WO2020061571A1 - Anticorps anti-il-33 destiné à être utilisé dans le traitement de l'asthme éosinophile - Google Patents

Anticorps anti-il-33 destiné à être utilisé dans le traitement de l'asthme éosinophile Download PDF

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WO2020061571A1
WO2020061571A1 PCT/US2019/052464 US2019052464W WO2020061571A1 WO 2020061571 A1 WO2020061571 A1 WO 2020061571A1 US 2019052464 W US2019052464 W US 2019052464W WO 2020061571 A1 WO2020061571 A1 WO 2020061571A1
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patient
antibody
binding fragment
antigen binding
dose
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PCT/US2019/052464
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English (en)
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Marco Londei
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Anaptysbio, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • 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
    • 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
    • A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies

Definitions

  • Eosinophilic asthma is a debilitating, chronic atopic disease. The resulting decreased lung function is associated with poor quality-of-life. Approximately 1.1 million US adults diagnosed with severe asthma and cannot be adequately controlled with inhaled corticosteroids and long-acting-beta-agonists (ICS/LABA). Approximately 50% of these patients are estimated to be eosinophilic asthmatics. Thus, there is a significant unmet medical need for an effective treatment regimen with a long functional pharmacological activity for patients with eosinophilic asthma.
  • the invention provides a method of treating eosinophilic asthma in a patient comprising administering to the patient a dose of an anti-IL-33 antibody or antigen binding fragment thereof.
  • the method comprises administering a dose of an anti-IL-33 antibody or antigen binding fragment thereof to the patient not more than once every two weeks, with alternative embodiments utilizing even longer dosing intervals (e.g., not more than once every three weeks, four weeks, six weeks, or eight weeks).
  • Additional embodiments provide methods of selecting a patient with eosinophilic asthma for treatment with an anti-IL-33 antibody or antigen binding fragment thereof, and optionally treating the patient. These methods can be used in conjunction with the method of treating eosinophilic asthma in a patient provided herein.
  • the method of selecting a patient comprises (a) administering an anti-IL-33 antibody or antigen binding fragment thereof to the patient; and (b) comparing the blood eosinophil level of the patient after administration of the anti-IL-33 antibody or antigen binding fragment thereof to the blood eosinophil level of the patient before administration of the anti-IL-33 antibody or antigen binding fragment thereof; wherein the patient is selected for treatment when a decrease in the blood eosinophil level is observed after administration of the anti-IL-33 antibody or antigen binding fragment thereof.
  • the method of selecting a patient comprises measuring the baseline blood eosinophil count of a patient, and selecting the patient for treatment with an anti-IL-33 antibody or antigen binding fragment thereof when the patient has a baseline blood eosinophil count of at least 50 per microliter, at least 100 per microliter, or at least 150 per microliter, at least 200 per microliter, at least 250 per microliter, or at least 300 per microliter.
  • the invention provides anti-IL-33 antibodies and antigen binding fragments, and compositions comprising same, suitable for use in the inventive method.
  • Interleukin-33 (hereinafter referred to as IL-33) is a cytokine of the interleukin- 1 family, which is involved in inflammatory conditions.
  • IL-33 is constitutively expressed in the nuclei of epithelial cells and vascular endothelial cells, is released during cell destruction following tissue injury caused by infections or physical or chemical stress, and then acts as alarmin.
  • the extracellularly released IL-33 binds to IL-33 receptors expressed on cells, thereby being capable of activating intracellular signal transduction.
  • IL-33 receptors are expressed on various immune cells and epithelial cells, where IL-33-induced intracellular signal transduction occurs.
  • IL-33 is believed to induce allergic inflammation (for example, eosinophilic asthma) by inducing production of Th2 cytokines (for example, IL-4, IL-5, IL-6, and IL-13) from Th2 cells, mast cells, eosinophils, basophils, natural killer T (NKT) cells, and Group 2 innate lymphocytes, among immune cells expressing IL-33 receptors (Ohno et al., Allergy, Vol. 67, p. 1203 (2012)).
  • Th2 cytokines for example, IL-4, IL-5, IL-6, and IL-13
  • Increased IL-33 expression is observed in various human inflammatory diseases (for example, rheumatoid arthritis, asthma, systemic sclerosis, fibrosis such as hepatic fibrosis and pulmonary fibrosis, psoriasis, ulcerative colitis, Crohn's disease, multiple sclerosis, and ankylosing spondylitis), and IL-33 is believed to be involved in the development and maintenance of various diseases (see e.g., Matsuyama et al., J. Rheumatology , Vol. 37, p. 18 (2010); Prefontaine et al., J. Allergy Clin. Immunol., Vol. 125, p. 752 (2010); Yanaba et al., Clin. Rheumatol., Vol. 30, p. 825 (2011); and Rankin et al., J. Immunol., Vol. 184, p. 1526 (2010).
  • rheumatoid arthritis for example,
  • IL-33 is believed to be involved in initiation and progression of eosinophilic asthma. Importantly IL-33 has been shown to be the essential molecule consolidating the function of pathogenic Th2 cells both in humans and rodents. IL-33 has been shown to drive Th2 responses in asthma by acting on a series of white cells intrinsically involved in the pathogenesis of atopic disorders. Furthermore, IL-33 is involved in controlling the rapid release of downstream cytokines such as IL-5, IL-4, and IL-13. Additionally, genetic and functional studies have demonstrated the central role of IL-33 and its receptor ST2 in predisposing to the development of eosinophilic asthma in patients and animal models.
  • the invention provides a method of treating eosinophilic asthma in a patient comprising administering to the patient a dose of an anti-IL-33 antibody or antigen binding fragment thereof not more than once every two weeks (e.g., about twice per month).
  • the term“dosing” refers to a single administration of a substance (i.e., IL-33 antibody or antigen binding fragment) to achieve a therapeutic objective.
  • Dosage administration of not more than once every two weeks (or even longer periods) has many advantages over weekly dosing including, but not limited to, a lower number of total injections, decreased number of injection site reactions (e.g., local pain and swelling), increased patient compliance, and lower cost to patients and health care providers.
  • the dosage route is not particularly limited, but subcutaneous dosing is advantageous because the patient may self-administer a therapeutic substance, e.g., an anti-IL-33 antibody or antigen fragment thereof, which is convenient for both the patient and the health care provider.
  • the dosage administration regimen of the inventive method may be adjusted to provide the optimum desired response (e.g., treatment of the patient) and, in some embodiments, even less frequent dosing is required.
  • the inventive method may comprise administering to the patient a dose of an anti-IL-33 antibody or antigen binding fragment thereof, for example, not more than once every three weeks, not more than once every four weeks (e.g., not more than about once every month), not more than once every six weeks, or not more than once every eight weeks (e.g., not more than about once every other month).
  • the method comprises administering to the patient a dose of an anti-IL-33 antibody or antigen binding fragment thereof not more than once every 10 weeks, not more than once every 12 weeks, or even not more than once every 16 weeks.
  • the individual dose of the invention may be a“therapeutically effective amount” or a“prophylactically effective amount” of an antibody or antibody portion of the invention.
  • A“therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result.
  • a therapeutically effective amount of the antibody or antibody portion may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of the antibody or antibody portion to elicit a desired response in the individual.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the antibody or antibody portion are outweighed by the therapeutically beneficial effects.
  • A“prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. The prophylactically effective amount may be less than the
  • An exemplary, non-limiting range for a therapeutically or prophylactically effective dose of an antibody or antibody binding fragment according to the invention is at least about 20 mg, at least about 30 mg, at least about 40 mg, such as at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, or at least about 100 mg.
  • the dose may be as at least about 200 mg, or at least about 300 mg.
  • the dose will be less than about 1000 mg, such as less than about 800 mg, or less than about 700 mg (e.g., less than about 600 mg, less than about 500 mg, or less than about 400 mg).
  • any of the foregoing can also be expressed as ranges (e.g., about 20-1000 mg, 20-800 mg, 20-600 mg, 20-400 mg, 30-1000 mg, 30-800 mg, 30-600 mg, 30- 400 mg, 40- 1000 mg, 40-800 mg, 40-600 mg, 40-400 mg, 50-1000 mg, 50-800 mg, 50-600 mg, 50-400 mg, 60-1000 mg, 60-800 mg, 60-600 mg, 60-400 mg, 70-1000 mg, 70-800 mg, 70-600 mg, 70-400 mg, 80-1000 mg, 80-800 mg, 80-600 mg, 80-400 mg, 100-1000 mg, 100- 800 mg, 100-600 mg, 100-400 mg, 200-1000 mg, 200-800 mg, 200-600 mg, 200-400 mg, 300-1000 mg, 300-800 mg, 300-600 mg, 300-400 mg, etc., including any sub-ranges thereof (e.g., about 250-350 mg., etc. ).
  • the single dose can be about 100
  • dosage values may vary with the type and severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
  • the dosages of the invention may include a“loading dose” and a “maintenance dose” of an antibody or antibody portion of the invention, each of which is in an amount as described above.
  • the loading dose may be higher than the maintenance dose, equivalent to the maintenance dose, or lower than the maintenance dose.
  • the loading dose is four times, three times, two times, one and one half times the maintenance dose, or equal to the maintenance dose.
  • the loading dose might be about 200-400 mg (e.g., about 300 mg), and the maintenance dose might be about 100-200 mg (e.g., about 150 mg).
  • the loading dose can be administered at any time before the first maintenance dose (e.g., at least 1, 2, 3, 5, 7, 10, or 14 days before; in some embodiments less than 3 weeks, less than 4 weeks, less than 8 weeks, or less than 12 weeks before).
  • the anti-IL-33 antibody or antigen binding fragment thereof is administered to a patient treatment according to a schedule, wherein a least one loading dose is first administered, and, then, at least one therapeutically effective maintenance dose is
  • the loading dose may be administered on day 1 and the maintenance dose may be administered not more than once every two weeks (e.g., not more than about twice per month) after administration of the loading dose.
  • the loading dose may be administered on day 1, and the maintenance dose may be administered not more than once every three weeks, not more than once every four weeks (e.g., not more than about once per month), not more than once every six weeks, or not more than once every eight weeks (e.g., not more than about once every other month) after administration of the loading dose.
  • the method could comprise, for instance, administering to an eosinophilic asthma patient a loading dose of an anti-IL-33 antibody or antigen binding fragment thereof of about 200-400 mg (e.g., about 300 mg), optionally subcutaneous, followed by a maintenance dose of about 100-200 mg (e.g., about 150 mg), optionally subcutaneous, about three-five weeks (e.g., four weeks) after the initial loading dose.
  • a loading dose of an anti-IL-33 antibody or antigen binding fragment thereof of about 200-400 mg (e.g., about 300 mg)
  • a maintenance dose of about 100-200 mg (e.g., about 150 mg)
  • optionally subcutaneous about three-five weeks (e.g., four weeks) after the initial loading dose.
  • the patient has a blood eosinophil count of at least 200 per microliter, or at least 300 per microliter, and/or a confirmed clinical diagnosis of moderate- to-severe asthma according to the Global Initiative for Asthma (GINA) 2016, i.e., GINA 4-5.
  • the patients are previously, simultaneously, and/or subsequently administered inhaled corticosteroids (ICS) and/or long-acting beta-2-agonists (LABA).
  • the method of treating eosinophilic asthma has a rapid and persistent effect.
  • This effect can be measured by any suitable metric.
  • one metric is the baseline blood eosinophil count of a patient.
  • Another metric is Forced Exhale Volume in 1 second (FEV1).
  • FEV1 Forced Exhale Volume in 1 second
  • the method of the invention provides a therapeutic effect such that the patient achieves a reduction in the patient’s baseline blood eosinophil count of at least 10%, at least 20%, at least 30%, or even at least 40% within six weeks, preferably within four weeks, more preferably within 3 weeks or even within 2 weeks (e.g., within 5 days) of beginning treatment (e.g., within receiving a first dose of anti-IL-33 antibody or antigen binding fragment thereof).
  • the method provides a therapeutic effect such that a population of at least 100 patients achieves an average reduction in the patient’s baseline blood eosinophil count of at least 10%, at least 20%, at least 30%, or even at least 40% within six weeks, preferably within four weeks, more preferably within 3 weeks or even within 2 weeks of beginning treatment (e.g., within receiving a first dose of anti-IL-33 antibody or antigen binding fragment thereof).
  • the method provides a therapeutic effect such that the patient achieves an increase in the patient’s baseline Forced Exhale Volume in 1 second (FEV1) of at least 5% or at least 10% within six weeks, preferably within four weeks, more preferably within 3 weeks or even within 2 weeks (e.g., within 5 days) of beginning treatment (e.g., within receiving a first dose of anti-IL-33 antibody or antigen binding fragment thereof).
  • FEV1 Forced Exhale Volume in 1 second
  • the method provides a therapeutic effect such that a population of at least 100 patients achieves an average increase in the patient’s baseline Forced Exhale Volume in 1 second (FEV1) of at least 5% or at least 10% within six weeks, preferably within four weeks, more preferably within 3 weeks or even within 2 weeks (e.g., within 5 days) of beginning treatment (e.g., within receiving a first dose of anti-IL-33 antibody or antigen binding fragment thereof).
  • FEV1 Forced Exhale Volume in 1 second
  • the method provides a persistent therapeutic effect such that the patient (or population of patients) maintains the reduced blood eosinophil count and/or improved FEV 1 over a significant period of time.
  • the patient or population of patients maintains the reduced blood eosinophil count and/or improved FEV 1 over a significant period of time.
  • about 20 days or more or even longer e.g., about 30 days or more, about 40 days or more, about 50 days or more, or even about 60 days or more or 90 days or more
  • a dose e.g., a single dose
  • the patient has a reduction in the patient’s baseline blood eosinophil count of at least 10%, at least 20%, at least 30%, or at least 40%.
  • the population of at least 100 patients has an average reduction in the patient’s baseline blood eosinophil count of at least 10%, at least 20%, at least 30%, or at least 40%.
  • about 20 days or more or even longer e.g., about 30 days or more, about 40 days or more, about 50 days or more, or even about 60 days or more or 90 days or more
  • a dose e.g., a single dose
  • the patient has an increase in the patient’s baseline Forced Exhale Volume in 1 second (FEV1) of at least 5% or at least 10%
  • a population of at least 100 patients achieves an average increase in the patient’s baseline Forced Exhale Volume in 1 second (FEV1) of at least 5% or at least 10%.
  • the method of treating a eosinophilic asthma in a patient can further comprise administering inhaled corticosteroids (ICS), optionally high-dose ICS (>1000 meg beclometasone dipropionate equivalent per day), before, after, or simultaneously with the administration of an anti-IL-33 antibody or antigen binding fragment thereof.
  • ICS inhaled corticosteroids
  • high-dose ICS >1000 meg beclometasone dipropionate equivalent per day
  • the method of treating eosinophilic asthma in a patient according to any of the foregoing embodiments can further comprise administering long-acting beta-2-agonists (LABA), before, after, or simultaneously with the administration of an anti-IL-33 antibody or antigen binding fragment thereof.
  • LSA long-acting beta-2-agonists
  • the method of treating eosinophilic asthma in a patient according to any of the foregoing embodiments can further comprise administering inhaled corticosteroids (ICS) and long-acting beta-2-agonists (LABA) co-administered during the same day or week, before, after, or simultaneously with the administration of an anti-IL-33 antibody or antigen binding fragment thereof.
  • ICS inhaled corticosteroids
  • LAA long-acting beta-2-agonists
  • the eosinophilic asthma patient to be treated by the methods provided herein has an eosinophilic blood count of at least 300 per microliter prior to administration of the anti-IL-33 antibody or antigen binding fragment thereof.
  • the patient has a baseline blood eosinophil count of less than 300 per microliter prior to administration of the anti-IL-33 antibody or antigen binding fragment thereof, and optionally wherein the patient has a baseline blood eosinophil count of at least 50 per microliter, at least 100 per microliter, or at least 150 per microliter prior to administration of the anti-IL-33 antibody or antigen binding fragment thereof.
  • the blood eosinophil level of the patient is, optionally, measured 1 week or less after administration of the anti-IL-33 antibody or antigen binding fragment thereof.
  • the patient has (in addition or alternatively to the above blood eosinophil blood count levels) one or more, two or more, or all three of the following characteristics: (a) has a confirmed clinical diagnosis of moderate-to-severe asthma according to the Global Initiative for Asthma (GINA) 2016; (b) has a pre-bronchodilator FEV 1 of less than 80% of predicted FEV1; (c) experienced at least one asthma exacerbation requiring use of rescue medication within 12 months of selection; and (d) has maintained high-dose inhaled corticosteroid (ICS) and long-acting beta-2-agonists (LABA) treatment for at least one month prior to selection, at least two months prior to selection, or at least three months prior to selection.
  • ICS inhaled corticosteroid
  • LAA long-acting beta-2-agonists
  • the method comprises (a) administering an anti-IL- 33 antibody or antigen binding fragment thereof to the patient; and (b) comparing the blood eosinophil level of the patient after administration of the anti-IL-33 antibody or antigen binding fragment thereof to the blood eosinophil level of the patient before administration of the anti-IL-33 antibody or antigen binding fragment thereof; wherein the patient is selected for treatment when a decrease in the blood eosinophil level is observed after administration of the anti-IL-33 antibody or antigen binding fragment thereof.
  • the method of selecting and optionally treating a patient with eosinophilic asthma for treatment with an anti-IL-33 antibody comprises measuring the baseline blood eosinophil count of a patient, and selecting the patient for treatment with an anti-IL-33 antibody or antigen binding fragment thereof when the patient has a baseline blood eosinophil count of at least 50 per microliter, at least 100 per microliter, or at least 150 per microliter, at least 200 per microliter, at least 250 per microliter, or at least 300 per microliter.
  • the blood eosinophil level of the patient is, optionally, measured 1 week or less after administration of the anti-IL-33 antibody or antigen binding fragment thereof.
  • any of the foregoing methods of selection can further comprise selecting the patient if the patient further satisfies one or more, two or more, three or more, or all four of the following criteria:
  • (a) has a confirmed clinical diagnosis of moderate-to-severe asthma according to the Global Initiative for Asthma (GINA) 2016;
  • (b) has a pre-bronchodilator FEV 1 of less than 80% of predicted FEV 1 ;
  • (d) has maintained high-dose inhaled corticosteroid (ICS) and long-acting beta-2- agonists (LAB A) treatment for at least one month prior to selection, at least two months prior to selection, or at least three months prior to selection
  • ICS corticosteroid
  • LAB A long-acting beta-2- agonists
  • the method can optionally further comprise treating such patient with an anti-IL-33 antibody or antigen binding fragment thereof.
  • the patient can be treated according to any of the methods described herein.
  • any of the foregoing methods are not limited to the use of any particular anti-IL- 33 antibody or antibody fragment, provided the antibody or antibody fragment has an effect that is sufficiently rapid and persistent to allow for a therapeutic effect within the dosing parameters described herein.
  • the anti-IL-33 antibody or antigen binding fragment thereof of the inventive method binds to, and neutralizes, IL-33, thereby inhibiting IL-33 activity.
  • the terms“inhibit” or“neutralize,” as used herein with respect to the activity of an anti-IL-33 antibody or antigen binding fragment, refer to the ability to substantially antagonize, prohibit, prevent, restrain, slow, disrupt, alter, eliminate, stop, or reverse the progression or severity of, for example, the biological activity of IL-33, or a disease or condition associated with IL-33, for example, eosinophilic asthma.
  • the inventive method preferably inhibits or neutralizes the activity of IL-33 by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 100%, or a range defined by any two of the foregoing values.
  • the anti-IL-33 antibody or antigen-binding fragment suitable for use in the inventive method can be a whole antibody or an antibody fragment.
  • the terms“fragment of an antibody,”“antibody fragment,” and“functional fragment of an antibody” are used interchangeably herein to mean one or more fragments of an antibody that retain the ability to specifically bind to an antigen (see, generally, Holliger et ah, Nat. Biotech ., 23(9): 1126-1129 (2005)).
  • the anti-IL-33 antibody can contain any anti-IL-33 antibody fragment.
  • the antibody fragment desirably comprises, for example, one or more CDRs, the variable region (or portions thereof), the constant region (or portions thereof), or combinations thereof.
  • antibody fragments include, but are not limited to, (i) a Fab fragment, which is a monovalent fragment consisting of the VL, VH, CL, and CHi domains, (ii) a F(ab’) 2 fragment, which is a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region, (iii) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (iv) a Fab’ fragment, which results from breaking the disulfide bridge of an F(ab’) 2 fragment using mild reducing conditions, (v) a disulfide- stabilized Fv fragment (dsFv), and (vi) a domain antibody (dAb), which is an antibody single variable region domain (VH or VF) polypeptide that specifically binds antigen.
  • a Fab fragment which is a monovalent fragment consisting of the VL, VH, CL, and CHi domains
  • the anti-IF-33 antibody or, in some embodiments, the antigen-binding fragment can comprises a heavy chain constant region (F c ) of any suitable class.
  • the antibody or antibody fragment comprises a heavy chain constant region that is based upon wild-type IgGl, IgG2, or IgG4 antibodies, or variants thereof.
  • anti- IF-33 antibody or antigen-binding fragment comprises an Fc region engineered to reduce or eliminate effector functions of the antibody.
  • Engineered Fc regions with reduced or abrogated effector function are known in the art and commercially available, as are techniques for engineering Fc regions to reduce or eliminate effector function, any of which can be used in conjunction with the invention.
  • the anti-IF-33 antibody or antigen-binding fragment also can be a single chain antibody fragment.
  • single chain antibody fragments include, but are not limited to, (i) a single chain Fv (scFv), which is a monovalent molecule consisting of the two domains of the Fv fragment (i.e., VL and VH) joined by a synthetic linker which enables the two domains to be synthesized as a single polypeptide chain (see, e.g., Bird et ah, Science , 242: 423-426 (1988); Huston et ah, Proc. Natl. Acad. Sci.
  • scFv single chain Fv
  • a diabody which is a dimer of polypeptide chains, wherein each polypeptide chain comprises a VH connected to a VL by a peptide linker that is too short to allow pairing between the VH and VL on the same polypeptide chain, thereby driving the pairing between the complementary domains on different VH - VL polypeptide chains to generate a dimeric molecule having two functional antigen binding sites.
  • Antibody fragments are known in the art and are described in more detail in, e.g., U.S. Patent Application Publication 2009/0093024 Al.
  • the anti-IL-33 antibody or antigen-binding fragment also can be an intrabody or fragment thereof.
  • An intrabody is an antibody which is expressed and which functions intracellularly. Intrabodies typically lack disulfide bonds and are capable of modulating the expression or activity of target genes through their specific binding activity. Intrabodies include single domain fragments such as isolated VH and VL domains and scFvs.
  • An intrabody can include sub-cellular trafficking signals attached to the N or C terminus of the intrabody to allow expression at high concentrations in the sub-cellular compartments where a target protein is located.
  • an intrabody Upon interaction with a target gene, an intrabody modulates target protein function and/or achieves phenotypic/functional knockout by mechanisms such as accelerating target protein degradation and sequestering the target protein in a non- physiological sub-cellular compartment.
  • Other mechanisms of intrabody-mediated gene inactivation can depend on the epitope to which the intrabody is directed, such as binding to the catalytic site on a target protein or to epitopes that are involved in protein-protein, protein-DNA, or protein-RNA interactions.
  • the anti-IL-33 antibody or antigen-binding fragment also can be an antibody conjugate.
  • the anti-IL-33 antibody or antigen-binding fragment can be a conjugate of (1) an antibody, an alternative scaffold, or fragments thereof, and (2) a protein or non-protein moiety comprising the anti-IL-33 antibody or antigen-binding fragment.
  • the anti-IL-33 antibody or antigen-binding fragment can be all or part of an antibody conjugated to a peptide, a fluorescent molecule, or a chemotherapeutic agent.
  • the anti-IL-33 antibody or antigen-binding fragment can be, or can be obtained from, a human antibody, a non-human antibody, or a chimeric antibody.
  • chimeric is meant an antibody or fragment thereof comprising both human and non-human regions.
  • the anti-IL-33 antibody or antigen-binding fragment is a humanized antibody.
  • a “humanized” antibody is a monoclonal antibody comprising a human antibody scaffold and at least one CDR obtained or derived from a non-human antibody.
  • Non-human antibodies include antibodies isolated from any non-human animal, such as, for example, a rodent (e.g., a mouse or rat).
  • a humanized antibody can comprise, one, two, or three CDRs obtained or derived from a non-human antibody.
  • CDRH3 of the inventive anti-IL-33 antibody or antigen-binding fragment may be obtained or derived from a mouse monoclonal antibody, while the remaining variable regions and constant region of the inventive anti-IL-33 antibody or antigen-binding fragment may be obtained or derived from a human monoclonal antibody.
  • a human antibody, a non-human antibody, a chimeric antibody, or a humanized antibody can be obtained by any means, including via in vitro sources (e.g., a hybridoma or a cell line producing an antibody recombinantly) and in vivo sources (e.g., rodents).
  • in vitro sources e.g., a hybridoma or a cell line producing an antibody recombinantly
  • in vivo sources e.g., rodents.
  • Methods for generating antibodies are known in the art and are described in, for example, Kohler and Milstein, Eur. J. Immunol ., 5: 511-519 (1976); Harlow and Lane (eds.), Antibodies: A Laboratory Manual, CSH Press (1988); and Janeway et al. (eds.), Immunobiology, 5th Ed., Garland Publishing, New York, NY (2001)).
  • a human antibody or a chimeric antibody can be generated using a
  • transgenic mice wherein endogenous antibody genes are effectively replaced with human antibody genes include, but are not limited to, the Medarex HUMAB-MOUSETM, the Kirin TC MOUSETM, and the Kyowa Kirin KM- MOUSETM (see, e.g., Lonberg, Nat. Biotechnol., 23(9): 1117-25 (2005), and Lonberg, Handb. Exp. Pharmacol., 181: 69-97 (2008)).
  • a humanized antibody can be generated using any suitable method known in the art (see, e.g., An, Z.
  • a humanized antibody can be produced using the methods described in, e.g., U.S. Patent Application Publication 2011/0287485 Al.
  • a CDR e.g., CDR1, CDR2, or CDR3
  • a variable region of the immunoglobulin heavy chain polypeptide and/or the immunoglobulin light chain polypeptide of the anti-IL-33 antibody or antigen-binding fragment suitable for the inventive method can be transplanted (i.e., grafted) into another molecule, such as an antibody or non antibody polypeptide, using either protein chemistry or recombinant DNA technology.
  • the invention provides an anti-IL-33 antibody or antigen-binding fragment comprising at least one CDR of an immunoglobulin heavy chain and/or light chain polypeptide as described herein.
  • the anti-IL-33 antibody or antigen-binding fragment can comprise one, two, or three CDRs of an immunoglobulin heavy chain and/or light chain variable region as described herein.
  • the anti-IL-33 antibody or antigen binding fragment of the invention may be comprised of an isolated immunoglobulin heavy chain polypeptide and/or an isolated immunoglobulin light chain polypeptide, or a fragment (e.g., antigen-binding fragment) thereof.
  • the term“antibody” or“immunoglobulin” as used herein, refers to a protein that is found in blood or other bodily fluids of vertebrates, which is used by the immune system to identify and neutralize foreign objects, such as bacteria and viruses.
  • an antibody or immunoglobulin is a protein that comprises at least one complementarity determining region (CDR).
  • CDRs form the“hypervariable region” of an antibody, which is responsible for antigen binding.
  • a whole immunoglobulin typically consists of four polypeptides: two identical copies of a heavy (H) chain polypeptide and two identical copies of a light (L) chain polypeptide.
  • Each of the heavy chains contains one N-terminal variable (VH) region and three C-terminal constant (Cnl, CH2, and CH3) regions, and each light chain contains one N-terminal variable (V L ) region and one C-terminal constant (C L ) region.
  • the light chains of antibodies can be assigned to one of two distinct types, either kappa (K) or lambda (l), based upon the amino acid sequences of their constant domains.
  • K kappa
  • l lambda
  • each light chain is linked to a heavy chain by disulfide bonds, and the two heavy chains are linked to each other by disulfide bonds.
  • the light chain variable region is aligned with the variable region of the heavy chain
  • the light chain constant region is aligned with the first constant region of the heavy chain.
  • the remaining constant regions of the heavy chains are aligned with each other.
  • variable regions of each pair of light and heavy chains form the antigen binding site of an antibody.
  • the V H and V L regions have the same general structure, with each region comprising four framework (FW or FR) regions.
  • framework region refers to the relatively conserved amino acid sequences within the variable region which are located between the hypervariable or complementary determining regions (CDRs).
  • CDRs hypervariable or complementary determining regions
  • the framework regions form the b sheets that provide the structural framework of the variable region (see, e.g., C.A. Janeway et al. (eds.),
  • the framework regions are connected by three complementarity determining regions (CDRs).
  • CDRs complementarity determining regions
  • the three CDRs known as CDR1, CDR2, and CDR3, form the
  • variable region of an antibody, which is responsible for antigen binding.
  • the CDRs form loops connecting, and in some cases comprising part of, the beta-sheet structure formed by the framework regions. While the constant regions of the light and heavy chains are not directly involved in binding of the antibody to an antigen, the constant regions can influence the orientation of the variable regions.
  • the constant regions also exhibit various effector functions, such as participation in antibody-dependent complement- mediated lysis or antibody-dependent cellular toxicity via interactions with effector molecules and cells.
  • anti-IL-33 antibodies or antigen binding fragments for use in the method are any of those described in WO 2015/106080 A2, the entire disclosure of which is specifically incorporated herein by reference.
  • the anti-IL-33 antibody or antigen binding fragment thereof comprises an immunoglobulin heavy chain variable region of SEQ ID NO: 7 and/or an immunoglobulin light chain variable region of SEQ ID NO: 8, or at least the complementary determining regions (CDRs) thereof.
  • CDR regions of the heavy chain can be determined according to any available numbering system, such as by Rabat, Chothia, Martin (Enhanced Chothia), Gelfand, Honneger's, or IMGT numbering systems (Wu et al., J Exp Med.
  • the anti-IL-33 antibody or antigen-binding fragment thereof may comprise: a heavy chain variable region comprising a complementary determining region (CDR) 1 domain (CDRL1) comprising the amino acid sequence of SEQ ID NO: 1; a CDRL2 domain comprising the amino acid sequence of SEQ ID NO:2; and a CDRL3 domain comprising the amino acid sequence of SEQ ID NO: 3, and a light chain variable region comprising a CDRH1 domain comprising the amino acid sequence of SEQ ID NO:4; a CDRH2 domain comprising the amino acid sequence of SEQ ID NO:5; and a CDRH3 domain comprising the amino acid sequence of SEQ ID NO: 6.
  • the anti-IL-33 antibody or antibody fragment comprises an immunoglobulin heavy chain variable region of SEQ ID NO: 7 and/or an immunoglobulin light chain variable region of SEQ ID NO: 8.
  • the -IL-33 antibody or antigen-binding fragment thereof comprises an immunoglobulin heavy chain variable region comprising a sufficient identity to SEQ ID NO: 7 and/or an immunoglobulin light chain variable region comprising sufficient identity to SEQ ID NO: 8 to retain substantially the same binding affinity for IL-33.
  • the immunoglobulin heavy chain polypeptide can comprise an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 7
  • the immunoglobulin light chain polypeptide can comprise an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 8.
  • the anti-IL-33 antibody or antigen-binding fragment thereof is an antibody or antibody fragment that competes with an antibody comprising a heavy chain variable region of SEQ ID NO: 7 and a light chain variable region of SEQ ID NO: 8 for binding to IL-33.
  • the anti-IL-33 antibody or antigen binding fragment thereof is an antibody or antibody fragment that competes with ST2 for binding to IL-33.
  • DNAs encoding partial or full-length light and heavy chains, obtained as described above, are inserted into expression vectors such that the genes are operatively linked to transcriptional and
  • translational control sequences In this context, the term“operatively linked” is intended to mean that an antibody gene is ligated into a vector such that transcriptional and translational control sequences within the vector serve their intended function of regulating the
  • the expression vector and expression control sequences are chosen to be compatible with the expression host cell used.
  • the antibody light chain gene and the antibody heavy chain gene can be inserted into separate vector or, more typically, both genes are inserted into the same expression vector.
  • the antibody genes are inserted into the expression vector by standard methods (e.g., ligation of complementary restriction sites on the antibody gene fragment and vector, or blunt end ligation if no restriction sites are present).
  • the expression vector may already carry antibody constant region sequences.
  • one approach to converting the anti-IL-33-related VH and VL sequences to full-length antibody genes is to insert them into expression vectors already encoding heavy chain constant and light chain constant regions, respectively, such that the VH segment is operatively linked to the CH segment(s) within the vector and the VL segment is operatively linked to the CL segment within the vector.
  • the recombinant expression vector can encode a signal peptide that facilitates secretion of the antibody chain from a host cell.
  • the antibody chain gene can be cloned into the vector such that the signal peptide is linked in-frame to the amino terminus of the antibody chain gene.
  • the signal peptide can be an immunoglobulin signal peptide or a heterologous signal peptide (i.e., a signal peptide from a non-immunoglobulin protein).
  • the recombinant expression vectors of the invention carry regulatory sequences that control the expression of the antibody chain genes in a host cell.
  • the term“regulatory sequence” is intended to include promoters, enhancers and other expression control elements (e.g., polyadenylation signals) that control the transcription or translation of the antibody chain genes.
  • Such regulatory sequences are described, for example, in Goeddel; Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, Calif. (1990). It will be appreciated by those skilled in the art that the design of the expression vector, including the selection of regulatory sequences may depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc.
  • Preferred regulatory sequences for mammalian host cell expression include viral elements that direct high levels of protein expression in mammalian cells, such as promoters and/or enhancers derived from cytomegalovirus (CMV) (such as the CMV promoter/enhancer), Simian Virus 40 (SV40) (such as the SV40 promoter/enhancer), adenovirus, (e.g., the adenovirus major late promoter (AdMLP)) and polyoma.
  • CMV cytomegalovirus
  • SV40 Simian Virus 40
  • AdMLP adenovirus major late promoter
  • the recombinant expression vectors which may be suitable for use in the inventive methods may carry additional sequences, such as sequences that regulate replication of the vector in host cells (e.g., origins of replication) and selectable marker genes.
  • the selectable marker gene facilitates selection of host cells into which the vector has been introduced (see e.g., U.S. Pat. Nos. 4,399,216, 4,634,665 and 5,179,017, all by Axel et al.).
  • the selectable marker gene confers resistance to drugs, such as G418, hygromycin or
  • selectable marker genes include the dihydrofolate reductase (DHFR) gene (for use in dhfr host cells with methotrexate selection/amplification) and the neo gene (for G418 selection).
  • DHFR dihydrofolate reductase
  • the expression vector(s) encoding the heavy and light chains is transfected into a host cell by standard techniques.
  • the various forms of the term“transfection” are intended to encompass a wide variety of techniques commonly used for the introduction of exogenous DNA into a prokaryotic or eukaryotic host cell, e.g., electroporation, calcium-phosphate precipitation, DEAE-dextran transfection and the like.
  • anti-IL-33 antibody or antigen binding fragment of the invention in either prokaryotic or eukaryotic host cells, expression of antibodies in eukaryotic cells, and most preferably mammalian host cells, is the most preferred because such eukaryotic cells, and in particular mammalian cells, are more likely than prokaryotic cells to assemble and secrete a properly folded and immunologically active antibody.
  • Prokaryotic expression of antibody genes has been reported to be ineffective for production of high yields of active antibody (Boss, M. A. and Wood, C. R. (1985)
  • Preferred mammalian host cells for expressing the antibodies of the invention include Chinese Hamster Ovary (CHO cells) (including dhfr CHO cells, described in Urlaub and Chasin, (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220, used with a DHFR selectable marker, e.g., as described in R. J. Kaufman and P. A. Sharp (1982) Mol. Biol. 159:601-621), NSO myeloma cells, COS cells and SP2 cells.
  • Chinese Hamster Ovary CHO cells
  • dhfr CHO cells described in Urlaub and Chasin, (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220
  • a DHFR selectable marker e.g., as described in R. J. Kaufman and P. A. Sharp (1982) Mol. Biol. 159:601-621
  • NSO myeloma cells COS cells and SP2 cells.
  • the antibodies When recombinant expression vectors encoding antibody genes are introduced into mammalian host cells, the antibodies are produced by culturing the host cells for a period of time sufficient to allow for expression of the antibody in the host cells or, more preferably, secretion of the antibody into the culture medium in which the host cells are grown. Antibodies can be recovered from the culture medium using standard protein purification methods.
  • Host cells can also be used to produce portions of intact antibodies, such as Fab fragments or scFv molecules. It will be understood that variations on the above procedure are within the scope of the present invention. For example, it may be desirable to transfect a host cell with DNA encoding either the light chain or the heavy chain (but not both) of an antibody of this invention. Recombinant DNA technology may also be used to remove some or all of the DNA encoding either or both of the light and heavy chains that is not necessary for binding to IF-33. The molecules expressed from such truncated DNA molecules are also encompassed by the antibodies of the invention.
  • bifunctional antibodies may be produced in which one heavy and one light chain are an antibody of the invention and the other heavy and light chain are specific for an antigen other than IF-33 by crosslinking an antibody of the invention to a second antibody by standard chemical crosslinking methods.
  • a recombinant expression vector encoding both the antibody heavy chain and the antibody light chain is introduced into dhfr CHO cells by calcium phosphate-mediated transfection.
  • the antibody heavy and light chain genes are each operatively linked to CMV enhancer/ AdMLP promoter regulatory elements to drive high levels of transcription of the genes.
  • the recombinant expression vector also carries a DHFR gene, which allows for selection of CHO cells that have been transfected with the vector using methotrexate selection/amplification.
  • the selected transformant host cells are culture to allow for expression of the antibody heavy and light chains and intact antibody is recovered from the culture medium. Standard molecular biology techniques are used to prepare the recombinant expression vector, transfect the host cells, select for transformants, culture the host cells and recover the antibody from the culture medium.
  • the anti-IL-33 antibody or antigen binding fragment of the inventive method can be formulated into a composition, such as a pharmaceutical composition, for administration to a patient.
  • the pharmaceutical composition comprises the antibody or antigen binding fragment thereof of the invention and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible and are suitable for administration to a subject for the methods described herein.
  • pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof.
  • isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
  • Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the antibody or antibody portion.
  • compositions of this invention may be in a variety of forms. These include, for example, liquid, semi- solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. Typical preferred compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with other antibodies.
  • the preferred mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular).
  • the anti-IL-33 antibody or antigen binding fragment thereof is administered by intravenous infusion or injection.
  • the antibody is administered by intramuscular injection.
  • the antibody is administered by subcutaneous injection.
  • compositions typically must be sterile and stable under the conditions of manufacture and storage.
  • the composition can be formulated as a solution,
  • Sterile injectable solutions can be prepared by incorporating the active compound (i.e., antibody or antigen binding fragment) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.
  • the active compound may be prepared with a carrier that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
  • a carrier that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyethylene glycol (PEG), polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are patented or generally known to those skilled in the art. See, e.g., Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.
  • inventive methods can provide any amount of any level of treatment or prevention of eosinophilic asthma.
  • “prevention” can encompass delaying the onset of the disease, or a symptom or condition thereof.
  • ICS corticosteroids
  • LAA beta-2-agonists
  • ACQ-5 Asthma Control Questionnaire 5
  • Etokimab-dosed patients rapidly improved lung function by Day 2, where FEV 1 increased by 8% over placebo.
  • FEV1 increase was sustained at Day 64, where etokimab- dosed patients demonstrated 11% increase over placebo.
  • the FEV 1 increase over placebo dissipated by Day 106, but ultimately, by Day 127, etokimab-dosed patients demonstrated 5% increase over placebo.
  • ACQ-5 scores which comprise patient-reported outcomes associated with asthma symptoms, decreased in the etokimab-dosed patients by 0.52 over placebo at Day 8, were sustained to 0.54 over placebo at Day 64, and maintained at 0.41 over placebo at Day 127.
  • the etokimab-dosed patients achieved the minimal clinically important difference (MCID) of 0.5 below baseline. [0069] Therefore, single dose of etokimab resulted in rapid and sustained improvement in FEV1 and ACQ-5 reduction through at least Day 64.
  • Blood eosinophil reduction which is a biomarker illustrative of etokimab’ s mechanistic breadth, was observed at 31% over placebo at Day 2, sustained to 46% over placebo at Day 64, and maintained at 8% over placebo at Day 127.

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Abstract

L'invention concerne des procédés de traitement de l'asthme, notamment l'asthme éosinophile, chez un patient avec un anticorps anti-IL-33, et des procédés de sélection de patients asthmatiques pour une thérapie anti-IL-33.
PCT/US2019/052464 2018-09-21 2019-09-23 Anticorps anti-il-33 destiné à être utilisé dans le traitement de l'asthme éosinophile WO2020061571A1 (fr)

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