WO2023048651A1 - Procédé de traitement de la dermatite atoptique modérée à grave - Google Patents

Procédé de traitement de la dermatite atoptique modérée à grave Download PDF

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Publication number
WO2023048651A1
WO2023048651A1 PCT/SG2022/050694 SG2022050694W WO2023048651A1 WO 2023048651 A1 WO2023048651 A1 WO 2023048651A1 SG 2022050694 W SG2022050694 W SG 2022050694W WO 2023048651 A1 WO2023048651 A1 WO 2023048651A1
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Prior art keywords
antibody
binding fragment
antigen binding
day
atopic dermatitis
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PCT/SG2022/050694
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English (en)
Inventor
Alison Ward
Ferda CEVIKBAS
Karen Veverka
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Aslan Pharmaceuticals Pte Ltd
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Priority claimed from PCT/SG2022/050102 external-priority patent/WO2022186772A1/fr
Priority claimed from PCT/SG2022/050103 external-priority patent/WO2022186773A1/fr
Application filed by Aslan Pharmaceuticals Pte Ltd filed Critical Aslan Pharmaceuticals Pte Ltd
Publication of WO2023048651A1 publication Critical patent/WO2023048651A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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

Definitions

  • the present disclosure relates to use of an anti-IL-13R ⁇ 1 antibody or a binding fragment thereof and pharmaceutical formulations comprising same to treat patients with atopic dermatitis (such as lesional atopic dermatitis) including a patient population that received prior treatment wit dupilumab, for example to stimulate disease modification.
  • atopic dermatitis such as lesional atopic dermatitis
  • a patient population that received prior treatment wit dupilumab, for example to stimulate disease modification.
  • 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-13R ⁇ l.
  • An effective antibody antagonist to IL-13R ⁇ l may also interfere with the binding of IL-13 and prevent heterodimerization of IL-4Ra and IL-13R ⁇ l.
  • Such an antibody could inhibit signaling of both IL-13 and IL-4 through the type II receptor 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 duringwhich Th2 cells differentiate. T cells do notexpress IL-13Rod so the type II receptor plays no role in Th2 differentiation.
  • an IL-13R ⁇ l antibody should 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.
  • blockade of the type II receptor should have a beneficial effect on many of the symptoms of allergic type disease, such as asthma, atopic dermatitis and other IL-13R-mediated conditions and should, therefore, be an effective disease modifying agent
  • Antibodies against IL-13R ⁇ l have been described in the art; see, eg, WO 97/15663, WO 03/80675; WO 03/46009; WO 06/072564; Gauchat et a/, 1998 Eur. J. Immunol. 28:4286-4298; Gauchat et a/, 2000 Eur. J. Immunol. 30:3157-3164; Clement et al, 1997 Cytokine 9(11) :959 (Meeting Abstract); Ogata et al, 1998 J. Biol. Chem. 273:9864-9871; Graber et al, 1998 Eur. J. Immunol.
  • Eblasakimab has been shown to bind to human IL-13R ⁇ l with a high affinity (for example Kd may be 500pM).
  • EBLASAKIMAB was shown to effectively antagonise IL-13 function through inhibiting the binding of IL- 13 to its receptor IL-13R ⁇ l 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.
  • Atopic dermatitis can be a very painful, demoralising and psychologically damaging disease.
  • One method of assessing the disease is the EASI score. The score is in the range 0-72.
  • Dupixent is an antibody inhibitor of the interleukin-4 receptor alpha (IL-4R ⁇ x, which is licensed for the treatment of atopic dermatitis.
  • IL-4R ⁇ x interleukin-4 receptor alpha
  • patients prescribed dupilumab stop treatment for one or more reasons, such as adverse side effects, inadequate control of symptoms and/or problems with dosing. This leaves some patients with in moderate to severe topic dermatitis in position where they don’t have suitable treatment
  • Moderate atopic dermatitis generally has a score in the range 7.1 to 21.0.
  • Severe atopic dermatitis has scope of 21.1 or above. Sometimes severe atopic dermatitis is divided into severe and very severe disease and these groups have the range 21.1 to 50 and 50.1 to 72.0 respectively.
  • the inventors have performed clinical trials and have a establishedthat whilst a whole range of atopic dermatitis patients may benefit from the treatment with an antibody or antigen binding fragment thereof, which is an inhibitor of signalling through of the IL-13R ⁇ l by binding the said receptor, it seems that those with a baseline EASI score of at least 16 may get the most benefit from the treatment and/or patients with lesional atopic derma.
  • the present invention provides a new patient population, for example patients that have had prior treatment with dupilumab and/or patients with lesional atopic dermatitis.
  • the baseline EASI score is combined with one or more other markers, such as baseline IgE, TARC and STAT6 to define the patient population. Surprisingly these patients show the greatest improvements with treatment according to the present disclosure.
  • the treatment is disease modifying.
  • TARC normal levels of TARC in healthy individuals is usually up to 450pg/ml.
  • IL-13Ralpha-l is upregulated in lesional atopic dermatitis so patients with lesional atopic dermatitis may especially benefit from treatment with an anti-IL-13 antibody, such as eblasakimab (for example as an independent aspect or as an embodiment of moderate/sever atopic dermatitis).
  • Non- lesional AD has immune abnormalities including expansion of T-cells. It has a variable immune phenotype, which is largely determined by disease extent and severity. There is decreased hydration and impaired synthesis of lipids have been found in non-lesional atopic skin in comparison to normal skin. There is also abnormal epidermal proliferation in non-lesional atopic dermatitis with increased expression of the proliferation marker (keratin 16), in association with altered expression of terminal differentiation proteins, including loricrin (LOR), involucrin (IVL), and FLG. Additionally, an increased infiltrate of inflammatory T-cells has been demonstrated in non- lesional atopic dermatitis skin compared to skin from healthy volunteers. In one embodiment non- lesional atopic dermatitis is characterised by the absence of lesions.
  • lesional AD is characterised by lesions.
  • An antibody or antigen binding fragment thereof which is an inhibitor of signalling through of the IL-13R ⁇ l by binding the said receptor, for use in the treatment of moderate, severe or very severe atopic dermatitis [in particular poorly controlled moderate to severe atopic dermatitis) by parenteral administration of a treatment cycle comprising a dose in the range 200mg to 600mg, [such as 400 to 600mg), 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).
  • a method of treatment by parenteral administration of a treatment cycle comprising a dose in the range 200mg to 600mg, (such as 400 to 600mg) of an antibody or antigen binding fragment thereof, which is an inhibitor of signalling through of the IL-13R ⁇ 1 by binding the said receptor, to a patient with moderate atopic dermatitis, severe or very severe atopic dermatitis
  • 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).
  • IB An antibody or antigen binding fragment thereof, which is an inhibitor of signalling through of the IL-13R ⁇ 1 by binding the said receptor, for use in the manufacture of a medicament for the treatment of moderate, severe or very severe atopic dermatitis (in particular poorly controlled moderate to severe atopic dermatitis) by parenteral administration of a treatment cycle comprising a dose in the range 200mg to 600mg, (such as 400 to 600mg), 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).
  • An antibody or antigen binding fragment thereof which is an inhibitor of signalling through of the IL-13R ⁇ 1 by binding the said receptor, for use in the treatment lesional atopic dermatitis (in particular poorly controlled moderate to severe atopic dermatitis) by parenteral administration of a treatment cycle comprising a dose in the range 200mg to 600mg, (such as 400 to 600mg).
  • the baseline TARC level is at least 701pg/ml, for example in the range 800 to 52,000pg/ml (such as 800, 900, 1,000, 1500, 2,000, 2,500, 3,000, 3,500, 4,000, 4,500, 5,000, 5,500, 6,000, 6,500, 7,000, 7,500, 8,000, 8,500, 9,000, 9,500, 10,000, 11,000, 12,000, 13,000, 14,000, 15,000, 16,000, 17,000, 18,000, 19,000, 20,000, 21,000, 22,000, 23,000, 24,000, 25,000, 26,000, 27,000, 28,000, 29,000, 30,000, 31,000, 32,000, 33,000, 34,000, 35,000, 36,000, 37,000, 38,000, 39,000, 40,000, 41,000, 42,000, 43,000, 44,000, 45,000, 46,000, 47,000, 48,000, 49,000, 50,000, 51,000 or 52,000pg/ml), in particular at least l,115pg
  • the baseline IgE levels are at a level of at least 13 OkU/L for example at 15 OkU/L such as 150 to 20, 000, more specifically 130, 150, 200, 300, 400, 500, 600, 700, 750, 800, 850, 900, 950, 1000, 1500, 2,000, 2,500, 3,000, 3500, 4,000, 4,500, 5,000, 5,500, 6,000, 6,500, 7,000, 7,500, 8,000, 8,500, 9,000, 9,500, 10,000, 11,000, 12,000, 13,000, 14,000, 15,000, 16,000, 17,000, 18,000, 19,000, 20,000kU/L, in particular at 10,000 KU/L +/-2,000.
  • the antibody or antigen binding fragment thereof, method or use according to any preceding paragraph, wherein the atopic dermatitis is severe for example with an EASI scope 21.1 or above, such as 21.1 to 50.0.
  • the antibody or binding fragment thereof, method or use according to any preceding paragraph, wherein there is a reduction from baseline in EASI score is in the range 15 to 60% (for example at about day 15), for example 25 to 60% (such as 39 to 59% in particular 40 to 59, more specifically 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58 or 59%) especially at about day 15.
  • the antibody or binding fragment thereof, method or use according to any preceding paragraph, wherein there is a reduction from baseline in EASI score is in the range 50 to 100% (for example 55 to 97%) in particular at about day 29.
  • An antibody or antigen binding fragment thereof or use according to any preceding paragraph, wherein there is a reduction in EASI score is in the range -40 to -85% (for example at about day 29).
  • the antibody or binding fragment thereof according to any preceding paragraph, wherein the reduction from baseline in EASI score is in the range 60 to 100% (for example 70 to 97%) in particular at about day 43.
  • an antibody or antigen binding fragment thereof according to any preceding paragraph wherein the reduction in EASI score is in the range -25 to -85% (for example at about day 43 or 57).
  • the antibody or binding fragment thereof, method or use according to any preceding paragraph, wherein there is a reduction from baseline in EASI score is in the range 65 to 100% (for example 70 to 100, such as 90 to 100, in particular 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100%) more specifically at about day 57.
  • the antibody or binding fragment thereof, method or use according to any preceding paragraph wherein 80% of the patient population has an EASI 50 score or less at about day 29 and/or day 57, in particular where the dosing of at least 350mg (such as 400mg) was employed.
  • the antibody or binding fragment thereof, method or use according to any preceding paragraph wherein 90% ofthe patient population has an EASI 50 score or less at about day 57, in particular where dosing of at least 550mg (such as 600mg) was employed.
  • the antibody or antigen binding fragment thereof, method or use according to any preceding paragraph wherein there is at least a 20% reduction from baseline in IgE by day 57, such as about 20 to 60% reduction from baseline.
  • the antibody or antigen binding fragment thereof, method or use according to any preceding paragraph wherein there is at least a 50% reduction from baseline in TARC, for example by about day 15.
  • the antibody or antigen binding fragment thereof, method or use according to any preceding paragraph wherein there is at least a 60% reduction in TARC from baseline, for example by about day 36.
  • the antibody or antigen binding fragment thereof, method or use according to any preceding paragraph wherein there is at least a 70% reduction in TARC from baseline, for example by about day 50.
  • the antibody or antigen binding fragment thereof, method or use according to any preceding paragraph wherein there is at least an 80% reduction in TARC from baseline, for example by about day 57.
  • maintenance therapy is administered, for example the same dose administered less frequently (for example monthly, such as 4 weekly, 5 weekly, 6 weekly, 7 weekly, 8 weekly), or a lower dose (such as 200mg) administered the same frequency or less frequently (such as about weekly, two weekly, about three weekly, or about four weekly.
  • a loading dose for example the range 400 to 900mg, such as 400, 500, 600, 700, 800 or 900mg
  • an antibody or antigen binding fragment thereof, method or use according to any preceding paragraph, wherein the dose is 200mg.
  • the antibody or binding fragment thereof, method or use according to any one of paragraphs 1, 1A, IB, 1C to 44, wherein the dose is in the range 350 to 450mg, such as 400mg.
  • the antibody or binding fragment thereof, method or use according to any preceding paragraphs, wherein the treatment cycles comprises, a first dose at 600mg, followed by three weekly doses of 400mg, for example wherein the treatment cycle is repeated twice i.e.
  • day 1 600mg, approximately day 8 400mg, approximately day 15 400mg, approximately day 22 400mg, approximately day 29 600mg, approximately day 36 400mg, approximately day 43 400mg, and approximately day 50400mg are administered.
  • day 4 wherein day 1 is the first administration of the antibody or binding fragment thereof.
  • the antibody or binding fragment thereof, method or use according to any preceding paragraph, wherein the disease modification is a reduction from baseline in: a.
  • EASI score for example wherein the reduction is a percentage from base line, for example the reductions is in the range 10 to 55%; and/or b. TARC, for example as described elsewhere herein; and/or c. IgE, for example as described elsewhere herein.
  • the anti-IL-13R antibody comprises a VH domain comprising an amino acid sequence shown in SEQ ID NO: 51 or a sequence at least 95% identical thereto.
  • the anti-IL-13R antibody comprises 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 anti-IL-13R antibody comprises a VL domain comprising an amino acid sequence shown in SEQ ID NO: 53 or a sequence at least 95% identical thereto.
  • 50 mM to 150 mM of arginine for example 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145 or 150, such as 100 mM arginine;
  • 15 to 25 mM histidine buffer for example 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25, such as 20 mM histidine buffer;
  • a non-ionic surfactant such as 0.02% w/v and wherein the pH of the formulation is in the range 5.5 to 7.5 for example 6.2 to 7.2 (such as 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2), such as 6.5 to 7.0, in particular 6.4 to 6.9)
  • the formulation comprises 50 to 150 mM of NaCl, for example50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, such as 62.5 or 140 mM NaCl.
  • the moderate to severe atopic dermatitis (such as severe AD), is lesional atopic dermatitis.
  • Also provided is method of treating a patient for atopic dermatitis (for example moderate to severe atopic dermatitis, in particular poorly controlled moderate to severe atopic dermatitis) according to the present disclosure comprising administering an antibody or antigen binding fragment thereof, or pharmaceutical formulation disclosed herein.
  • atopic dermatitis for example moderate to severe atopic dermatitis, in particular poorly controlled moderate to severe atopic dermatitis
  • Poorly controlled as employed herein refers to poor controlled by existing approved medicaments, for example topical medicine, oral medicines and/or biological medicines such as dupilumab (in particular topical medicine or dupilumab).
  • Eblasakimab has a comparable or in some cases a higher efficacy compared to Dupilumab, thus demonstrating the potential of ablasakimab as an alternative therapy for the treatment and management of atopic dermatitis, in particular for patients that have previously taken dupilumab.
  • the patient population is those who received prior treatment with dupilumab, in particular a patient that has failed with dupilumab.
  • an antibody or antigen binding fragment or an pharmaceutical formulation disclosed herein for use in the manufacture of a medicament for the treatment of atopic dermatitis according to the present disclosure.
  • combination therapy comprising the antibody, antigen binding fragment thereof or a formulation according to the present disclosure and a further medicament.
  • the further medicament is for the treatment of atopic dermatitis, for example topical steroids, oral steroids, and/or antihistamines.
  • disease modification following treatment with an anti IL-13R ⁇ 1 antibody or binding fragment thereof according to the present disclosure closely follows reduction in TARC, in fact the TARC reduction and EASI reduction correlate closely in treatment according to the present disclosure.
  • Disease modification as employed herein relates to improvements in the disease status, in particular a reduction in the EASI score. In one embodiment this reduction is maintained for at least a period even after treatment is stopped.
  • Baseline as employed herein refers to the levels before treatment according to the present disclosure commences. Generally, the baseline is measured and/or recorded.
  • Loading dose refers to a dose higher than the "normal doses” in the treatment cycle.
  • a loading dose is usually employed to load the patient’s system with drug so that when subsequent doses are administered the levels in the requisite tissue are maintained at or above a minimum predefined level.
  • “About day” as employed herein means administration approximately at the day, for example +/- 1, 2, 3, 4, 5, 6 or 7 days. Doses early in the treatment cycle may need to be administered close to the specified day, for example +/- 1 day. Later doses may be allowed more latitude i.e. +/- up to 7 days.
  • Atopic dermatitis as employed herein refers to inflammation of the skin and includes: dry/itchy skin and red rashes.
  • Moderate to severe atopic dermatitis are defined by one or more, such as all the parameters defined herein.
  • Severe atopic dermatitis includes very severe atopic dermatitis. Very severe atopic dermatitis is a subset of atopic dermatitis.
  • IGA global assessment
  • Interleukin- 13 receptor as used herein is a type I cytokine receptor, which binds to Interleukin- 13. It consists of two subunits, encoded by IL13R ⁇ 1 and IL4R, respectively. These two genes encode the proteins IL-13R ⁇ 1 and IL-4Ra. These form a dimer with IL-13 binding to the IL- 13R ⁇ l chain and IL-4R ⁇ stabilises this interaction. Due to the presence of the IL4R subunit, IL13R can also instigate IL-4 signalling.
  • IL-13R ⁇ 2 previously called IL-13R and IL-13R ⁇ , is another receptor which is able to bind to IL-13. However, in contrast to IL-13R ⁇ 1, this protein binds IL-13 with high affinity, but it does not bind IL-4. Human IL-13R ⁇ 2 has the Uniprot number Q14627.
  • CDRH1 comprises an amino acid sequence GYSFTSYWIG (SEQ ID NO: 1). In one embodiment CDRH2 comprises an amino acid sequence VIYPGDSYTR (SEQ ID NO: 2).
  • CDRH3 comprises the formula:
  • Xi denotes Phe, Met, Gin, Leu or Vai
  • X ft denotes Ser or Ala
  • X 7 denotes Phe, Leu, Ala or Met
  • X 9 denotes Tyr, Gin, Lys, Arg, Trp, His, Ala, Thr,
  • the IL13-Rlccl antibody or 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-IL13R 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 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.
  • CDRL1 is an amino acid sequence comprising RASQSISSSYLA SEQ ID NO: 31.
  • CDRL2 is an amino acid sequence comprising GASSRAT SEQ ID NO: 32
  • CDL3 comprises the formula:
  • X 2 denotes Gin, Arg, Met, Ser, Thr or Vai.
  • X3 denotes Tyr or Vai.
  • X4 denotes Glu, Ala, Gly or Ser.
  • X 5 denotes Thr, Ala or Ser.
  • the IL-13R ⁇ 1 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-IL-13R ⁇ antibody or binding fragment employed in the present disclosure comprises a CDRL1 comprising an amino acid sequence SEQ ID NO: 31, a CDRL2 comprising an amino acid sequence SEQ ID NO: 32, and a CDRL3 comprising an amino acid sequence as set forth in SEQ ID NO: 33.
  • the anti-IL-13R ⁇ antibody of the present disclosure comprises a VL CDR1 comprising an amino acid sequence SEQ ID NO: 84, a VL CDR2 comprising an amino acid sequence SEQ ID NO: 85, and a VL CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 34 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, or 47.
  • the anti-IL-13R ⁇ antibody of the present disclosure comprises a CDRL1 comprising an amino acid sequence SEQ ID NO: 31, a CDRL2 comprising an amino acid sequence SEQ ID NO: 32, and a CDRL3 comprising an amino acid sequence as set forth in SEQ ID NO: 45.
  • the anti-IL13R antibody of 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: or 3, a CDRL1 comprising an amino acid sequence SEQ ID NO: 31, a CDRL2 comprising an amino acid sequence SEQ ID NO: 32, and a CDRL3 comprising an amino acid sequence as set forth in SEQ ID NO: 33.
  • the anti-IL13R antibody of 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: 3 or 10, a CDRL1 comprising an amino acid sequence SEQ ID NO: 31, a CDRL2 comprising an amino acid sequence SEQ ID NO: 32, and a CDRL3 comprising an amino acid sequence as set forth in SEQ ID NO: 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, or 47.
  • the anti-IL13R antibody of 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: 3 or 10, a CDRL1 comprising an amino acid sequence SEQ ID NO: 31, a CDRL2 comprising an amino acid sequence SEQ ID NO: 32, and a CDRL3 comprising an amino acid sequence as set forth in SEQ ID NO: 45.
  • the anti-IL13R antibody of 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, a CDRL1 comprising an amino acid sequence SEQ ID NO: 31, a CDRL2 comprising an amino acid sequence SEQ ID NO: 32, and a CDRL3 comprising an amino acid sequence as set forth in SEQ ID NO: 45.
  • SEQ ID NO: 51 EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTIS ADKSISTAYLQWSSLKASDTAMYYCARMPNWGSLDHWGQGTLVTVSS, or a sequence at least 95% identical to any one of the same.
  • SEQ ID NO: 55 (null sequence) or a sequence at least 95% identical to any one of the same (* K deleted in a post translational modification).
  • 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, SEQ ID NO: 54 or SEQ ID NO: 55 (or a sequence at least 95% identical to any one of the 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, SEQ ID NO: 54 or SEQ ID NO: 55 (or a sequence at least 95% identical to any one of the 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, SEQ ID NO: 54 or SEQ ID NO: 55 (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, SEQ ID NO: 54 or SEQ ID NO: 55 (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, SEQID NO: 49, SEQ ID NO: 50 or SEQID 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 VL sequence is SEQ ID NO: 55 (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).
  • 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 atleast 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: SEQ ID NO: 56 EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGVIYPGDSYTRYSPSFQGQVTIS ADKSISTAYLQWSSLKASDTAMYYCARMPNWGSFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTA ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVD KRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYVDGVEVHN AKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY
  • the heavy chain is independently selected from SEQ ID NO: 56, 57, 58, 59, 60 and 61 [or a sequence at least 95% identical to any one of the same) and the light chain is independently selected from SEQ ID NO: 62, 63 and 64 (or a sequence at least 95% identical to any one of the same).
  • the heavy chain is SEQ ID NO: 56 (or a sequence atleast 95% identical thereto] and the light chain is independently selected from SEQ ID NO: 62, 63 and 64 (or a sequence at least 95% identical to any one of the same).
  • the heavy chain is SEQ ID NO: 57 (or a sequence atleast 95% identical thereto) and the light chain is independently selected from SEQ ID NO: 62, 63 and 64 (or a sequence at least 95% identical to any one of the same).
  • the heavy chain is SEQ ID NO: 58 (or a sequence atleast 95% identical thereto) and the light chain is independently selected from SEQ ID NO: 62, 63 and 64 (or a sequence at least 95% identical to any one of the same).
  • the heavy chain is SEQ ID NO: 59 (or a sequence atleast 95% identical thereto) and the light chain is independently selected from SEQ ID NO: 62, 63 and 64 (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: 62, 63 and 64 (or a sequence at least 95% identical to any one of the same).
  • the heavy chain is SEQ ID NO: 61 (or a sequence at least 95% identical thereto) and the light chain is independently selected from SEQ ID NO: 62, 63 and 64 (or a sequence at least 95% identical to any one of the same).
  • the heavy chain is SEQ ID NO: 59 or 61 (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: 62 (or a sequence at least 95% identical thereto).
  • the heavy chain is SEQ ID NO: 59 (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: 62 (or a sequence at least 95% identical thereto).
  • the heavy chain is SEQ ID NO: 61 (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: 62 (or a sequence at least 95% identical thereto).
  • 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., atan 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 may be 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 US 5,585,089; 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 etal., 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.
  • 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 Bl, US 5,545,806, US 5,569,825, US 5,625,126, US 5,633,425, US 5,661,016, US5,770,429, EP 0438474 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-IL13R antibody may comprise one or more constant regions, such as a naturally occurring constant domain or a derivate of a naturally occurring domain.
  • 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.
  • an antibody for use in the present invention 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 of 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 et al., 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 U.S. Patent No. 4,741,900 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.
  • polymers include lactose, amylose, dextran, glycogen or derivatives thereof.
  • derivatives as used herein is intended to include reactive derivatives, for example thiol- selective 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.
  • 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 (see for example US 5,219,996; US 5,667,425; WO98/25971, W02008/038024).
  • 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 formulation herein is administered in combination with another therapy.
  • Treatment refers to amelioration of symptoms or conditions of a disease including stabilising disease and/or sending disease into remission, rendering flares less likely to occur and similar, in particular without eliciting dose limiting side effects.
  • Suitable therapeutic doses are generally a balance between therapeutic effect and tolerable toxicity, for example where the side-effect and toxicity are tolerable given the benefit achieved by the therapy.
  • an antibody or antigen binding fragment thereof which is an inhibitor of signalling through of the IL-13R ⁇ 1 by binding the said receptor, for use in the treatment of atopic dermatitis (moderate, severe or very severe atopic dermatitis in particular poorly controlled moderate to severe atopic dermatitis) by parenteral administration of a treatment cycle comprising a dose in the range 200mgto 600mg, (such as 400 to 600mg), wherein occurrence conjunctivitis is minimised, for example as detailed herein.
  • Conjunctivitis can be a side effect of biological treatments for atopic dermatitis.
  • side effects are minimised in therapy according to the present disclosure, in particular no such side effects were observed with Eblasakimab treatment
  • a formulation according to the present disclosure is administered monthly, for example in a treatment cycle or as maintenance therapy.
  • “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.
  • Figure 1A shows patient demographics of full analysis set
  • Figure 1C shows base line characteristics of data evaluable for efficacy
  • Figure 2 A shows % change from baseline in EASI score at day 57
  • Figure 2B shows % change from baseline in EASI score at day 57.
  • Figure 2C shows % change from baseline in EASI score at day 57
  • Figure 3 A shows % change from baseline in EASI score at day 29
  • Figure 3B shows % change from baseline in EASI score at day 29
  • Figure 4A shows % change from baseline in EASI score over time
  • Figure 4B shows % change from baseline in EASI score over time
  • Figure 5A shows % change from baseline in EASI score over time for individual patients
  • Figure 5B shows % change from baseline in EASI score over time for individual patients 200mg
  • Figure 5C show % change from baseline in EASI score over time for individual patients 400mg
  • Figure 5D show % change from baseline in EASI score over time for individual patients 600mg
  • Figure 6A shows day 57 sensitivity analysis in the mITT
  • Figure 6B shows sensitivity analysis in the mITT (200, 400 and 600mg)
  • Figure 6C shows analysis it in the mITT (low dose and high dose]
  • Figure 7A shows EASI 50, EASI 75 and EASI 90 at day 57
  • Figure 7B shows EASI 50 at day 57 (200, 400 and 600mg)
  • Figure 7C shows EASI 50 atday 57 (lowandhigh dose)
  • Figure 7D shows EASI 75 atday 57 (200, 400 and 600mg)
  • Figure 7E shows EASI 75 atday 57 (lowandhigh dose)
  • Figure 7F shows EASI 90 atday 57 (200, 400 and 600mg)
  • Figure 7G shows EASI 90 atday 57 (lowandhigh dose)
  • Figure 8A show % EASI 50 reduction over time
  • Figure 8B shows % EASI 75 reduction over time
  • Figure 8C shows % EASI 90 reduction over time
  • Figure 9 shows sensitivity analysis in the Mitt Figure IDA shows the proportion of patients with IGA score 0 or 1 at day 57 in a summary table
  • Figure 10B shows the proportion of patients with IGA score 0 or 1 at day 57
  • Figure 10C shows the proportion of patients with IGA score of 0 or 1
  • FIG. 11 shows baseline TARC and IgE of patients
  • Figure 12A show average % change from baseline TARC [200mg and 400mg)
  • Figure 12B show average % change from baseline TARC [400mg and placebo)
  • Figure 12C show % change from baseline TARC for individual patients
  • Figure 13A shows IgE % change from baseline (200mg and 400mg)
  • Figure 13B shows average IgE % change from baseline (200mg and 400mg)
  • Figure 13C shows % IgE change from baseline for 3 individual patients
  • Figure 13D shows % IgE change from baseline for 4 individual patients on 200mg
  • Figure 13E shows % IgE change from baseline for 6 individual patients on 400mg
  • Figure 14 shows eblasakimab exposure, average EASI score, average TARC levels and average Ige levels.
  • Figure 15 shows eblasakimab efficacy versus dupilumab efficacy
  • Figure 16 shows median percentage change from baseline in IgE dupilumab
  • Figure 17 shows % change from baseline for dupiluman 300mg weekly dosing
  • Figure 18 shows staining intensity for IL-13R ⁇ 1 expression in healthy skin, non-lesional atopic dermatitis and lesional atopic dermatitis
  • Figure 19 shows staining IL-13R ⁇ 1 expression on mast cells and eosinophils for ealthy skin, non-lesional atopic dermatitis and lesional atopic dermatitis
  • Figure 20 shows gene expression for type I and type II IL-13 receptors
  • EBLASAKIMAB Patients enrolled in ascending dose cohorts of EBLASAKIMAB (SEQ ID NO: 51, 53 and 59 herein): 200 mg, 400 mg, 600 mg.
  • ASLAN low dose EBLASAKIMAB 200 mg
  • ASLAN high dose EBLASAKIMAB 400 mg + EBLASAKIMAB 600 mg.
  • Table 1 shows the % change in baseline in EASI score at Day 57 (8 weeks).
  • Table 2 shows the % change in baseline in EASI score at Day 29 (4 weeks].
  • Table 3 shows the sensitivity analysis in the mITT (modified intention to treat) set at Day 57 J i
  • Table 4 shows a summary of the proportion of patients achieving EASI 50, EASI 75 and EASI 90 at
  • Eblasakimab achieved a statistically significant improvement (p ⁇ 0.025) versus placebo in the primary efficacy endpoint of percent change from baseline in the Eczema Area Severity Index (EASI), and also showed significant improvements (p ⁇ 0.05 ) in other key efficacy endpoints: EASI- 50, EASI-75, peakpruritis and the Patient-Oriented Eczema Measure (POEM).
  • EBLASAKIMAB In the RITT population, which is more comparable to other published studies in moderate-to-severe AD, EBLASAKIMAB also achieved a statistically significant improvement [p ⁇ 0.025) versus placebo in percent change from baseline in EASI and showed a greater improvement over placebo in the key efficacy endpoints versus the ITT population.
  • a topic dermatitis patients were enrolled in a multi-center, randomized, double-blind, placebo- controlled, multiple ascending dose study of the safety, tolerability, and pharmacokinetics of subcutaneously delivered Eblasakimab. Whilst patients with "symptoms” such as itchy skin may present in the clinic, the underlying cause of this can be a whole plethora of pathologies.
  • the range of TARC levels presented in the clinical trial for patients with moderate to severe atopic dermatitis was from 214pg/ml to about 22,600pg/ml.
  • Baseline IgE levels in patients determined to have the relevant criteria for moderate to severe atopic dermatitis ranged from 434pg/ml to 19,175pg/ml.
  • IHC was performed on lesional (L) and non-lesional (NL) skin from 14 AD patients and 10 matched controls (HC). Skin samples were stained for IL-13R ⁇ 1, tryptase, and major basic protein to determine the distribution of IL-13R ⁇ 1 in AD and its relation to mast cells and eosinophils.
  • U937 cells a monocyte line, were used to evaluate the function of the type I and II receptor as these cells express both receptors.
  • Cells were incubated with eblasakimab (anti-IL-13R01) to block type II, anti-common y chain to block type I, and anti- IL4R0 to block both type I and type II receptors. After 24 hour incubations, cells were stimulated with vehicle or a mixture of IL-4 + IL- 13 and subjected to RNA sequencing. IHC data were quantified using Image). A differential expression analysis was conducted on RNA sequencing data using the DESeq2 package for R.
  • Type I receptor blockade with an anti-common y chain antibody resulted in upregulation of genes such as MMP9 (P ⁇ 0.001).
  • Figure 20 shows differentially expressed genes with type I receptor blockade using an anti- chain antibody.
  • IL-13R ⁇ 1 expression is increased in both L and NL AD skin compared to HCs

Abstract

La présente invention concerne l'utilisation d'un anticorps anti-IL-13 Rα1 (tel que l'eblasakimab) ou d'un fragment de liaison de celui-ci et des formulations pharmaceutiques le comprenant pour traiter des patients atteints de dermatite atopique (telle que la dermatite atopique lésionnelle), y compris une population de patients ayant reçu un traitement préalable avec du dupilumab, par exemple pour stimuler une modification de maladie.
PCT/SG2022/050694 2021-09-27 2022-09-27 Procédé de traitement de la dermatite atoptique modérée à grave WO2023048651A1 (fr)

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PCT/SG2022/050103 WO2022186773A1 (fr) 2021-03-01 2022-03-01 TRAITEMENT DE LA DERMATITE ATOPIQUE À L'AIDE D'UN ANTICORPS ANTI-IL-13Rα1 OU D'UN FRAGMENT DE LIAISON ASSOCIÉ CHEZ UNE POPULATION ALLERGIQUE
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US17/929,874 US20230091430A1 (en) 2021-03-01 2022-09-06 TREATMENT OF ATOPIC DERMATITIS EMPLOYING ANTI-IL-13Ra1 ANTIBODY OR BINDING FRAGMENT THEREOF IN AN ALLERGIC POPULATION
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US17/929,824 US20230002484A1 (en) 2021-03-01 2022-09-06 TREATMENT OF ATOPIC DERMATITIS EMPLOYING ANTI-IL-13Ra1 ANTIBODY OR BINDING FRAGMENT THEREOF
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