF

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Publication number
WO2023140780A1
WO2023140780A1 PCT/SG2022/050909 SG2022050909W WO2023140780A1 WO 2023140780 A1 WO2023140780 A1 WO 2023140780A1 SG 2022050909 W SG2022050909 W SG 2022050909W WO 2023140780 A1 WO2023140780 A1 WO 2023140780A1
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Prior art keywords
dose
sequence
seq
antibody
loading
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PCT/SG2022/050909
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French (fr)
Inventor
Karen Veverka
Kenneth Kobayashi
Josemund MENEZES
Alexandre Kaoukhov
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Aslan Pharmaceuticals Pte Ltd.
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Publication of WO2023140780A1 publication Critical patent/WO2023140780A1/en

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    • 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
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • 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
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
    • 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
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present disclosure relates to a dosing regimen for the treatment of inflammatory disease, such as atopic dermatitis, comprising inhibiting IL-13Rwith an antibody or antigen-binding fragment thereof specific for the receptor and formulations thereof.
  • IL-13 has been associated with various conditions including, but not limited to, various respiratory and allergy-mediated disorders, fibrosis, scleroderma, inflammatory bowel disease and certain cancers; see, e.g., Wynn, T.A., 2003 Annu. Rev. Immunol. 21:425-456; Terabe et al, 2000 Nat Immunol. 1 (6): 515-520; Fuss etal, 2004 J. Clin. Invest 113 (10): 1490-1497; Simms etal, 2002 Curr. Opin. Rheumatol. 14 (6) :717-722; and Hasegawa etal, 1997 J. Rheumatol. 24 (2): 328-332.
  • IL- 13 is an attractive target for the treatment of such diseases.
  • One possible way to inhibit the activity of IL-13 is to interfere with the binding of IL-13 to its receptor IL-13R, for example by using an antibody specific to IL-13R, such as an antibody specific to IL-13Ral.
  • An effective antibody antagonist specific to IL-13Ral may also interfere with the binding of IL-13 and prevent heterodimerization of IL-4Ra and IL-13Ral.
  • Such an antibody will inhibit signalling of both IL- 13 and IL-4 through the type II receptor [formed by IL- 13Ral and IL-4Ra) while sparing IL-4 signalling through the type I receptor. Signalling through the type I receptor is essential in the induction phase of the immune response during which Th2 cells differentiate.
  • T cells do not express IL-13Ral so the type II receptor plays no role in Th2 differentiation. Hence, an IL-13Ral antibody may not affect the overall Thl/Th2 balance. Signalling through the type II IL-4/IL-13 receptor is critical during the effector-A-stage of the immune response during established allergic inflammation.
  • 10G5-6 is an IgG4 with a hinge stabilising serine to proline mutation (S241P Kabat numbering) which is now known as eblasakimab (previously called ASLAN004). Eblasakimab has been shown to bind to human IL-13Ral with a high affinity.
  • Eblasakimab was shown to effectively antagonise IL-13 function through inhibiting the binding of IL-13 to its receptor IL-13Ral and to inhibit IL-13 and IL-4 induced eotaxin release in NHDF cells, IL-13 and IL-4 induced STAT6 phosphorylation in NHDF cells and IL-13 stimulated release of TARC in blood or peripheral blood mononuclear cells.
  • the antibody of the present disclosure needs to bind the epitope on the receptor IL-13Rod to prevent the ligand binding and block the requisite signalling.
  • the receptor distribution, the off-rate and the on-rate of the antibody have a big impact on the pharmacokinetics and pharmacodynamics of the antibody, in particularly the occupancy of the receptor. These relationships can be very complex and specific to the particular antibody or pathway.
  • a loading dose is beneficial for antibodies and binding fragments thereof is dependent on their pharmacokinetic and pharmacodynamic profile.
  • Pharmacokinetics are a function of the dose administered, the dosing interval, the peak plasma concentration that the antibody reaches after administration (Cmax), the time taken to reach Cmax, the lowest trough concentration that the antibody reaches before the next dose is administered (Cmin), the mean plasma concentration of the antibody over a specific interval of time (Cmean), the volume distribution of the antibody (i.e. the ratio of antibody in plasma vs the body), amount of antibody in the plasma, the absorption half-life, the absorption rate constant, the elimination half-life, the elimination rate constant, the area under the curve (i.e. the integral of the concentration time curve after a single dose or a steady state), the volume of plasma cleared of antibody per unit time, the bioavailability of the antibody and the fluctuation within one dosing interval at steady state.
  • the binding of ligands (in this case antibody) to receptors is governed by the law of mass action which relates the large-scale status to the rate of numerous molecular processes.
  • the rates of formation and un-formation can be used to determine the equilibrium concentration of bound receptors.
  • the equilibrium dissociation constant is defined by: where Wigand, R»receptor, square brackete [] denote concentration.
  • the fraction of bound receptors is is the fraction ⁇ if receptor bound by the ligand.
  • receptor reserve refers to a phenomenon whereby stimulation of only a fraction of the whole receptor population apparently elicits the maximal effect achievable in a particular tissue.
  • the situation where the receptor has to be fully occupied to prevent binding of the native ligand, to reduce signalling may in fact require almost all the free receptors to be bound by the antibody.
  • the faster that this situation is achieved i.e. the quicker the "full occupancy” of the receptor can be achieved, the faster the onset of therapeutic activity.
  • Target mediated drug disposition TMDD
  • TMDD Target mediated drug disposition
  • Additional influential factors include sink and clearance mechanisms body for antibodies administered as therapeutics.
  • the present inventors have established that at least one loading dose, for example two or three loading doses are useful to adequately occupy the target receptor IL-13Ral. This allows a rapid onset of therapeutic effect, for example where there is a link between the pharmacodynamic effect and pharmacokinetic effect. Adequate occupancy of the receptor may in turn result in complete or significant inhibition of STAT6 signalling. What is more this occupancy of the receptor can then be maintained by lower and/or less frequent dosing.
  • a method of treating inflammatory disease in a human patient comprising administering multiple doses of an anti-IL-13Ral antibody molecule or antigen binding fragment thereof comprising a VH sequence of SEQ ID NO: 51 or a sequence at least 95% identical thereto, such as 95, 96, 97, 98 or 99% identical thereto, and VL sequence of SEQ ID NO: 53 or a sequence at least 95% identical thereto, such as 95, 96, 97, 98 or 99% identical thereto; characterised in that at least one loading dose in the range 400-900mg (for example 400, 500, 600, 700, 800 or 900mg, such as 400 to 600mg, in particular 600mg) is employed prior to commencing the "therapeutic” dosing administered once every two, three or four weeks thereafter.
  • an anti-IL-13Ral antibody molecule or antigen binding fragment thereof comprising a VH sequence of SEQ ID NO: 51 or a sequence at least 95% identical thereto, such as 95, 96, 97, 98 or
  • a method of treating inflammatory disease in a human patient comprising administering multiple doses of an anti-IL-13Ral antibody molecule or antigen binding fragment thereof comprising:
  • CDRH1 comprising an amino acid sequence GYSFTSYWIG (SEQ ID NO: 1]
  • CDRH2 comprising a sequence VIYPGDSYTR (SEQ ID NO: 2)
  • Xi denotes Phe, Met, Gin, Leu or Vai
  • X 6 denotes Ser or Ala
  • X 7 denotes Phe, Leu, Ala or Met
  • X 9 denotes Tyr, Gin, Lys, Arg, Trp, His, Ala, Thr, Ser, Asn or Gly
  • CDRL1 is a sequence comprising RASQSISSSYLA (SEQ ID NO: 31).
  • CDRL2 is a sequence comprising GASSRAT (SEQ ID NO: 32).
  • CDRL3 comprising the formula:
  • Gin X 2 X 3 X4X 5 X? denotes Gin, Arg, Met, Ser, Thr or Vai.
  • X 3 denotes Tyr or Vai
  • X4 denotes Glu, Ala, Gly or Ser
  • X5 denotes Thr, Ala or Ser characterised in that at least one loading dose in the range 400-900mg (for example 400, 500, 600, 700, 800 or 900mg, such as 400 to 600mg in particular 600mg] is employed prior to commencing the "therapeutic” dosing administered once every two, three or four weeks.
  • 400-900mg for example 400, 500, 600, 700, 800 or 900mg, such as 400 to 600mg in particular 600mg
  • affinity is 500pM or a lower numerical value (for example 50 to 500pM], for example 250pM or a lower numerical number (for example 50 to 300pM], such as 125pM or a lower number (100 to 150pM).
  • a loading dose is a dose which is higher and/or administered more frequently than the therapeutic dose.
  • the antibody or antigen binding fragment comprises an Fc region, for example isotype IgG or a derivative thereof, such as 241P.
  • CDRL3 is SEQ ID NO: 33 or 45.
  • each dose is administered by infusion, such as intravenous infusion.
  • atopic dermatitis is moderate to severe
  • the disease baseline is characterised by a EASI score of 16 or above (such as 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 , 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72).
  • the therapeutic dose is administered weekly.
  • one or more subsequent loading doses are administered in the same location as a previous loading dose, for example to minimise the rate of clearance by maximising saturation of receptor occupancy.
  • one or more subsequent therapeutic doses are administered in the same location as a previous loading dose and/or therapeutic dose, for example to minimise the rate of clearance by maximising saturation of receptor occupancy.
  • Same location as employed here refers to actual collocation albeit temporally off-set, for example if a previous loading dose was administered in the upper left arm, then a subsequent therapeutic dose would be administered to the upper left arm. To track this accurately the location of the injection may need to be recorded for the patient
  • the volume of a single dose such as a loading and/or therapeutic dose is administered as multiple injections, for example as two or more individual subcutaneous injections, wherein the two or more injections are administered in the same location.
  • the volume of a single loading and/or therapeutic dose is administered as two or more, for example two individual injections, wherein the two or more injections are administered in the same location, for example administered on the same location (also referred to as same side) of the patient, such as wherein both injection sites are located within 10cm or less of each other, in particular within 9, 8, 7, 6, 5, 4, 3, 2 or 1 cm’s of each other.
  • the volume of a single loading dose is administered as two individual injections, wherein the two injections are administered in the same location, for example two individual injections, wherein the two or more injections are administered in the same location, for example administered on the same location (also referred to as same side] of the patient, such as wherein both injection sites are located within 10cm or less of each other, in particular within 9, 8, 7, 6, 5, 4, 3, 2 or 1 cm's of each other.
  • this type of co-location of administration is more or less at the time (i.e. is not temporally off-set].
  • the site of injection is rotated, for example for a single dose administered as multiple injections.
  • the site of injection is rotated, between doses, for example between loading doses and/or therapeutic doses.
  • the antibody or antigen binding fragment will inhibit signalling of both IL- 13 and IL-4 through the type II receptor. In one embodiment the antibody does not inhibit signalling through the type I receptor.
  • the dose administered according to the present disclosure is a fixed dose, i.e. is an absolute dose which is not based on the mass or surface area of the patient
  • the dose is based on the mass of the patient. In one embodiment a loading dose of the anti-IL13R antibody or binding fragment thereof is 8 to lOmg/Kg.
  • all the doses are administered by the same route, for example a route described herein, in particular subcutaneously.
  • one or more loading doses are administered by one route, for example IV, and the further loading doses and/or therapeutic doses are administered by a different route, for example subcutaneously.
  • the loading dose or doses is/are administered by IV and the therapeutic dose or doses are administered subcutaneously.
  • the patient is a human.
  • the present disclosure extends to an antibody, antigen binding fragment or formulation for use in a treatment regimen described herein.
  • the presently disclosed method results in inhibition, such as complete inhibition of ST AT 6 signalling and complete IL-13 receptor occupancy for around 1 week (7 days] or more, such as 2 weeks, 3 weeks or 4 weeks (or one month].
  • inhibition of STAT6 is maintained (for example ata therapeutic level] for a period of 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 days, such as 29 days.
  • the receptor bound by the antibody or binding fragment is fully occupied, for example for a period of 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 days, such as 29 days.
  • a pharmacodynamic (for example full pharmacodynamic] effect is provided for a period of atleast 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 days, such as 29 days.
  • the onset of action is within 12 hours or less, such as 11, 10, 9, 8, 7, 6, 5, 4, 3 or 2 hours, more specifically 1 hour, in particular 1 hour after IV administration, intramuscular or subcutaneous administration.
  • the present inventors have demonstrated that the inhibitory action of the anti-IL13R antibody or binding fragment thereof is rapid, with complete inhibition achievable within 1 hour following administration (such as intravenous administration] of the antibody or binding fragment thereof.
  • administration such as intravenous administration
  • the antibody is administered subcutaneously with the loading dose regime of the present disclosure there is a rapid onset of action. This may be manifest as a quick onset of reduced symptoms, for example using a score disclosure herein.
  • the dosing regimen of the present disclosure may inhibit other allergic mediators, such as TARC (thymus and activated regulated chemokine].
  • TARC thymus and activated regulated chemokine
  • the pharmacodynamic effect is linked to the pharmacokinetic effect.
  • the dosing regimen of the present disclosure may minimise side effects, for example reduced or eliminate incidences of conjunctivitis and/or have reduced reaction at the injection site.
  • the present inventors have established that the presently disclosed dosage levels can be safely tolerated with no evidence of adverse side effects.
  • the loading dose regime of the present invention does not change the pharmacokinetics of the antibody.
  • the loading dose regime of the present invention does change the pharmacokinetics of the antibody, for example it minimised clearance, in particular by occupy the receptors.
  • the present inventors have established that the duration of IL-13R inhibition is closely associated with the dosage level. Specifically, by increasing the dosage, the duration of IL-13R inhibition can be increased, and by extension the frequency of dosing can be reduced. Accordingly, the claimed method can be specifically tailored according to treatment requirements.
  • the lowest concentration for a pharmacodynamic effect is in the range 0.5 to 70mg/L, such as 50 to 70mg/L, for example 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 60, 60.5, 61, 61.5, 62, 63, 64, 65, 66, 67, 68, 69 or 70mg/L, for example drug serum levels.
  • serum levels may be achieved by the dosing regimen of the present disclosure.
  • the lowest concentration for a pharmacodynamic effect (such as a full pharmacodynamic effect] is in the range 0.5 to 20mg/L, such as 0.5, 1 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20mg/L. In one embodiment the lowest concentration for a pharmacodynamic effect (such as a full pharmacodynamic effect] is in the range 1 to lOmg/L. In one embodiment the lowest concentration for a pharmacodynamic effect (such as a full pharmacodynamic effect) is in the range 0.5 to 2.5mg/L.
  • the drug serum levels between doses is in the range 0.5 to 20mg/L, such as 0.5, 1 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20mg/L.
  • the drug serum levels between doses is in the range 1 to lOmg/L. In one embodiment the drug serum levels between doses (trough levels) is in the range 0.5 to 2.5mg/L.
  • the dose, dose frequency and route of administration is selected so as to maintain a drug serum level above from about 0.5 to 20mg/L (such as 1 to lOmg/L) between doses.
  • the dose, dose frequency and route of administration is selected so as to maintain a drug plasma level above from about 0.5 to 20mg/L (such as 1 to lOmg/L) between doses.
  • the dose or doses is/are administered intravenously, for example by infusion.
  • the anti-IL-13R antibody or binding fragment is administered by infusion over a period of about 60 mins, such as 55, 56, 57, 58, 59, 60, 61, 62, 63, 64 or 65 mins.
  • the dose or doses is/are administered subcutaneously.
  • the dose or doses is/are administered intramuscularly.
  • the IL-13R antibody or binding fragment is administered via a syringe driver.
  • the anti-IL-13R antibody or binding fragment is in the form of a pharmaceutical formulation, such as a parenteral formulation in particular as subcutaneous formulation.
  • the antibody, binding fragment or formulation is provided as a unit dose, for example for subcutaneous administration.
  • the antibody, binding fragment or formulation is provided in an autoinjection device, for example as a unit dose, in particular for subcutaneous injection.
  • the anti-IL-13R antibody or binding fragment is eblasakimab as disclosed herein.
  • the antibody or binding fragment specific for IL-13R comprises a VH CDR1 comprising an amino acid sequence as set forth in SEQ ID NO: 1, a VH CDR2 comprising an amino acid sequence as set forth in SEQ ID NO: 2, and a VH CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 10.
  • VL CDR1 comprising an amino acid sequence as set forth in SEQ ID NO: 31
  • VL CDR2 comprising an amino acid sequence as set forth in SEQ ID NO: 32
  • VL CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 45.
  • the antibody or binding fragment specific for IL-13R comprises a VH CDR1 comprising an amino acid sequence as set forth in SEQ ID NO: 1, a VH CDR2 comprising an amino acid sequence as set forth in SEQ ID NO: 2, and a VH CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 10 and a VL CDR1 comprising an amino acid sequence as set forth in SEQ ID NO: 31, a VL CDR2 comprising an amino acid sequence as set forth in SEQ ID NO: 32, and a VL CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 45.
  • the antibody or antigen binding fragment thereof comprises a VH sequence of SEQ ID NO: 51 and a VL sequence of SEQ ID NO: 53.
  • the disclosure employs a sequence or combination of sequences disclosed herein.
  • Loading dose as employed herein refers to a dose which is higher and/or given more frequently at the beginning of a treatment cycle.
  • the purposes of the loading dose is to quickly "saturate” the system in vivo to provide a drug level that is therapeutic and that can be maintained by lower and/or less frequent "therapeutic” doses. In some embodiments this may be achieved locally quicker by co-locating administrations in the same part of the body.
  • therapeutic doses The subsequent doses given after the loading doses are referred to herein as therapeutic doses.
  • Therapeutic dose as employed herein refers to a dose which maintains the antibody or binding fragment thereof, at a therapeutic level i.e. it is not a loading dose, unless indicated otherwise.
  • a loading dose it not considered a therapeutic dose in the context of the present specification, even though the loading dose may have therapeutic activity.
  • Treatment cycle refers to complete cycle comprising loading doses and therapeutic doses for a defined period, for example 3 months or more, such as 4, 5 or 6 months.
  • the cycle may be repeated after a break in treatment, starting again with a loading dose.
  • the treatment cycle is followed by a maintenance dose with the purpose of keeping the disease in remission.
  • the therapeutic dose is continuous.
  • the first dose is nominally timepoint 0, i.e. in week 0.
  • Weekly dosing as employed herein is a dose administered in the week following the previous administration, generally about 7 days, for example +up to 2 days, -up to 3 days thereafter, such as 5, 6, 7 or 8 days after pervious administration, particularly 7 days after previous administration.
  • Two weekly dosing as employed herein is a dose administered in the two weeks following the previous administration (usually more than 1 week), generally about 14 days, for example + up to 2 days, - up to 3 days thereafter, such as 10, 11, 12, 13, 14, 15 or 16 days after the previous administration, particularly 13, 14 or 15 days after previous dose.
  • Three weekly dosing as employed herein is a dose administered in the three weeks following the previous administration (usually more than 2 weeks), generally about 21 days, for example + up to 3 days or -4 days thereafter, such as 18, 19, 20, 21, 22 or 23 after previous dose.
  • Four weekly dosing as employed herein is a dose administered in the four weeks following the previous administration (usually more than 3 weeks), generally about 28 to 31 days after the previous administration, for example + up to 4 days or - up to 4 days, such as 27, 28, 29, 30 or 31 days, in particular 28, 29 or 30 days after the previous administration.
  • a month or 1 month as used herein refers to one calendar month, which includes all possible months in a year, including a leap year February which has 29 days.
  • “once a month” may refer to once every 28 days, once every 29 days, once every 30 days or once every 31 days.
  • Unit dose as used herein generally refers to a product (such as a vial or a prefilled syringe, including an auto -injector] comprising the amount of anti-IL13R antibody or binding fragment thereof of the present disclosure that is administered in a single dose including any overage.
  • a product such as a vial or a prefilled syringe, including an auto -injector
  • a unit dose of the presently claimed anti-IL13R antibody or antigen binding fragment thereof may refer to the marketed form of the product, such as a formulation of the anti-IL13R antibody or binding fragment thereof, wherein the product is apportioned into the amount of anti-IL13R antibody that is required for a single dose.
  • the manufacturer is able to determine and control the exact amount of anti-13R antibody or binding fragment thereof to be included in each unit dose.
  • the product may be in various forms, familiar to the skilled addressee, such as vials, ampoules, infusion bags or a device (including an auto-injection device].
  • the exact amount as employed herein refers to the amount to be administer as a dose to the patient and any overage.
  • the disclosure provides a group of unit doses (including devices], for example 1 to 4 loading doses and 1 to 10 therapeutic doses, or 3 to 6 months of therapeutic doses.
  • the unit dose or unit doses are for use according to a method of the present disclosure.
  • a unit dose for use according to a method of the present disclosure as defined herein.
  • the formulation is a parenteral formulation.
  • Parenteral formulation as employed herein refers to a formulation designed not to be delivered through the GI tract Typical parenteral delivery routes include injection (including subcutaneous administration, bolus injection], implantation or infusion. In one embodiment the formulation is provided in a form for bolus delivery.
  • the subcutaneous dose of the anti-IL13R antibody or binding fragment thereof is in the range 300mg to 600 mg.
  • the parenteral formulation is administered subcutaneously, for example 300, 305, 310, 315, 320, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, or 600 mg of the anti-ILl 3 R antibody or binding fragment thereof, in particular once a month.
  • the parenteral formulation is a depot formulation, for example administered with a dose of 300, 305, 310, 315, 320, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, or 600 of the anti-IL13R antibody or binding fragment thereof, in particular once a month.
  • Injection refers to the administration of a liquid formulation into the body via a syringe or syringe driver.
  • Injection includes intravenous, subcutaneous, or intramuscular administration.
  • the injection is generally over a short period of time, such as 5 minutes or less.
  • injection can be administered slowly or continuously, for example using a syringe driver.
  • Injections generally involve administration of smaller volumes than infusions.
  • the injection is administered as a slow injection, for example over a period of 1.5 to 30 minutes.
  • Slow injection as employed herein is manual injection with syringe or syringe driver.
  • Injections are usually smaller volumes than infusions, for example 30mLs or less will usually be considered an injection.
  • one dose of the formulation less than lOOmls, for example 30mls, such as administered by a syringe driver.
  • Infusion as employed herein means the administration of fluids by drip, infusion pump, or equivalent device.
  • the infusion is administered over a period in the range of 1 to 120 minutes (for example 1 to 5 minutes), such as about 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 65, 80, 85, 90, 95, 100, 105, 110, 115 or 120 minutes.
  • the infusion is administered over a period of about 60 mins, such as 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69 or 70 mins, in particular over 60 mins.
  • Infusion usually involves administration of larger volumes than injections, for example the volume will generally be more than 30mL.
  • Bolus injection refers to the administration of a large amount of formulation in a single "shot”. This may be administered intravenously, intramuscularly or subcutaneously. It may be formulated for slow release , for example as a depot injection.
  • Depot formulation as employed herein refers to formulations which has an increased residence time in vivo (also referred to as injectable modified release product), which provides slow release of the active agent (the antibody or binding fragment). Generally, the depot formulation will be for subcutaneous or intramuscular administration.
  • depot formulations include where the antibody or binding fragment is PEGylated or modified to comprise a further binding domain which binds serum albumin. Formulations such as these may also be administered intravenously, as the skilled person is aware.
  • depot formulations include providing the antibody or binding fragment in an oil, such as sesame seed oil.
  • Protamine may be employed in depot formulations.
  • Polymer carriers may be employed in depot formulations, for example PLA, PLGA, PLGA-glucose, PLGA formulated with N-methyl-2-pyrollidone, PLGA polyesters (such as Eligard®, Atridox®, H.P. Acthar Gel), gelatin, amino acid polymers, DL-lactic and glycolic acid copolymer, AtrigelTM, and polylactide/glycolide formulations.
  • Liposomes may be employed in depot formulations, including lipid nanoparticles coated with PEG.
  • Baseline refers to the status of the patient before administration of a dose of the IL13Rla antibody (even before administration of a loading dose). This baseline can be empirical observation, such as a score described herein and/or measurement of a biological marker.
  • Human IL-13Ral has the Uniprotnumber P3597.
  • IL-13Ra2 previously called IL-13R and IL- 13Ra, is another receptor which is able to bind to IL-13.
  • this protein binds IL-13 with high affinity, but it does not bind IL-4.
  • Human IL-13Ra2 has the Uniprot number Q14627.
  • antibody molecules of the present disclosure comprise an Fc region, for example a complete antibody molecule having full length heavy and light chains. This includes a multi-specific antibody comprising an Fc region or full-length antibody. Multi-specific antibody formats often include antibody fragments, such as scFvs and the like.
  • the antibody molecule is a "simple” full length antibody comprising a heavy chain and a light chain.
  • the antibody molecule will consist of an antibody.
  • antibody molecule and antibody are employed interchangeably herein.
  • Binding fragments include but are not limited to Fab, modified Fab, Fab’, F(ab’)2, Fv, single domain antibodies (such as VH, VL, VHH, IgNAR V domains), scFv, bi, tri or tetra-valent antibodies, Bis-scFv, diabodies, triabodies, tetrabodies and epitope-binding fragments of any of the above (see for example Holliger and Hudson, 2005, Nature Biotech. 23(9):1126-1136; Adair and Lawson, 2005, Drug Design Reviews - Online 2(3), 209-217). As employed herein an antibody binding fragment does not contain an Fc.
  • antibody fragments for use in the present invention include the Fab and Fab’ fragments described in W02005/003169, W02005/003170 and W02005/003171.
  • Other antibody fragments include Fab- Fv and Fab-dsFv fragments described in W02010/035012 and antibody fragments comprising those fragments.
  • Multi-valent antibodies may comprise multiple specificities or may be monospecific (see for example WO 92/22853 and W005/113605).
  • the antibodies and fragments thereof, for use in the present disclosure may be from any species including for example mouse, rat, shark, rabbit, pig, hamster, camel, llama, goat or human.
  • the antibody molecule or antigen binding fragment thereof is chimeric.
  • Chimeric antibodies have a non-human variable regions and human constant regions. In one embodiment the antibody is fully human.
  • An antibody or binding fragment for use in the present invention can be derived from any class (e.g. IgG, IgE, IgM, IgD or IgA) or subclass of immunoglobulin molecule.
  • the antibody employed in the present disclosure is IgG4 or IgG4 with a hinge stabilising S241P (Kabat numbering) mutation.
  • CDRH1 is an amino acid sequence GYSFTSYWIG (SEQ ID NO: 1).
  • CDRH2 is an amino acid sequence VIYPGDSYTR (SEQ ID NO: 2)
  • CDRH3 has the formula:
  • Xi denotes Phe, Met, Gin, Leu or Vai
  • X 6 denotes Ser or Ala
  • X 7 denotes Phe, Leu, Ala or Met
  • X 9 denotes Tyr, Gin, Lys, Arg, Trp, His, Ala, Thr,
  • the IL13Rlal antibody molecule or antigen binding fragment employed in the formulation of the present disclosure comprises a CDRH3 independently selected from a sequence comprising SEQ ID NO: 4 to 30:
  • the anti- IL13Rla antibody or binding fragment employed in the present disclosure comprises a VH CDR1 comprising an amino acid sequence as set forth in SEQ ID NO: 1, a VH CDR2 comprising an amino acid sequence as set forth in SEQ ID NO: 2, and a VH CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: or 3.
  • the anti-IL13R antibody or binding fragment employed in the present disclosure comprises a CDRH1 comprising an amino acid sequence as set forth in SEQ ID NO: 1, a CDRH2 comprising an amino acid sequence as set forth in SEQ ID NO: 2, and a CDRH3 comprising an amino acid sequence as set forth in SEQ ID NO: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30.
  • the IL- 13 Rai antibody employed in the formulation of the present disclosure comprises a CDRL3 independently selected from a sequence comprising SEQ ID NO: 34 to 47:
  • the anti-IL13R antibody or binding fragment employed in the present disclosure comprises a CDRH1 comprising an amino acid sequence as set forth in SEQ ID NO: 1, a CDRH2 comprising an amino acid sequence as set forth in SEQ ID NO: 2, and a CDRH3 comprising an amino acid sequence as set forth in SEQ ID NO: 10.
  • the IL- 13 Rai antibody employed in the formulation of the present disclosure comprises a CDRL3 independently selected from a sequence comprising SEQ ID NO: 34 to 47.
  • CDRL3 comprising an amino acid sequence as setforth in SEQ ID NO: 33.
  • the VH region is independently selected from a sequence from the group comprising: SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51 and a sequence at least 95% identical to any one of the same.
  • the VL is independently selected from a sequence from the group comprising: SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54and a sequence at least 95% identical to any one of the same (* K deleted in a post translational modification for example from the C-terminus).
  • the VH sequence is SEQ ID NO: 48 (or a sequence at least 95% identical thereto) and the VL sequence is SEQ ID NO: 52, SEQ ID NO: 53 or SEQ ID NO: 54 (or a sequence atleast95% identical to any one ofthe same).
  • the VH sequence is SEQ ID NO: 49 (or a sequence at least 95% identical thereto) and the VL sequence is SEQ ID NO: 52, SEQ ID NO: 53 or SEQ ID NO: 54 (or a sequence at least 95% identical to any one ofthe same).
  • the VH sequence is SEQ ID NO: 50 (or a sequence at least 95% identical thereto) and the VL sequence is SEQ ID NO: 52, SEQ ID NO: 53 or SEQ ID NO: 54 (or a sequence at least 95% identical to any one of the same).
  • the VH sequence is SEQ ID NO: 51 (or a sequence at least 95% identical thereto) and the VL sequence is SEQ ID NO: 52, SEQ ID NO: 53 or SEQ ID NO: 54 (or a sequence at least 95% identical to any one of the same).
  • the VL sequence is SEQ ID NO: 52 (or a sequence at least 95% identical thereto) and the VH sequence is SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50 or SEQ ID NO: 51. (or a sequence at least 95% identical to any one of the same).
  • the VL sequence is SEQ ID NO: 53 (or a sequence at least 95% identical thereto) and the VH sequence is SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50 or SEQ ID NO: 51 (or a sequence at least 95% identical to any one of the same).
  • the VL sequence is SEQ ID NO: 54 (or a sequence at least 95% identical thereto) and the VH sequence is SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50 or SEQ ID NO: 51 (or a sequence at least 95% identical to any one of the same).
  • the VH sequence is SEQ ID NO: 51 (or a sequence at least 95% identical thereto) and the VL sequence is SEQ ID NO: 53 (or a sequence at least 95% identical thereto).
  • Variable region as employed herein refers to the region in an antibody chain comprising the CDRs and a suitable framework.
  • the heavy chain comprises a sequence independently selected from the group comprising: SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, and a sequence at least 95% identical to any one of the same (K can deleted in a post translational modification for example from the C-terminus).
  • the light chain is independently selected from a group comprising: SEQ ID NO: 61: SEQ ID NO: 62; SEQ ID NO: 63 and a sequence at least 95% identical to any one of the same.
  • the heavy chain is independently selected from SEQ ID NO: 55, 56, 57, 58, 59 and 60 (or a sequence atleast95% identical to anyone of the same) and the light chain is independently selected from SEQ ID NO: 61 62 and 63 (or a sequence at least 95% identical to any one of the same).
  • the heavy chain is SEQ ID NO: 55 (or a sequence at least 95% identical thereto) and the light chain is independently selected from SEQ ID NO: 61 or 62 and 63 (or a sequence at least 95% identical to anyone of the same).
  • the heavy chain is SEQ ID NO: 56 (or a sequence at least 95% identical thereto) and the light chain is independently selected from SEQ ID NO: 61 or 62 and 63 (or a sequence at least 95% identical to any one of the same).
  • the heavy chain is SEQ ID NO: 57 (or a sequence at least 95% identical thereto) and the light chain is independently selected from SEQ ID NO: 62 or 63 and 63(or a sequence atleast95% identical to any one of the same).
  • the heavy chain is SEQ ID NO: 58 (or a sequence at least 95% identical thereto) and the light chain is independently selected from SEQ ID NO: 61 62 and 63 (or a sequence at least 95% identical to any one of the same).
  • the heavy chain is SEQ ID NO: 59 (or a sequence atleast95% identical thereto) and the lightchain is independently selected from SEQ ID NO: 61 62 and 63 (or a sequence at least 95% identical to any one of the same).
  • the heavy chain is SEQ ID NO: 60 (or a sequence at least 95% identical thereto) and the light chain is independently selected from SEQ ID NO: 61 61 and 63 (or a sequence at least 95% identical to any one of the same).
  • the heavy chain is SEQ ID NO: 58 or 60 (or a sequence at least 95% identical to any one of the same) and a light chain with the sequence shown in SEQ ID NO: 61 (or a sequence at least 95% identical thereto).
  • the heavy chain is SEQ ID NO: 58 (or a sequence at least 95% identical to any one of the same) and a light chain with the sequence shown in SEQ ID NO: 61 (or a sequence at least 95% identical thereto).
  • the heavy chain is SEQ ID NO: 60 (or a sequence at least 95% identical to any one of the same) and a light chain with the sequence shown in SEQ ID NO: 61 (or a sequence at least 95% identical thereto).
  • the anti-IL13R antibody is eblasakimab.
  • Derived from as employed herein refers to the fact that the sequence employed or a sequence highly similar to the sequence employed was obtained from the original genetic material, such as the light or heavy chain of an antibody.
  • At least 95% identical as employed herein is intended to refer to an amino acid sequence which over its full length is 95% identical or more to a reference sequence, such as 96, 97, 98 or 99% identical.
  • Software programmes can be employed to calculate percentage identity.
  • any discussion of a protein, antibody or amino acid sequence herein will be understood to include any variants of the protein, antibody or amino acid sequence produced during manufacturing and/or storage.
  • an antibody can be deamidated (e.g., at an asparagine or a glutamine residue) and/or have altered glycosylation and/or have a glutamine residue converted to pyroglutamate and/or have a N-terminal or C-terminal residue removed or "clipped” (C-terminal lysine residues of encoded antibodies are often removed during the manufacturing process) and/ or have part or all of a signal sequence incompletely processed and, as a consequence, remain at the terminus of the antibody.
  • an antibody comprising a particular amino acid sequence or binding fragment thereof maybe a heterogeneous mixture of the stated or encoded sequence and/or variants of that stated or encoded sequence or binding fragment thereof.
  • the present disclosure extends to a sequence explicitly disclosed herein where the C-terminal lysine has been cleaved.
  • an antibody or binding fragment thereof, employed in a formulation of the present disclosure is humanised.
  • Humanised which include CDR-grafted antibodies
  • CDR-grafted antibodies refers to molecules having one or more complementarity determining regions (CDRs) from a non-human species and a framework region from a human immunoglobulin molecule (see, for example US5,585,089; WO91/09967). It will be appreciated that it may only be necessary to transfer the specificity determining residues of the CDRs rather than the entire CDR (see for example, Kashmiri et al., 2005, Methods, 36, 25-34). Humanised antibodies may optionally further comprise one or more framework residues derived from the non-human species from which the CDRs were derived. For a review, see Vaughan et al, Nature Biotechnology, 16, 535-539, 1998.
  • any appropriate acceptor variable region framework sequence may be used having regard to the class/type of the donor antibody from which the CDRs are derived, including mouse, primate and human framework regions.
  • human frameworks which can be used in the present invention are KOL, NEWM, REI, EU, TUR, TEI, LAY and POM (Kabat et al.,).
  • KOL and NEWM can be used for the heavy chain
  • REI can be used for the light chain and EU
  • LAY and POM can be used for both the heavy chain and the light chain.
  • human germline sequences may be used; these are available at: http://vbase.mrc-cpe.cam.ac.uk/
  • the acceptor heavy and light chains do not necessarily need to be derived from the same antibody and may, if desired, comprise composite chains having framework regions derived from different chains.
  • the framework regions need not have exactly the same sequence as those of the acceptor antibody. For instance, unusual residues may be changed to more frequently occurring residues for that acceptor chain class or type. Alternatively, selected residues in the acceptor framework regions may be changed so that they correspond to the residue found at the same position in the donor antibody (see Reichmann et al., 1998, Nature, 332, 323-324). Such changes should be kept to the minimum necessary to recover the affinity of the donor antibody.
  • a protocol for selecting residues in the acceptor framework regions which may need to be changed is set forth in WO91/09967.
  • the anti-IL13R antibodies of the present disclosure are fully human, in particular one or more of the variable domains are fully human.
  • Fully human molecules are those in which the variable regions and the constant regions [where present) of both the heavy and the light chains are all of human origin, or substantially identical to sequences of human origin, not necessarily from the same antibody.
  • Examples of fully human antibodies may include antibodies produced, for example by the phage display methods described above and antibodies produced by mice in which the murine immunoglobulin variable and optionally the constant region genes have been replaced by their human counterparts e.g. as described in general terms in EP0546073, US5,545,806, US5,569,825, US5,625,126, US5,633,425, US5,661,016, US5,770,429, EP0438474 and EP0463151.
  • Constant region as employed herein is intended to refer to the constant region portion located between two variable domains, for example non-cognate variable domains, in the heavy chain.
  • the presently disclosed anti-ILl 3R antibody may comprise one or more constant regions, such as a naturally occurring constant domain or a derivate of a naturally occurring domain.
  • Fc as employed herein is the part of the constant region found after the hinge, for example -CH2CH3 in IgG.
  • a derivative of a naturally occurring domain as employed herein is intended to refer to where one, two, three, four or five amino acids in a naturally occurring sequence have been replaced or deleted, for example to optimize the properties of the domain such as by eliminating undesirable properties but wherein the characterizing feature(s) of the domain is/are retained.
  • 241P is a common mutation in the constant region.
  • an antibody for use in the present disclosure may be conjugated to one or more effector molecule [s).
  • the effector molecule may comprise a single effector molecule or two or more such molecules so linked as to form a single moiety that can be attached to the antibodies used in the present invention.
  • this may be prepared by standard chemical or recombinant DNA procedures in which the antibody fragment is linked either directly or via a coupling agent to the effector molecule.
  • Techniques for conjugating such effector molecules to antibodies are well known in the art (see, Hellstrom et al., Controlled Drug Delivery, 2nd Ed., Robinson etal., eds., 1987, pp.
  • effector molecule includes, for example, biologically active proteins, for example enzymes, other antibody or antibody fragments, synthetic or naturally occurring polymers, nucleic acids and fragments thereof e.g. DNA, RNA and fragments thereof, radionuclides, particularly radioiodide, radioisotopes, chelated metals, nanoparticles and reporter groups such as fluorescent compounds or compounds which may be detected by NMR or ESR spectroscopy.
  • biologically active proteins for example enzymes, other antibody or antibody fragments, synthetic or naturally occurring polymers, nucleic acids and fragments thereof e.g. DNA, RNA and fragments thereof, radionuclides, particularly radioiodide, radioisotopes, chelated metals, nanoparticles and reporter groups such as fluorescent compounds or compounds which may be detected by NMR or ESR spectroscopy.
  • effector molecules may include detectable substances useful, for example in diagnosis.
  • detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, radioactive nuclides, positron emitting metals (for use in positron emission tomography), and nonradioactive paramagnetic metal ions. See generally US4,741,900 for metal ions which can be conjugated to antibodies for use as diagnostics.
  • Suitable enzymes include horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase; suitable prosthetic groups include streptavidin, avidin and biotin; suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride and phycoerythrin; suitable luminescent materials include luminol; suitable bioluminescent materials include luciferase, luciferin, and aequorin; and suitable radioactive nuclides include 1251, 1311, lllln and 99Tc.
  • the effector molecule may increase the half-life of the antibody in vivo, and/or reduce immunogenicity of the antibody and/or enhance the delivery of an antibody across an epithelial barrier to the immune system.
  • suitable effector molecules of this type include polymers, albumin, albumin binding proteins or albumin binding compounds such as those described in WO05/117984.
  • the effector molecule is a polymer it may, in general, be a synthetic or a naturally occurring polymer, for example an optionally substituted straight or branched chain polyalkylene, polyalkenylene or polyoxyalkylene polymer or a branched or unbranched polysaccharide, e.g. a homo- or hetero- polysaccharide.
  • synthetic polymers include optionally substituted straight or branched chain poly(ethyleneglycol), poly(propyleneglycol) poly(vinylalcohol) or derivatives thereof, especially optionally substituted poly(ethyleneglycol) such as methoxypoly(ethyleneglycol) or derivatives thereof.
  • Specific naturally occurring polymers include lactose, amylose, dextran, glycogen or derivatives thereof.
  • Derivatives as used herein is intended to include reactive derivatives, for example thiolselective reactive groups such as maleimides and the like.
  • the reactive group may be linked directly or through a linker segment to the polymer. It will be appreciated that the residue of such a group will in some instances form part of the product as the linking group between the antibody fragment and the polymer.
  • Suitable polymers include a polyalkylene polymer, such as a poly(ethyleneglycol) or, especially, a methoxypoly(ethyleneglycol) or a derivative thereof, and especially with a molecular weight in the range from about 15000Da to about 40000Da.
  • antibodies for use in the present invention are attached to poly(ethyleneglycol) (PEG) moieties.
  • PEG poly(ethyleneglycol)
  • the antibody is an antibody fragment and the PEG molecules may be attached through any available amino acid side-chain or terminal amino acid functional group located in the antibody fragment, for example any free amino, imino, thiol, hydroxyl or carboxyl group.
  • the antibody molecule of the present invention is a modified Fab fragment wherein the modification is the addition to the C-terminal end of its heavy chain one or more amino acids to allow the attachment of an effector molecule.
  • the additional amino acids form a modified hinge region containing one or more cysteine residues to which the effector molecule may be attached. Multiple sites can be used to attach two or more PEG molecules.
  • the antibody or binding fragment employed in the formulation of the present disclosure is monoclonal.
  • the antibody or binding fragment employed in the formulation of the present disclosure is human.
  • the antibody or binding fragment employed in the formulation of the present disclosure is chimeric or humanised.
  • the presently claimed method of treatment results in the improvement in the symptoms, for example ameloriation of atopic dermatitis across a range of different clinical scores and measures.
  • the disease is modified by a percentage reduction in Eczema Area and Severity Index (EASI) score in the range -20 to -100% from the baseline, such as EASI 50, EASI 75 or EASI 90.
  • EASI Eczema Area and Severity Index
  • Eczema Area and Severity Index (EASI) score as used herein is a tool used to measure the area (which indicates the extent of disease) and severity of atopic eczema.
  • the number after the term “EASI” indicates the % decrease in the score from baseline.
  • EASI 50 for example refers to 50% decrease in the score and EASI 90 refers to a 90% decrease in the score.
  • the disease is modified by a percentage improvement in Scoring Atopic Dermatitis (SCORAD) score in the range -20 to -100% from the baseline.
  • Scoring Atopic Dermatitis SCORAD
  • Scoring Atopic Dermatitis refers to a composite score that takes into account the body surface area of involvement in AD and the severity of 6 clinical signs on a 4-point. scale (erythema, edema/papulation, oozing/ crusting, excoriation, lichenification, and dryness), and it incorporates a patient-reported component assessing pruritus and sleep loss.
  • the disease is modified by a reduction in Body Surface Area (BSA) in the range -20 to -100% from the baseline.
  • BSA Body Surface Area
  • Body Surface Area as used herein is a simple measure of percent body surface area involved with atopic dermatitis which does not incorporate an assessment of disease severity.
  • the disease is modified by a reduction in validated Investigator Global Assessment Scale (vIGA) score in the range -1 to -4 from the baseline.
  • vIGA Investigator Global Assessment Scale
  • Validated Investigator Global Assessment Scale as used herein refers to the standardised and validated version of the Investigator Global Assessment Scale (IGA) which is used primarily by health agencies for drug registration in atopic dermatitis. A score of 0 to 4 corresponding to increasing disease severity is used.
  • the disease is modified by a reduction in Pruritus Numerical Rating Scale (P-NRS) in the range -2 to -10 from the baseline.
  • P-NRS Pruritus Numerical Rating Scale
  • Pruritus Numerical Rating Scale is patient assessed score of the intensity of his or her itch. A score of 0 refers to “no itch” whilst a top score of 10 refers to “worst imaginable itch”. Thus in one embodiment pruritus is improved.
  • the disease is modified by a reduction in Sleep Disturbance Numerical Rating Scale (SD-NRS) in the range -2 to -10 from the baseline.
  • SD-NRS Sleep Disturbance Numerical Rating Scale
  • the Sleep Disturbance Numerical Rating Scale (SD-NRS) is a single-item, selfreported 11-point scale ranging from zero to 10 for reporting the degree of sleep loss related to atopic dermatitis.
  • the disease is modified by a reduction in Dermatology Life Quality Index (DLQI) score in the range of -4 to - 30 from the baseline.
  • DLQI Dermatology Life Quality Index
  • DLQI refers to a simple, patient-administered, 10-question, validated, quality- of-life questionnaire that covers 6 domains, including symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment. Responses include “not at all” or “not relevant”; “a little”; “a lot”; and “very much” - with corresponding scores of 0, 1, 2 and 3 respectively. Totals range from 0 to 30 (less to more impairment) and a 5-point change from Baseline is considered clinically relevant.
  • the disease is modified by reduction in Patient-Oriented Eczema Measure (POEM) score in the range of -20 to -100% from the baseline.
  • POEM Patient-Oriented Eczema Measure
  • POEM Patient Oriented Eczema Measure
  • the disease is modified by a reduction in European Qualify of life-5 Dimensions, 5 Levels (EQ-5D-5L) score in the range of -20 to -100% from the baseline.
  • EQ-5D-5L European Qualify of life-5 Dimensions, 5 Levels
  • EQ-5D-5L European Qualify of life-5 Dimensions, 5 Levels as used herein refers to a preference-based HRQL measure with one question for each of the five dimensions that include mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.
  • the disease is modified by a reduction in Hospital Anxiety and Depression Scale (HADS) in the range of -20 to -100% from the baseline.
  • HADS Hospital Anxiety and Depression Scale
  • HADS Hospital Anxiety and Depression Scale as used herein refers to a self-assessment 14 item scale with 7 items each of anxiety and depression subscales. HADS focuses on non-physical symptoms so that it can be used to diagnose depression in people with significant physical ill-health.
  • the disease is modifiedby a reduction in Asthma Control Test (ACT) score in the range of -20 to -100% from the baseline.
  • ACT Asthma Control Test
  • Asthma Control Test refers to a patient-centred/completed questionnaire that recalls the patient's experience of 5 items: asthma symptoms (nocturnal and daytime), the use of rescue medications, the effect of asthma on daily functioning, and the patient's perception of asthma control over the previous 4 weeks.
  • Less than twice a month as employed herein refers to the average of doses over at least a two- month period, for example 3 doses in two months is on average 1.5 doses per month. However, in practice it will mean administration of one dose in one month and two doses in the next month.
  • the anti-IL13R antibody or binding fragment thereof or formulation thereof according to the present disclosure may be used for treatment or in the manufacture of a medicament.
  • the disclosed anti anti-IL13R antibody or binding fragment thereof or formulation thereof is suitable for use in treating atopic dermatitis.
  • the antibody, binding fragment or formulation of the present disclosure is used for the treatment of dermatitis (such as atopic dermatitis] or is used for the manufacture of a medicament for the treatment of the same.
  • the antibody, binding fragment or formulation of the present disclosure is employed as a monotherapy.
  • the formulation herein is administered in combination with another therapy, for example an anti-inflammatory agent, such as a non-steroidal anti-inflammatory and/or a steroid orally and/or topically as appropriate (eg prednisolone, betamethasone, dexamethasone, hydrocortisone, methylprednisolone, deflazacort, such as prednisolone).
  • an anti-inflammatory agent such as a non-steroidal anti-inflammatory and/or a steroid orally and/or topically as appropriate (eg prednisolone, betamethasone, dexamethasone, hydrocortisone, methylprednisolone, deflazacort, such as prednisolone).
  • Combination therapy refers to the fact that the pharmacological effects of the two or more therapies co-exist (overlap] in the body for a period time.
  • the formulation employed in method of the present disclosure is a high concentration formulation.
  • Antibodies such as eblasakimab need to be formulated at a high concentration to allow the desired dose in man to be administered in the smallest possible volume.
  • High concentration formulations pose unique challenges as phenomena like phase separation can be observed. Aggregation is also a common feature at high antibody concentration.
  • the formulation needs to contain very high levels of antibody molecules as "monomer”, for example 95% monomer or more.
  • the formulation needs to be stable when stored.
  • Eblasakimab seems to have a hydrophobic portion in the protein, which for example interacts with hydrophobic interaction columns in the absence of high salt concentrations. This hypothesised hydrophobic portion adds additional complexity when formulating the antibody and preventing aggregation.
  • the antibodies of the present disclosure are particularly difficult to formulate.
  • the present inventors have optimised the formulation of the present disclosure and established that the IL-13R antibodies, such as eblasakimab, are most suitable for formulation within a narrow set of parameters.
  • the formulations of the present disclosure are highly monomeric, for example at least 95% monomeric (such as 98 to 99.5% monomeric] even when formulated with high antibody concentration.
  • the formulation is suitably stable, for example in some embodiments no change in monomer or less than a 0.5% reduction in monomer was observed when stored at4°C or 25° for 90 days. Accelerated 'stress test’ studies at 40°C also show the formulations used in the present disclosure to be stable over a period of 60 days, for example using potency measurements.
  • the formulations of the present disclosure have a viscosity in the range of 4.5 to 5.5, such as 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4 or 5.5 cP (centipoise), such as 4.9 cP, for example at ambient temperature.
  • the viscosity of the formations of the present disclosure are relatively low even at high concentrations of antibody.
  • the osmolarity of the formulation is in the range 350 to 450 mOsmo/kg, such as 390 to 430 mOsmo/kg, in particular 410 +/-5m0smo/kg.
  • the formulation further comprises 10 to 145 mg/ml anti-IL13Rantibody, for example 10 to 125mg/ml, such as 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110 or 120 mg/ml, in particular 20 mg/ml or 100 mg/ml of anti-IL13R antibody.
  • 10 to 145 mg/ml anti-IL13Rantibody for example 10 to 125mg/ml, such as 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110 or 120 mg/ml, in particular 20 mg/ml or 100 mg/ml of anti-IL13R antibody.
  • certain formulations of the present disclosure have 5% or less protein aggregation, such 4, 3, 2, 1% or less, for example when stored for 90 days at temperature in the range 2 to 25°C.
  • the presently disclosed anti-IL13R antibody formulation is particularly suitable for stable long-term storage of the anti-IL13R antibody.
  • Long term as used herein refers to a period of at least 6 months, such as 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 months.
  • the disclosed formulation storage for at least 12 months, such as 12 months, 18 months and 24 months.
  • the formulation is stored at a temperature in the range 2 to 8°C, such as 2, 3, 4, 5, 6, 7 or 8 °C, such as 4 °C.
  • the formulation comprises: 150 to 210 mg/ml of an anti-IL-13R antibody or antigen binding fragment thereof, for example 150, 155, 160, 165, 170, 175, 180, 185, 190, 195 or 200 mg/ml, in particular 150 mg/ml, 175 mg/ml or 200 mg/ml; 170 to 250 mM of arginine (such as Arg-HCl or Arg-Glu), for example 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245 or 250 mM, in particular 150 mM, 175 mM or 250 mM; 20 to 50 mM histidine buffer, for example 20, 25, 30, 35, 40, 45 or 50 mM, such as 20 mM or 50 mM histidine buffer; 0.01-0.03% of a non-ionic surfactant, for example 0.01-0.03% w/w, such as
  • a parenteral formulation for example for infusion or injection.
  • liquid parenteral formulation as a concentrate for dilution with a liquid for injection, such as glucose, saline or water for injection.
  • liquid parenteral formulation is provided in a final concentration for administration without dilution, for example for injection or for infusion.
  • the priority documents may be used as basis for corrections.
  • Figure 1 shows the planned treatment arms
  • LD - AU treatment anus receive 600 mg loading doses according to the dosing schedule (except placebo, which receive placebo loading dose)
  • FIG. 2 shows the injection scheme for each dose level.
  • IP Investigational product
  • PBO placebo
  • mg milligram
  • mL milliliter.
  • each patient will get 3 injections at every scheduled treatment visit.
  • Each vial of eblaskaimab is provided as a sterile 100 mg/mL solution and has an extractable volume of 2 mL.
  • Placebo is a matching, sterile 0 mg/mL solution with extractable volume of 2 mL.
  • Figure 3 shows the randomisation scheme. * Patients randomized to arms 4 and 5 (Q4W) will receive placebo injections at weeks 6, 10 and 14 to match the injection schedule of arms 1, 2 and 3 (Q2W)
  • FIG 4 shows a table of the injection type by visit.
  • W week
  • Q2W every two weeks
  • Q4W every two weeks
  • Figure 5 shows study treatment arms with dosing schedule
  • Figure 6 shows the baseline demographics and disease characteristics of the patients. Demographics are from screened points, disease characteristics are from randomised points.
  • Figure 7 shows the median Eczema area and severity index (EASI) % change from baseline (CFBL) from week 0 to 20
  • Secondary endpoints include: Proportion of patients achieving vIGA response of 0 (dear) or 1 [almost clear) [5 point scale] at W eek 16; Proportion of patients with a 75% reduction from Baseline in EASI [EASI 75) at Week 16: Proportion of patients achieving EASI 50 and EASI 90 at Week 16; Proportion of patients with EASI ⁇ 7 at Week 16; Change in EASI score from Baseline over time; Absolute and percent change in peak P-NRS from Baseline to Week 16; Proportion of patients achieving a 4-point reduction in peak P-NRS at Week 16; Change in BSA affected with AD from Baseline to Week 16; Change in SCORAD from Baseline to Week 16; Change in DLQI from Baseline to Week 16; Change in POEM from Baseline to Week 16; Change in EQ-5D-5L from Baseline to Week 16; Change in HADS from Baseline
  • the study consists of a 16-week treatment period, 8-week follow-up period up to Week 24, followed by a telephone safety’ follow-up call at Week 28.
  • the primary efficacy endpoint will be assessed at Week 16.
  • a Screening period of not greater than 35 days and the reconfirmation of key eligibility criteria at Day 1 are pre-requisites for the randomization of patients.
  • RTSM Randomization Trial Supply Management
  • Study patients, principal investigators, study centre personnel, study sponsor personnel, and CRO personnel in regular contact with study centres will be blinded to treatment assignment during the study, and allocation will be concealed.
  • Drug kits will be coded, providing blinding to treatment assignment.
  • eblasakimab is provided as a sterile 100 mg/mL solution and has an extractable volume of 2 mL. The dedicated site personnel preparing and/or administering the treatment doses at each site will be unblinded.
  • Treatment Arm 1
  • Week 0 LD of 600 mg (Three 2 mL injections of drug product [100 mg/mL]) Week 2, 4, 6, 8, 10, 12, 14: Regular dose of 300 mg [One 2 mL injection of drug product [100 mg/mL], one 1 mL injection of drug product [100 mg/mL] and one 2 mL injection of placebo) Treatment Arm 3:
  • Week 0, 1 LD of 600 mg (Three 2 mL injections of drug product [100 mg/mL])
  • Week 2, 4, 6, 8, 10, 12, 14 Regular dose of 400 mg (Two 2 mL injections of drug product [100 mg/mL] and one 2 mL injection of placebo).
  • Week 4, 8, 12 Regular dose of 400 mg (Two 2 mL injections of drug product [100 mg/mL] and one 2 mL injection of placebo)
  • Patients will receive the LD for the arm to which they have been randomized. Patients will be closely monitored at the study site, according to the Investigator’s judgement, for 30 to 60 minutes, after every dose administration. After completing the loading doses, patients will receive treatment in accordance with the treatment arm to which they have been randomized. At the end of this treatment period, patients will return for follow-up visits as listed for a total of 12 weeks in the safety followup period.
  • Eblasakimab is currently being investigated as a potential solution to address this gap for patients with moderate-to-severe AD.
  • IL-13Ral a receptor with a narrower cellular distribution than the IL-4 receptor
  • the potential is being investigated for eblasakimab to offer both a lower dose and lower dosing frequency, which are advantageous features for SC injections, providing greater patient convenience.
  • This Phase 2b study will evaluate the efficacy and safety of eblasakimab in adult patients with moderate to severe AD. Patients will be randomly assigned to receive subcutaneously for 16 weeks either placebo or one of four active treatment arms with the following dose levels of eblasakimab: 400 mg Q2W, 300 mg Q2W, 600 mg Q4W or 400 mg Q4W.
  • All treatment arms will receive loading doses; 0 mg QW in the first two weeks for the placebo arm, 600 mg QW eblasakimab in the first two weeks for the 300 mg Q2W and 400 mg Q2W eblasakimab treatment arms, and 600 mg eblasakimab in the first three weeks for the 400 mg and 600 mg Q4W eblasakimab treatment arms.
  • Dose selection rationale is based on safety assessments from the completed SAD and ongoing MAD clinical trial with eblasakimab, PK:PD measurements from the SAD study, and interim analysis of the ongoing MAD study.
  • Eblasakimab is provided as a sterile 100 mg/mL solution for SC injection.
  • Eblasakimab is formulated in a buffer containing Histidine (20 mM], Arginine (100 mM], Sucrose (180 mM) and PolysorbatePolysorbate- 20 (0.02%).
  • the pH value of the IP is 6.5 (specification pH 6.5 ⁇ 0.3) and the protein solution is slightly hypertonic.
  • the first arm will be administered the placebo in a regimen matching active treatment arms to maintain the double-blind.
  • the placebo will consist solely of the excipients of eblasakimab, i.e., the same formulation without the active ingredient and will be identical in appearance to eblasakimab. Patients will be closely monitored at the study site, according to the Investigator’s judgement, for 30 to 60 minutes, after every dose administration.
  • SC injections of eblasakimab 100 mg/mL are administered into the thigh or abdomen, except for the 2 inches (5 cm) around the navel.
  • the upper arm can also be used.
  • Rotating the site with each injection will be compared to injection at the same site . Do not inject into skin that is bruised, tender, damaged or scarred.
  • Each patient will receive eblasakimab or placebo SC injection as described in Figure 3.
  • Study drug administration and site of injection will be recorded in the source documents and transcribed in the eCRF.
  • the maximum injection volume will be 2 m (200 mg), with multiple injections being given to achieve doses higher than 200 mg.
  • the maximum number of injections, per visit, will be 3 (600 mg).
  • the injection type by visit is provided in Figure 4.
  • Investigational drug dosing may be delayed by the Investigator, by agreement with sponsor and CRO, in the event of clinically significant laboratory abnormalities, such as:
  • study treatment will be permanently discontinued. If a causal relationship can be reasonably excluded, study treatment may be resumed when the abnormality has sufficiently normalized. The decision to resume study treatment will be made jointly by the Investigator and the Sponsor MM. ULN is defined by site reference ranges for the purpose of this study.
  • All patients should be encouraged to be compliant with treatment [i.e. not miss any doses) during the study. Patients are not permitted to miss any doses from Week 0 through Week 4 inclusive and from Week 12 through Weekl4 inclusive. In the event that a patient misses two doses from Week 6 through Week 10 inclusive, that patient will remain eligible for continued treatment in the study. If a patient misses more than 2 doses between Week 6 and Week 10, in consultation with the Sponsor MM, they will be discontinued from treatment, must complete Week 16/End of Treatment assessments and should be strongly encouraged to continue in the safety follow-up period and complete all visits and assessments. The extent of exposure to study drug, and the number of missed doses will be assessed. A dose is considered as the full set of three [3] injections as specified by the protocol. A patient will be considered compliant with the dosing regimen if the patient received >80% of the expected number of doses while enrolled in the study.
  • EASI evaluates 4 natural anatomical regions for severity and extent of key disease signs and focuses on the key acute and chronic signs of inflammation (erythema, induration/papulation, excoriation, and lichenification). The maximum total score is 72, with higher values indicating more severe disease.
  • a participant has vl GA response if they achieve a score of 0 (clear) or 1 (almost clear) and at least a 2 -grade reduction from Baseline.
  • the patient’s palm is measured from the wrist to the proximal interphalangeal (PIP) and thumb. Estimate the number of patient palms it takes to cover the affected AD area. Add up the number of palms to give a total estimate of the area covered in AD.
  • Trunk (axillae and groin) 30% (30 palms)
  • SCORAD is a clinical tool for assessing the severity (that is, extent, intensity) of AD.
  • the tool evaluates the extent and intensity of the AD lesions, along with participant symptoms.
  • the maximum total score is 103, with higher values indicating more severe disease.
  • NRS 11-point scale
  • e-PRO electronic diaries
  • SD-NRS is a single-item, self-reported 11-point scale ranging from zero to 10 for reporting the degree of sleep loss related to AD (Dias-Barbosa C et al 2020).
  • DLQI is a simple, patient-administered, 10-question, validated, quality-of-life questionnaire that covers 6 domains, including symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment Responses include “not at all” or “not relevant”, “a little”, “a lot”, and “very much” with corresponding scores of 0, 1, 2 and 3, respectively (Basra MKA 2008).
  • POEM is a 7-item questionnaire that assesses presence of disease symptoms (dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping) over the last week using a scoring system of 0 (no days) to 4 (every day). The total score ranges from 0 to 28 with higher scores indicating greater intensity of eczema.
  • EQ-5D-5L essentially consists of 2 pages: the EQ-5D descriptive system and the EQ VAS.
  • the EQ-5D- 5L descriptive system comprises the following five dimensions: mobility, self-care, usual activities, pain/discomfortand anxiety/depression. Each dimension has 5 levels: “no problems”, “slight problems”, “moderate problems”, “severe problems”, and “unable to”.
  • the patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. This decision results into a 1-digit number that expresses the level selected for that dimension.
  • the digits for the five dimensions can be combined into a 5 -digit number that describes the patient’s health state.
  • the EQ VAS records the patient’s self-rated health on a vertical VAS where the endpoints are labelled ‘Best imaginable health state’ and ‘Worst imaginable health state’.
  • the VAS can be used as a quantitative measure of health outcome that reflects the patient’s own judgement (www.euroqol.org).
  • HADS is commonly used by doctors to determine the levels of anxiety and depression that a patient is experiencing.
  • the HADS is a 14-item scale. Seven items relate to anxiety and seven relate to depression. Each item on the questionnaire is scored from 0-3 and this means that a person can score between 0 and 21 for anxiety and/or depression.
  • the ACT is a patient-centered/completed questionnaire that recalls the patient's experience of 5 items: asthma symptoms (nocturnal and daytime), the use of rescue medications, the effect of asthma on daily functioning, and the patient's perception of asthma control over the previous 4 weeks.
  • Figure 7 shows the median EASI % change from baseline (CFBL) for the patients from week 0 (commencement of study) to week 20.
  • the data is currently blinded. Nonetheless, this early data suggests a noticeable reduction in EASI score was observed in the treated patients over the course of the study.

Abstract

A method of treating an inflammatory disease, such as atopic dermatitis, comprising inhibiting IL-13R with an antibody or antigen-binding fragment thereof specific for the receptor and formulations thereof, characterised in that at least one loading dose is employed. Also provided is an anti-IL1313Rα1 antibody or antigen binding fragment thereof for use in the method disclosed.

Description

METHOD OF TREATING INFLAMMATORY DISEASE
The present disclosure relates to a dosing regimen for the treatment of inflammatory disease, such as atopic dermatitis, comprising inhibiting IL-13Rwith an antibody or antigen-binding fragment thereof specific for the receptor and formulations thereof.
BACKGROUND
IL-13 has been associated with various conditions including, but not limited to, various respiratory and allergy-mediated disorders, fibrosis, scleroderma, inflammatory bowel disease and certain cancers; see, e.g., Wynn, T.A., 2003 Annu. Rev. Immunol. 21:425-456; Terabe et al, 2000 Nat Immunol. 1 (6): 515-520; Fuss etal, 2004 J. Clin. Invest 113 (10): 1490-1497; Simms etal, 2002 Curr. Opin. Rheumatol. 14 (6) :717-722; and Hasegawa etal, 1997 J. Rheumatol. 24 (2): 328-332. Thus, IL- 13 is an attractive target for the treatment of such diseases.
One possible way to inhibit the activity of IL-13 is to interfere with the binding of IL-13 to its receptor IL-13R, for example by using an antibody specific to IL-13R, such as an antibody specific to IL-13Ral. An effective antibody antagonist specific to IL-13Ral may also interfere with the binding of IL-13 and prevent heterodimerization of IL-4Ra and IL-13Ral. Such an antibody will inhibit signalling of both IL- 13 and IL-4 through the type II receptor [formed by IL- 13Ral and IL-4Ra) while sparing IL-4 signalling through the type I receptor. Signalling through the type I receptor is essential in the induction phase of the immune response during which Th2 cells differentiate. T cells do not express IL-13Ral so the type II receptor plays no role in Th2 differentiation. Hence, an IL-13Ral antibody may not affect the overall Thl/Th2 balance. Signalling through the type II IL-4/IL-13 receptor is critical during the effector-A-stage of the immune response during established allergic inflammation.
One particularly promising anti-IL-13Ral antibody is described in W02008/060813 as antibody 10G5-6. 10G5-6 is an IgG4 with a hinge stabilising serine to proline mutation (S241P Kabat numbering) which is now known as eblasakimab (previously called ASLAN004). Eblasakimab has been shown to bind to human IL-13Ral with a high affinity. Eblasakimab was shown to effectively antagonise IL-13 function through inhibiting the binding of IL-13 to its receptor IL-13Ral and to inhibit IL-13 and IL-4 induced eotaxin release in NHDF cells, IL-13 and IL-4 induced STAT6 phosphorylation in NHDF cells and IL-13 stimulated release of TARC in blood or peripheral blood mononuclear cells.
There are no approved antibody therapeutics targeting the 13Ral and so the pharmacokinetics and pharmacodynamics of these IL-13Ral antibodies in humans has not been characterised. Thus, the most effective dosing schedules for administering this type of antibody has not been established. Therefore, an optimised dosage regimen for IL-13R antibodies, such as eblasakimab, is required in order to maximise therapeutic effect and/or minimise adverse effects.
To be effective, the antibody of the present disclosure needs to bind the epitope on the receptor IL-13Rod to prevent the ligand binding and block the requisite signalling. The receptor distribution, the off-rate and the on-rate of the antibody have a big impact on the pharmacokinetics and pharmacodynamics of the antibody, in particularly the occupancy of the receptor. These relationships can be very complex and specific to the particular antibody or pathway.
Thus, whether a loading dose is beneficial for antibodies and binding fragments thereof is dependent on their pharmacokinetic and pharmacodynamic profile. Pharmacokinetics are a function of the dose administered, the dosing interval, the peak plasma concentration that the antibody reaches after administration (Cmax), the time taken to reach Cmax, the lowest trough concentration that the antibody reaches before the next dose is administered (Cmin), the mean plasma concentration of the antibody over a specific interval of time (Cmean), the volume distribution of the antibody (i.e. the ratio of antibody in plasma vs the body), amount of antibody in the plasma, the absorption half-life, the absorption rate constant, the elimination half-life, the elimination rate constant, the area under the curve (i.e. the integral of the concentration time curve after a single dose or a steady state), the volume of plasma cleared of antibody per unit time, the bioavailability of the antibody and the fluctuation within one dosing interval at steady state.
The binding of ligands (in this case antibody) to receptors is governed by the law of mass action which relates the large-scale status to the rate of numerous molecular processes. The rates of formation and un-formation can be used to determine the equilibrium concentration of bound receptors. The equilibrium dissociation constant is defined by:
Figure imgf000003_0001
where Wigand, R»receptor, square brackete [] denote concentration. The fraction of bound receptors is
Figure imgf000003_0002
is the fraction <if receptor bound by the ligand.
This expression is one way to consider the effect of an antibody, in which the response is related to the fraction of bound receptors (see: Hill equation). The fraction of bound receptors is known as occupancy. The relationship between occupancy and pharmacological response is usually non-linear. This explains the so-called receptor reserve phenomenon i.e. the concentration producing 50% occupancy is typically higher than the concentration producing 50% of maximum response. More precisely, receptor reserve refers to a phenomenon whereby stimulation of only a fraction of the whole receptor population apparently elicits the maximal effect achievable in a particular tissue.
The simplest interpretation of receptor reserve is that it is a model that states that there are excess receptors on the cell surface than what is necessary for full effect
Having said this, the situation where the receptor has to be fully occupied to prevent binding of the native ligand, to reduce signalling, may in fact require almost all the free receptors to be bound by the antibody. The faster that this situation is achieved, i.e. the quicker the "full occupancy” of the receptor can be achieved, the faster the onset of therapeutic activity.
Where drug binds with high affinity to its pharmacological target (e.g., receptor) it can be to such an extent that this affects the pharmacokinetic characteristics of the drug, so called Target mediated drug disposition (TMDD). At higher doses and concentrations, the TMDD elimination pathway is often saturated due to the limited availability of the target receptors, thereby resulting in a limited or "irrelevant contribution” to overall clearance of the mAb, and manifests as decreases in clearance and volume of distribution with increasing dose as a result of saturable, high affinity target binding.
Additional influential factors include sink and clearance mechanisms body for antibodies administered as therapeutics.
The review article "Monoclonal antibodies: Pharmacokinetics as a basis for new dosage regimens; J-RAzanza eta/ Journal of Oncology Pharmacy Practice, indicates thatlgG antibodies don’t require loading doses because the first dose results in minimum concentrations that are above the threshold concentrations required to be effective.
Surprisingly, the present inventors have established that at least one loading dose, for example two or three loading doses are useful to adequately occupy the target receptor IL-13Ral. This allows a rapid onset of therapeutic effect, for example where there is a link between the pharmacodynamic effect and pharmacokinetic effect. Adequate occupancy of the receptor may in turn result in complete or significant inhibition of STAT6 signalling. What is more this occupancy of the receptor can then be maintained by lower and/or less frequent dosing.
Use of multiple loading doses is not a common practice in the field. However, in the context of the present disclosure it seems to be particularly beneficial.
SUMMARY OF THE DISCLOSURE
The present disclosure is summarised by the following paragraphs:
1. A method of treating inflammatory disease in a human patient, comprising administering multiple doses of an anti-IL-13Ral antibody molecule or antigen binding fragment thereof comprising a VH sequence of SEQ ID NO: 51 or a sequence at least 95% identical thereto, such as 95, 96, 97, 98 or 99% identical thereto, and VL sequence of SEQ ID NO: 53 or a sequence at least 95% identical thereto, such as 95, 96, 97, 98 or 99% identical thereto; characterised in that at least one loading dose in the range 400-900mg (for example 400, 500, 600, 700, 800 or 900mg, such as 400 to 600mg, in particular 600mg) is employed prior to commencing the "therapeutic” dosing administered once every two, three or four weeks thereafter.
2. A method of treating inflammatory disease in a human patient, comprising administering multiple doses of an anti-IL-13Ral antibody molecule or antigen binding fragment thereof comprising:
CDRH1 comprising an amino acid sequence GYSFTSYWIG (SEQ ID NO: 1]
CDRH2 comprising a sequence VIYPGDSYTR (SEQ ID NO: 2)
CDRH3 comprising the formula:
SEQ ID NO: 3 Xi Pro Asn Trp Gly X6 X7 Asp X9
Xi denotes Phe, Met, Gin, Leu or Vai
X6 denotes Ser or Ala
X7 denotes Phe, Leu, Ala or Met
X9 denotes Tyr, Gin, Lys, Arg, Trp, His, Ala, Thr, Ser, Asn or Gly
CDRL1 is a sequence comprising RASQSISSSYLA (SEQ ID NO: 31).
CDRL2 is a sequence comprising GASSRAT (SEQ ID NO: 32).
CDRL3 comprising the formula:
SEQ ID NO: 33 Gin X2X3X4X5 X? denotes Gin, Arg, Met, Ser, Thr or Vai.
X3 denotes Tyr or Vai
X4 denotes Glu, Ala, Gly or Ser
X5 denotes Thr, Ala or Ser characterised in that at least one loading dose in the range 400-900mg (for example 400, 500, 600, 700, 800 or 900mg, such as 400 to 600mg in particular 600mg] is employed prior to commencing the "therapeutic” dosing administered once every two, three or four weeks.
3. A method according to paragraph 1 or 2, wherein affinity is 500pM or a lower numerical value (for example 50 to 500pM], for example 250pM or a lower numerical number (for example 50 to 300pM], such as 125pM or a lower number (100 to 150pM).
4. A method according to any one of paragraphs 1 to 3, wherein a loading dose is a dose which is higher and/or administered more frequently than the therapeutic dose.
5. A method according to any one of paragraphs 1 to 4, wherein only one loading dose is employed.
6. A method according to any one of paragraphs 1 to 4, wherein multiple loading doses are employed.
7. A method according to any one of paragraphs 1 to 6, wherein 1 to 4 loading doses are employed, for example 1, 2, 3 or 4.
8. A method according to paragraph 7, wherein 1 loading dose is employed.
9. A method according to paragraph 7, wherein 2 loading doses are employed.
10. A method according to paragraph 7, wherein 3 loading doses are employed.
11. A method according to paragraph 7, wherein 4 loading doses are employed.
12. A method according to any one of paragraphs 1 to 11, wherein the loading dose is 400mg.
13. A method according to any one of paragraphs 1 to 11, wherein the loading dose is 500mg
14. A method according to any one of paragraphs 1 to 11, wherein the loading dose is 600mg.
15. A method according to any one of paragraphs 1 to 14, wherein the loading dose is administered weekly.
16. A method according to any one of paragraphs 1 to 15, wherein the therapeutic dose is in the range 200 to 600mg.
17. A method according to paragraph 16, wherein the therapeutic dose is 200mg.
18. A method according to paragraph 16, wherein the therapeutic dose is 300mg.
19. A method according to paragraph 16, wherein the therapeutic dose is 400mg.
20. A method according to paragraph 16, wherein the therapeutic dose is 500mg.
21. A method according to paragraph 16, wherein the therapeutic dose is 600mg.
22. A method according to any one of paragraphs 1 to 21, wherein the therapeutic dose is commenced 1 to 4 weeks after the last loading dose.
23. A method according to paragraph 22, wherein the therapeutic dose is commenced within 1 week after the last loading dose.
24. A method according to paragraph 22, wherein the therapeutic dose is commenced within 2 weeks after the last loading dose (generally more than 1 week],
25. A method according to paragraph 22, wherein the therapeutic dose is commenced within 3 weeks after the last loading dose (generally more than 2 weeks]. 26. A method according to paragraph 22, wherein the therapeutic dose is commenced within 4 weeks after the last loading dose (generally more than 3 weeks],
27. A method according to any one of paragraphs 1 to 26, wherein the therapeutic dose is administered once every 2 to 4 weeks.
28. A method according to paragraph 27, wherein the therapeutic dose is administered once every two weeks.
29. A method according to paragraph 27, wherein the therapeutic dose is administered once every three weeks.
30. A method according to according to paragraph 27, wherein the therapeutic dose is administered once every four weeks.
31. The method according to any one of paragraphs 1 to 30, wherein the antibody or antigen binding fragment thereof binds to the epitope FFYQ.
32. The method according to any one of paragraphs 1 to 31, wherein the antibody or antigen binding fragment comprises an Fc region, for example isotype IgG or a derivative thereof, such as 241P.
33. The method according to any one of paragraphs 2 to 32, wherein CDRH3 is SEQ ID NO: 10.
34. The method according to any one of paragraphs 2 to 33, wherein CDRL3 is SEQ ID NO: 33 or 45.
35. The method according to any one of paragraphs 1 to 34, wherein each dose is administered subcutaneously.
36. The method according to any one of paragraphs 1 to 34, wherein each dose is administered by infusion, such as intravenous infusion.
37. The method of any one of paragraphs 1 to 36, wherein the inflammatory disease has an allergic component, for example IgE mediated, TARC-level associated, and/or phosphoSTAT6-increased.
38. The method according to any one of paragraphs 1 to 37, wherein the inflammatory disease is atopic dermatitis.
39. The method according to paragraph 38, wherein the atopic dermatitis is moderate to severe, for example wherein the disease baseline is characterised by a EASI score of 16 or above (such as 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 , 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72).
40. The method according to any one of paragraphs 1 to 39, wherein the disease is ameliorated, characterised by a percentage reduction in Eczema Area and Severity Index (EASI) score in the range -20 to -100% from the baseline, such as -20, -30, -40, -50, -60, -70, -80, -90 or -100%.
41. The method according to any one of paragraphs 1 to 40, wherein the disease is ameliorated, characterised a percentage improvement in Scoring Atopic Dermatitis (SCORAD) score in the range -20 to -100% from the baseline, such as -20, -30, -40, -50, -60, -70, -80, -90 or -100%.
42. The method according to any one of paragraphs 1 to 41, wherein the disease is ameliorated, characterised by a reduction in Body Surface Area (BSA) in the range -20 to -100% from the baseline, such as -20, -30, -40, -50, -60, -70, -80, -90 or -100%.
43. The method according to any one of paragraphs 1 to 42, wherein the disease is ameliorated, characterised by a reduction in validated Investigator Global Assessment Scale (vIGA) score in the range -1 to -4 from the baseline, such as -1, -2, -3 or -4. 44. The method according to any one of paragraphs 1 to 43, wherein the disease is ameliorated, characterised by a reduction in Dermatology Life Quality Index (DLQI) score in the range of -4 to -30 from the baseline, such as -4, -5, -6, -7, -8, -9, -10, -11, -12, -13, -14, -15, -16, -17, -18, -19, -20, -21, -22, -23, -24, -25, -26, -27, -28, -29 or -30.
45. The method according to any one of paragraphs 1 to 44, wherein the disease is ameliorated characterised by reduction in Patient-Oriented Eczema Measure (POEM) score in the range of -20 to -100% from the baseline.
46. The method according to any one of paragraphs 1 to 45, wherein the disease is ameliorated characterisedby a reduction in European Qualify of life-5 Dimensions, 5 Levels (EQ-5D-5L) score in the range of-20 to -100% from the baseline.
47. The method according to any one of paragraphs 1 to 45, wherein the antibody or antigen binding fragment thereof is administered as a pharmaceutical formulation, such as a parenteral formulation, in particular a formulation for subcutaneous injection or for intravenous infusion.
48. An antibody or antigen binding fragment thereof, for use in treatment of an inflammatory disease as defined according to any one of the preceding paragraphs.
49. An antibody or antigen binding fragment thereof, for use in the manufacture of a medicament for the treatment of an inflammatory disease as defined according to any one of the preceding paragraphs.
In one embodiment the therapeutic dose is administered weekly.
In one embodiment, one or more subsequent loading doses (such as all the subsequent loading doses) are administered in the same location as a previous loading dose, for example to minimise the rate of clearance by maximising saturation of receptor occupancy.
Same location as employed here refers to actual collocation albeit temporally off-set, for example if a first loading dose was administered in the upper left arm, then a subsequent dose perhaps a week later would also be administered to the upper left arm. To track this accurately the location of the injection may need to be recorded for the patient
In one embodiment, one or more subsequent therapeutic doses (such as all the subsequent doses) are administered in the same location as a previous loading dose and/or therapeutic dose, for example to minimise the rate of clearance by maximising saturation of receptor occupancy. Same location as employed here refers to actual collocation albeit temporally off-set, for example if a previous loading dose was administered in the upper left arm, then a subsequent therapeutic dose would be administered to the upper left arm. To track this accurately the location of the injection may need to be recorded for the patient
In one embodiment, the volume of a single dose, such as a loading and/or therapeutic dose is administered as multiple injections, for example as two or more individual subcutaneous injections, wherein the two or more injections are administered in the same location. In one embodiment, the volume of a single loading and/or therapeutic dose is administered as two or more, for example two individual injections, wherein the two or more injections are administered in the same location, for example administered on the same location (also referred to as same side) of the patient, such as wherein both injection sites are located within 10cm or less of each other, in particular within 9, 8, 7, 6, 5, 4, 3, 2 or 1 cm’s of each other. In one embodiment, the volume of a single loading dose is administered as two individual injections, wherein the two injections are administered in the same location, for example two individual injections, wherein the two or more injections are administered in the same location, for example administered on the same location (also referred to as same side] of the patient, such as wherein both injection sites are located within 10cm or less of each other, in particular within 9, 8, 7, 6, 5, 4, 3, 2 or 1 cm's of each other.
In an independent aspect, (which may also be an embodiment of the previously described invention] there is provided a method of minimising the rate of clearance of anti-IL-13Ral antibody molecule or antigen binding fragment thereof the features of which are defined above in paragraph 1 or 2, wherein the volume of a single dose (such as a dose of 600mg including a therapeutic dose and/or a loading dose] is such that it is administered as two individual injections characterised in that the two injections are co-located, for example administered on the same location (also referred to as same side] of the patient, such as wherein both injection sites are located within 10cm or less of each other, in particular within 9, 8, 7, 6, 5, 4, 3, 2 or 1 cm’s of each other. In particular, this type of co-location of administration is more or less at the time (i.e. is not temporally off-set].
In one embodiment the site of injection is rotated, for example for a single dose administered as multiple injections.
In one embodiment the site of injection is rotated, between doses, for example between loading doses and/or therapeutic doses.
DETAILED DISCLOSURE
In one embodiment the antibody or antigen binding fragment will inhibit signalling of both IL- 13 and IL-4 through the type II receptor. In one embodiment the antibody does not inhibit signalling through the type I receptor.
In one embodiment the dose administered according to the present disclosure is a fixed dose, i.e. is an absolute dose which is not based on the mass or surface area of the patient
In one embodiment the dose is based on the mass of the patient. In one embodiment a loading dose of the anti-IL13R antibody or binding fragment thereof is 8 to lOmg/Kg.
In one embodiment the dose is based on the surface area of the patient
In one embodiment all the doses are administered by the same route, for example a route described herein, in particular subcutaneously.
In one embodiment one or more loading doses are administered by one route, for example IV, and the further loading doses and/or therapeutic doses are administered by a different route, for example subcutaneously. In particular, the loading dose or doses is/are administered by IV and the therapeutic dose or doses are administered subcutaneously.
In one embodiment the patient is a human.
The present disclosure extends to an antibody, antigen binding fragment or formulation for use in a treatment regimen described herein.
Advantageously, the presently disclosed method results in inhibition, such as complete inhibition of ST AT 6 signalling and complete IL-13 receptor occupancy for around 1 week (7 days] or more, such as 2 weeks, 3 weeks or 4 weeks (or one month].
In one embodiment inhibition of STAT6 is maintained (for example ata therapeutic level] for a period of 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 days, such as 29 days. In one embodiment the receptor bound by the antibody or binding fragment is fully occupied, for example for a period of 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 days, such as 29 days.
Thus, in one embodiment a pharmacodynamic (for example full pharmacodynamic] effect is provided for a period of atleast 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 days, such as 29 days.
Furthermore, after administration there is rapid onset of action, for example the onset of action is within 12 hours or less, such as 11, 10, 9, 8, 7, 6, 5, 4, 3 or 2 hours, more specifically 1 hour, in particular 1 hour after IV administration, intramuscular or subcutaneous administration.
The present inventors have demonstrated that the inhibitory action of the anti-IL13R antibody or binding fragment thereof is rapid, with complete inhibition achievable within 1 hour following administration (such as intravenous administration] of the antibody or binding fragment thereof. When the antibody is administered subcutaneously with the loading dose regime of the present disclosure there is a rapid onset of action. This may be manifest as a quick onset of reduced symptoms, for example using a score disclosure herein.
Furthermore, the dosing regimen of the present disclosure may inhibit other allergic mediators, such as TARC (thymus and activated regulated chemokine].
In one embodiment in the dosing of the present disclosure the pharmacodynamic effect is linked to the pharmacokinetic effect.
In addition, the dosing regimen of the present disclosure may minimise side effects, for example reduced or eliminate incidences of conjunctivitis and/or have reduced reaction at the injection site. Thus, the present inventors have established that the presently disclosed dosage levels can be safely tolerated with no evidence of adverse side effects.
In one embodiment the loading dose regime of the present invention does not change the pharmacokinetics of the antibody.
In one embodiment the loading dose regime of the present invention does change the pharmacokinetics of the antibody, for example it minimised clearance, in particular by occupy the receptors.
Further advantageously, the present inventors have established that the duration of IL-13R inhibition is closely associated with the dosage level. Specifically, by increasing the dosage, the duration of IL-13R inhibition can be increased, and by extension the frequency of dosing can be reduced. Accordingly, the claimed method can be specifically tailored according to treatment requirements.
In one embodiment the lowest concentration for a pharmacodynamic effect (such as a full pharmacodynamic effect] is in the range 0.5 to 70mg/L, such as 50 to 70mg/L, for example 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 60, 60.5, 61, 61.5, 62, 63, 64, 65, 66, 67, 68, 69 or 70mg/L, for example drug serum levels. These serum levels may be achieved by the dosing regimen of the present disclosure.
In one embodiment the lowest concentration for a pharmacodynamic effect (such as a full pharmacodynamic effect] is in the range 0.5 to 20mg/L, such as 0.5, 1 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20mg/L. In one embodiment the lowest concentration for a pharmacodynamic effect (such as a full pharmacodynamic effect] is in the range 1 to lOmg/L. In one embodiment the lowest concentration for a pharmacodynamic effect (such as a full pharmacodynamic effect) is in the range 0.5 to 2.5mg/L.
In one embodiment the drug serum levels between doses (trough levels) is in the range 0.5 to 20mg/L, such as 0.5, 1 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20mg/L.
In one embodiment the drug serum levels between doses (trough levels) is in the range 1 to lOmg/L. In one embodiment the drug serum levels between doses (trough levels) is in the range 0.5 to 2.5mg/L. Thus, in one embodiment, the dose, dose frequency and route of administration is selected so as to maintain a drug serum level above from about 0.5 to 20mg/L (such as 1 to lOmg/L) between doses.
Thus, in one embodiment, the dose, dose frequency and route of administration is selected so as to maintain a drug plasma level above from about 0.5 to 20mg/L (such as 1 to lOmg/L) between doses.
In one embodiment the dose or doses is/are administered intravenously, for example by infusion.
In one embodiment, the anti-IL-13R antibody or binding fragment is administered by infusion over a period of about 60 mins, such as 55, 56, 57, 58, 59, 60, 61, 62, 63, 64 or 65 mins.
In one embodiment the dose or doses is/are administered subcutaneously.
In one embodiment the dose or doses is/are administered intramuscularly.
In one embodiment the IL-13R antibody or binding fragment is administered via a syringe driver.
In one embodiment, the anti-IL-13R antibody or binding fragment is in the form of a pharmaceutical formulation, such as a parenteral formulation in particular as subcutaneous formulation.
In one embodiment the antibody, binding fragment or formulation is provided as a unit dose, for example for subcutaneous administration.
In one embodiment the antibody, binding fragment or formulation is provided in an autoinjection device, for example as a unit dose, in particular for subcutaneous injection.
In one embodiment, the anti-IL-13R antibody or binding fragment is eblasakimab as disclosed herein.
In one embodiment, the antibody or binding fragment specific for IL-13R comprises a VH CDR1 comprising an amino acid sequence as set forth in SEQ ID NO: 1, a VH CDR2 comprising an amino acid sequence as set forth in SEQ ID NO: 2, and a VH CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 10.
In one embodiment VL CDR1 comprising an amino acid sequence as set forth in SEQ ID NO: 31, a VL CDR2 comprising an amino acid sequence as set forth in SEQ ID NO: 32, and a VL CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 45.
In one embodiment, the antibody or binding fragment specific for IL-13R comprises a VH CDR1 comprising an amino acid sequence as set forth in SEQ ID NO: 1, a VH CDR2 comprising an amino acid sequence as set forth in SEQ ID NO: 2, and a VH CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 10 and a VL CDR1 comprising an amino acid sequence as set forth in SEQ ID NO: 31, a VL CDR2 comprising an amino acid sequence as set forth in SEQ ID NO: 32, and a VL CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 45. In one embodiment the antibody or antigen binding fragment thereof comprises a VH sequence of SEQ ID NO: 51 and a VL sequence of SEQ ID NO: 53.
In one embodiment the disclosure employs a sequence or combination of sequences disclosed herein.
DEFINITIONS
Loading dose as employed herein refers to a dose which is higher and/or given more frequently at the beginning of a treatment cycle.
The purposes of the loading dose is to quickly "saturate” the system in vivo to provide a drug level that is therapeutic and that can be maintained by lower and/or less frequent "therapeutic” doses. In some embodiments this may be achieved locally quicker by co-locating administrations in the same part of the body.
The subsequent doses given after the loading doses are referred to herein as therapeutic doses.
Therapeutic dose as employed herein refers to a dose which maintains the antibody or binding fragment thereof, at a therapeutic level i.e. it is not a loading dose, unless indicated otherwise.
A loading dose it not considered a therapeutic dose in the context of the present specification, even though the loading dose may have therapeutic activity.
Treatment cycle as employed herein refers to complete cycle comprising loading doses and therapeutic doses for a defined period, for example 3 months or more, such as 4, 5 or 6 months. The cycle may be repeated after a break in treatment, starting again with a loading dose.
In one embodiment the treatment cycle is followed by a maintenance dose with the purpose of keeping the disease in remission.
In one embodiment the therapeutic dose is continuous.
The first dose is nominally timepoint 0, i.e. in week 0.
Weekly dosing as employed herein is a dose administered in the week following the previous administration, generally about 7 days, for example +up to 2 days, -up to 3 days thereafter, such as 5, 6, 7 or 8 days after pervious administration, particularly 7 days after previous administration.
Two weekly dosing as employed herein is a dose administered in the two weeks following the previous administration (usually more than 1 week), generally about 14 days, for example + up to 2 days, - up to 3 days thereafter, such as 10, 11, 12, 13, 14, 15 or 16 days after the previous administration, particularly 13, 14 or 15 days after previous dose.
Three weekly dosing as employed herein is a dose administered in the three weeks following the previous administration (usually more than 2 weeks), generally about 21 days, for example + up to 3 days or -4 days thereafter, such as 18, 19, 20, 21, 22 or 23 after previous dose.
Four weekly dosing as employed herein is a dose administered in the four weeks following the previous administration (usually more than 3 weeks), generally about 28 to 31 days after the previous administration, for example + up to 4 days or - up to 4 days, such as 27, 28, 29, 30 or 31 days, in particular 28, 29 or 30 days after the previous administration.
In the context of the present disclosure the terms "once every 4 weeks and "once a month” are used interchangeably. A month or 1 month as used herein refers to one calendar month, which includes all possible months in a year, including a leap year February which has 29 days. Thus, "once a month” may refer to once every 28 days, once every 29 days, once every 30 days or once every 31 days.
Unit dose as used herein generally refers to a product (such as a vial or a prefilled syringe, including an auto -injector] comprising the amount of anti-IL13R antibody or binding fragment thereof of the present disclosure that is administered in a single dose including any overage.
A unit dose of the presently claimed anti-IL13R antibody or antigen binding fragment thereof may refer to the marketed form of the product, such as a formulation of the anti-IL13R antibody or binding fragment thereof, wherein the product is apportioned into the amount of anti-IL13R antibody that is required for a single dose. Thus, the manufacturer is able to determine and control the exact amount of anti-13R antibody or binding fragment thereof to be included in each unit dose.
The product may be in various forms, familiar to the skilled addressee, such as vials, ampoules, infusion bags or a device (including an auto-injection device].
The exact amount as employed herein refers to the amount to be administer as a dose to the patient and any overage.
In one embodiment the disclosure provides a group of unit doses (including devices], for example 1 to 4 loading doses and 1 to 10 therapeutic doses, or 3 to 6 months of therapeutic doses.
In one embodiment, the unit dose or unit doses are for use according to a method of the present disclosure. Thus, in one aspect, there is provided a unit dose for use according to a method of the present disclosure as defined herein.
In one embodiment, the formulation is a parenteral formulation.
Parenteral formulation as employed herein refers to a formulation designed not to be delivered through the GI tract Typical parenteral delivery routes include injection (including subcutaneous administration, bolus injection], implantation or infusion. In one embodiment the formulation is provided in a form for bolus delivery.
In one embodiment the subcutaneous dose of the anti-IL13R antibody or binding fragment thereof is in the range 300mg to 600 mg.
In one embodiment the parenteral formulation is administered subcutaneously, for example 300, 305, 310, 315, 320, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, or 600 mg of the anti-ILl 3 R antibody or binding fragment thereof, in particular once a month.
In one embodiment the parenteral formulation is a depot formulation, for example administered with a dose of 300, 305, 310, 315, 320, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, or 600 of the anti-IL13R antibody or binding fragment thereof, in particular once a month.
Injection as employed herein refers to the administration of a liquid formulation into the body via a syringe or syringe driver. Injection includes intravenous, subcutaneous, or intramuscular administration. The injection is generally over a short period of time, such as 5 minutes or less. However, injection can be administered slowly or continuously, for example using a syringe driver. Injections generally involve administration of smaller volumes than infusions. In one embodiment the injection is administered as a slow injection, for example over a period of 1.5 to 30 minutes. Slow injection as employed herein is manual injection with syringe or syringe driver.
Injections are usually smaller volumes than infusions, for example 30mLs or less will usually be considered an injection.
In one embodiment one dose of the formulation less than lOOmls, for example 30mls, such as administered by a syringe driver.
Infusion as employed herein means the administration of fluids by drip, infusion pump, or equivalent device. In one embodiment the infusion is administered over a period in the range of 1 to 120 minutes (for example 1 to 5 minutes), such as about 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 65, 80, 85, 90, 95, 100, 105, 110, 115 or 120 minutes. In one embodiment, the infusion is administered over a period of about 60 mins, such as 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69 or 70 mins, in particular over 60 mins.
Infusion usually involves administration of larger volumes than injections, for example the volume will generally be more than 30mL.
Bolus injection as employed herein refers to the administration of a large amount of formulation in a single "shot”. This may be administered intravenously, intramuscularly or subcutaneously. It may be formulated for slow release , for example as a depot injection.
Depot formulation as employed herein refers to formulations which has an increased residence time in vivo (also referred to as injectable modified release product), which provides slow release of the active agent (the antibody or binding fragment). Generally, the depot formulation will be for subcutaneous or intramuscular administration.
Examples of depot formulations include where the antibody or binding fragment is PEGylated or modified to comprise a further binding domain which binds serum albumin. Formulations such as these may also be administered intravenously, as the skilled person is aware.
Other types of depot formulations include providing the antibody or binding fragment in an oil, such as sesame seed oil. Protamine may be employed in depot formulations. Polymer carriers may be employed in depot formulations, for example PLA, PLGA, PLGA-glucose, PLGA formulated with N-methyl-2-pyrollidone, PLGA polyesters (such as Eligard®, Atridox®, H.P. Acthar Gel), gelatin, amino acid polymers, DL-lactic and glycolic acid copolymer, Atrigel™, and polylactide/glycolide formulations. Liposomes may be employed in depot formulations, including lipid nanoparticles coated with PEG.
Baseline refers to the status of the patient before administration of a dose of the IL13Rla antibody (even before administration of a loading dose). This baseline can be empirical observation, such as a score described herein and/or measurement of a biological marker.
Anti-IL13R antibody
Human IL-13Ral has the Uniprotnumber P3597. IL-13Ra2, previously called IL-13R and IL- 13Ra, is another receptor which is able to bind to IL-13. However, in contrast to IL-13Ral, this protein binds IL-13 with high affinity, but it does not bind IL-4. Human IL-13Ra2 has the Uniprot number Q14627.
As employed herein antibody molecules of the present disclosure comprise an Fc region, for example a complete antibody molecule having full length heavy and light chains. This includes a multi-specific antibody comprising an Fc region or full-length antibody. Multi-specific antibody formats often include antibody fragments, such as scFvs and the like.
In one embodiment the antibody molecule is a "simple” full length antibody comprising a heavy chain and a light chain. Thus, in one embodiment the antibody molecule will consist of an antibody.
Unless the context indicates otherwise (i.e. as in the previous paragraph) antibody molecule and antibody are employed interchangeably herein.
Binding fragments include but are not limited to Fab, modified Fab, Fab’, F(ab’)2, Fv, single domain antibodies (such as VH, VL, VHH, IgNAR V domains), scFv, bi, tri or tetra-valent antibodies, Bis-scFv, diabodies, triabodies, tetrabodies and epitope-binding fragments of any of the above (see for example Holliger and Hudson, 2005, Nature Biotech. 23(9):1126-1136; Adair and Lawson, 2005, Drug Design Reviews - Online 2(3), 209-217). As employed herein an antibody binding fragment does not contain an Fc.
The methods for creating and manufacturing these antibody fragments are well known in the art (see for example Verma et al, 1998, Journal of Immunological Methods, 216, 165-181). Other antibody fragments for use in the present invention include the Fab and Fab’ fragments described in W02005/003169, W02005/003170 and W02005/003171. Other antibody fragments include Fab- Fv and Fab-dsFv fragments described in W02010/035012 and antibody fragments comprising those fragments. Multi-valent antibodies may comprise multiple specificities or may be monospecific (see for example WO 92/22853 and W005/113605).
The antibodies and fragments thereof, for use in the present disclosure may be from any species including for example mouse, rat, shark, rabbit, pig, hamster, camel, llama, goat or human.
In one embodiment the antibody molecule or antigen binding fragment thereof is chimeric. Chimeric antibodies have a non-human variable regions and human constant regions. In one embodiment the antibody is fully human.
An antibody or binding fragment for use in the present invention can be derived from any class (e.g. IgG, IgE, IgM, IgD or IgA) or subclass of immunoglobulin molecule. In one embodiment the antibody employed in the present disclosure is IgG4 or IgG4 with a hinge stabilising S241P (Kabat numbering) mutation.
In one embodiment CDRH1 is an amino acid sequence GYSFTSYWIG (SEQ ID NO: 1).
In one embodiment CDRH2 is an amino acid sequence VIYPGDSYTR (SEQ ID NO: 2)
In one embodiment CDRH3 has the formula:
SEQ ID NO: 3 Xi Pro Asn Trp Gly X6 X7 Asp X9
Xi denotes Phe, Met, Gin, Leu or Vai
X6 denotes Ser or Ala
X7 denotes Phe, Leu, Ala or Met
X9 denotes Tyr, Gin, Lys, Arg, Trp, His, Ala, Thr,
Ser, Asn or Gly
In one embodiment the IL13Rlal antibody molecule or antigen binding fragment employed in the formulation of the present disclosure comprises a CDRH3 independently selected from a sequence comprising SEQ ID NO: 4 to 30: In one embodiment, the anti- IL13Rla antibody or binding fragment employed in the present disclosure comprises a VH CDR1 comprising an amino acid sequence as set forth in SEQ ID NO: 1, a VH CDR2 comprising an amino acid sequence as set forth in SEQ ID NO: 2, and a VH CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: or 3.
In one embodiment, the anti-IL13R antibody or binding fragment employed in the present disclosure comprises a CDRH1 comprising an amino acid sequence as set forth in SEQ ID NO: 1, a CDRH2 comprising an amino acid sequence as set forth in SEQ ID NO: 2, and a CDRH3 comprising an amino acid sequence as set forth in SEQ ID NO: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30.
In one embodiment the IL- 13 Rai antibody employed in the formulation of the present disclosure comprises a CDRL3 independently selected from a sequence comprising SEQ ID NO: 34 to 47:
In one embodiment, the anti-IL13R antibody or binding fragment employed in the present disclosure comprises a CDRH1 comprising an amino acid sequence as set forth in SEQ ID NO: 1, a CDRH2 comprising an amino acid sequence as set forth in SEQ ID NO: 2, and a CDRH3 comprising an amino acid sequence as set forth in SEQ ID NO: 10.
In one embodiment the IL- 13 Rai antibody employed in the formulation of the present disclosure comprises a CDRL3 independently selected from a sequence comprising SEQ ID NO: 34 to 47. In one embodiment CDRL3 comprising an amino acid sequence as setforth in SEQ ID NO: 33.
In one embodiment the VH region is independently selected from a sequence from the group comprising: SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51 and a sequence at least 95% identical to any one of the same. In one embodiment the VL is independently selected from a sequence from the group comprising: SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54and a sequence at least 95% identical to any one of the same (* K deleted in a post translational modification for example from the C-terminus). In one embodimentthe VH sequence is SEQ ID NO: 48 (or a sequence at least 95% identical thereto) and the VL sequence is SEQ ID NO: 52, SEQ ID NO: 53 or SEQ ID NO: 54 (or a sequence atleast95% identical to any one ofthe same). In one embodimentthe VH sequence is SEQ ID NO: 49 (or a sequence at least 95% identical thereto) and the VL sequence is SEQ ID NO: 52, SEQ ID NO: 53 or SEQ ID NO: 54 (or a sequence at least 95% identical to any one ofthe same). In one embodiment the VH sequence is SEQ ID NO: 50 (or a sequence at least 95% identical thereto) and the VL sequence is SEQ ID NO: 52, SEQ ID NO: 53 or SEQ ID NO: 54 (or a sequence at least 95% identical to any one of the same). In one embodiment the VH sequence is SEQ ID NO: 51 (or a sequence at least 95% identical thereto) and the VL sequence is SEQ ID NO: 52, SEQ ID NO: 53 or SEQ ID NO: 54 (or a sequence at least 95% identical to any one of the same). In one embodiment the VL sequence is SEQ ID NO: 52 (or a sequence at least 95% identical thereto) and the VH sequence is SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50 or SEQ ID NO: 51. (or a sequence at least 95% identical to any one of the same). In one embodiment the VL sequence is SEQ ID NO: 53 (or a sequence at least 95% identical thereto) and the VH sequence is SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50 or SEQ ID NO: 51 (or a sequence at least 95% identical to any one of the same). In one embodiment the VL sequence is SEQ ID NO: 54 (or a sequence at least 95% identical thereto) and the VH sequence is SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50 or SEQ ID NO: 51 (or a sequence at least 95% identical to any one of the same). In one embodiment the VH sequence is SEQ ID NO: 51 (or a sequence at least 95% identical thereto) and the VL sequence is SEQ ID NO: 53 (or a sequence at least 95% identical thereto). Variable region as employed herein refers to the region in an antibody chain comprising the CDRs and a suitable framework. In one embodiment the heavy chain comprises a sequence independently selected from the group comprising: SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, and a sequence at least 95% identical to any one of the same (K can deleted in a post translational modification for example from the C-terminus). In one embodiment the light chain is independently selected from a group comprising: SEQ ID NO: 61: SEQ ID NO: 62; SEQ ID NO: 63 and a sequence at least 95% identical to any one of the same. In one embodimentthe heavy chain is independently selected from SEQ ID NO: 55, 56, 57, 58, 59 and 60 (or a sequence atleast95% identical to anyone of the same) and the light chain is independently selected from SEQ ID NO: 61 62 and 63 (or a sequence at least 95% identical to any one of the same). In one embodimentthe heavy chain is SEQ ID NO: 55 (or a sequence at least 95% identical thereto) and the light chain is independently selected from SEQ ID NO: 61 or 62 and 63 (or a sequence at least 95% identical to anyone of the same). In one embodiment the heavy chain is SEQ ID NO: 56 (or a sequence at least 95% identical thereto) and the light chain is independently selected from SEQ ID NO: 61 or 62 and 63 (or a sequence at least 95% identical to any one of the same). In one embodiment the heavy chain is SEQ ID NO: 57 (or a sequence at least 95% identical thereto) and the light chain is independently selected from SEQ ID NO: 62 or 63 and 63(or a sequence atleast95% identical to any one of the same). In one embodiment the heavy chain is SEQ ID NO: 58 (or a sequence at least 95% identical thereto) and the light chain is independently selected from SEQ ID NO: 61 62 and 63 (or a sequence at least 95% identical to any one of the same). In one embodimentthe heavy chain is SEQ ID NO: 59 (or a sequence atleast95% identical thereto) and the lightchain is independently selected from SEQ ID NO: 61 62 and 63 (or a sequence at least 95% identical to any one of the same). In one embodimentthe heavy chain is SEQ ID NO: 60 (or a sequence at least 95% identical thereto) and the light chain is independently selected from SEQ ID NO: 61 61 and 63 (or a sequence at least 95% identical to any one of the same). In one embodiment the heavy chain is SEQ ID NO: 58 or 60 (or a sequence at least 95% identical to any one of the same) and a light chain with the sequence shown in SEQ ID NO: 61 (or a sequence at least 95% identical thereto). In one embodimentthe heavy chain is SEQ ID NO: 58 (or a sequence at least 95% identical to any one of the same) and a light chain with the sequence shown in SEQ ID NO: 61 (or a sequence at least 95% identical thereto). In one embodimentthe heavy chain is SEQ ID NO: 60 (or a sequence at least 95% identical to any one of the same) and a light chain with the sequence shown in SEQ ID NO: 61 (or a sequence at least 95% identical thereto).
In one embodiment, the anti-IL13R antibody is eblasakimab.
Derived from as employed herein refers to the fact that the sequence employed or a sequence highly similar to the sequence employed was obtained from the original genetic material, such as the light or heavy chain of an antibody.
"At least 95% identical” as employed herein is intended to refer to an amino acid sequence which over its full length is 95% identical or more to a reference sequence, such as 96, 97, 98 or 99% identical. Software programmes can be employed to calculate percentage identity.
Any discussion of a protein, antibody or amino acid sequence herein will be understood to include any variants of the protein, antibody or amino acid sequence produced during manufacturing and/or storage. For example, during manufacturing or storage an antibody can be deamidated (e.g., at an asparagine or a glutamine residue) and/or have altered glycosylation and/or have a glutamine residue converted to pyroglutamate and/or have a N-terminal or C-terminal residue removed or "clipped” (C-terminal lysine residues of encoded antibodies are often removed during the manufacturing process) and/ or have part or all of a signal sequence incompletely processed and, as a consequence, remain at the terminus of the antibody. It is understood that an antibody comprising a particular amino acid sequence or binding fragment thereof maybe a heterogeneous mixture of the stated or encoded sequence and/or variants of that stated or encoded sequence or binding fragment thereof.
In one embodiment the present disclosure extends to a sequence explicitly disclosed herein where the C-terminal lysine has been cleaved.
In one embodiment an antibody or binding fragment thereof, employed in a formulation of the present disclosure is humanised.
Humanised (which include CDR-grafted antibodies) as employed herein refers to molecules having one or more complementarity determining regions (CDRs) from a non-human species and a framework region from a human immunoglobulin molecule (see, for example US5,585,089; WO91/09967). It will be appreciated that it may only be necessary to transfer the specificity determining residues of the CDRs rather than the entire CDR (see for example, Kashmiri et al., 2005, Methods, 36, 25-34). Humanised antibodies may optionally further comprise one or more framework residues derived from the non-human species from which the CDRs were derived. For a review, see Vaughan et al, Nature Biotechnology, 16, 535-539, 1998.
When the CDRs or specificity determining residues are grafted, any appropriate acceptor variable region framework sequence may be used having regard to the class/type of the donor antibody from which the CDRs are derived, including mouse, primate and human framework regions. Examples of human frameworks which can be used in the present invention are KOL, NEWM, REI, EU, TUR, TEI, LAY and POM (Kabat et al.,). For example, KOL and NEWM can be used for the heavy chain, REI can be used for the light chain and EU, LAY and POM can be used for both the heavy chain and the light chain. Alternatively, human germline sequences may be used; these are available at: http://vbase.mrc-cpe.cam.ac.uk/
In a humanised antibody employed in the present invention, the acceptor heavy and light chains do not necessarily need to be derived from the same antibody and may, if desired, comprise composite chains having framework regions derived from different chains.
The framework regions need not have exactly the same sequence as those of the acceptor antibody. For instance, unusual residues may be changed to more frequently occurring residues for that acceptor chain class or type. Alternatively, selected residues in the acceptor framework regions may be changed so that they correspond to the residue found at the same position in the donor antibody (see Reichmann et al., 1998, Nature, 332, 323-324). Such changes should be kept to the minimum necessary to recover the affinity of the donor antibody. A protocol for selecting residues in the acceptor framework regions which may need to be changed is set forth in WO91/09967.
In one embodiment the anti-IL13R antibodies of the present disclosure are fully human, in particular one or more of the variable domains are fully human. Fully human molecules are those in which the variable regions and the constant regions [where present) of both the heavy and the light chains are all of human origin, or substantially identical to sequences of human origin, not necessarily from the same antibody. Examples of fully human antibodies may include antibodies produced, for example by the phage display methods described above and antibodies produced by mice in which the murine immunoglobulin variable and optionally the constant region genes have been replaced by their human counterparts e.g. as described in general terms in EP0546073, US5,545,806, US5,569,825, US5,625,126, US5,633,425, US5,661,016, US5,770,429, EP0438474 and EP0463151.
Constant region as employed herein is intended to refer to the constant region portion located between two variable domains, for example non-cognate variable domains, in the heavy chain. Thus, the presently disclosed anti-ILl 3R antibody may comprise one or more constant regions, such as a naturally occurring constant domain or a derivate of a naturally occurring domain.
Fc as employed herein is the part of the constant region found after the hinge, for example -CH2CH3 in IgG.
A derivative of a naturally occurring domain as employed herein is intended to refer to where one, two, three, four or five amino acids in a naturally occurring sequence have been replaced or deleted, for example to optimize the properties of the domain such as by eliminating undesirable properties but wherein the characterizing feature(s) of the domain is/are retained. 241P is a common mutation in the constant region.
If desired an antibody for use in the present disclosure may be conjugated to one or more effector molecule [s). It will be appreciated that the effector molecule may comprise a single effector molecule or two or more such molecules so linked as to form a single moiety that can be attached to the antibodies used in the present invention. Where it is desired to obtain an antibody fragment linked to an effector molecule, this may be prepared by standard chemical or recombinant DNA procedures in which the antibody fragment is linked either directly or via a coupling agent to the effector molecule. Techniques for conjugating such effector molecules to antibodies are well known in the art (see, Hellstrom et al., Controlled Drug Delivery, 2nd Ed., Robinson etal., eds., 1987, pp. 623- 53; Thorpe et al., 1982, Immunol. Rev., 62:119-58 and Dubowchik et al., 1999, Pharmacology and Therapeutics, 83, 67-123). Particular chemical procedures include, for example, those described in WO93/06231, WO92/22583, W089/00195, W089/01476 andW003/031581. Alternatively, where the effector molecule is a protein or polypeptide the linkage may be achieved using recombinant DNA procedures, for example as described in WO86/01533 and EP0392745.
The term effector molecule as used herein includes, for example, biologically active proteins, for example enzymes, other antibody or antibody fragments, synthetic or naturally occurring polymers, nucleic acids and fragments thereof e.g. DNA, RNA and fragments thereof, radionuclides, particularly radioiodide, radioisotopes, chelated metals, nanoparticles and reporter groups such as fluorescent compounds or compounds which may be detected by NMR or ESR spectroscopy.
Other effector molecules may include detectable substances useful, for example in diagnosis. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, radioactive nuclides, positron emitting metals (for use in positron emission tomography), and nonradioactive paramagnetic metal ions. See generally US4,741,900 for metal ions which can be conjugated to antibodies for use as diagnostics. Suitable enzymes include horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase; suitable prosthetic groups include streptavidin, avidin and biotin; suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride and phycoerythrin; suitable luminescent materials include luminol; suitable bioluminescent materials include luciferase, luciferin, and aequorin; and suitable radioactive nuclides include 1251, 1311, lllln and 99Tc.
In another example the effector molecule may increase the half-life of the antibody in vivo, and/or reduce immunogenicity of the antibody and/or enhance the delivery of an antibody across an epithelial barrier to the immune system. Examples of suitable effector molecules of this type include polymers, albumin, albumin binding proteins or albumin binding compounds such as those described in WO05/117984. Where the effector molecule is a polymer it may, in general, be a synthetic or a naturally occurring polymer, for example an optionally substituted straight or branched chain polyalkylene, polyalkenylene or polyoxyalkylene polymer or a branched or unbranched polysaccharide, e.g. a homo- or hetero- polysaccharide.
Specific optional substituents which may be present on the above-mentioned synthetic polymers include one or more hydroxy, methyl or methoxy groups.
Specific examples of synthetic polymers include optionally substituted straight or branched chain poly(ethyleneglycol), poly(propyleneglycol) poly(vinylalcohol) or derivatives thereof, especially optionally substituted poly(ethyleneglycol) such as methoxypoly(ethyleneglycol) or derivatives thereof.
Specific naturally occurring polymers include lactose, amylose, dextran, glycogen or derivatives thereof.
"Derivatives” as used herein is intended to include reactive derivatives, for example thiolselective reactive groups such as maleimides and the like. The reactive group may be linked directly or through a linker segment to the polymer. It will be appreciated that the residue of such a group will in some instances form part of the product as the linking group between the antibody fragment and the polymer.
Suitable polymers include a polyalkylene polymer, such as a poly(ethyleneglycol) or, especially, a methoxypoly(ethyleneglycol) or a derivative thereof, and especially with a molecular weight in the range from about 15000Da to about 40000Da. In one example antibodies for use in the present invention are attached to poly(ethyleneglycol) (PEG) moieties. In one particular example the antibody is an antibody fragment and the PEG molecules may be attached through any available amino acid side-chain or terminal amino acid functional group located in the antibody fragment, for example any free amino, imino, thiol, hydroxyl or carboxyl group. Such amino acids may occur naturally in the antibody fragment or may be engineered into the fragment using recombinant DNA methods (e.g. US5,219,996; US5,667,425; W098/25971, W02008/038024). In one example the antibody molecule of the present invention is a modified Fab fragment wherein the modification is the addition to the C-terminal end of its heavy chain one or more amino acids to allow the attachment of an effector molecule. Suitably, the additional amino acids form a modified hinge region containing one or more cysteine residues to which the effector molecule may be attached. Multiple sites can be used to attach two or more PEG molecules. In one embodiment the antibody or binding fragment employed in the formulation of the present disclosure is monoclonal.
In one embodiment the antibody or binding fragment employed in the formulation of the present disclosure is human.
In one embodiment the antibody or binding fragment employed in the formulation of the present disclosure is chimeric or humanised.
Treatment
Advantageously, the presently claimed method of treatment results in the improvement in the symptoms, for example ameloriation of atopic dermatitis across a range of different clinical scores and measures.
In one embodiment the disease is modified by a percentage reduction in Eczema Area and Severity Index (EASI) score in the range -20 to -100% from the baseline, such as EASI 50, EASI 75 or EASI 90.
Eczema Area and Severity Index (EASI) score as used herein is a tool used to measure the area (which indicates the extent of disease) and severity of atopic eczema. The number after the term "EASI” indicates the % decrease in the score from baseline. Thus, EASI 50 for example refers to 50% decrease in the score and EASI 90 refers to a 90% decrease in the score.
In one embodiment the disease is modified by a percentage improvement in Scoring Atopic Dermatitis (SCORAD) score in the range -20 to -100% from the baseline.
Scoring Atopic Dermatitis (SCORAD) score as used herein refers to a composite score that takes into account the body surface area of involvement in AD and the severity of 6 clinical signs on a 4-point. scale (erythema, edema/papulation, oozing/ crusting, excoriation, lichenification, and dryness), and it incorporates a patient-reported component assessing pruritus and sleep loss.
In one embodiment the disease is modified by a reduction in Body Surface Area (BSA) in the range -20 to -100% from the baseline.
Body Surface Area (BSA) as used herein is a simple measure of percent body surface area involved with atopic dermatitis which does not incorporate an assessment of disease severity.
In one embodiment the disease is modified by a reduction in validated Investigator Global Assessment Scale (vIGA) score in the range -1 to -4 from the baseline.
Validated Investigator Global Assessment Scale (vIGA) as used herein refers to the standardised and validated version of the Investigator Global Assessment Scale (IGA) which is used primarily by health agencies for drug registration in atopic dermatitis. A score of 0 to 4 corresponding to increasing disease severity is used.
In one embodiment the disease is modified by a reduction in Pruritus Numerical Rating Scale (P-NRS) in the range -2 to -10 from the baseline.
Pruritus Numerical Rating Scale (P-NRS) as used herein is patient assessed score of the intensity of his or her itch. A score of 0 refers to "no itch” whilst a top score of 10 refers to "worst imaginable itch”. Thus in one embodiment pruritus is improved.
In one embodiment the disease is modified by a reduction in Sleep Disturbance Numerical Rating Scale (SD-NRS) in the range -2 to -10 from the baseline. As used herein, the Sleep Disturbance Numerical Rating Scale (SD-NRS) is a single-item, selfreported 11-point scale ranging from zero to 10 for reporting the degree of sleep loss related to atopic dermatitis.
In one embodiment the disease is modified by a reduction in Dermatology Life Quality Index (DLQI) score in the range of -4 to - 30 from the baseline.
DLQI as used herein refers to a simple, patient-administered, 10-question, validated, quality- of-life questionnaire that covers 6 domains, including symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment. Responses include "not at all” or "not relevant”; "a little”; "a lot”; and "very much” - with corresponding scores of 0, 1, 2 and 3 respectively. Totals range from 0 to 30 (less to more impairment) and a 5-point change from Baseline is considered clinically relevant.
In one embodiment the disease is modified by reduction in Patient-Oriented Eczema Measure (POEM) score in the range of -20 to -100% from the baseline.
Patient Oriented Eczema Measure (POEM) as used herein refers to a 7-item questionnaire for patients that assesses presence of disease symptoms (dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping) over the last week using a scoring system of 0 (no days) to 4 (every day). The total score ranges from 0 to 28 with higher scores indicating greater intensity of eczema.
In one embodiment the disease is modified by a reduction in European Qualify of life-5 Dimensions, 5 Levels (EQ-5D-5L) score in the range of -20 to -100% from the baseline.
European Qualify of life-5 Dimensions, 5 Levels (EQ-5D-5L) as used herein refers to a preference-based HRQL measure with one question for each of the five dimensions that include mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.
In one embodiment the disease is modified by a reduction in Hospital Anxiety and Depression Scale (HADS) in the range of -20 to -100% from the baseline.
Hospital Anxiety and Depression Scale (HADS) as used herein refers to a self-assessment 14 item scale with 7 items each of anxiety and depression subscales. HADS focuses on non-physical symptoms so that it can be used to diagnose depression in people with significant physical ill-health.
In one embodiment the disease is modifiedby a reduction in Asthma Control Test (ACT) score in the range of -20 to -100% from the baseline.
Asthma Control Test (ACT) as used herein refers to a patient-centred/completed questionnaire that recalls the patient's experience of 5 items: asthma symptoms (nocturnal and daytime), the use of rescue medications, the effect of asthma on daily functioning, and the patient's perception of asthma control over the previous 4 weeks.
Less than twice a month as employed herein refers to the average of doses over at least a two- month period, for example 3 doses in two months is on average 1.5 doses per month. However, in practice it will mean administration of one dose in one month and two doses in the next month.
The anti-IL13R antibody or binding fragment thereof or formulation thereof according to the present disclosure may be used for treatment or in the manufacture of a medicament. In particular, the disclosed anti anti-IL13R antibody or binding fragment thereof or formulation thereof is suitable for use in treating atopic dermatitis. Thus, in one embodiment the antibody, binding fragment or formulation of the present disclosure is used for the treatment of dermatitis (such as atopic dermatitis] or is used for the manufacture of a medicament for the treatment of the same.
In one embodiment the antibody, binding fragment or formulation of the present disclosure is employed as a monotherapy.
In one embodiment the formulation herein is administered in combination with another therapy, for example an anti-inflammatory agent, such as a non-steroidal anti-inflammatory and/or a steroid orally and/or topically as appropriate (eg prednisolone, betamethasone, dexamethasone, hydrocortisone, methylprednisolone, deflazacort, such as prednisolone).
"In combination” as employed herein is intended to encompass where the anti-IL13R antibody is administered before, concurrently or after with another therapy. Combination therapy refers to the fact that the pharmacological effects of the two or more therapies co-exist (overlap] in the body for a period time.
Formulations of anti-IL-13R antibodies
In one embodiment the formulation employed in method of the present disclosure is a high concentration formulation.
Antibodies, such as eblasakimab need to be formulated at a high concentration to allow the desired dose in man to be administered in the smallest possible volume. High concentration formulations pose unique challenges as phenomena like phase separation can be observed. Aggregation is also a common feature at high antibody concentration. However, the formulation needs to contain very high levels of antibody molecules as "monomer”, for example 95% monomer or more. In addition, the formulation needs to be stable when stored. Eblasakimab seems to have a hydrophobic portion in the protein, which for example interacts with hydrophobic interaction columns in the absence of high salt concentrations. This hypothesised hydrophobic portion adds additional complexity when formulating the antibody and preventing aggregation. Thus, the antibodies of the present disclosure are particularly difficult to formulate.
The present inventors have optimised the formulation of the present disclosure and established that the IL-13R antibodies, such as eblasakimab, are most suitable for formulation within a narrow set of parameters. The formulations of the present disclosure are highly monomeric, for example at least 95% monomeric (such as 98 to 99.5% monomeric] even when formulated with high antibody concentration. In addition, the formulation is suitably stable, for example in some embodiments no change in monomer or less than a 0.5% reduction in monomer was observed when stored at4°C or 25° for 90 days. Accelerated 'stress test’ studies at 40°C also show the formulations used in the present disclosure to be stable over a period of 60 days, for example using potency measurements.
The combination of features of the formulation of the present disclosure, including the pH, contributing to stabilising the IL-13 receptor antibody or binding fragment thereof.
In one embodiment the formulations of the present disclosure have a viscosity in the range of 4.5 to 5.5, such as 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4 or 5.5 cP (centipoise), such as 4.9 cP, for example at ambient temperature. Surprisingly, the viscosity of the formations of the present disclosure are relatively low even at high concentrations of antibody. In one embodiment the osmolarity of the formulation is in the range 350 to 450 mOsmo/kg, such as 390 to 430 mOsmo/kg, in particular 410 +/-5m0smo/kg.
In one embodiment, the formulation further comprises 10 to 145 mg/ml anti-IL13Rantibody, for example 10 to 125mg/ml, such as 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110 or 120 mg/ml, in particular 20 mg/ml or 100 mg/ml of anti-IL13R antibody.
In one embodiment certain formulations of the present disclosure have 5% or less protein aggregation, such 4, 3, 2, 1% or less, for example when stored for 90 days at temperature in the range 2 to 25°C.
The presently disclosed anti-IL13R antibody formulation is particularly suitable for stable long-term storage of the anti-IL13R antibody.
Long term as used herein refers to a period of at least 6 months, such as 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 months. In one embodiment, the disclosed formulation storage for at least 12 months, such as 12 months, 18 months and 24 months.
In one embodiment the formulation is stored at a temperature in the range 2 to 8°C, such as 2, 3, 4, 5, 6, 7 or 8 °C, such as 4 °C.
In one embodiment, the formulation comprises: 150 to 210 mg/ml of an anti-IL-13R antibody or antigen binding fragment thereof, for example 150, 155, 160, 165, 170, 175, 180, 185, 190, 195 or 200 mg/ml, in particular 150 mg/ml, 175 mg/ml or 200 mg/ml; 170 to 250 mM of arginine (such as Arg-HCl or Arg-Glu), for example 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245 or 250 mM, in particular 150 mM, 175 mM or 250 mM; 20 to 50 mM histidine buffer, for example 20, 25, 30, 35, 40, 45 or 50 mM, such as 20 mM or 50 mM histidine buffer; 0.01-0.03% of a non-ionic surfactant, for example 0.01-0.03% w/w, such as 0.02% w/w; and wherein the pH of the formulation is in the range 6.0 to 7.0, such as 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.0, in particular 6.5.
In one embodiment there is provided a parenteral formulation (in particular a liquid formulation] for example for infusion or injection. In one embodiment there is provided liquid parenteral formulation as a concentrate for dilution with a liquid for injection, such as glucose, saline or water for injection. In one embodiment the liquid parenteral formulation is provided in a final concentration for administration without dilution, for example for injection or for infusion.
In the context of this specification "comprising" is to be interpreted as "including". Embodiments of the invention comprising certain features/elements are also intended to extend to alternative embodiments "consisting" or "consisting essentially" of the relevant elements/features.
Where technically appropriate, embodiments of the invention may be combined.
Technical references such as patents and applications are incorporated herein by reference.
Any embodiments specifically and explicitly recited herein may form the basis of a disclaimer either alone or in combination with one or more further embodiments.
Subject headings herein are employed to divide the document into sections and are not intended to be used to construe the meaning of the disclosure provided herein.
The priority documents may be used as basis for corrections.
A sequence listing is filed herewith and incorporated by reference. The present invention is further described by way of illustration only in the following examples.
BRIEF SUMMARY OF THE FIGURES
Figure 1 shows the planned treatment arms
Set - Screening Period (<35 days)
R - Randomization
BL - Baseline
LD - AU treatment anus receive 600 mg loading doses according to the dosing schedule (except placebo, which receive placebo loading dose)
E - Evaluation only visit (no dose administered)
D - Dosing (Loading and/or Regular) and evaluation visit
EOT - End of Treatment visit (no dose administered)
EOS - End of Study visit by telephone
1® EP - Primary Endpoint Evaluation
® - Phone call
Figure 2 shows the injection scheme for each dose level. IP = Investigational product; PBO = placebo; mg = milligram; mL = milliliter. To maintain the double-blind for this study, each patient will get 3 injections at every scheduled treatment visit. Each vial of eblaskaimab is provided as a sterile 100 mg/mL solution and has an extractable volume of 2 mL. Placebo is a matching, sterile 0 mg/mL solution with extractable volume of 2 mL.
Figure 3 shows the randomisation scheme. * Patients randomized to arms 4 and 5 (Q4W) will receive placebo injections at weeks 6, 10 and 14 to match the injection schedule of arms 1, 2 and 3 (Q2W)
Figure 4 shows a table of the injection type by visit. W = week, Q2W = every two weeks, Q4W
= every 4 weeks, LD = loading dose, D = regular dose, P = placebo dose
Figure 5 shows study treatment arms with dosing schedule
Figure 6 shows the baseline demographics and disease characteristics of the patients. Demographics are from screened points, disease characteristics are from randomised points.
Figure 7 shows the median Eczema area and severity index (EASI) % change from baseline (CFBL) from week 0 to 20
EXAMPLES
Example 1 - Study Objectives and Endpoints In patients with moderate-to-severe AD
To evaluate the safety and efficacy of eblasakimab including the dose-response , and tolerability in patients with the disease. Efficacy on biomarkers and other exploratory efficacy will also be analysed and the parameters compared with placebo.
Primary Endpoint & Secondary Endpoints
Primary endpoint is percentage change in EASI (Hanifin et al 2001} score from Baseline to Week 16. Secondary endpoints include: Proportion of patients achieving vIGA response of 0 (dear) or 1 [almost clear) [5 point scale] at W eek 16; Proportion of patients with a 75% reduction from Baseline in EASI [EASI 75) at Week 16: Proportion of patients achieving EASI 50 and EASI 90 at Week 16; Proportion of patients with EASI <7 at Week 16; Change in EASI score from Baseline over time; Absolute and percent change in peak P-NRS from Baseline to Week 16; Proportion of patients achieving a 4-point reduction in peak P-NRS at Week 16; Change in BSA affected with AD from Baseline to Week 16; Change in SCORAD from Baseline to Week 16; Change in DLQI from Baseline to Week 16; Change in POEM from Baseline to Week 16; Change in EQ-5D-5L from Baseline to Week 16; Change in HADS from Baseline to Week 16; Absolute and percent change in SD-NRS from Baseline to Week 16; Proportion of patients achieving a 4-point reduction in SD-NRS at Week 16; TEAEs and TESAEs, including incidence of clinically significant changes in vital signs, clinical; and laboratory tests, and ECGs.
Exploratory endpoints
® Number and percent of patients with AD flare(s) during the study period
® Number and percent of patients with asthma flare(s) (only for patients with asthma comorbidity)
« during the study period
• Change from Baseline in biomarkers
Example 2 - Study Design
Overall Study Design
This is a Phase 2b, multicenter, randomized, double-blind, placebo-controlled, parallel, dose-ranging clinical study designed to evaluate the efficacy and safety of eblasakimab in adult patients with moderate-to-severe AD who are candidates for systemic therapy. The study consists of a 16-week treatment period, 8-week follow-up period up to Week 24, followed by a telephone safety’ follow-up call at Week 28. The primary efficacy endpoint will be assessed at Week 16. A Screening period of not greater than 35 days and the reconfirmation of key eligibility criteria at Day 1 are pre-requisites for the randomization of patients.
Approximately 295 patients meeting the eligibility criteria will be randomized automatically and randomly through RTSM (Randomization Trial Supply Management) and will be allocated into one of the 5 treatment arms (4 active treatment arms and 1 placebo arm) in a 1 :1:1:1:1 equal ratio as described in Figure 3.
Randomization will be stratified by disease severity (vIGA = 3 vs vIGA = 4).
Study patients, principal investigators, study centre personnel, study sponsor personnel, and CRO personnel in regular contact with study centres will be blinded to treatment assignment during the study, and allocation will be concealed. Drug kits will be coded, providing blinding to treatment assignment.
To maintain the blinding, patients randomized to the Q4W treatment arms (Arms 4 and 5) will observe the same 2 weekly visit schedules as patients randomized to the Q2W arms (Arms 1-3) and following the initial loading dose (LD) period, will receive placebo injections at alternate visits. Each via] of eblasakimab is provided as a sterile 100 mg/mL solution and has an extractable volume of 2 mL. The dedicated site personnel preparing and/or administering the treatment doses at each site will be unblinded.
Details of the 5 treatment arms are as follo ws:
Treatment Arm 1:
Week 0, 1, 2, 4, 6, 8, 10, 12, 14: Three 2 mL injections of placebo
Treatment Arm 2:
Week 0, 1: LD of 600 mg (Three 2 mL injections of drug product [100 mg/mL]) Week 2, 4, 6, 8, 10, 12, 14: Regular dose of 300 mg [One 2 mL injection of drug product [100 mg/mL], one 1 mL injection of drug product [100 mg/mL] and one 2 mL injection of placebo) Treatment Arm 3:
Week 0, 1: LD of 600 mg (Three 2 mL injections of drug product [100 mg/mL])
Week 2, 4, 6, 8, 10, 12, 14: Regular dose of 400 mg (Two 2 mL injections of drug product [100 mg/mL] and one 2 mL injection of placebo).
Treatment Arm 4:
Week 0, 1, 2: LD of 600 mg (Three 2 mL injections of drug product [100 mg/mL])
Week 4, 8, 12: Regular dose of 400 mg (Two 2 mL injections of drug product [100 mg/mL] and one 2 mL injection of placebo)
Week 6, 10, 14: Three 2 mL injections of placebo
Treatment Arm 5:
Week 0, 1, 2: LD of 600 mg (Three 2 mL injections of drug product [100 mg/mL])
Week 4, 8, 12: Regular dose of 600 mg (Three 2 mL injections of drug product [100 mg/mL])
Week 6, 10, 14: Three 2 mL injections of placebo
Patients will receive the LD for the arm to which they have been randomized. Patients will be closely monitored at the study site, according to the Investigator’s judgement, for 30 to 60 minutes, after every dose administration. After completing the loading doses, patients will receive treatment in accordance with the treatment arm to which they have been randomized. At the end of this treatment period, patients will return for follow-up visits as listed for a total of 12 weeks in the safety followup period.
Rationale for Study Design
Eblasakimab is currently being investigated as a potential solution to address this gap for patients with moderate-to-severe AD. By targeting IL-13Ral, a receptor with a narrower cellular distribution than the IL-4 receptor, the potential is being investigated for eblasakimab to offer both a lower dose and lower dosing frequency, which are advantageous features for SC injections, providing greater patient convenience.
In the phase 2b study, 3 different dose levels of eblasakimab will be assessed - 300 mg, 400 mg, and 600 mg. In addition, two dosing frequencies of 400 mg will be assessed - once every 2 weeks (Q2W) and once every four weeks (Q4W).
Dose
This Phase 2b study will evaluate the efficacy and safety of eblasakimab in adult patients with moderate to severe AD. Patients will be randomly assigned to receive subcutaneously for 16 weeks either placebo or one of four active treatment arms with the following dose levels of eblasakimab: 400 mg Q2W, 300 mg Q2W, 600 mg Q4W or 400 mg Q4W. All treatment arms will receive loading doses; 0 mg QW in the first two weeks for the placebo arm, 600 mg QW eblasakimab in the first two weeks for the 300 mg Q2W and 400 mg Q2W eblasakimab treatment arms, and 600 mg eblasakimab in the first three weeks for the 400 mg and 600 mg Q4W eblasakimab treatment arms.
Dose selection rationale is based on safety assessments from the completed SAD and ongoing MAD clinical trial with eblasakimab, PK:PD measurements from the SAD study, and interim analysis of the ongoing MAD study.
No new or unexpected safety signals have been observed in clinical trials conducted to date with single IV or SC doses up to 600 mg in healthy adult male volunteers or multiple doses administered SC weekly for 8 weeks to patients with moderate to severe AD. Example 3 - Study Intervention
Study Intervention Administration
The investigational drug product, eblasakimab is provided as a sterile 100 mg/mL solution for SC injection. Eblasakimab is formulated in a buffer containing Histidine (20 mM], Arginine (100 mM], Sucrose (180 mM) and PolysorbatePolysorbate- 20 (0.02%).
The pH value of the IP is 6.5 (specification pH 6.5 ± 0.3) and the protein solution is slightly hypertonic. The first arm will be administered the placebo in a regimen matching active treatment arms to maintain the double-blind. The placebo will consist solely of the excipients of eblasakimab, i.e., the same formulation without the active ingredient and will be identical in appearance to eblasakimab. Patients will be closely monitored at the study site, according to the Investigator’s judgement, for 30 to 60 minutes, after every dose administration.
Dosing and Administration
SC injections of eblasakimab 100 mg/mL are administered into the thigh or abdomen, except for the 2 inches (5 cm) around the navel. The upper arm can also be used.
Rotating the site with each injection will be compared to injection at the same site . Do not inject into skin that is bruised, tender, damaged or scarred.
Each patient will receive eblasakimab or placebo SC injection as described in Figure 3. Study drug administration and site of injection will be recorded in the source documents and transcribed in the eCRF. The maximum injection volume will be 2 m (200 mg), with multiple injections being given to achieve doses higher than 200 mg. The maximum number of injections, per visit, will be 3 (600 mg). The injection type by visit is provided in Figure 4.
Delayed Doses
Investigational drug dosing may be delayed by the Investigator, by agreement with sponsor and CRO, in the event of clinically significant laboratory abnormalities, such as:
• Neutrophil count < 1.0 x 103/pL but > 0.5 x 103/pL
• Platelet count < 100 x 103/pL but > 50 x 103/pL
• Creatine phosphokinase > 10 x ULN
If the clinically significant laboratory abnormality is considered causally related to the investigational drug by the Investigator, the study treatment will be permanently discontinued. If a causal relationship can be reasonably excluded, study treatment may be resumed when the abnormality has sufficiently normalized. The decision to resume study treatment will be made jointly by the Investigator and the Sponsor MM. ULN is defined by site reference ranges for the purpose of this study.
Missed Doses
All patients should be encouraged to be compliant with treatment [i.e. not miss any doses) during the study. Patients are not permitted to miss any doses from Week 0 through Week 4 inclusive and from Week 12 through Weekl4 inclusive. In the event that a patient misses two doses from Week 6 through Week 10 inclusive, that patient will remain eligible for continued treatment in the study. If a patient misses more than 2 doses between Week 6 and Week 10, in consultation with the Sponsor MM, they will be discontinued from treatment, must complete Week 16/End of Treatment assessments and should be strongly encouraged to continue in the safety follow-up period and complete all visits and assessments. The extent of exposure to study drug, and the number of missed doses will be assessed. A dose is considered as the full set of three [3] injections as specified by the protocol. A patient will be considered compliant with the dosing regimen if the patient received >80% of the expected number of doses while enrolled in the study.
The dosing sequence planned for eblasakimab is shown in Figure 1.
Example 4 - Study Assessments and procedures
EASI
EASI evaluates 4 natural anatomical regions for severity and extent of key disease signs and focuses on the key acute and chronic signs of inflammation (erythema, induration/papulation, excoriation, and lichenification). The maximum total score is 72, with higher values indicating more severe disease. vIGA-AD vIGA allows investigators to assess overall disease severity at one given time point and consists of a 5-point severity scale from clear to very severe disease (0 = clear, 1 = almost clear, 2 = mild disease, 3 = moderate disease, and 4 = severe disease). A participant has vl GA response if they achieve a score of 0 (clear) or 1 (almost clear) and at least a 2 -grade reduction from Baseline.
BSA
The extent (%) to which each the body surface is involved with eczema will be evaluated using the patient’s palm = 1% rule. The patient’s palm is measured from the wrist to the proximal interphalangeal (PIP) and thumb. Estimate the number of patient palms it takes to cover the affected AD area. Add up the number of palms to give a total estimate of the area covered in AD.
Below are estimates when entire areas (anterior and posterior) are covered:
• Head and Neck = 10% (10 palms)
• Upper Extremities = 20% (20 palms)
• Trunk (axillae and groin) = 30% (30 palms)
• Lower extremities (buttocks) = 40% (40 palms)
• Total BSA = 100% (100 palms)
Additional rules:
1. When many small lesions are present, try to put several together to make one patient palm.
2. Only include the area of current lesions, not areas that have cleared.
3. Double check to see if area derived matches eyeball method.
SCORAD
SCORAD is a clinical tool for assessing the severity (that is, extent, intensity) of AD. The tool evaluates the extent and intensity of the AD lesions, along with participant symptoms. The maximum total score is 103, with higher values indicating more severe disease.
Patient Reported Outcomes
Pruritus will be assessed by patients using an 11-point scale NRS (0-10) to assess their worst itch severity over the past 24 hours with 0 = no itch and 10 = worst imaginable itch. Patients will use electronic diaries (e-PRO) to record their daily ratings.
SD-NRS is a single-item, self-reported 11-point scale ranging from zero to 10 for reporting the degree of sleep loss related to AD (Dias-Barbosa C et al 2020).
DLQI is a simple, patient-administered, 10-question, validated, quality-of-life questionnaire that covers 6 domains, including symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment Responses include "not at all” or "not relevant”, "a little", “a lot”, and "very much” with corresponding scores of 0, 1, 2 and 3, respectively (Basra MKA 2008). POEM is a 7-item questionnaire that assesses presence of disease symptoms (dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping) over the last week using a scoring system of 0 (no days) to 4 (every day). The total score ranges from 0 to 28 with higher scores indicating greater intensity of eczema.
EQ-5D-5L essentially consists of 2 pages: the EQ-5D descriptive system and the EQ VAS. The EQ-5D- 5L descriptive system comprises the following five dimensions: mobility, self-care, usual activities, pain/discomfortand anxiety/depression. Each dimension has 5 levels: "no problems”, "slight problems”, "moderate problems”, "severe problems”, and "unable to". The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. This decision results into a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5 -digit number that describes the patient’s health state. The EQ VAS records the patient’s self-rated health on a vertical VAS where the endpoints are labelled ‘Best imaginable health state’ and ‘Worst imaginable health state’. The VAS can be used as a quantitative measure of health outcome that reflects the patient’s own judgement (www.euroqol.org).
HADS is commonly used by doctors to determine the levels of anxiety and depression that a patient is experiencing. The HADS is a 14-item scale. Seven items relate to anxiety and seven relate to depression. Each item on the questionnaire is scored from 0-3 and this means that a person can score between 0 and 21 for anxiety and/or depression.
The ACT is a patient-centered/completed questionnaire that recalls the patient's experience of 5 items: asthma symptoms (nocturnal and daytime), the use of rescue medications, the effect of asthma on daily functioning, and the patient's perception of asthma control over the previous 4 weeks.
Example 5 - Phase 2b Study Update Enrollment
• 135 /295 patients randomized globally across 7 countries (US, CA, SG, IN, AU, PL, NZ)
• In addition, 54 in screening awaiting outcome
• 4 have completed end of study (EOS) visit (Week 28)
• 14/135 (~10%) enrolled with prior dupilumab experience (cap set at 44)
Study progress
• 135 patients have received at least 1 dose
• ~90 patients have received 4 doses (Week 4)
• ~34 patients have received all 9 doses (Week 14)
• ~32 patients have a Week 16 EASI score recorded (primary endpoint)
Baseline characteristics of the patients is shown in Figure 6.
Figure 7 shows the median EASI % change from baseline (CFBL) for the patients from week 0 (commencement of study) to week 20. The data is currently blinded. Nonetheless, this early data suggests a noticeable reduction in EASI score was observed in the treated patients over the course of the study.

Claims

CLAIMS A method of treating inflammatory disease in a human patient, comprising administering multiple doses of an anti-IL-13Ral antibody molecule or antigen binding fragment thereof comprising a VH sequence of SEQ ID NO: 51 or a sequence atleast 95% identical thereto, and VL sequence of SEQ ID NO: 53 or a sequence atleast 95% identical thereto, characterised in that at least one loading dose in the range 400-900mg (for example 400, 500, 600, 700, 800 or 900mg, such as 400 to 600mg in particular 600mg) is employed prior to commencing the "therapeutic” dosing administered once every two, three or four weeks thereafter. A method of treating inflammatory disease in a human patient, comprising administering multiple doses of an anti-IL-13Ral antibody molecule or antigen binding fragment thereof comprising:
CDRH1 comprising an amino acid sequence GYSFTSYWIG (SEQ ID NO: 1]
CDRH2 comprising a sequence VIYPGDSYTR (SEQ ID NO: 2)
CDRH3 comprising the formula:
SEQ ID NO: 3 Xi Pro Asn Trp Gly X6 X7 Asp X9
Xi denotes Phe, Met, Gin, Leu or Vai
X6 denotes Ser or Ala
X7 denotes Phe, Leu, Ala or Met
X9 denotes Tyr, Gin, Lys, Arg, Trp, His, Ala, Thr, Ser, Asn or Gly
CDRL1 is a sequence comprising RASQSISSSYLA [SEQ ID NO: 31).
CDRL2 is a sequence comprising GASSRAT (SEQ ID NO: 32).
CDRL3 comprising the formula:
SEQ ID NO: 33 Gin X2X3X4X5
X2 denotes Gin, Arg, Met, Ser, Thr or Vai
X3 denotes Tyr or Vai
X4 denotes Glu, Ala, Gly or Ser
X5 denotes Thr, Ala or Ser characterised in that at least one loading dose in the range 400-900mg (for example 400, 500, 600, 700, 800 or 900mg, such as 400 to 600mg in particular 600mg) is employed prior to commencing the "therapeutic” dosing administered once every two, three or four weeks. A method according to claim 1 or 2, wherein the loading dose is higher than the therapeutic dose. A method according to any one of claims 1 to 3, wherein a loading dose is a dose which is administered more frequently than the therapeutic dose. A method according to any one of claims 1 to 4, wherein multiple loading doses are employed, for example 1 to 4 loading doses are employed, such as 1, 2, 3 or 4. A method according to claim 5, wherein 1 loading dose is employed. A method according to claim 5, wherein 2 loading doses are employed. A method according to claim 5, wherein 3 loading doses are employed. A method according to any one of claims 1 to 8, wherein the loading dose is 600mg, for example administered as two injections per dose, in particular wherein administration of said two doses is co-located. A method according to any one of claims 1 to 9, wherein the loading dose is administered weekly. A method according to any one of claims 1 to 10, wherein the therapeutic dose is in the range 200 to 600mg.
12. A method according to claim 11, wherein the therapeutic dose is 300 mg.
13. A method according to claim 11, wherein the therapeutic dose is 400mg.
14. A method according to claim 11, wherein the therapeutic dose is 600mg.
15. A method according to any one of claims 1 to 14, wherein the therapeutic dose is commenced 1 to 4 weeks after the last loading dose, for example 1, 2, 3 or 4 weeks after the last loading dose.
16. A method according to any one of claims 1 to 14, wherein the therapeutic dose is administered once every 2 to 4 weeks, for example 2, 3 or 4 weeks.
17. A method according to claim 16, wherein the therapeutic dose is administered once every 2 weeks.
18. A method according to claim 16, wherein the therapeutic dose is administered once every 4 weeks.
19. A method according to any one of claims 1 to 18, wherein the therapeutic dose is administered in a location of a previous dose (where the previous dose is a loading dose, and/or a therapeutic dose],
20. The method according to any one of claims 2 to 19, wherein CDRL3 is SEQ ID NO: 33 or 45.
21. The method according to any one of claims 1 to 20, wherein each dose is administered subcutaneously.
22. The method according to claim any one of claims 1 to 21, wherein the inflammatory disease is atopic dermatitis, for example moderate to severe atopic dermatitis.
23. An anti-IL-13Ral antibody or antigen binding fragment thereof, comprising a VH sequence of SEQ ID NO: 51 or a sequence at least 95% identical thereto, and VL sequence of SEQ ID NO: 53 or a sequence at least 95% identical thereto for use in treatment of an inflammatory disease characterised in that at least one loading dose in the range 400-900mg (for example 400, 500, 600, 700, 800 or 900mg, such as 400 to 600mg in particular 600mg] is employed prior to commencing the "therapeutic” dosing administered once every two, three or four weeks thereafter.
24. Use of an anti-IL-13Ral antibody or antigen binding fragment thereof, comprising a VH sequence of SEQ ID NO: 51 or a sequence at least 95% identical thereto, and VL sequence of SEQ ID NO: 53 or a sequence at least 95% identical thereto in the manufacture of a medicament for treatment of an inflammatory disease characterised in that at least one loading dose in the range 400- 900mg (for example 400, 500, 600, 700, 800 or 900mg, such as 400 to 600mg in particular 600mg] is employed prior to commencing the "therapeutic” dosing administered once every two, three or four weeks.
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