WO2015028666A1 - Neutralizing antibody or a fragment thereof specifically binding primate gm-csf for use in the treatment and/or prevention of psoriasis - Google Patents

Neutralizing antibody or a fragment thereof specifically binding primate gm-csf for use in the treatment and/or prevention of psoriasis Download PDF

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Publication number
WO2015028666A1
WO2015028666A1 PCT/EP2014/068508 EP2014068508W WO2015028666A1 WO 2015028666 A1 WO2015028666 A1 WO 2015028666A1 EP 2014068508 W EP2014068508 W EP 2014068508W WO 2015028666 A1 WO2015028666 A1 WO 2015028666A1
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Prior art keywords
fragment
antibody
psoriasis
neutralizing antibody
dose
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PCT/EP2014/068508
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French (fr)
Inventor
Thomas Wagner
Malin CARLSSON
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Takeda Gmbh
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Publication of WO2015028666A1 publication Critical patent/WO2015028666A1/en

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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
    • C07K16/243—Colony Stimulating Factors
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present invention relates to neutralizing antibodies or fragments thereof specifically binding primate GM-CSF for use in the treatment and/or prevention of psoriasis.
  • the invention further relates to methods of treatment and/or prevention of psoriasis of a patient in need thereof, to pharmaceutical compositions for use in the treatment and/or prevention of psoriasis and to a kit comprising said antibodies or fragments thereof.
  • Psoriasis is a chronic immune-mediated inflammatory disease of the skin, involving most areas of the body such as the scalp, the extremities, the lower back and genitals. However, the condition is also associated with extra-cutaneous effects including an increased incidence of certain malignancies, metabolic syndrome, depression, cardiovascular disease and psoriatic arthritis (Ref Griffiths et al. (2007) Lancet, 370(9583):263-71. The most common form of psoriasis - Psoriasis vulgaris or plaque-type psoriasis - accounts for 85% to 90% of all cases.
  • Plaque psoriasis is characterized by the presence of red raised scaly plaques that affect any surface of the body. These clinical features are explained by growth and dilation of superficial blood vessels (elongated and/or hyperplastic capillaries in the papillary dermal region) and hyperplasia of the epidermis caused by keratinocyte hyperproliferation. Keratinocytes produce a number of cytokines, either spontaneously or after stimulation, with pro-inflammatory and growth-promoting activities including IL-1, IL-6, IL-8, TNF and granulocyte/macrophage colony-stimulating factor (GM-CSF).
  • IL-1 interleukin-1
  • IL-6 interleukin-6
  • IL-8 granulocyte/macrophage colony-stimulating factor
  • cytokine-neutralizing agents e.g. infliximab, etanercept, adalimumab acting against TNFa and ustekinumab acting against IL12/IL-2
  • cytokine-neutralizing agents e.g. infliximab, etanercept, adalimumab acting against TNFa and ustekinumab acting against IL12/IL-2
  • GM-CSF granulocyte macrophage colony stimulating factor
  • the neutralizing antibody or a fragment thereof for use according to any of items 1-5 wherein the doses of the neutralizing antibody or a fragment thereof according to (b) and (c) and optionally (d) are independently selected from about 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, l lO mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg 190 mg or 200 mg, optionally independently selected from about 20 mg, 50 mg, 80 mg or 150 mg.
  • the neutralizing antibody or a fragment thereof for use according to any of items 1-15 wherein said antibody or a fragment thereof comprises a light chain variable region sequence set out in SEQ ID NO: 19 and/or a heavy chain variable region sequence set out in SEQ ID NO: 21, optionally a light chain variable region sequence set out in SEQ ID NO: 19 and a heavy chain variable region sequence set out in SEQ ID NO: 21.
  • the neutralizing antibody or a fragment thereof for use according to any of items 1-17 wherein said neutralizing antibody or fragment thereof comprises at least one amino acid sequence having at least 70%, at least 80%, at least 90% or at least 95% identity to the amino acid sequence of any of SEQ ID NO: 1-48 and/or 52-56.
  • Psoriasis vulgaris 22.
  • Method of treatment and/or prevention of psoriasis in a patient comprising administering a neutralizing antibody or a fragment thereof to said patient according to the dosing scheme according to any of items 1 to 11.
  • Psoriasis vulgaris 36.
  • a further active agent suitable for the treatment of psoriasis optionally selected from the group comprising methotrexate, sulphasalazine, azathioprine, cyclosporine, fumaric acid esters, efalizumab, alefacept, infliximab, adalimumab, golimumab, certolizumab pegol, ustekinumab, etanercept, mineral oil, urea, salicylic acid, petroleum jelly, coal tar, dithranol, corticosteroids, fluocinonide, vitamin D 3 analogues, vitamin Bi 2 , and retinoids is administered to said patient.
  • a further active agent suitable for the treatment of psoriasis optionally selected from the group comprising methotrexate, sulphasalazine, azathioprine, cyclosporine, fumaric acid esters, efalizumab, alefacept
  • the method steps (a), (b) and (c), optionally including any intermediate steps defined herein, are performed in chronological order.
  • any numerical value indicated is typically associated with an interval of accuracy that the person skilled in the art will understand to still ensure the technical effect of the feature in question.
  • the deviation from the indicated numerical value is in the range of ⁇ 10%, and preferably of ⁇ 5%.
  • the aforementioned deviation from the indicated numerical interval of ⁇ 10%, and preferably of ⁇ 5% is also indicated by the terms "about” and "approximately” used herein with respect to a numerical value.
  • a second option refers to the applicability of the second element without the first.
  • a third option refers to the applicability of the first and second elements together. Any one of these options is understood to fall within the meaning, and therefore satisfy the requirement of the term "and/or” as used herein. Concurrent applicability of more than one of the options is also understood to fall within the meaning, and therefore satisfy the requirement of the term "and/or” as used herein.
  • the present invention relates to a neutralizing antibody or a fragment thereof specifically binding primate granulocyte macrophage colony stimulating factor (GM-CSF) for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to a dosage regimen comprising:
  • the present invention relates to a neutralizing antibody or a fragment thereof specifically binding primate granulocyte macrophage colony stimulating factor (GM-CSF) for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to a dosage regimen comprising:
  • the doses of the neutralizing antibody or a fragment thereof according to (b) and (c) and optionally (d) are independently in the range of about 10 - 200 mg, optionally of about 20 - 150 mg.
  • the doses of the neutralizing antibody or a fragment thereof according to (b) and (c) and optionally (d) are independently selected from about 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg 190 mg or 200 mg, optionally independently selected from about 20 mg, 50 mg, 80 mg or 150 mg.
  • the term "loading dose” denotes the first dose of the neutralizing antibody or a fragment thereof which is administered at the beginning of the treatment, i.e. at day 1 of the treatment. This includes the first dose of the anti-GM- CSF antibody or a fragment thereof as described herein administered to a patient, who has never before been treated with a neutralizing antibody. However, the term also relates to the first dose of the anti-GM-CSF antibody or a fragment thereof as described herein which is administered to a patient, who has been treated with the neutralizing antibody or fragment thereof as described herein before, but who has interrupted taking of the neutralizing antibody or a fragment thereof, thus showing insufficient blood serum levels of the neutralizing antibody or a fragment thereof.
  • Insufficient blood serum levels of the neutralizing antibody or a fragment thereof as used herein includes any blood serum levels measured in a patient not sufficient for treatment and/or prevention of psoriasis. This also includes no measurable levels of the neutralizing antibody or a fragment thereof in the blood serum at all.
  • Interruptions in the taking of the neutralizing antibody or a fragment thereof may, for example, be due to a remission of the symptoms of psoriasis or a drug holiday.
  • the loading dose is used to achieve optimal blood serum levels of the neutralizing antibody or a fragment thereof as described herein right at the beginning of the treatment.
  • Optimal blood serum levels denote any blood serum levels of the neutralizing antibody or a fragment useful in the treatment and/or prevention of psoriasis. This may include any blood serum levels able to obtain any of the effects defined herein with respect to the definition of the terms "treatment" and/or
  • the loading dose may be the same dose as the doses according to (b), (c) or (d) or the double dose as the doses according to (b), (c) or (d).
  • the loading dose of the neutralizing antibody or a fragment thereof as described herein is in the range of 20 - 400 mg.
  • the loading dose of the neutralizing antibody or a fragment thereof may also be in the range of 40 - 300 mg.
  • the loading dose of the neutralizing antibody or a fragment thereof as described herein is selected from 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg,
  • the loading dose of the neutralizing antibody or a fragment thereof as described herein may also be selected from 20 mg, 40 mg, 50 mg, 80 mg, 100 mg, 150 mg, 160 mg or 300 mg. In one embodiment, the loading dose of the neutralizing antibody or a fragment thereof as described herein is 20 mg. In one embodiment, the loading dose of the neutralizing antibody or a fragment thereof as described herein is 40 mg. In a further embodiment, the loading dose of the neutralizing antibody or a fragment thereof as described herein is 50 mg. In yet another embodiment, the loading dose of the neutralizing antibody or a fragment thereof as described herein is 80 mg. In another embodiment, the loading dose of the neutralizing antibody or a fragment thereof as described herein is 100 mg.
  • the loading dose of the neutralizing antibody or a fragment thereof as described herein is 150 mg. In yet another embodiment, the loading dose of the neutralizing antibody or a fragment thereof as described herein is 160 mg. In a further embodiment, the loading dose of the neutralizing antibody or a fragment thereof as described herein is 300 mg.
  • the loading dose is used to obtain optimal blood levels of the neutralizing antibody or a fragment thereof as described herein at the beginning of the treatment.
  • the loading dose may be chosen in accordance with the further doses to be administered, such as doses (b), (c) and/or (d).
  • the loading dose thus may be the double dose of the doses according to (b), (c) and/or (d) of the dosage regimen as described herein. If doses (b), (c) and optionally (d) of the dosage regimen as described herein are the same, the loading dose may be a double dose of doses (b), (c) and, optionally (d) of the dosage regimen as described herein.
  • the loading dose may be a double dose of dose (b). In another embodiment, the loading dose may be a double dose of dose (c). In a further embodiment, the loading dose may be a double dose of the further doses (d).
  • the loading dose (a) is 40 mg. In another embodiment, wherein doses (b), (c) and optionally (d) are 50 mg, the loading dose (a) is 100 mg. In yet another embodiment, wherein doses (b), (c) and optionally (d) are 80 mg, the loading dose (a) is 160 mg. In a further embodiment, wherein doses (b), (c) and optionally (d) are 150 mg, the loading dose (a) is 300 mg.
  • the present invention relates to a neutralizing antibody or a fragment thereof specifically binding primate granulocyte macrophage colony stimulating factor (GM-CSF) for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to a dosage regimen comprising:
  • the present invention relates to neutralizing antibody or a fragment thereof specifically binding primate granulocyte macrophage colony stimulating factor (GM-CSF) for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to a dosage regimen comprising:
  • the loading dose may also be the same dose as any of the doses according to (b), (c) and/or (d) of the dosage regimen as described herein. If doses (b), (c) and, optionally (d), of the dosage regimen as described herein are the same, accordingly the loading dose may correspond to said doses (b), (c) and, optionally (d) of the dosage regimen as described herein.
  • doses (a), (b), (c) and (d) are 20 mg. In another embodiment, doses (a), (b), (c) and (d) are 50 mg. In yet another embodiment, doses (a), (b), (c) and (d) are 80 mg.
  • doses (a), (b), (c) and (d) are 150 mg.
  • the loading dose may be the same dose as dose (b).
  • the loading dose may be the same dose as dose (c).
  • the loading dose may be the same dose as the further doses (d).
  • the present invention relates to a neutralizing antibody or a fragment thereof specifically binding primate granulocyte macrophage colony stimulating factor (GM-CSF) for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to a dosage regimen comprising:
  • the present invention relates to neutralizing antibody or a fragment thereof specifically binding primate granulocyte macrophage colony stimulating factor (GM-CSF) for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to a dosage regimen comprising:
  • the loading dose may be administered to the patient as a single dose, for example as a single injection of 40 mg of the neutralizing antibody or a fragment thereof as described herein or in the form of two doses, for example as two separate injections of 20 mg of the neutralizing antibody or a fragment thereof as described herein.
  • both injections should be administered in a short interval of time on day 1, such as in an interval of 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours or 5 hours.
  • the second dose (b) of the neutralizing antibody or a fragment thereof of the dosage regimen described herein may be administered 7-21 days after administration of the loading dose, optionally 10 -15 days after administration of the loading dose.
  • the second dose is administered on day 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 after administration of the loading dose, in particular on day 14 after administration of the loading dose.
  • the second dose (b) of the neutralizing antibody or a fragment thereof of the dosage regimen described herein may also be administered 21-35 days after administration of the loading dose, optionally 25 -20 days after administration of the loading dose.
  • the second dose is administered on day 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 after administration of the loading dose, in particular on day 28 after administration of the loading dose.
  • the second dose (b) of the neutralizing antibody or a fragment thereof of the dosage regimen described herein may be in the range of 10-200 mg of the neutralizing antibody or a fragment thereof, optionally in the range of 20-150 mg of the neutralizing antibody or a fragment thereof.
  • the second dose (b) is selected from 10 mg, 20mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, l lO mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg or 200 mg, optionally selected from 20 mg, 50 mg, 80 mg or 150 mg of the neutralizing antibody or a fragment thereof.
  • the second dose (b) is 20 mg of the neutralizing antibody or a fragment thereof. In another embodiment, the second dose (b) is 50 mg of the neutralizing antibody or a fragment thereof. In yet another embodiment, the second dose (b) is 80 mg of the neutralizing antibody or a fragment thereof. In a further embodiment, the second dose (b) is 150 mg of the neutralizing antibody or a fragment thereof.
  • the third dose (c) of the neutralizing antibody or a fragment thereof of the dosage regimen described herein may be in the range of 10-200 mg of the neutralizing antibody or a fragment thereof, optionally in the range of 20-150 mg of the neutralizing antibody or a fragment thereof.
  • the third dose (c) is selected from 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, l lO mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg or 200 mg, optionally selected from 20 mg, 50 mg, 80 mg or 150 mg of the neutralizing antibody or a fragment thereof.
  • the third dose (c) is 20 mg of the neutralizing antibody or a fragment thereof.
  • the third dose (c) is 50 mg of the neutralizing antibody or a fragment thereof.
  • the third dose (c) is 80 mg of the neutralizing antibody or a fragment thereof.
  • the third dose (c) is 150 mg of the neutralizing antibody or a fragment thereof.
  • the third dose (c) of the neutralizing antibody or a fragment thereof of the dosage regimen as described herein may be administered 21-35 days after administration of the second dose, optionally 25-30 days after administration of the second dose. In one embodiment, the third dose is administered on day 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or 35 after administration of the second, in particular on day 28 after administration of the second dose.
  • further doses (d) may be administered to the patient in order to maintain the desired blood serum levels of the neutralizing antibody or a fragment thereof as described herein. These further doses (d) may be administered to the patient in certain intervals, which are chosen according to the half-life of the neutralizing antibody or a fragment thereof in the blood of the patient.
  • the serum may contain 50% of the anti-primate GM-CSF antibody of fragment thereof at least 7 days, at least 14 days, at least 21 days, e.g., at least 28 days after the last administration of the neutralizing antibody or fragment thereof according to the invention.
  • the serum may contain about 50% of the anti-primate GM-CSF antibody of fragment thereof at 28 days after the last administration.
  • the serum may contain about 50% of the anti-primate GM-CSF antibody of fragment thereof at 21 days after the last administration.
  • the half life of the anti-primate GM-CSF antibody or fragment thereof in the blood serum is at least 17, at least 21 or at least 25 days. Accordingly, intervals in which doses (d) are administered may be in the range of 21-35 days between each of the doses, in particular in the range of 25-30 days between each of the doses. In one embodiment, the interval between doses (d) is selected from 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or 35 days. In another embodiment, the interval between doses (d) is 28 days.
  • the further doses (d) of the neutralizing antibody or a fragment thereof of the dosage regimen described herein may be in the range of 10-200 mg of the neutralizing antibody or a fragment thereof, optionally in the range of 20-150 mg of the neutralizing antibody or a fragment thereof.
  • the further doses (d) are selected from 10 mg, 20mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg or 200 mg, optionally selected from 20 mg, 50 mg, 80 mg or 150 mg of the neutralizing antibody or a fragment thereof.
  • the further doses (d) are 20 mg of the neutralizing antibody or a fragment thereof. In another embodiment, the further doses (d) are 50 mg of the neutralizing antibody or a fragment thereof. In yet another embodiment, the further doses (d) are 80 mg of the neutralizing antibody or a fragment thereof. In a further embodiment, the further doses (d) are 150 mg of the neutralizing antibody or a fragment thereof.
  • the further doses (d) may be administered to the patient as long he is in need of a treatment and/or prevention of psoriasis.
  • the further doses (d) may be administered to the patient until a full or partial remission and/or alleviation symptoms of the psoriasis as described herein, a reduction of the body surface area affected by psoriasis, a reduction of the PASI score or a downscaling of the severity of the psoriasis on the EMEA's severity scale for psoriasis is achieved such as the reductions and downscaling described herein with respect to the definition of the term "treatment".
  • further doses (d) may be administered to the patient over a period of at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 weeks, in particular over a period of at least 8 weeks.
  • the neutralizing antibody or a fragment thereof may be administered to the patient over a period of at least 10, at least 14, at least 18, at least 22, at least 24, at least 26, at least 30, at least 34, at least 38 or at least 42 weeks, in particular over a period of at least 18 weeks.
  • the neutralizing antibody or a fragment thereof is used for the prevention of psoriasis, further doses (d) may be administered to the patient to the patient as long as full or partial prevention of psoriasis and/or any of its symptoms is desired. It is to be understood that the administration of the neutralizing antibody or a fragment thereof may also be stopped after a certain period of treatment with the neutralizing antibody or fragment thereof after which the desired effects (such as a reduction of the PASI score, a reduction of the PGA, a reduction of the BSA or a change of the grade of the severity of the psoriasis) have been achieved. This is due to the fact that the effects of the antibody or fragment thereof last for a certain period of time after the administration has been stopped.
  • the desired effects such as a reduction of the PASI score, a reduction of the PGA, a reduction of the BSA or a change of the grade of the severity of the psoriasis
  • Such a “drug holiday” may reduce the risk of side effects and may maintain the sensitivity to the neutralizing antibody or fragment thereof, may lead to the recovery of some normal physiologic functions in the patient or may improve patient compliance.
  • the time point for a drug holiday may vary from patient to patient and may be chosen based on the basis of the clinical assessment by the treating physician. This clinical assessment may be based on biomarkers or on the basis of the effect achieved by the administration of the neutralizing antibody or fragment thereof. Any effect defined herein with respect to the term "treatment” may be indicative that a drug holiday may be made.
  • a drug holiday is made when the patient shows a reduction of the initial PASI score of about 75% or about 90%. In another embodiment, a drug holiday is made when the patient shows a reduction of the initial BSA of about 50%, about 75% or about 90%. In another embodiment of the invention, a drug holiday is made when the patient shows a downscaling of the EMEA's severity grade of at least one grade (e.g. from severe to moderate to severe).
  • a drug holiday may be made at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months or at least 12 months after administration of the loading dose (a). In yet another embodiment, a drug holiday may be made at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months or at least 12 months after administration of the second dose (b).
  • the clinical parameters of the patient such as the PASI score, the PGA, the BSA or the grade of the psoriasis on the EMEA's severity scale
  • regular intervals such as monthly. If the clinical parameters worsen, e.g.
  • such a worsening of the clinical parameters may be an increase of the PASI score measured at the beginning of the drug holidays of about 25%, about 35%, about 45% or about 50% or more.
  • such a worsening of the clinical parameters may be an increase of the PSA at the beginning of the drug holidays of about 5%, about 7%, about 10%> or about 15% or more.
  • such a worsening of the clinical parameters may be an increase of the BSA measured at the beginning of the drug holidays of about 5%, about 7%, about 10% or about 15% or more.
  • the worsening of the clinical parameter is an upscaling of the EMEA's severity grade for at least one grade.
  • the neutralizing antibody or a fragment thereof may again be used according to any the dosage regimen described herein.
  • One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
  • One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
  • Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising: (a) a loading dose of 40 mg of the neutralizing antibody or a fragment thereof on the first day of administration ,
  • Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
  • Yet another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising: (a) a loading dose of 160 mg of the neutralizing antibody or a fragment thereof on the first day of administration ,
  • Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
  • Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
  • the dose of the antibody or a fragment thereof for use according to the invention may be administered as a single dose or as multiple doses per day, e.g. two separate injections of 150 mg, one in the morning and one in the evening in order to administer a daily dose of 300 mg of the antibody or a fragment thereof according to the invention.
  • the present invention relates to a neutralizing antibody or a fragment thereof specifically binding primate GM-CSF for use in the treatment and/or prevention of psoriasis, wherein said antibody comprises a light chain variable region selected from the group consisting of SEQ ID NOs: 19, 34, 54 or 55 and a heavy chain variable region selected from the group consisting of SEQ ID NOs: 20- 33, 35-48, 52 or 53.
  • antibody or its grammatically related variations relate to full length antibodies, human antibodies, humanized antibodies, fully human antibodies, genetically engineered antibodies (e.g.
  • the antibody used in the present invention is a human antibody, in particular a human monoclonal antibody. It is particularly difficult to prepare human antibodies which are monoclonal. In contrast to fusions of murine B cells with immortalized cell lines, fusions of human B cells with immortalized cell lines are not viable. Thus, the human monoclonal antibody of the invention is the result of overcoming significant technical hurdles generally acknowledged to exist in the field of antibody technology.
  • the monoclonal nature of the antibody makes it particularly well suited for use as a therapeutic agent, since such antibody will exist as a single, homogeneous molecular species which can be well-characterized and reproducibly made and purified. These factors result in a product whose biological activity can be predicted with a high level of precision. This is very important if such a molecule is going to gain regulatory approval for therapeutic administration in humans. It is especially desirable that the monoclonal antibody (or the corresponding fragment) according to the invention be a human antibody (or the corresponding fragment). In contemplating an antibody agent intended for therapeutic
  • this antibody is of human origin. Following administration to a human patient, a human antibody or fragment thereof will most probably not elicit a strong immunogenic response by the patient's immune system, i.e. will not be recognized as being a "foreign", that is a non-human protein. This means that no patient antibodies will be generated against the therapeutic antibody which would otherwise block the therapeutic antibody's activity and/or accelerate the therapeutic antibody's elimination from the body of the patient, thus preventing it from exerting its desired therapeutic effect.
  • human antibody as used herein is to be understood as meaning that the antibody of the invention, or its fragment, comprises (an) amino acid sequence(s) contained in the human germ line antibody repertoire.
  • an antibody, or its fragment may therefore be considered human if it consists of such (a) human germ line amino acid sequence(s), i.e. if the amino acid sequence(s) of the antibody in question or fragment thereof is (are) identical to (an) expressed human germ line amino acid sequence(s).
  • An antibody or fragment thereof may also be regarded as human if it consists of (a) sequence(s) that deviate(s) from its (their) closest human germ line sequence(s) by no more than would be expected due to the imprint of somatic hyper mutation.
  • the antibodies of many non-human mammals for example rodents such as mice and rats, comprise VH CDR3 amino acid sequences which one may expect to exist in the expressed human antibody repertoire as well. Any such sequence(s) of human or non-human origin which may be expected to exist in the expressed human repertoire would also be considered "human" for the purposes of the present invention.
  • the human monoclonal antibody may be an IgG antibody.
  • IgG antibody relates to a therapeutically useful antibody or fragment thereof falling within the IgG class (isotype) of antibodies and having a gamma-type ( ⁇ ) heavy chain.
  • an IgG antibody comprises not only the variable antibody regions responsible for the highly discriminative antigen recognition and binding, but also the constant regions of the heavy and light antibody polypeptide chains normally present in endogenously produced antibodies and, in some cases, even decoration at one or more sites with carbohydrates.
  • Such glycosylation is generally a hallmark of the IgG format, and portions of these constant regions make up the so-called Fc region of a full antibody which is known to elicit various effector functions in vivo.
  • the Fc region mediates binding of IgG to Fc receptor, hence prolonging half life in vivo as well as facilitating homing of the IgG to locations with increased Fc receptor presence.
  • the IgG antibody is an IgGl antibody or an IgG4 antibody, formats which are particulary desirable in the context of the present invention since their mechanism of action in vivo is
  • the antibody according to the present invention is an IgGl antibody.
  • antibody fragment or “fragment thereof or its grammatically related variations relate to a part of a full length antibody specifically binding with the same antigen, i.e. primate GM-CSF as the full length antibody.
  • a pharmaceutically active fragment of an antibody i.e. having the same pharmaceutical effects as the full length anti-GM-CSF antibody.
  • This part of a full length antibody may be at least the antigen binding portion or at least the variable region thereof.
  • Genetically engineered proteins acting like an antibody are also included within the meaning of antibody fragment as used herein.
  • Such genetically engineered antibodies may be scFv, i.e. fusion proteins of a heavy and a light chain variable region connected by a peptide linker.
  • antibody fragments according to the present invention are Fab, Fab', F(ab') 2 , VHH antibodies, diabodies, tandem antibodies, single domain antibodies and Fv.
  • These formats may generally be divided into two subclasses, namely those which consist of a single polypeptide chain, and those which comprise at least two polypeptide chains.
  • Members of the former subclass include an scFv (comprising one VH region and one VL region joined into a single polypeptide chain via a polypeptide linker); a single domain antibody (comprising a single antibody variable region) such as a VHH antibody (comprising a single VH region).
  • Fv comprising one VH region and one VL region as separate polypeptide chains which are non-covalently associated with one another
  • a diabody comprising two non-covalently associated polypeptide chains, each of which comprises two antibody variable regions - normally one VH and one VL per polypeptide chain - the two polypeptide chains being arranged in a head-to-tail conformation so that a bivalent antibody molecule results
  • a tandem diabody bispecific single-chain Fv antibodies comprising four covalently linked
  • Fab comprising as one polypeptide chain an entire antibody light chain, itself comprising a VL region and the entire light chain constant region and, as another polypeptide chain, a part of an antibody heavy chain comprising a complete VH region and part of the heavy chain constant region, said two polypeptide chains being
  • antibody fragments of the type described herein allow great flexibility in tailoring, for example, the pharmacokinetic properties of an antibody desired for therapeutic administration to the particular exigencies at hand. For example, it may be desirable to reduce the size of the antibody administered in order to increase the degree of tissue penetration when treating tissues known to be poorly vascularized (for example, joints).
  • the antibody according to the present invention or the fragment thereof neutralize the activity of primate GM-CSF.
  • neutralization refers to partial or complete attenuation of the biological effect(s) of GM-CSF.
  • Such partial or complete attenuation of the biological effect(s) of GM-CSF results from modification, interruption and/or abrogation of GM-CSF-mediated signal transduction, as manifested, for example, in altering activation of cells, e.g.
  • neurons in particular nociceptive neurons, intracellular signaling, cellular proliferation or release of soluble substances, up- or down-regulation of intracellular gene activation, for example that resulting in expression of surface receptors for ligands other than GM- CSF.
  • intracellular signaling for example that resulting in expression of surface receptors for ligands other than GM- CSF.
  • determining whether an agent, for example an antibody in question or a fragment thereof is to be classified as a neutralizer may be accomplished by a standard in vitro test performed generally as follows: In a first proliferation experiment, a cell line, the degree of proliferation of which is known to depend on the activity of GM-CSF, is incubated in a series of samples with varying
  • proliferation experiment is then performed employing in each of a series of samples the same number of cells as used in the first proliferation experiment, the above- determined concentration of GM-CSF and, this time, varying concentrations of an antibody or fragment thereof suspected of being a neutralizer of GM-CSF.
  • Cell proliferation is again measured to determine the concentration of antibody or fragment thereof sufficient to effect half-maximal growth inhibition. If the resulting graph of growth inhibition vs. concentration of antibody (or fragment thereof) is sigmoid in shape, resulting in decreased cell proliferation with increasing
  • the antibody or fragment thereof may be considered a "neutralizer" in the sense of the present invention.
  • a cell line the degree of proliferation of which is known to depend on the activity of GM-CSF, is the TF-1 cell line, as described in Kitamura, T. et al. (1989). J Cell Physiol 140, 323-34.
  • the degree of cellular proliferation is not the only parameter by which neutralizing capacity may be established. For example, measurement of the level of signaling molecules (e.g.
  • cytokines the level of secretion of which depends on GM-CSF, may be used to identify a suspected GM-CSF neutralizer.
  • Other examples of cell lines which can be used to determine whether an antibody in question or fragment thereof is a neutralizer of primate GM-CSF activity include AML-193 (Lange, B. et al. (1987). Blood 70, 192-9); GF-D8 (Rambaldi, A. et al. (1993). Blood 81 , 1376-83); GM/SO (Oez, S. et al. (1990). Experimental Hematology 18, 1 108-1 1); M07E (Avanzi, G. C. et al. (1990).
  • binds specifically or “specifically binding” or grammatically related variations thereof relate to an antibody having a binding affinity to primate GM-CSF as defined herein of ⁇ 10 ⁇ 9 mol/1.
  • the antibody or a fragment thereof bind to primate GM-CSF with extremely high affinity.
  • K D values of from about 4 x 10 ⁇ 9 M down to as low as about 0.04 x 10 ⁇ 9 M, the latter corresponding to about 40 pM, have been observed for molecules of this class.
  • the high binding affinity of human monoclonal antibodies or fragments thereof to primate GM-CSF has an additional advantage. Normally, antibodies or fragments thereof will be eliminated from the bloodstream of a patient in a size-dependent fashion, with smaller molecules being excreted and eliminated before larger ones. Since the complex of the two polypeptides - antibody or antibody fragment and bound GM-CSF - is obviously larger than the antibody alone, the low k 0 s mentioned above has the effect that therapeutic neutralizer is excreted and eliminated from the patient's body more slowly than would be the case, were it not bound to GM-CSF. Thus, not only the magnitude of the neutralizing activity but also its duration in vivo is increased.
  • the primate GM-CSF to which the antibody or fragment thereof specifically binds is human GM-CSF (Homo sapiens, SEQ ID NO: 49) or non-human primate GM-CSF.
  • non-human primate GM-CSF include gibbon monkey GM-CSF (Nomascus concolor, also known as the western black crested gibbon, SEQ ID NO: 51) and GM-CSF of monkeys of the macaca family (SEQ ID NO: 50), for example rhesus monkey (Macaca mulatto) GM-CSF and cynomolgous monkey GM-CSF (Macaca
  • the human monoclonal antibody or fragment thereof exhibits cross reactivity between both human and at least one of the monkey species mentioned above. This is especially desirable for an antibody molecule which is intended for therapeutic administration in human subjects, since such an antibody will normally have to proceed through a multitude of tests prior to regulatory approval, of which certain early tests involve non-human animal species. In performing such tests, it is generally desirable to use as a non- human species a species bearing a high degree of genetic similarity to humans, since the results so obtained will generally be highly predictive of corresponding results which may be expected when administering the same molecule to humans.
  • the human monoclonal antibody or fragment thereof specifically binds to an epitope, in particular to a discontinuous epitope, of human or non-human primate GM-CSF comprising amino acids 23-27 (RRLLN) and/or amino acids 65-77 (GLR/QGSLTKLKGPL).
  • the variability at position 67 within the amino acid sequence stretch 65-77 depicted above reflects the heterogeneity in this portion of primate GM-CSF between, on the one hand, human and gibbon GM-CSF (in which position 67 is R) and, on the other hand, monkeys of the macaca family, for example cynomolgous and rhesus monkeys (in which position 67 is Q).
  • the numbering of human and non-human primate GM-CSF refers to that of mature GM-CSF, i.e. GM-CSF without its 17 amino acid signal sequence (the total length of mature GM-CSF in both human and non-human primate species described above is 127 amino acids).
  • the sequence of human GM-CSF and gibbon GM-CSF is as follows: APARSPSPST QPWEHVNAIQ EARRLLNLST? DTAAEMNETV EVISEMFDLQ EPTCLQTRLE LYKQGLRGSL TKLKGPLTMM ASHYKQHCPP TPETSCATQl ITFESFKENL KDFLLVIPFD CWEPVQE. (SEQ ID NO: 49)
  • GM-CSF The sequence of GM-CSF in certain members of the macaca monkey family such as for example rhesus monkey and cynomolgous monkey is as follows:
  • discontinuous epitope is to be understood as at least two non-adjacent amino acid sequence stretches within a given polypeptide chain, here mature human and non- human primate GM-CSF, which are simultaneously and specifically (as defined above) bound by an antibody. According to this definition, such simultaneous specific binding may be of the GM-CSF polypeptide in linear form.
  • the mature GM-CSF polypeptide forming an extended loop, in one region of which the two sequences indicated in boldface above line up, for example more or less in parallel and in proximity of one another. In this state they are specifically and simultaneously bound by the antibody fragment of the invention.
  • simultaneous specific binding of the two sequence stretches of mature GM-CSF indicated above may also take the form of antibody binding to a conformational epitope.
  • mature GM-CSF has already formed its tertiary conformation as it normally exists in vivo (Sun, H. W., J. Bernhagen, et al. (1996). Proc Natl Acad Sci USA 93, 5191-6).
  • the polypeptide chain of mature GM-CSF is folded in such a manner as to bring the two sequence stretches indicated above into spatial proximity, for example on the outer surface of a particular region of mature, folded GM-CSF, where they are then recognized by virtue of their three-dimensional conformation in the context of the surrounding polypeptide sequences.
  • the above (discontinuous) epitope to which the antibody or the fragment thereof specifically binds further comprises amino acids 28-31 (LSRD), italicized in the above sequences of human and non-human primate GM-CSF.
  • either of the above (discontinuous) epitopes further comprises amino acids 32-33 (TA) and/or amino acids 21-22 (EA), each of which stretch is underlined in the above sequences of human and non-human primate GM-CSF.
  • the human monoclonal antibody or fragment thereof, or compositions or medicaments according to the invention comprising such antibodies or fragments comprise in its heavy chain variable region a CDR3 comprising an amino acid sequence chosen from the group consisting of those set out in any of the SEQ ID NOs: 1-13 or 56, optionally SEQ ID NO: 2.
  • One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
  • Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising: (a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration, which is a double dose of the doses administered according to (b) and (c),
  • (d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days, wherein the doses of the neutralizing antibody or a fragment thereof according to (b) and (c) and optionally (d) are in the range of 20-150 mg and wherein said antibody or a fragment thereof comprises a heavy chain variable region CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 1-13 or 56, optionally SEQ ID NO: 2, in combination with a heavy chain variable region CDR1 sequence having an amino acid sequence set out in SEQ ID NO: 14 and a heavy chain variable region sequence having an amino acid sequence set out in SEQ ID NO: 15.
  • One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
  • Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising: (a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration, which is a double dose of the doses administered according to (b) and (c),
  • (d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days, wherein the doses of the neutralizing antibody or a fragment thereof according to (b) and (c) and optionally (d) are in the range of 20-150 mg and wherein said antibody or a fragment thereof comprises a heavy chain variable region CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 1-13 or 56, optionally SEQ ID NO: 2, in combination with a heavy chain variable region CDRl sequence having an amino acid sequence set out in SEQ ID NO: 14 and a heavy chain variable region sequence having an amino acid sequence set out in SEQ ID NO: 15.
  • One embodiment relates to a human monoclonal antibody or fragment thereof comprising a heavy chain variable region CDRl sequence as set out in SEQ ID NO: 14, a heavy chain variable region CDR2 sequence as set out in SEQ ID NO: 15 and a heavy chain variable region CDR3 sequence as set out in SEQ ID NO: 1; or comprising a heavy chain variable region CDRl sequence as set out in SEQ ID NO: 14, a heavy chain variable region CDR2 sequence as set out in SEQ ID NO: 15 and a heavy chain variable region CDR3 sequence as set out in SEQ ID NO: 2; or comprising a heavy chain variable region CDRl sequence as set out in SEQ ID NO: 14, a heavy chain variable region CDR2 sequence as set out in SEQ ID NO: 15 and a heavy chain variable region CDR3 sequence as set out in SEQ ID NO: 3; or comprising a heavy chain variable region CDRl sequence as set out in SEQ ID NO: 14, a heavy chain variable region CDR2 sequence as set out in SEQ ID NO: 15 and
  • any of the above 14 combinations of CDRl, CDR2 and CDR3 sequences exists in a human monoclonal antibody or fragment thereof further comprising in its light chain variable region a CDRl comprising the amino acid sequence set out in SEQ ID NO: 16, a CDR2 comprising the amino acid sequence set out in SEQ ID NO: 17, and a CDR3 comprising the amino acid sequence set out in SEQ ID NO: 18.
  • one embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
  • Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising: (a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration, which is a double dose of the doses administered according to (b) and (c),
  • a further embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising: (a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration, (b) a second dose of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
  • Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising: (a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration, which is a double dose of the doses administered according to (b) and (c) and optionally (d),
  • (d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days, wherein the doses of the neutralizing antibody or a fragment thereof according to (b) and (c) and optionally (d) are in the range of about 20-150 mg and wherein said antibody or a fragment thereof comprises a heavy chain variable region CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 1-13 or 56, optionally SEQ ID NO: 2, in combination with a heavy chain variable region CDRl having an amino acid sequence set out in SEQ ID NO: 14 and a heavy chain variable region CDR2 having an amino acid sequence set out in SEQ ID NO: 15 and further comprising in its light chain variable region a CDRl comprising the amino acid sequence set out in SEQ ID NO: 16, a CDR2 comprising the amino acid sequence set out in SEQ ID NO: 17, and a CDR3 comprising the amino acid sequence set out in SEQ ID NO: 18.
  • Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising: (a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration,
  • Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising: (a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration, which is a double dose of the doses administered according to (b) and (c),
  • Yet a further embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
  • Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
  • (d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days, wherein the doses of the neutralizing antibody or a fragment thereof according to (b) and (c) and optionally (d) are in the range of about 20-150 mg and wherein said antibody or a fragment thereof comprises a heavy chain variable region CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 1-13 or 56, optionally SEQ ID NO: 2, in combination with a heavy chain variable region CDRl having an amino acid sequence set out in SEQ ID NO: 14 and a heavy chain variable region CDR2 having an amino acid sequence set out in SEQ ID NO: 15 and further comprising in its light chain variable region a CDRl comprising the amino acid sequence set out in SEQ ID NO: 16, a CDR2 comprising the amino acid sequence set out in SEQ ID NO: 17, and a CDR3 comprising the amino acid sequence set out in SEQ ID NO: 18.
  • the human monoclonal antibody of the invention or fragment thereof comprises in its light chain variable region an amino acid sequence as set out in SEQ ID NO: 19.
  • Preferred is a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 19 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 20; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 19 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 21; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 19 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 22; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 19 and a heavy
  • the human monoclonal antibody of the invention or fragment thereof comprises in its light chain variable region an amino acid sequence as set out in SEQ ID NO: 54.
  • a human monoclonal antibody or fragment thereof the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 54 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 20; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 54 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 21; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 54 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 22; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 54 and
  • the human monoclonal antibody of the invention or fragment thereof comprises in its light chain variable region an amino acid sequence as set out in SEQ ID NO: 55.
  • a human monoclonal antibody or fragment thereof the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 55 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 20; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 55 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 21; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 55 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 22; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 55 and
  • One embodiment provides a human monoclonal antibody or fragment thereof comprising in its light chain a variable region a CDRl region comprising an amino acid sequence as set out in SEQ ID NO: 16, a CDR2 region having an amino acid sequence as set out in SEQ ID NO: 17 and a CDR3 having an amino acid sequence as set out in SEQ ID NO: 18 and comprising in its heavy chain variable region a CDRl region comprising an amino acid sequence as set out in SEQ ID NO: 14, a CDR2 region having an amino acid sequence as set out in SEQ ID NO: 15 and a CDR3 having an amino acid sequence as set out in any of SEQ ID NOs. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 56, optionally SEQ ID NO: 2.
  • the human monoclonal antibody comprises in its light chain an amino acid sequence as set out in SEQ ID NO: 34 and in its heavy chain an amino acid sequence as set out in SEQ ID NO: 35; or in its light chain an amino acid sequence as set out in SEQ ID NO: 34 and in its heavy chain an amino acid sequence as set out in SEQ ID NO: 36; or in its light chain an amino acid sequence as set out in SEQ ID NO: 34 and in its heavy chain an amino acid sequence as set out in SEQ ID NO: 37; or in its light chain an amino acid sequence as set out in SEQ ID NO: 34 and in its heavy chain an amino acid sequence as set out in SEQ ID NO: 38; or in its light chain an amino acid sequence as set out in SEQ ID NO: 34 and in its heavy chain an amino acid sequence as set out in SEQ ID NO: 39; or in its light chain an amino acid sequence as set out in SEQ ID NO: 34 and in its heavy chain an amino acid sequence as set out in SEQ ID NO: 40; or in its light chain an amino acid sequence as set out in
  • One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
  • (d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days, wherein the doses of the neutralizing antibody or a fragment thereof according to (b) and (c) and optionally (d) are in the range of about 20-150 mg and wherein said antibody or a fragment thereof comprises in its light chain an amino acid sequence as set out in SEQ ID NO: 34 and/or in its heavy chain an amino acid sequence as set out in SEQ ID NO: 35, optionally wherein said antibody or a fragment thereof comprises in its light chain an amino acid sequence as set out in SEQ ID NO: 34 and in its heavy chain an amino acid sequence as set out in SEQ ID NO: 35.
  • One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
  • Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising: (a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration, which is a double dose of the doses administered according to (b) and (c) and optionally (d),
  • (d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days, wherein the doses of the neutralizing antibody or a fragment thereof according to (b) and (c) and optionally (d) are in the range of about 20-150 mg and wherein said antibody or a fragment thereof comprises in its light chain an amino acid sequence as set out in SEQ ID NO: 34 and/or in its heavy chain an amino acid sequence as set out in SEQ ID NO: 35, optionally wherein said antibody or a fragment thereof comprises in its light chain an amino acid sequence as set out in SEQ ID NO: 34 and in its heavy chain an amino acid sequence as set out in SEQ ID NO: 35.
  • the neutralizing antibody or a fragment thereof for use according to the present invention comprises in its light chain variable region a CDR1 sequence having an amino acid sequence as set out in SEQ ID NO: 16, a CDR2 sequence having an amino acid sequence set out in SEQ ID NO: 17 and a CDR3 sequence having an amino acid sequence set out in SEQ ID NO: 18 and comprising in its heavy chain variable region a CDR1 sequence having an amino acid sequence set out in SEQ ID NO: 14, a CDR2 sequence having an amino acid sequence set out in SEQ ID NO: 15 and a CDR3 sequence having an amino acid sequence set out in SEQ ID NO: 2.
  • a further embodiment of the invention relates to a human monoclonal antibody or fragment thereof comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 98% identity on the amino acid level with at least one amino acid as set out in any of SEQ ID NOs: 1- 48 and/or 52-56.
  • a further embodiment of the invention relates to a human monoclonal antibody or fragment thereof comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 98% identity on the amino acid level with at least one, optionally with all amino acid as set out in SEQ ID NOs: 2, 14, 15, 16, 17 and 18.
  • a further embodiment of the invention relates to a human monoclonal antibody or fragment thereof comprising an amino acid sequence having at least 70%>, at least 75%, at least 80%>, at least 85%, at least 90%, at least 95% or at least 98% identity on the amino acid level with at least one, optionally with all amino acid as set out in SEQ ID NOs: 19 and 21.
  • a further embodiment of the invention relates to a human monoclonal antibody or fragment thereof comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 98% identity on the amino acid level with at least one, optionally with all amino acid as set out in SEQ ID NOs: 34 and 35.
  • the human monoclonal antibody or a fragment thereof specifically binding primate GM-CSF according to the present invention comprise an amino acid sequence having at least 70%>, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 98% identity on the amino acid level with an antibody or fragment thereof comprising in its light chain variable region a CDR1 sequence having an amino acid sequence as set out in SEQ ID NO: 16, a CDR2 sequence having an amino acid sequence set out in SEQ ID NO: 17 and a CDR3 sequence having an amino acid sequence set out in SEQ ID NO: 18 and comprising in its heavy chain variable region a CDR1 sequence having an amino acid sequence set out in SEQ ID NO: 14, a CDR2 sequence having an amino acid sequence set out in SEQ ID NO: 15 and a CDR3 sequence having an amino acid sequence set out in SEQ ID NOs: 1-13 or 56, optionally comprising a CDR3 sequence having an amino acid sequence set out in SEQ ID NO: 2.
  • the antibody or the fragment thereof according to the present invention specifically binding primate GM- CSF comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 98% identity on the amino acid level with an antibody or fragment thereof comprising a light chain variable region as set out in SEQ ID NO: 19 and/or a heavy chain variable region as set out in SEQ ID NO: 21, optionally comprising a light chain variable region as set out in SEQ ID NO: 19 and a heavy chain variable region as set out in SEQ ID NO: 21.
  • the SEQ ID NOs used herein, denote the same sequences as disclosed in
  • Sequence identity may be determined by standard sequence alignment programs such as Vector NTI (InforMax (TM) , Maryland, USA), BLAST
  • Such programs compare aligned sequences on an amino acid-by-amino acid basis, and can be set to various levels of stringency for the comparison (e.g. identical amino acid, conservative amino acid substitution, etc.).
  • the grade of identity is determined by using the standard parameters provided by the sequence alignment program, in particular the standard parameters provided by the sequence alignment programs specifically mentioned herein.
  • two amino acids in question are considered as being "conservative substitutions" of one another if they each belong to the same chemical class, i.e. acidic, nonpolar, uncharged polar and basic.
  • Determination of the "identity on the amino acid level” also includes comparison of a nucleotide sequence encoding an amino acid sequence with another nucleotide sequence, wherein a nucleotide in the sequence in question is considered identical on the amino acid level if it is either identical to the corresponding nucleotide in the nucleotide sequence to which it is compared, thus encoding a corresponding amino acid sequence or if one or more nucleotide deviation(s) in the sequence in question from the corresponding one or more nucleotide(s) in the nucleotide sequence to which it is compared encoding an amino acid sequence results in a nucleotide triplet which, when translated, results in an amino acid which is either identical to (due to a degenerate triplet) or a conservative substitution of the corresponding amino acid in the corresponding amino acid sequence to which it is compared.
  • a further embodiment of the invention provides a polynucleotide molecule having a nucleotide sequence encoding an amino acid sequence as set out in any of SEQ ID NOs: 1-48 and/or 52 to 56 or a nucleotide sequence exhibiting at least 70% identity, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 98% identity therewith, wherein sequence identity may be determined by comparing a nucleotide sequence encoding an amino acid sequence of any of SEQ ID NOS: 1-48 and/or 52- 56 with a nucleotide sequence in question by sequence alignment (as described above for amino acid sequences), wherein a nucleotide in the sequence in question is considered identical on the amino acid level if it is either identical to the
  • the term "conservative substitution” is to be understood as described above.
  • the human monoclonal antibody or fragment thereof may be derivatized, for example with an organic polymer, for example with one or more molecules of polyethylene glycol (“PEG”) and/or polyvinyl pyrrolidone (“PVP").
  • PEG polyethylene glycol
  • PVP polyvinyl pyrrolidone
  • PEG molecules derivatized as PEG-maleimide, enabling conjugation with the antibody or fragment thereof in a site-specific manner via the sulfhydryl group of a cysteine amino acid.
  • PEG-maleimide especially preferred are 20 kD and/or 40 kD PEG-maleimide, in either branched or straight-chain form. It may be especially desirable to increase the effective molecular weight of smaller human anti- primate GM-CSF antibody fragments such as scFv fragments by coupling the latter to one or more molecules of PEG, especially PEG-maleimide.
  • the production of the neutralizing antibodies and fragments may be conducted through any method known in the art and is disclosed in detail in WO 2006/111353, the contents of which are incorporated herein in their entirety.
  • compositions for use in the treatment and/or prevention of psoriasis comprising a neutralizing antibody or a fragment thereof specifically binding primate GM-CSF as defined herein to be administered according to the dosage regimen described herein.
  • the pharmaceutical composition for use according to the present invention may further comprise at least one pharmaceutically acceptable carriers.
  • pharmaceutically acceptable relates to any compound which may be used in a pharmaceutical composition without causing any undesired effects (such as negative side effects) in a patient to which the composition is administered.
  • compositions for use according to the present invention may further include any compound considered suitable by the person skilled in the art, selected e.g. depending from the mode of administration for which the pharmaceutical composition is prepared. Preparations for parenteral
  • aqueous or non-aqueous solutions examples include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils.
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like.
  • Preservatives and other additives may also be present in the composition of the present invention such as, for example, antimicrobials, anti-oxidants, chelating agents, inert gases and the like.
  • the pharmaceutical composition of the present invention might comprise proteinaceous carriers, like, e.g., serum albumin or immunoglobulin, preferably of human origin.
  • compositions comprising the same should provide sufficient stability upon storage. It is possible to produce a wide variety of proteins for therapeutic applications. After their production, protein pharmaceuticals are usually stored prior to their use. Due to the fact that proteins are generally larger and more complex than "traditional" pharmaceuticals, formulation and processing of protein pharmaceuticals that are suitable for storage can be particularly challenging. For reviews of protein pharmaceutical formulation and process design, see Carpenter et al. (1997), Pharm. Res. 14: 969-975; Wang (2000), Int. J. Pharmaceutics 203: 1 -60; and Tang and Pikal (2004), Pharm. Res. 21 : 191-200. Several factors can be considered in designing formulations and processes for protein pharmaceutical production.
  • Stable formulation comprising the neutralizing anti-GM-CSF antibody or fragments thereof according to the present invention may be an aqueous solution, wherein the antibody or fragments thereof are directly dissolved and/or dispersed therein.
  • One embodiment of the present invention is a liquid formulation containing the antibody or fragments thereof which is stable and does not undergo the formation of conjugates/aggregates or fragments/degradation products when stored for a long period, and which formulation is suitable for subcutaneous administration.
  • the neutralizing anti-GM-CSF antibody or fragments thereof could be stabilized if a tonicity modifier is added to the solution which is to be stored.
  • tonicity modifiers include, but are not limited to, sugars and sugar alcohols.
  • Simple sugars are called monosaccharides and include glucose, fructose, galactose, xylose, ribose, mannose, lactulose, allose, altrose, gulose, idose, talose, arabinose and lyxose.
  • disaccharides which include for example sucrose, maltose, lactose, isomaltose, trehalose and cellubiose may be used.
  • Sugar alcohols include sorbitol, mannitol, glycerin, erythritol, maltitol, xylitol, polyglycitol.
  • the sugar is a non-reducing sugar such as sucrose or trehalose.
  • Non-reducing sugars are characterized by the absence of an open chain structure, so they are not susceptible to oxidation-reduction reactions.
  • non-reducing sugars such as sucrose or trehalose
  • sugar alcohols such as mannitol or sorbitol
  • combinations of non-reducing sugars and sugar alcohols could be added to the solution, such as sucrose and mannitol, sucrose and sorbitol, trehalose and mannitol, or trehalose and sorbitol.
  • the sugar alcohols mannitol and/or sorbitol are added, optionally in their D-form, more specifically sorbitol is added to the solution.
  • the concentration of the tonicity modifier, optionally sorbitol is between about 1% and about 15% (w/v), optionally between about 2% and about 10% (w/v), specifically between about 3% and about 7% (w/v), more specifically between about 4% and about 6% (w/v) and most preferably about 5% (w/v).
  • a buffer system with a pH of between about 4 and about 10, optionally between about 4 and about 7, specifically between about 4 and about 6 or between about 5 and about 7, more specifically between about 5.5 and about 6.5, or with a pH of about 5.8.
  • the buffer may be selected from a histidine buffer, an acetate buffer and a citrate buffer.
  • an amino acid is meant to be an L-amino acid or D-amino acid, wherein L-amino is preferred.
  • histidine or a salt thereof is used for the buffer system.
  • the salt is a chloride, phosphate, acetate or sulphate, optionally the salt is a chloride.
  • the pH of the histidine buffer system is between about 5 and about 7, optionally between about 5.5 and about 6.5, specifically the pH is about or exactly 5.8. The pH may be adjusted by the use of conventionally used bases and acids, optionally NaOH.
  • the concentration of the buffer system, optionally the histidine buffer system is between about 10 mM and about 50 mM, optionally between about 20 mM and about 40 mM, specifically about 30mM.
  • a combination of the buffer system, optionally the histidine buffer, and the tonicity modifier, optionally the sugar alcohol, specifically mannitol or sorbitol is used to stabilize the neutralizing anti-GM-CSF antibody or fragments thereof in the solution, in order to prevent aggregation and to render the formulation sufficiently stable for long-term storage and/or for one or more freeze/thaw cycles. It was shown that it is preferable in terms of stability to have about 6% (w/v) and higher of sugar alcohol, optionally sorbitol, in the formulation. However, the upper limit for osmolality of the formulation is set to be about
  • the concentration of sugar alcohol, optionally sorbitol is therefore between about 3% and about 7% (w/v), optionally between about 4% and about 6% (w/v) and specifically about 5% (w/v).
  • the formulations or compositions of the invention comprising the neutralizing anti-GM-CSF antibody or fragments thereof do not require further excipients in addition to those disclosed above (i.e., a buffer and a tonicity modifier), such as, for example, surfactants and amino acids, which are used in traditional formulations to stabilize proteins in solution.
  • the formulations described herein are preferred over standard formulations because they have decreased immunogenicity due to the lack of additional agents commonly needed for protein stabilization. It is known that amino acids are useful to stabilize proteins at a high concentration by, inter alia, mediating protein solubility and/or inhibiting protein aggregation. Although threonine (e.g. at 250mM) indicates a minor stabilizing effect, the liquid formulation comprising the neutralizing anti-GM-CSF antibody or fragments thereof is optionally free from further amino acids.
  • the present formulation is free or essentially free of sodium chloride.
  • essentially free is meant that the concentration of sodium chloride is at or very near to 0 (zero) mM, e.g. less than about 50 mM, optionally less than about 20 mM, less than about 10 mM, less than about 5 mM, less than about 2 mM or even less than about 1 mM.
  • the addition of surfactants can be useful to reduce protein degradation during storage.
  • the polysorbates 20 and 80 (Tween 20 and Tween 80) are well established excipients for this purpose.
  • the polysorbate 20 to protein ratio is between about 0.01 : 1 to about 3 :1, preferably between about 0.05:1 to about 2: 1, more preferably between about 0.1 : 1 and about 1.5: 1, even more preferably between about 0.1 : 1 to about 0.8: l, and most preferably between about 0.1 : 1 to about 0.2: l .
  • the polysorbate 20 concentration is between about 0.001%(w/v) and about 0.2%(w/v), preferably between about 0.005%(w/v) and about 0.15%(w/v), more preferably between about 0.007%(w/v) and about 0.1%(w/v), even more preferably between about 0.007%(w/v) and about 0.06%(w/v) and most preferably about 0.01%(w/v).
  • the polysorbate 20 concentration is between about 0.001%(w/v) and about 0.4%(w/v), preferably between about 0.006%(w/v) and about 0.25%(w/v), more preferably between about 0.01%(w/v) and about 0.18%(w/v), even more preferably between about 0.01 %(w/v) and about 0.1 %(w/v) and most preferably about 0.02%(w/v).
  • the polysorbate 80 to protein ratio is between about 0.01 : 1 to about 3: 1, preferably between about 0.05: 1 to about 2: 1, more preferably between about 0.1 : 1 and about 1.5: 1, even more preferably between about 0.1 : 1 to about 0.6: 1, and most preferably from about 0.3: 1 to about 0.6:1.
  • the polysorbate 80 concentration is between about 0.001%(w/v) and about 0.2%(w/v), preferably between about 0.004%(w/v) and about 0.14%(w/v), more preferably between about 0.007%(w/v) and about
  • the polysorbate 80 concentration is between about 0.001%(w/v) and about 0.4%(w/v), preferably between about 0.007%(w/v) and about 0.26%(w/v), more preferably between about 0.01%(w/v) and about 0.2%(w/v), even more preferably between about 0.01%(w/v) and about 0.08%(w/v), most preferably about 0.04%(w/v).
  • the concentration of the neutralizing anti-GM-CSF antibody or functional fragments thereof used is at least about 20 mg/ml, preferably at least about 50 mg/ml, more preferably at least about 100 mg/ml in the liquid formulation which is to be stored, freeze/thawed and/or ready to use. Concentrations of about 20 mg/ml to about 200mg/mg, preferably about 50 mg/ml to about 200 mg/ml, more preferably about 100 mg/ml to about 180 mg/ml, even more preferably about 130 mg/ml to about 170 mg/ml, even more preferably about 135 mg/ml to about 165 mg/ml and most preferred about 150 mg/ml of the neutralizing antibody or a fragment thereof are used in the present invention. Another preferred concentration of the neutralizing anti-GM-CSF antibody or functional fragments thereof used is about 80 mg/ml.
  • the present formulation of the neutralizing anti- GM-CSF antibody or a functional fragment thereof comprises from about 135 mg/ml to about 165 mg/ml of the neutralizing antibody, about 5% (w/v) sorbitol, about 30mM L-histidine and has a pH of about 5.8.
  • the present formulation of the neutralizing anti- GM-CSF antibody or functional fragments thereof comprises from about 80 mg/ml to about 150 mg/ml of the neutralizing antibody, about 5% (w/v) sorbitol, about 30mM L-histidine, and from about 0.01% to about 0.08% (w/v) polysorbate 80 and has a pH of about 5.8.
  • the present formulation of the neutralizing anti- GM-CSF antibody or functional fragments thereof comprises about 80 mg/ml of the neutralizing antibody, about 5% (w/v) sorbitol, about 30mM L-histidine, about 0.04%) (w/v) polysorbate 80 and has a pH of about 5.8. Furthermore, in one embodiment, the present formulation of the neutralizing anti- GM-CSF antibody or functional fragments thereof comprises about 150 mg/ml of the neutralizing antibody, about 5% (w/v) sorbitol, about 30mM L-histidine, about 0.04% (w/v) polysorbate 80 and has a pH of about 5.8.
  • the shelf life of the produced formulation may have a minimum requirement of 24 months at 2 to 8°C, 36 months at 2 to 8°C, 48 months at 2 to 8°C or at least 28 days at ambient temperature (25°C ⁇ 2°C).
  • the neutralizing anti-GM-CSF antibody or fragments thereof may be provided in a stable formulation, optionally a stable liquid formulation that allows for long-term storage of compounds neutralizing GM-CSF.
  • This formulation is useful, in part, because it is more convenient to use for the patient, as the neutralizing anti-GM-CSF antibody or fragments thereof of this formulation are highly concentrated so as to reduce side effects like pain due to high volume injection.
  • the formulations comprising a neutralizing anti-GM-CSF antibody or fragments thereof according to the invention comprise a buffer system optionally selected from a histidine buffer, an acetate buffer and/or a citrate buffer with a preferred pH of between 5 and 7, and a tonicity modifier optionally selected from non-reducing sugars, such as sucrose or trehalose, or sugar alcohols, such as mannitol or sorbitol are rendered sufficiently stable for long-term storage and/or freeze/thaw cycles.
  • the formulation of the invention has many advantages over standard buffered formulations. In one aspect, the formulation shows minimal aggregation behaviour upon long-term storage without deleterious effects that might be expected with high protein formulations.
  • formulation according to the invention are: minimal fragmentation of neutralizing anti-GM-CSF antibody or fragments thereof and no significant impact on bioactivity of neutralizing anti-GM-CSF antibody or fragments thereof over long-term storage, and low viscosity of the composition.
  • the formulation is free of further excipients such as surfactants, additional amino acids and/or sodium chloride.
  • the neutralizing antibody or a fragment thereof or the pharmaceutical composition comprising the same according to the present invention is for use in the treatment and/or prevention of psoriasis.
  • the neutralizing antibody or a fragment thereof as described herein may be used for the treatment and/or prevention of any type of psoriasis known in the art.
  • psoriasis may be classified in the non-pustular and pustular type, whereby in the latter type pustules can be found on the patient's skin.
  • Non-pustular psoriasis includes Psoriasis vulgaris or plaque -type psoriasis (i.e. the most common type of psoriasis) and Psoriasis erythroderma.
  • Psoriasis vulgaris is characterized by the presence of red, raised scaly plaques that affect any surface of the body, however can be most often found on the scalp, knees, elbows and lower back of the patient. Different types of Psoriasis vulgaris may be distinguished, i.e. type I with an onset before the age of forty and type II with an onset after the age of forty. Psoriasis erythroderma is a generalized, inflammatory form of psoriasis affecting most of the body surface.
  • Pustular psoriasis includes generalized pustular psoriasis (type Zumbusch), pustulosis palmaris et plantaris (Barber type), annular pustular psoriasis, Acrodermatits continua and Impetigo herpetiformis. Further types of psoriasis include drug-induced psoriasis, inverse psoriasis, napkin psoriasis, nail psoriasis, guttate psoriasis and seborrheic-like psoriasis. In one specific
  • the neutralizing antibody or a fragment thereof according to the invention is for use in the treatment and/or prevention of pustular psoriasis, in particular selected from the group consisting of generalized pustular psoriasis (type Zumbusch), pustulosis palmaris et plantaris (Barber type), annular pustular psoriasis, Acrodermatits continua and Impetigo herpetiformis.
  • generalized pustular psoriasis type Zumbusch
  • pustulosis palmaris et plantaris Barber type
  • annular pustular psoriasis Acrodermatits continua
  • Impetigo herpetiformis in another specific
  • the neutralizing antibody or a fragment thereof according to the invention is for use in the treatment and/or prevention of non-pustular psoriasis, in particular for use in the treatment and/or prevention of Psoriasis vulgaris and/or Psoriasis erythroderma.
  • the neutralizing antibody or a fragment thereof according to the invention is for use in the treatment and/or prevention of Psoriasis vulgaris, optionally type I or type II Psoriasis vulgaris.
  • the neutralizing antibody or a fragment thereof according to the invention is for use in the treatment of type I Psoriasis vulgaris.
  • the neutralizing antibody or a fragment thereof according to the invention is for use in the prevention of type II Psoriasis vulgaris. In another embodiment, the neutralizing antibody or a fragment thereof according to the invention is for use in the treatment and/or prevention of drug-induced psoriasis (e.g.
  • beta blockers lithium, antimalarials, terbinafme, calcium channel blockers, captopril, glyburide, granulocyte colony-stimulating factor, interleukins, interferons and/or lipid-lowering drugs), inverse psoriasis, napkin psoriasis, nail psoriasis, guttate psoriasis and/or seborrheic-like psoriasis.
  • the neutralizing antibody or a fragment thereof according to the invention is for use in the treatment of psoriatic arthritis.
  • One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of non-pustular psoriasis, optionally Psoriasis vulgaris, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
  • One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of non-pustular psoriasis, optionally Psoriasis vulgaris, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising: (a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration, which is a double dose of the doses administered according to (b) and/or (c),
  • Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of non-pustular psoriasis, optionally Psoriasis vulgaris, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
  • the psoriasis to be the treated with the neutralizing antibody or fragment thereof or composition comprising the same may be a clinically stable psoriasis or a relapse- remitting psoriasis.
  • Clinically stable psoriasis as used herein relates to any course of disease that does not show any significant variations in e.g. the severity of the disease (i.e. no up-or downgrading in the EMEA's severity classification as described below), the PASI score (i.e. no change of PASI score of more than about 10% from the initial score), the PGA scale (i.e. no up-or downgrading of the PGA) or the BSA affected by psoriasis (i.e.
  • the neutralizing antibody or a fragment thereof is for use in the treatment of clinically stable psoriasis.
  • the clinically stable psoriasis to be treated with the neutralizing antibody or a fragment thereof may be clinically stable non-pustular psoriasis, optionally clinically stable Psoriasis vulgaris.
  • One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of clinically stable non-pustular psoriasis, optionally clinically stable Psoriasis vulgaris, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
  • One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of clinically stable non-pustular psoriasis, optionally clinically stable Psoriasis vulgaris, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
  • Relapse of psoriasis as used herein relates to any course of disease that involves a reduction of the maximal improvement from the baseline by >50%. Relapse may, however, also relate to any course of disease which necessitates re -initiation of the treatment (cf. EMEA, Guideline on clinical investigation of medicinal products indicated for the treatment of psoriasis (2004)). Hence, the neutralizing antibody or a fragment thereof may also be used for the treatment and/or prevention of relapse- remitting psoriasis.
  • the neutralizing antibody or a fragment thereof is for use in the treatment and/or prevention of a relapse-remitting non- pustular psoriasis, optionally of relapse-remitting Psoriasis vulgaris.
  • the neutralizing antibody or a fragment thereof may also be used for the treatment and/or prevention of a rebound of psoriasis.
  • a rebound of psoriasis may lead to a significant worsening of psoriasis (i.e. to a level worse than before the therapy was started) or a change of the character of the psoriasis.
  • the term "rebound" of psoriasis relates to worsening of psoriasis over a baseline, or a new pustular, erythrodermic or more inflammatory psoriasis occurring within two months after stopping therapy (cf. EMEA, Guideline on clinical investigation of medicinal products indicated for the treatment of psoriasis (2004)).
  • Worsening of psoriasis over a baseline which was assessed before the start of the treatment may relate to an increase of the initial PASI score by at least 10%, at least 20%, at least 30%, at least 40% or at least 50%, to an increase of the initial BSA by at least 10%, at least 20%, at least 30% at least 40% or at least 50% and/or to an upscaling of the severity grade of the psoriasis according to the EMEA's classification described below.
  • the neutralizing antibody or a fragment thereof may be used to treat a rebound of psoriasis in a patient currently treated with any active agent suitable for the treatment of psoriasis and/or any of its symptoms excluding the neutralizing antibody or a fragment thereof according to the invention.
  • Psoriasis severity may range from mild to severe.
  • EMEA Evaluation Agency
  • BSA body surface area
  • PESI Psoriasis Area and Severity Index
  • Topical therapy still possible to control the disease.
  • BSA involvement >10% or PASI 10 or more.
  • Category "moderate” on PGA.
  • Topical therapies fail to control the disease.
  • Very thick lesions located in "difficult to treat" regions e.g. palmo-plantar
  • BSA involvement ⁇ 10% may also be considered.
  • any reference to severity grades of psoriasis as used herein relates to the above defined severity grades according to the EMEA's guidelines, unless indicated otherwise.
  • the Psoriasis Area and Severity Index takes into account the severity of the lesions and the area affected on four body regions, i.e. the head, the trunk, the arms and the legs. For each of these body regions the percent of skin involved is assessed and transformed into a certain value from 1-6:
  • the severity of the lesions in each of the body regions is estimated, whereby three clinical signs, i.e. erythema, infiltration and desquamation are determined and associated with a value from 0-4:
  • the PASI score is calculated according to the following formula taking into account the percentage of each body region assessed to the overall body surface area (cf. Appendix of Guideline on clinical investigation of medicinal products indicated for the treatment of psoriasis (2004),
  • PASI 0.1(E h +I h +D h )A h +0.2(E u +I u +D u )A u +0.3(E,+I t +D t )A t +0.4(Ei+Ii+Di)Ai
  • the antibody or fragment thereof or the pharmaceutical composition comprising the same may be used for treatment of patients having any PASI score >1.
  • the clinical benefit of using the neutralizing antibody or functional fragment thereof according to the invention may be an improvement of at least 50 %, at least 55 %, at least 60 %, at least 65 %, at least 70 %, at least 75 % (PASI75) or at least 90 % (PASI90) of the initial PASI score of a patient before start of treatment.
  • the clinical benefit may also comprise achieving PASI75 in at least 60, 65, 70, 75, 80 or 85 % of patients of a group of patients, in particular in at least 60% of patients of a group of patients.
  • PASI90 may comprise achieving PASI90 in at least 40, 45, 50, 55, 60 or 65 % of patients of a group of patients. It is to be understood, that the group of patients in which PASI75 or PASI90 may be achieved relates to about 100, about 125, about 150, about 200, about 300 or about 400 patients, in particular about 125 patients.
  • the antibody or fragment thereof or the pharmaceutical composition comprising the same may also be able to preserve the improved PASI score for at least about 50 weeks, at least about 55 weeks at least, about 60 weeks, at least about 65 weeks, at least about 70 weeks, or at least about 75 weeks.
  • Physican's global assessment is another method for defining the severity of psoriasis, whereby there are two possible forms of PGA, i.e. the static form, wherein the physician assesses all lesions at a single time point and rates them on a six or seven point scale or the dynamic form, wherein the improvement of the disease from a baseline is assessed.
  • the following exemplary scale for static PGA is provided in the Appendix of the EMEA's Guideline on clinical investigation of medicinal products indicated for the treatment of psoriasis (2004):
  • hyperpigmentation may be present
  • references to PGA as used herein refer to the PGA according to the Appendix of the EMEA's guidelines shown above. Briefly, static PGA determines the severity of psoriasis at a single timepoint, whereby erythema, plaque elevation and scale of all involved lesions is taken into account. However, BSA involved is not considered in PGA assessment. It is understood, that the antibody or fragment thereof or the pharmaceutical composition comprising the same according to the invention may be used for treatment and/or prevention of psoriasis in patients having an almost clear, mild, moderate, moderate to severe or severe psoriasis according to PGA.
  • the neutralizing antibody or the fragment thereof or the pharmaceutical composition comprising the same is for use in the treatment and/or prevention of psoriasis in a patient having mild psoriasis, moderate psoriasis, moderate to severe psoriasis or severe psoriasis according to PGA.
  • the neutralizing antibody or a fragment thereof or the pharmaceutical composition comprising the same according to the invention is for use in the treatment of psoriasis of any severity, in particular any grade of severity according to the EMEA's guidelines described herein.
  • minimal or borderline psoriasis not defined by the EMEA wherein the patient does not show any psoriatic lesions but only signs of psoriasis such as nail pitting and severe dandruff may also be treated with the antibody or fragment thereof or the
  • the neutralizing antibody or a fragment thereof or the pharmaceutical composition comprising the same is for use in the treatment and/or prevention of moderate psoriasis, moderate to severe psoriasis and/or severe psoriasis.
  • the neutralizing antibody or a fragment thereof or the pharmaceutical composition comprising the same is for use in the treatment and/or prevention of moderate psoriasis.
  • the neutralizing antibody or a fragment thereof or the pharmaceutical composition comprising the same is for use in the treatment and/or prevention of moderate to severe psoriasis.
  • the neutralizing antibody or a fragment thereof or the pharmaceutical composition comprising the same is for use in the treatment and/or prevention of severe psoriasis.
  • the neutralizing antibody or the fragment thereof or the pharmaceutical composition comprising the same according to the present invention is for use in the treatment of a patient having a PASI score of >1, >5 or >10, in particular >10.
  • the neutralizing antibody or the fragment or the pharmaceutical composition comprising the same according to the present invention is for use in the treatment of a patient having a PASI score of >12, >15, or >20, in particular of >12.
  • the neutralizing antibody or a fragment thereof or the pharmaceutical composition comprising the same is used for treatment of a patient, wherein >1% body surface area , >5% body surface area, >10% body surface area, >15% body surface area, >20% body surface area, >30% body surface area, >40% body surface area or >50% body surface area, in particular >10% body surface area are affected by psoriasis.
  • the neutralizing antibody or the fragment thereof or a pharmaceutical composition comprising the same according to the present invention is for use in the treatment of a patient having a PASI score of >12 and wherein >10% body surface area are affected by psoriasis.
  • One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of moderate to severe Psoriasis vulgaris, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
  • One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of moderate to severe Psoriasis vulgaris, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
  • Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of moderate to severe Psoriasis vulgaris, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
  • the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of Psoriasis vulgaris in a patient having a PASI score of about 10-20, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
  • One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of moderate to severe Psoriasis vulgaris in a patient having a PASI score of about 10-20, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
  • Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of moderate to severe Psoriasis vulgaris in a patient having a PASI score of about 10-20, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
  • One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of Psoriasis vulgaris in a patient having a BSA of >10, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
  • One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of moderate to severe Psoriasis vulgaris in a patient having a BSA of >10, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
  • Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of moderate to severe Psoriasis vulgaris in a patient having a BSA of >10, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
  • treatment includes any treatment of an animal and/or human which leads to a full or partial remission and/or alleviation of the symptoms or the disease to be treated, i.e. psoriasis. Alleviation of the symptoms of psoriasis may include a reduction in dandruff, a reduction of itching, a reduction of plaques, a reduction of redness of the skin and/or a reduction of the discoloring of the nail plate.
  • Treatment as used in the context of the present invention also includes any treatment with the antibody or a fragment thereof or the pharmaceutical composition comprising the same of the present invention leading to a reduction of the body surface area affected by psoriasis, a reduction of the PASI score, a reduction of the PGA score or a downscaling of the severity of the psoriasis on the EMEA's severity scale for psoriasis described herein.
  • treatment with the antibody or fragment thereof or a pharmaceutical composition comprising the same according to the invention leads to a downscaling of the EMEA's severity grade from severe to moderate to severe, from moderate to mild or from mild to minimal psoriasis.
  • treatment may also lead to downscaling over more than one of the EMEA's severity grades, e.g. from severe psoriasis to moderate psoriasis.
  • treatment includes any treatment with the antibody or fragment thereof or the pharmaceutical composition comprising the same according to the present invention, leading to a reduction of about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or about 95% of the initial PASI score.
  • treatment includes any treatment with the antibody or fragment thereof or the pharmaceutical composition comprising the same according to the present invention, leading to a reduction of about 5%, about 10%>, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or about 95% of the initial BSA affected by psoriasis.
  • the term "initial PASI score" or “initial BSA” relates to said PASI score or BSA determined for the patient before starting the treatment with the antibody or fragment thereof according to the present invention or a pharmaceutical composition comprising the same.
  • treatment as used herein relates to a treatment with the antibody or fragment thereof or a pharmaceutical composition comprising the same according to the present invention, leading to full remission of the psoriasis.
  • full remission relates to about 100% reduction of the initial PASI score or a reduction of psoriasis symptoms in the treated patient so that no psoriatic lesions and only signs of borderline psoriasis such as severe dandruff and/or nail pitting may be observed or a reduction to minimal psoriasis as defined herein or a PGA grade of clear psoriasis. It is to be understood that this full remission does not have to be permanently.
  • Prevention includes any treatment of an animal and/or human which fully or partially prevents the outbreak of a disease which should be prevented.
  • This also includes treatment with the antibody or a fragment thereof or a pharmaceutical composition comprising the same according to the present invention which fully or partially prevents the development of any symptoms associated with psoriasis, such as the development of lesions, pustules, severe dandruff and/or nail pitting.
  • Preventive treatment with the antibody or a fragment thereof or a pharmaceutical composition comprising the same may be in particular useful for treatment of patients suffering from relapse-remitting psoriasis. In this case it may be appropriate to administer the antibody or a fragment thereof or a pharmaceutical composition comprising the same during the remission phase in order to prevent and/or reduce the severity of the next relapse.
  • the antibody or a fragment thereof or the pharmaceutical composition comprising the same of the invention may be used for treatment of a patient who has been diagnosed with psoriasis, in particular non-pustular psoriasis such as Psoriasis vulgaris at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months, in particular at least 12 months before the beginning of the treatment.
  • the patient has been diagnosed with clinically stable Psoriasis vulgaris at least 12 months before the beginning of the treatment.
  • One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of clinically stable Psoriasis vulgaris diagnosed at least 12 months before the beginning of the treatment, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
  • the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of clinically stable Psoriasis vulgaris in a patient diagnosed at least 12 months before the beginning of the treatment, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
  • Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of clinically stable Psoriasis vulgaris in a patient diagnosed at least 12 months before the beginning of the treatment, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
  • the antibody or fragment thereof or the pharmaceutical composition comprising the same of the invention may be administered to a patient either orally or parenteraly. In one embodiment, the antibody or fragment thereof or the pharmaceutical composition comprising the same is administered subcutaneously or by other parenteral routes.
  • parenteral routes include administration by intravenous, intradermal, intramusclar, intramammary, intraperitoneal, intrathecal, retrobulbar, intrapulmonary injection and/or surgical implantation at a particular site and/or topical administration.
  • parenteral routes include administration by intravenous, intradermal, intramusclar, intramammary, intraperitoneal, intrathecal, retrobulbar, intrapulmonary injection and/or surgical implantation at a particular site and/or topical administration.
  • the antibody or fragment thereof may be
  • the antibody or fragment thereof or the pharmaceutical is administered intravesically, intranasally, intratumourally and/or intralesionally.
  • the antibody or fragment thereof or the pharmaceutical is administered intravesically, intranasally, intratumourally and/or intralesionally.
  • the antibody or fragment thereof or the pharmaceutical is administered intravesically, intranasally, intratumourally and/or intralesionally.
  • the antibody or fragment thereof or the pharmaceutical is administered intravesically, intranasally, intratumourally and/or intralesionally.
  • composition comprising the same according to the present invention is administered parenteraly, in particular intravenously, subcutaneously or topically.
  • Subcutaneous administration is particularly desirable.
  • One advantage provided by subcutaneous injections is that they may be performed in short time, in particular when compared to intravenous injection (e.g. approximately 10 minutes for subcutaneous administration compared to about an hour for intravenous infusion).
  • Another advantage is, that while intravenous administration requires an intravenous access which has to be established by trained personnel, subcutaneous injections may even performed by the patient himself, e.g. by using automatic injection devices, thus rendering the therapy more convenient for the patient.
  • Subcutaneous (SC) administration may be performed via a syringe, optionally a prefilled syringe, an injector pen, optionally an autoinjector pen, an injection device or an infusion pump or a suitable needleless device.
  • Subcutaneous administration may be performed at a single site of the body or at different sites of the body, e.g. at sites adjacent to each other. Suitable sites for subcutaneous administration are known to the person skilled in the art and include, e.g. the thighs or the upper arms.
  • another embodiment of the present invention relates to intravenous administration of the antibody or a fragment thereof or a pharmaceutical composition comprising the same according to the present invention. Intravenous administration may be in particular useful e.g. when higher concentrations of the antibody which may not be formulated for subcutaneous administration should be administered to the patient.
  • the antibody or the fragment thereof or a pharmaceutical composition comprising the same according to the present invention may also be administered topically.
  • the antibody or fragment thereof or the pharmaceutical composition comprising the same according to the present invention may be administered in any therapeutically effective pharmaceutical dosage form for topical administration.
  • Such pharmaceutical dosage forms include inter alia solutions, suspensions, dispersions, tinctures, gels, topical sprays, topical foams, gels, water-in-oil emulsions such as ointments, and oil-in water emulsions such as creams, lotions, and balms.
  • the pharmaceutical dosage form comprising the antibody or fragment thereof or the pharmaceutical composition comprising the same according to the present invention to the skin by means of an applicator or dispenser device to ensure administration of a particular amount of the compound to a given skin area (that is to avoid overdosing of the dosage form).
  • topical dosage forms may also be applied without such an applicator or dispenser device, e.g. by using a spatula or hands.
  • the neutralizing antibody or a fragment thereof for use according to the invention may be administered in combination with at least one further pharmaceutically active agent suitable for the treatment of psoriasis.
  • Pharmaceutically active agents which may be administered in combination with the antibody or fragment thereof as described herein include in particular active agents labeled for use in the treatment of psoriasis and/or any of its symptoms, active agents currently studied in clinical trials for the treatment of psoriasis and/or any of its symptoms and/or any other active agent which is suitable for the treatment of psoriasis and/or any of its symptoms (e.g. use of known active agents not approved by the competent agencies for the treatment of psoriasis and/or any of its symptoms but which are used off-label).
  • each active agent mentioned herein may be used in combination with the antibody or fragment thereof for use as described herein either alone or in combination with (a) further active agents mentioned herein.
  • therapies for psoriasis include topical agents, phototherapy, systemic agents, e.g. active agents which may be administered orally (e.g. as liquid or solid oral dosage forms), intravenously or subcutaneously and alternative therapies such as changes in diet and lifestyle.
  • any active agent useful in any of the aforementioned therapies may be administered in combination with the antibody or fragment thereof according to the invention.
  • the further active agent may be administered separately, concurrently or sequentially with the antibody or fragment thereof or the composition comprising the same according to the present invention.
  • topical agents currently used for treatment of psoriasis and/or any of its symptoms includes bath solutions, moisturizers, mineral oil, urea, salicylic acid, petroleum jelly, coal tar, dithranol, corticosteroids (e.g.
  • phototherapy is included in the definition of further therapeutic agent for topical treatment of psoriasis and/or any of its symptoms.
  • Phototherapy includes narrow spectrum UVB therapy, selective ultraviolet phototherapy, PUVA therapy (i.e. psoralen in combination with ultraviolet A therapy) and laser therapy.
  • the antibody or fragment thereof is used in combination with phototherapy.
  • Exemplary systemic agents useful for the treatment of psoriasis and/or any of its symptoms are methotrexate, cyclosporine, retinoids, fumaric acid esters (e.g.
  • efalizumab monoclonal antibodies
  • sulphasalazine immunosupressants
  • alefacept a recombinant LFA-3/IgGl fusion protein, tacrolimus and mycophenolat mofetil
  • azathioprine TNF-alpha inhibitors
  • infliximab adalimumab, golimumab, certolizumab pegol, etanercept
  • IL-12 and/or IL-23 inhibitors e.g.
  • the neutralizing antibody or a fragment thereof for use as described herein is administered in combination with at least one non-biologic disease-modifying antirheumatic drug (DMARD).
  • DMARD non-biologic disease-modifying antirheumatic drug
  • the at least one non-biologic DMARD may be selected from the group consisting of methotrexate, sulphasalazine, azathioprine, cyclosporine, retinoids, fumaric acid esters and immunosuppressants.
  • immunosuppressants useful for the treatment of psoriasis are tacrolimus and mycophenolate mofetil.
  • the neutralizing antibody or a fragment thereof for use as described herein is administered in combination with at least one biologic.
  • the term "biologies" designates drugs that have been produced using biotechnological methods, e.g. therapeutic antibodies such as adalimumab, etanercept, golimumab, infliximab, and others.
  • the at least one biologic may be selected from the group consisting of recombinant LFA-3/IgGl human fusion proteins, anti-cytokine antibodies and cytokine receptor antagonists, such as TNF- alpha inhibitors, IL-12 and/or IL-23 inhibitors, and IL-17 inhibitors.
  • TNF-alpha inhibitor designates a biological drug that specifically targets TNFa or a receptor of TNFa.
  • Drugs targeting TNF are for example the above-mentioned adalimumab, etanercept, certoluzimab pegol, golimumab, or infliximab.
  • the neutralizing antibody or a fragment thereof may be administered in combination with at least one biologic selected from the group consisting of efalizumab, infliximab, adalimumab, golimumab, certolizumab pegol, etanercept, ustekinumab, secukinumab, ixekizumab, brodalumab, RG7624, MK-3222 and alefacept.
  • the neutralizing antibody or a fragment thereof for use as described herein is administered in combination with at least one non-biologic DMARD and at least one biologic.
  • the neutralizing antibody or a fragment thereof for use as described herein may be administered in combination with at least one non-biologic DMARD selected from methotrexate, sulphasalazine, azathioprine, cyclosporine, retinoids, fumaric acid esters and immunosuppressants and with at least one biologic selected from recombinant LFA-3/lgGl human fusion proteins, anti-cytokine antibodies and cytokine receptor antagonists, such as TNF-alpha inhibitors, IL-12 and/or IL-23 inhibitors, IL-17 inhibitors or.
  • non-biologic DMARD selected from methotrexate, sulphasalazine, azathioprine, cyclosporine, retinoids, fumaric acid esters and immunosuppressants
  • the neutralizing antibody or a fragment thereof for use as described herein is administered in combination with at least one further active agent suitable for the treatment of psoriasis, optionally selected from the group comprising methotrexate, sulphasalazine, azathiopine, cyclosporine, retinoids, fumaric acid esters, efalizumab, alefacept, infliximab, adalimumab, golimumab, certolizumab pegol, ustekinumab, etanercept, secukinumab, ixekizumab, brodalumab, RG7624, MK-3222, mineral oil, urea, salicylic acid, petroleum jelly, coal tar, dithranol, corticosteroids, fluocinonide, vitamin D 3 analogues, vitamin Bi 2 , and retinoids.
  • at least one further active agent suitable for the treatment of psoriasis optional
  • the antibody or fragment thereof or the pharmaceutical composition comprising the same for use as described herein is used in combination with methotrexate.
  • the antibody or fragment thereof or the pharmaceutical composition comprising the same for use as described herein is used in combination with non-biologic DMARDS, optionally selected from the group consisting of methotrexate, sulphasalazine, azathioprine, cyclosporine, retinoids, fumaric acid esters and immunosuppressants.
  • the antibody or fragment thereof or the pharmaceutical composition comprising the same for use as described herein is used in combination with immunosuppressants, optionally in combination with tacrolimus and/or mycophenolate mofetil.
  • the antibody or fragment thereof or the pharmaceutical composition comprising the same for use as described herein is used in combination with TNF-alpha inhibitors. In a further embodiment of the invention, the antibody or fragment thereof or the pharmaceutical composition comprising the same for use as described herein, is used in combination with IL-12 and/or IL-23 inhibitors.
  • the antibody or a fragment thereof or the pharmaceutical composition comprising the same for use as described herein is used in combination with IL-17 inhibitors.
  • the antibody or a fragment thereof or a pharmaceutical composition comprising the same for use as described herein is used in combination with LFA-3/IgGl human fusion proteins.
  • the antibody or fragment thereof or the pharmaceutical composition comprising the same for use as described herein is used in combination with topical agents useful in the treatment of psoriasis.
  • the antibody or fragment thereof or the pharmaceutical composition comprising the same for use as described herein is used in combination with a biologic optionally selected from the group consisting of efalizumab, alefacept, infliximab, adalimumab, golimumab, certolizumab pegol, ustekinumab, infliximab, etanercept, secukinumab, ixekizumab, brodalumab, RG7624, MK-3222 and ustekinumab.
  • a biologic optionally selected from the group consisting of efalizumab, alefacept, infliximab, adalimumab, golimumab, certolizumab pegol, ustekinumab, infliximab, etanercept, secukinumab, ixekizumab, brodalumab, RG7624, MK-3222 and ustekinuma
  • the antibody or fragment thereof or the pharmaceutical composition comprising the same for use as described herein is used in combination with a further active agent selected from the group consisting of moisturizers, mineral oil, urea, salicylic acid, petroleum jelly, coal tar, dithranol, corticosteroids, fluocinonide, vitamin D 3 analogues, vitamin Bi 2 and retinoids.
  • a further active agent selected from the group consisting of moisturizers, mineral oil, urea, salicylic acid, petroleum jelly, coal tar, dithranol, corticosteroids, fluocinonide, vitamin D 3 analogues, vitamin Bi 2 and retinoids.
  • Such combination therapies are particularly useful when the patient suffering from psoriasis and/or any of its symptoms does not adequately respond to or whose psoriasis is insufficiently controlled by a therapy with any of the active agents suitable for the treatment of psoriasis and/or any of its symptoms.
  • the term "patients not adequately responding to” or “patients with insufficiently controlled psoriasis” and any variations thereof refers to patient not showing the expected treatment response to an active agent, e.g.
  • Patients not adequately responding to the treatment with an active agent or patients with insufficiently controlled psoriasis also relates to patients not showing a reduction of the BSA involved of at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 70% or at least 75% of the initial BSA involved after treatment with the active agent for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks or 8 weeks, in particular to patients not showing a reduction of the BSA involved of at least 30% of the initial BSA involved after treatment with the active agent for 4 weeks.
  • patients not adequately responding to a therapy with an active agent suitable for the treatment of psoriasis do also include patients developing unwanted or severe side effects such as infections, headache, ulcerative stomatitis, pulmonary alveolar proteinosis (PAP), low white blood cell count, nausea, abdominal pain, fatigue or fever in response to the treatment with said active agent.
  • PAP pulmonary alveolar proteinosis
  • the active agent to which the patient does not adequately respond or which insufficiently controls the psoriasis may be any active agent useful in the treatment of psoriasis and/or any of its symptoms, e.g. any of the active agents mentioned specifically herein, thus necessitating a combined treatment with the antibody or fragment thereof according to the invention or a pharmaceutical composition comprising the same and the further active agent or the treatment with the antibody or fragment thereof or a pharmaceutical composition comprising the same without co-administration of the active agent to which the patient does not adequately respond, or which insufficiently controls psoriasis in said patient.
  • One embodiment of the present invention thus relates to the neutralizing antibody or a fragment thereof or a pharmaceutical composition comprising the same for use in the treatment of psoriasis in a patient not adequately responding to or having a psoriasis which is insufficiently controlled by the treatment with a non-biologic DMARD.
  • the patient not adequately responding to or having a psoriasis which is insufficiently controlled by the treatment with a non-biologic DMARD is a patient whose psoriasis has not been treated with a biologic, i.e. a patient who is biologic treatment naive.
  • the non-biologic DMARD to which the patient does not adequately respond or which insufficiently controls the psoriasis of the patient may be selected from the group consisting of methotrexate, sulphasalazine, azathioprine, cyclosporine, retinoids, fumaric acid esters and immunosuppressants.
  • one embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis which is insufficiently controlled by the treatment with a non-biologic DMARD, and wherein optionally the patient is biologic treatment naive, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising: (a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration,
  • Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis which is insufficiently controlled by the treatment with a non-biologic DMARD, and wherein optionally the patient is biologic treatment naive, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
  • a further embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis which is insufficiently controlled by the treatment with a non-biologic DMARD, and wherein optionally the patient is biologic treatment naive, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
  • the neutralizing antibody or fragment thereof or a composition comprising the same is for use in the treatment and/or prevention of psoriasis in a patient not adequately responding to or having a psoriasis which is insufficiently controlled by the treatment with the non-biologic DMARD
  • methotrexat wherein optionally the patient is biologic treatment naive.
  • the antibody or a fragment thereof or a composition comprising the same is for use in the treatment and/or prevention of psoriasis in a patient not adequately responding to or having a psoriasis which is insufficiently controlled by the treatment with immunosuppressants, wherein optionally the patient is biologic treatment naive.
  • the immune- suppressant may be selected from tacrolimus and mycophenolat mofetil.
  • the antibody or a fragment thereof or a composition comprising the same is for use in the treatment and/or prevention of psoriasis in a patient not adequately responding to or having a psoriasis which is insuffciently controlled by the treatment with sulphasalazine, wherein optionally the patient is biologic treatment naive.
  • the antibody or a fragment thereof or a composition comprising the same is for use in the treatment and/or prevention of psoriasis in a patient not adequately responding to or having a psoriasis which is insuffciently controlled by the treatment with azathioprine, wherein optionally the patient is biologic treatment naive.
  • the antibody or a fragment thereof or a composition comprising the same is for use in the treatment and/or prevention of psoriasis in a patient not adequately responding to or having a psoriasis which is insuffciently controlled by the treatment with cyclosporine, wherein optionally the patient is biologic treatment naive.
  • the antibody or a fragment thereof or a composition comprising the same is for use in the treatment and/or prevention of psoriasis in a patient not adequately responding to or having a psoriasis which is insuffciently controlled by the treatment with retinoids, wherein optionally the patient is biologic treatment naive.
  • the antibody or a fragment thereof or a composition comprising the same is for use in the treatment and/or prevention of psoriasis in a patient not adequately responding to or having a psoriasis which is insuffciently controlled by the treatment with fumaric acid esters, wherein optionally the patient is biologic treatment naive.
  • the antibody or fragment thereof or a composition comprising the same is for use in the treatment and/or prevention of psoriasis in a patient not adequately responding to the treatment with or having a psoriasis which is insufficiently controlled by biologic treatment such as treatment with monoclonal antibodies.
  • the antibody or fragment thereof or a composition comprising the same is for use in the treatment and/or prevention of psoriasis in patients having developed an immune response (e.g. antibodies) to biologies, such as monoclonal antibodies used in the treatment of psoriasis. This includes patients having developed anti-drug antibodies against anti-GM-CSF antibodies that are different from the neutralizing antibodies or fragments thereof as described herein.
  • the antibody or a fragment thereof is for use in the treatment and/or prevention of psoriasis in a patient not adequately responding to or having a psoriasis which is insufficiently controlled by the treatment with a cytokine antibody or a cytokine receptor antagonist, optionally selected from the group consisting of TNF-alpha inhibitors, IL-12/IL-23 inhibitors and IL-17 inhibitors.
  • the antibody or fragment thereof or a composition comprising the same is for use in the treatment and/or prevention of psoriasis in a patient not adequately responding to or having a psoriasis which is insufficiently controlled by the treatment with TNF-alpha inhibitors, optionally the treatment with infliximab, adalimumab, golumumab, certolizumab pegol and/or etanercept.
  • the antibody or fragment thereof or a composition comprising the same is for use in the treatment and/or prevention of psoriasis in a patient not adequately responding to or having a psoriasis which is insufficiently controlled by the treatment with IL-12 and/or IL-23 inhibitors optionally the treatment with ustekinumab and/or MK-3222.
  • the antibody or fragment thereof or a composition comprising the same is for use in the treatment and/or prevention of psoriasis in a patient not adequately responding to or having a psoriasis which is insufficiently controlled by the treatment with IL-17 inhibitors, optionally the treatment with brodalumab, ixekizumab, secukinumab and/or RG7624.
  • the antibody or fragment thereof or a composition comprising the same is for use in the treatment and/or prevention of psoriasis in a patient not adequately responding to or having a psoriasis which is insufficiently controlled by the treatment with recombinant LFA-3/lgGl human fusion proteins, optionally the treatment with alefacept.
  • the antibody or a fragment thereof or a composition comprising the same is for use in the treatment and/or prevention of psoriasis in a patient not adequately responding to or having a psoriasis which is insufficiently controlled by biologic treatment, in particular the treatment with an active agent selected from the group consisting of efalizumab, alefacept, infliximab, adalimumab, golimumab, certolizumab pegol, etanercept, brodalumab, ixekizumab, secukinumab, RG7624, MK-3222 and ustekinumab.
  • an active agent selected from the group consisting of efalizumab, alefacept, infliximab, adalimumab, golimumab, certolizumab pegol, etanercept, brodalumab, ixekizumab, secukinumab, RG7624
  • the antibody or a fragment thereof or a composition comprising the same is for use in the treatment and/or prevention of psoriasis in a patient not adequately responding to or having a psoriasis which is insufficiently controlled by a combination of a non-biologic DMARD and a biologic treatment.
  • the patient is not adequately responding to or has a psoriasis which is insufficiently controlled by a treatment with a non-biologic DMARD selected from methotrexate, sulphasalazine, azathioprine, cyclosporine, retinoids, fumaric acid esters and immunosuppressants in combination with the treatment with a biologic selected from anti-cytokine antibodies and cytokine receptor antagonists, optionally selected from TNF-alpha neutralizing agents, IL-12 and/or IL-23 neutralizing agents, IL-17 neutralizing agents and recombinant LFA-3/lgGl human fusion proteins.
  • a non-biologic DMARD selected from methotrexate, sulphasalazine, azathioprine, cyclosporine, retinoids, fumaric acid esters and immunosuppressants in combination with the treatment with a biologic selected from anti-cytokine antibodies and cytokine receptor antagonists, optionally selected from T
  • the patient is not adequately responding to or has a psoriasis which is insufficiently controlled by a treatment with methotrexate in combination with the treatment with a biologic selected from anti-cytokine antibodies, cytokine receptor antagonists, optionally selected from TNF-alpha neutralizing agents, IL-12 and/or IL-23 neutralizing agents, IL-17 neutralizing agents and recombinant LFA- 3/lgGl human fusion proteins.
  • the patient is not adequately responding to or has a psoriasis which is insufficiently controlled by a treatment with a biologic selected from anti-cytokine antibodies, cytokine receptor antagonists, optionally selected from TNF-alpha neutralizing agents, IL-12 and/or IL-23 neutralizing agents, IL-17 neutralizing agents and recombinant LFA- 3/lgGl human fusion proteins.
  • the patient is not adequately responding to or has a psoriasis which is insufficiently controlled by a treatment with
  • sulphasalazine in combination with the treatment with a biologic selected from anti- cytokine antibodies, cytokine receptor antagonists, optionally selected from TNF- alpha neutralizing agents, IL-12 and/or IL-23 neutralizing agents, IL-17 neutralizing agents and recombinant LFA-3/lgGl human fusion proteins.
  • a biologic selected from anti- cytokine antibodies, cytokine receptor antagonists, optionally selected from TNF- alpha neutralizing agents, IL-12 and/or IL-23 neutralizing agents, IL-17 neutralizing agents and recombinant LFA-3/lgGl human fusion proteins.
  • the patient is not adequately responding to or has a psoriasis which is insufficiently controlled by a treatment with azathioprine in combination with the treatment with a biologic selected from anti-cytokine antibodies, cytokine receptor antagonists, optionally selected from TNF-alpha neutralizing agents, IL-12 and/or IL-23 neutralizing agents, IL-17 neutralizing agents and recombinant LFA-3/lgGl human fusion proteins.
  • a biologic selected from anti-cytokine antibodies, cytokine receptor antagonists, optionally selected from TNF-alpha neutralizing agents, IL-12 and/or IL-23 neutralizing agents, IL-17 neutralizing agents and recombinant LFA-3/lgGl human fusion proteins.
  • the patient is not adequately responding to or has a psoriasis which is insufficiently controlled by a treatment with cyclosporine in combination with the treatment with a biologic selected from anti-cytokine antibodies, cytokine receptor antagonists, optionally selected from TNF-alpha neutralizing agents, IL-12 and/or IL-23 neutralizing agents, IL-17 neutralizing agents and recombinant LFA-3/lgGl human fusion proteins.
  • a biologic selected from anti-cytokine antibodies, cytokine receptor antagonists, optionally selected from TNF-alpha neutralizing agents, IL-12 and/or IL-23 neutralizing agents, IL-17 neutralizing agents and recombinant LFA-3/lgGl human fusion proteins.
  • the patient is not adequately responding to or has a psoriasis which is insufficiently controlled by a treatment with retinoids in combination with the treatment with a biologic selected from anti-cytokine antibodies, cytokine receptor antagonists, optionally selected from TNF-alpha neutralizing agents, IL-12 and/or IL-23 neutralizing agents, IL-17 neutralizing agents and recombinant LFA-3/lgGl human fusion proteins.
  • a biologic selected from anti-cytokine antibodies, cytokine receptor antagonists, optionally selected from TNF-alpha neutralizing agents, IL-12 and/or IL-23 neutralizing agents, IL-17 neutralizing agents and recombinant LFA-3/lgGl human fusion proteins.
  • the patient is not adequately responding to or has a psoriasis which is insufficiently controlled by a treatment with fumaric acid esters in combination with the treatment with a biologic selected from anti-cytokine antibodies, cytokine receptor antagonists, optionally selected from TNF-alpha neutralizing agents, IL-12 and/or IL-23 neutralizing agents, IL-17 neutralizing agents and recombinant LFA-3/lgGl human fusion proteins.
  • a biologic selected from anti-cytokine antibodies, cytokine receptor antagonists, optionally selected from TNF-alpha neutralizing agents, IL-12 and/or IL-23 neutralizing agents, IL-17 neutralizing agents and recombinant LFA-3/lgGl human fusion proteins.
  • the patient is not adequately responding to or has a psoriasis which is insufficiently controlled by a treatment with immunosuppressants in combination with the treatment with a biologic selected from anti-cytokine antibodies, cytokine receptor antagonists, optionally selected from TNF-alpha neutralizing agents, IL-12 and/or IL-23 neutralizing agents, IL-17 neutralizing agents and recombinant LFA-3/lgGl human fusion proteins.
  • a biologic selected from anti-cytokine antibodies, cytokine receptor antagonists, optionally selected from TNF-alpha neutralizing agents, IL-12 and/or IL-23 neutralizing agents, IL-17 neutralizing agents and recombinant LFA-3/lgGl human fusion proteins.
  • the patient is not adequately responding to or has a psoriasis which is insufficiently controlled by a treatment with a non-biologic DMARD selected from methotrexate, sulphasalazine, azathioprine, cyclosporine, retinoids, fumaric acid esters and immunosuppressants in combination with the treatment with anti-cytokine antibodies or cytokine receptor antagonists.
  • a non-biologic DMARD selected from methotrexate, sulphasalazine, azathioprine, cyclosporine, retinoids, fumaric acid esters and immunosuppressants in combination with the treatment with anti-cytokine antibodies or cytokine receptor antagonists.
  • the patient is not adequately responding to or has a psoriasis which is insufficiently controlled by a treatment with a non-biologic DMARD selected from methotrexate, sulphasalazine, azathioprine, cyclosporine, retinoids, fumaric acid esters and immunosuppressants in combination with the treatment with TNF-alpha inhibitors, optionally in combination with the treatment with infliximab, adalimumab, adumumab, certolizumab pegol and/or etanercept.
  • a non-biologic DMARD selected from methotrexate, sulphasalazine, azathioprine, cyclosporine, retinoids, fumaric acid esters and immunosuppressants in combination with the treatment with TNF-alpha inhibitors, optionally in combination with the treatment with infliximab, adalimumab, adumumab,
  • the patient is not adequately responding to or has a psoriasis which is insufficiently controlled by a treatment with a non-biologic DMARD selected from methotrexate, sulphasalazine, azathioprine, cyclosporine, retinoids, fumaric acid esters and immunosuppressants in combination with the treatment with IL-12 and/or IL-23 inhibitors, optionally in combination with the treatment with ustekinumab and/or MK-3222.
  • a non-biologic DMARD selected from methotrexate, sulphasalazine, azathioprine, cyclosporine, retinoids, fumaric acid esters and immunosuppressants in combination with the treatment with IL-12 and/or IL-23 inhibitors, optionally in combination with the treatment with ustekinumab and/or MK-3222.
  • the patient is not adequately responding to or has a psoriasis which is insufficiently controlled by a treatment with a non-biologic DMARD selected from methotrexate, sulphasalazine, azathioprine, cyclosporine, retinoids, fumaric acid esters and immunosuppressants in combination with the treatment with IL-17 inhibitors, optionally in combination with the treatment with brodalumab, ixekizumab, secukinumab and/or RG7624.
  • a non-biologic DMARD selected from methotrexate, sulphasalazine, azathioprine, cyclosporine, retinoids, fumaric acid esters and immunosuppressants in combination with the treatment with IL-17 inhibitors, optionally in combination with the treatment with brodalumab, ixekizumab, secukinumab and/or RG7624.
  • the patient is not adequately responding to or has a psoriasis which is insufficiently controlled by a treatment with a non-biologic DMARD selected from methotrexate, sulphasalazine, azathioprine, cyclosporine, retinoids, fumaric acid esters and immunosuppressants in combination with the treatment with recombinant LFA-3/lgGl human fusion proteins, optionally in combination with the treatment with alefacept.
  • a non-biologic DMARD selected from methotrexate, sulphasalazine, azathioprine, cyclosporine, retinoids, fumaric acid esters and immunosuppressants in combination with the treatment with recombinant LFA-3/lgGl human fusion proteins, optionally in combination with the treatment with alefacept.
  • the antibody or fragment thereof or a composition comprising the same is for use in the treatment of psoriasis in a patient not adequately responding to or having a psoriasis which is insufficiently controlled by topical treatment, in particular the treatment with an active agent selected from the group consisting of moisturizers, mineral oil, urea, salicylic acid, petroleum jelly, coal tar, dithranol, corticosteroids, fluocinonide, vitamin D 3 analogues, vitamin Bi 2 and retinoids.
  • an active agent selected from the group consisting of moisturizers, mineral oil, urea, salicylic acid, petroleum jelly, coal tar, dithranol, corticosteroids, fluocinonide, vitamin D 3 analogues, vitamin Bi 2 and retinoids.
  • the present invention relates to a method of treatment of psoriasis in a patient, comprising administering a neutralizing antibody or a fragment thereof as defined herein to said patient according to the dosage regimen as described herein.
  • Patient as used herein relates to any mammalian, in particular a human, suffering from psoriasis in any of its forms mentioned herein, having been diagnosed with psoriasis in any of its forms mentioned herein, being predisposed to psoriasis in any of its forms mentioned herein or susceptible to psoriasis in any of its forms mentioned herein.
  • the patient to be treated with the method according to the invention includes a patient suffering from any type of psoriasis specifically mentioned herein, such as pustular and non-pustular psoriasis.
  • the method of the invention relates to the treatment of patients suffering from non-pustular psoriasis, optionally selected from Psoriasis vulgaris and Psoriasis erythroderma.
  • the patients to be treated with the method according to the invention include patients not adequately responding to or insufficiently controlled by a treatment with a further active agent useful in the treatment of psoriasis as described herein.
  • the antibody or fragment thereof or a composition comprising the same may be administered in any form described herein, e.g. subcutaneously, intravenously or topically.
  • the method of the present invention also includes the administration of a further active agent suitable for the treatment of psoriasis to a patient suffering from psoriasis.
  • a further active agent suitable for the treatment of psoriasis to a patient suffering from psoriasis.
  • These further active agents which may be administered in combination with the antibody or fragment thereof or a composition comprising the same include any active agents suitable for the treatment of psoriasis as defined herein. It is to be understood that within the context of the method of the invention, these active agents may be either administered simultaneously or subsequently with the antibody, the fragment thereof or a composition comprising the same.
  • Another of its embodiments relates to the method of the present invention, wherein the administration of the antibody or fragment thereof or the composition comprising the same of the invention results in a reduction of about 20%, of about 25%, of about 30% , of about 35%, of about 40%, of about 45%, of about 50%, of about 55%, of about 60%, of about 65%, of about 70%, of about 75% , of about 80%, of about 85%, of about 90% or of about 95% of the initial PASI evaluated in said patient at the beginning of the treatment.
  • the administration of the antibody or a fragment thereof or the composition comprising the same according to the invention leads to a reduction of about 25% of the initial PASI evaluated in said patient at the beginning of the treatment.
  • the administration of the antibody or a fragment thereof or the composition comprising the same according to the invention leads to a reduction of about 50% of the initial PASI evaluated in said patient at the beginning of the treatment. In one specific embodiment, the administration of the antibody or a fragment thereof or the composition comprising the same according to the invention leads to a reduction of about 75% of the initial PASI evaluated in said patient at the beginning of the treatment. In one specific embodiment, the administration of the antibody or a fragment thereof or the composition comprising the same according to the invention leads to a reduction of about 90% of the initial PASI evaluated in said patient at the beginning of the treatment.
  • the reduction of the initial PASI may be determined after 5 weeks from the beginning of the treatment, after 6 weeks from the beginning of the treatment, after 7 weeks from the beginning of the treatment, after 8 weeks from the beginning of the treatment, after 9 weeks from the beginning of the treatment, after 10 weeks from the beginning of the treatment, after 11 weeks from the beginning of the treatment or after 12 weeks from the beginning of the treatment. In one embodiment, the reduction of the initial PASI is determined after 10 weeks from the beginning of the treatment.
  • the present invention relates to a kit comprising the antibody or fragment thereof or a pharmaceutical composition comprising the same according to the invention.
  • the kit may include the antibody or fragment thereof or a pharmaceutical composition comprising the same packed in single or multiple dosage forms.
  • These dosage forms may be any dosage form suitable for e.g.
  • the kit may also include a container comprising the antibody or a fragment thereof according to the invention in lyophilized form and, optionally, in another container liquid suitable for
  • Example 1 A phase 2 multicenter, randomised, double-blind, placebo-controlled, parallel group dose finding trial to compare four different dose levels of an antibody neutralizing GM-CSF (hereinafter referred to as "anti-GM-CSF-1") comprising a light chain CDR1 as depicted in SEQ ID NO: 16, a light chain CDR2 shown in SEQ ID NO: 17, a light chain CDR3 according to SEQ ID NO: 18, a heavy chain CDR1 shown in SEQ ID NO: 14, a heavy chain CDR2 shown in SEQ ID NO: 15, and a heavy chain CDR3 as depicted in SEQ ID NO: 2 (an antibody having a variable heavy chain and light chain as specified in SEQ ID Nos. 34 and 35).
  • anti-GM-CSF-1 an antibody neutralizing GM-CSF
  • WO 2006/111353 Preparation of this antibody is disclosed in WO 2006/111353.
  • the antibody is used at doses of 20 mg, 50 mg, 80 mg or 150 mg and administered subcutaneously to subjects with clinically stable plaque psoriasis at week 0, 2, 6, and 10 versus placebo.
  • the effects of the subcutaneous administration of anti-GM-CSF-1 on psoriasis manifestation is assessed using PASI score, PGA score and biopsies.
  • the study comprises three different periods, i.e. the screening period, the treatment period and the follow-up period.
  • the total trial duration being from at least 84 to up to 185 days or up to 448 days. It is noted that the duration of any drug holiday which may optionally be made is not included in the total trial duration.
  • the primary endpoint is a 75% reduction in the PASI score (PASI75) versus baseline at week 12. PASI50 and PASI90 will also be assessed.
  • Eligibility criteria include inter alia:
  • the time points provided herein for the treatment period and the follow-up period are based on an overall study duration of 185 days. It is to be understood that when a shorter study duration is envisaged, the time points have to be adapted accordingly. Eligible subjects return to the clinic on day 1 when eligibility criteria including vital signs, lung function tests, blood sampling and pharmakokinetic evaluations are assessed. The subjects are randomly assigned to one of the five treatment groups (20 mg, 50 mg, 80 mg or 150 mg of anti-GM-CSF-1 or placebo) in a 1 : 1 : 1 :1 : 1 ratio.
  • the subject has two subcutaneous injections ("loading dose") of 20 mg, 50 mg, 80 mg or 150 mg of anti-GM-CSF-1 or placebo, depending on which treatment group they have been assigned to in order to allow for optimal onset of efficacy of anti-GM- CSF-1. Furthermore, non-lesional biopsies as well as biopsies from one distinct plaque are taken from approximately 5 subjects per dosage group.

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Abstract

The present invention relates to neutralizing antibodies or fragments thereof specifically binding primate GM-CSF for use in the treatment and/or prevention of psoriasis. The invention further relates to methods of treatment and/or prevention of psoriasis of a patient in need thereof, to pharmaceutical compositions for use in the treatment and/or prevention of psoriasis and to a kit comprising said antibodies or fragments thereof.

Description

NEUTRALIZING ANTIBODY OR A FRAGMENT THEREOF SPECIFICALLY BINDING PRIMATE GM-CSF FOR USE IN THE TREATMENT AND/OR PREVENTION OF PSORIASIS
The present invention relates to neutralizing antibodies or fragments thereof specifically binding primate GM-CSF for use in the treatment and/or prevention of psoriasis. The invention further relates to methods of treatment and/or prevention of psoriasis of a patient in need thereof, to pharmaceutical compositions for use in the treatment and/or prevention of psoriasis and to a kit comprising said antibodies or fragments thereof.
TECHNICAL BACKGROUND
Psoriasis is a chronic immune-mediated inflammatory disease of the skin, involving most areas of the body such as the scalp, the extremities, the lower back and genitals. However, the condition is also associated with extra-cutaneous effects including an increased incidence of certain malignancies, metabolic syndrome, depression, cardiovascular disease and psoriatic arthritis (Ref Griffiths et al. (2007) Lancet, 370(9583):263-71. The most common form of psoriasis - Psoriasis vulgaris or plaque-type psoriasis - accounts for 85% to 90% of all cases. Approximately one- third of these are classified as moderate -to-severe, based either on the body surface area involved or significant impact on psychological and/or physical health (e.g. quality of life). Generally, the degree of severity in psoriasis cases depends upon heredity and environmental factors.
Plaque psoriasis is characterized by the presence of red raised scaly plaques that affect any surface of the body. These clinical features are explained by growth and dilation of superficial blood vessels (elongated and/or hyperplastic capillaries in the papillary dermal region) and hyperplasia of the epidermis caused by keratinocyte hyperproliferation. Keratinocytes produce a number of cytokines, either spontaneously or after stimulation, with pro-inflammatory and growth-promoting activities including IL-1, IL-6, IL-8, TNF and granulocyte/macrophage colony-stimulating factor (GM-CSF). At present no curative therapy exists for psoriasis, and the disease may become progressively worse with age or wax and wane in its severity. In approximately 50% of cases symptoms appear before the age of 21 years, and in most cases the condition becomes a chronic relapsing disease for which life-long therapy is needed. Among treatment modalities available for use in modern clinical practice,
immunomodulation with cytokine-neutralizing agents (e.g. infliximab, etanercept, adalimumab acting against TNFa and ustekinumab acting against IL12/IL-23) have shown efficacy and acceptable safety, and have been approved for treatment of moderate to severe psoriasis unresponsive to topical and systemic therapy. Despite therapeutic advances over the past decade, a significant portion of patients, in particular patients with moderate to severe psoriasis, remain inadequately treated as the duration of effect of available agents is limited in life-long disease, onset of action is often unsatisfactorily delayed, efficacy varies from patient to patient and long-term adverse effects of some treatments outweigh the benefit of short term relief.
Hence, there still remains a need for further medicaments useful in the treatment of psoriasis.
SHORT SUMMARY OF THE INVENTION The present invention relates to the following aspects and embodiments:
1. A neutralizing antibody or a fragment thereof specifically binding primate
granulocyte macrophage colony stimulating factor (GM-CSF) for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to a dosage regimen comprising: (a) a loading dose on the first day of administration, which is a double dose of the doses administered according to (b) and/or (c), and/or optionally (d)
(b) a second dose 7-21 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof 21-35 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of 21-35 days.
The neutralizing antibody or a fragment thereof for use according to item 1 , wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration, which is a double dose of the doses administered according to (b) and/or (c), and/or optionally (d)
(b) a second dose of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days.
A neutralizing antibody or a fragment thereof specifically binding primate granulocyte macrophage colony stimulating factor (GM-CSF) for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to a dosage regimen comprising:
(a) a loading dose on the first day of administration (t=d0), which is the same as the doses administered according to (b) and/or (c), and/or optionally (d)
(b) a second dose 7-21 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof 21-35 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of 21-35 days. A neutralizing antibody or a fragment thereof specifically binding primate granulocyte macrophage colony stimulating factor (GM-CSF) for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to a dosage regimen comprising:
(a) a loading dose on the first day of administration (t=d0), which is either the same or a double of the doses administered according to (b) and/or (c), and/or optionally (d)
(b) a second dose 21-35 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof 21-35 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of 21-35 days.
The neutralizing antibody or a fragment thereof for use according to items 1 to 4, wherein the doses of the neutralizing antibody or a fragment thereof according to (b) and (c) and optionally (d) are independently in the range of about 10 - 200 mg, optionally of about 20 - 150 mg.
The neutralizing antibody or a fragment thereof for use according to any of items 1-5, wherein the doses of the neutralizing antibody or a fragment thereof according to (b) and (c) and optionally (d) are independently selected from about 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, l lO mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg 190 mg or 200 mg, optionally independently selected from about 20 mg, 50 mg, 80 mg or 150 mg.
The neutralizing antibody or a fragment thereof for use according to any of items 1-6, wherein the doses of the neutralizing antibody or a fragment thereof according to (b) and (c) and optionally (d) are about 20 mg.
The neutralizing antibody or a fragment thereof for use according to any of items 1-6, wherein the doses of the neutralizing antibody or a fragment thereof according to (b) and (c) and optionally (d) are about 50 mg. 9. The neutralizing antibody or a fragment thereof for use according to any of 1-6, wherein the doses of the neutralizing antibody or a fragment thereof according to (b) and (c) and optionally (d) are about 80 mg.
10. The neutralizing antibody or a fragment thereof for use according to any of items 1-6, wherein the doses of the neutralizing antibody or a fragment thereof according to (b) and (c) and optionally (d) are about 150 mg.
11. The neutralizing antibody or a fragment thereof for use according to any items 1- 10, wherein the neutralizing antibody or fragment thereof is administered over a period of at least 10 weeks starting from the first day of administration. 12. The neutralizing antibody or a fragment thereof for use according to any of items 1-11, wherein said antibody or fragment thereof comprises in its heavy chain variable region a CDR 3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-13 or 56.
13. The neutralizing antibody or a fragment thereof for use according to any of items 1-12, wherein said antibody or a fragment thereof comprises a heavy chain variable region CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-13 or 56 in combination with a heavy chain variable region CDR1 having an amino acid sequence set out in SEQ ID NO: 14 and a heavy chain variable region CDR2 having an amino acid sequence set out in SEQ ID NO: 15.
14. The neutralizing antibody or a fragment thereof for use according to any of items 1-13, wherein said antibody or a fragment thereof comprises a light chain variable region a CDR1 having an amino acid sequence set out in SEQ ID NO: 16, a CDR2 having an amino acid sequence set out in SEQ ID NO: 17 and a CDR3 having an amino acid sequence set out in SEQ ID NO: 18.
15. The neutralizing antibody or a fragment thereof for use according to any of items 1-14, wherein said antibody comprises a light chain variable region CDR1 having an amino acid sequence set out in SEQ ID NO: 16, a CDR2 having an amino acid sequence set out in SEQ ID NO: 17 and a CDR3 having an amino acid sequence set out in SEQ ID NO: 18 and comprising a heavy chain variable region CDR1 having an amino acid sequence set out in SEQ ID NO: 14, a CDR2 having an amino acid sequence set out in SEQ ID NO: 15 and a CDR3 having an amino acid sequence set out in SEQ ID NO: 2. The neutralizing antibody or a fragment thereof for use according to any of items 1-15, wherein said antibody or a fragment thereof comprises a light chain variable region sequence set out in SEQ ID NO: 19 and/or a heavy chain variable region sequence set out in SEQ ID NO: 21, optionally a light chain variable region sequence set out in SEQ ID NO: 19 and a heavy chain variable region sequence set out in SEQ ID NO: 21.
The neutralizing antibody or a fragment thereof for use according to any of items 1-16, wherein said antibody or a fragment thereof comprises a light chain sequence set out in SEQ ID NO: 34 and/or a heavy chain sequence set out in SEQ ID NO: 35, optionally a light chain sequence set out in SEQ ID NO: 34 and a heavy chain sequence set out in SEQ ID NO: 35.
The neutralizing antibody or a fragment thereof for use according to any of items 1-17, wherein said neutralizing antibody or fragment thereof comprises at least one amino acid sequence having at least 70%, at least 80%, at least 90% or at least 95% identity to the amino acid sequence of any of SEQ ID NO: 1-48 and/or 52-56. The neutralizing antibody or a fragment thereof for use according to any of items 1-18, wherein said fragment specifically binding primate GM-CSF is an scFv, a single domain antibody, an Fv, a VHH antibody, a diabody, a tandem antibody, a Fab, a Fab' or a F(ab)2. The neutralizing antibody or a fragment thereof for use according to any of items 1-19, wherein the psoriasis is a pustular or a non-pustular psoriasis. 21. The neutralizing antibody or a fragment thereof for use according to any of items 1-20, wherein the psoriasis is a non-pustular psoriasis selected from the group consisting of Psoriasis vulgaris and Psoriasis erythroderma, optionally
Psoriasis vulgaris. 22. The neutralizing antibody or a fragment thereof for use according to any of items 1-21, wherein the psoriasis is a mild to moderate psoriasis, moderate psoriasis, moderate to severe psoriasis or severe psoriasis, optionally moderate to severe psoriasis.
23. The neutralizing antibody or a fragment thereof for use according to any of items 1-22, wherein said antibody or said fragment thereof is administered
parenterally.
24. The neutralizing antibody or a fragment thereof for use according to item 23, wherein said antibody or a fragment thereof is administered subcutaneously, intravenously or topically, optionally subcutaneously. 25. The neutralizing antibody or a fragment thereof for use according to any of items 1-24, wherein said antibody or fragment thereof is administered in combination with at least one further active agent suitable for the treatment of psoriasis, optionally selected from the group comprising methotrexate, sulphasalazine, azathioprine, cyclosporine, fumaric acid esters, efalizumab, alefacept, infliximab, adalimumab, golimumab, certolizumab pegol, ustekinumab, etanercept, mineral oil, urea, salicylic acid, petroleum jelly, coal tar, dithranol, corticosteroids, fluocinonide, vitamin D3 analogues, vitamin Bi2, and retinoids.
26. The neutralizing antibody or a fragment thereof for use according to any of items 1-25, wherein the patient in whom psoriasis is treated and/or prevented is a patient not previously treated for psoriasis or a patient with insufficiently controlled psoriasis. 27. The neutralizing antibody or a fragment thereof for use according to item 26, wherein the patient with insufficiently controlled psoriasis is a patient treated with a non-biologic DMARD, optionally a biologic treatment naive patient treated with a non-biologic DMARD. 28. The neutralizing antibody or a fragment thereof for use according to item 26, wherein the patient with insufficiently controlled psoriasis is a patient treated with a non-biologic DMARD in combination with a biologic.
29. The neutralizing antibody or a fragment thereof for use according to item 27 or 28, wherein the non-biologic DMARD is selected from the group consisting of methotrexate, sulphasalazine, azathioprine, cyclosporine, retinoids, fumaric acid esters and immunosuppressants.
30. The neutralizing antibody or a fragment thereof for use according to item 28, wherein the biologic is selected from the group consisting of recombinant LFA-3/IgGl human fusion protein, TNF inhibitors, IL-12 and/or IL-23 inhibitors or IL- 17 inhibitors.
31. Method of treatment and/or prevention of psoriasis in a patient, comprising administering a neutralizing antibody or a fragment thereof to said patient according to the dosing scheme according to any of items 1 to 11.
32. The method of treatment and/or prevention according to item 31 , wherein the antibody or a neutralizing fragment thereof is a neutralizing antibody or a fragment thereof according to any of items 12 to 19.
33. The method of treatment and/or prevention according to item 31 or 32, wherein said antibody or a said fragment thereof is administered subcutaneously, intravenously or topically, optionally subcutaneously. 34. The method of treatment and/or prevention according to any of items 31 to 33, wherein the patient is suffering from pustular or non-pustular psoriasis. 35. The method of treatment and/or prevention according to item 34, wherein the patient is suffering from non-pustular psoriasis selected from the group consisting of Psoriasis vulgaris and Psoriasis erythroderma, optionally
Psoriasis vulgaris. 36. The method of treatment and/or prevention according to any of items 31 to 35, wherein the psoriasis to be treated and/or prevented is a mild to moderate psoriasis, moderate psoriasis, moderate to severe psoriasis or severe psoriasis, optionally moderate to severe psoriasis.
The method of treatment and/or prevention according to any of items 31 to 36, wherein the patient in whom psoriasis is treated and/or prevented is a patient not previously treated for psoriasis or a patient with insufficiently controlled psoriasis.
38. The method of treatment and/or prevention according to any of items 31 to 37, wherein additionally a further active agent suitable for the treatment of psoriasis, optionally selected from the group comprising methotrexate, sulphasalazine, azathioprine, cyclosporine, fumaric acid esters, efalizumab, alefacept, infliximab, adalimumab, golimumab, certolizumab pegol, ustekinumab, etanercept, mineral oil, urea, salicylic acid, petroleum jelly, coal tar, dithranol, corticosteroids, fluocinonide, vitamin D3 analogues, vitamin Bi2, and retinoids is administered to said patient.
39. The method of treatment and/or prevention according to any of items 31 to 38, wherein the treatment with said neutralizing antibody or fragment thereof results in a reduction of at least 75% of the initial Psoriasis Area and Severity Index (PASI) evaluated in said patient at the beginning of the treatment. DETAILED DESCRIPTION OF THE INVENTION
Where the term "comprise" or "comprising" is used in the present description and claims, it does not exclude other elements or steps. For the purpose of the present invention, the term "consisting of is considered to be an optional embodiment of the term "comprising of. If hereinafter a group is defined to comprise at least a certain number of embodiments, this is also to be understood to disclose a group which optionally consists only of these embodiments.
Where an indefinite or a definite article is used when referring to a singular noun e.g. "a" or "an" or "the", this includes a plural form of that noun unless specifically stated. Vice versa, when the plural form of a noun is used, it refers also to the singular form. For example, when neutralizing antibodies are mentioned, this is also to be understood as a single neutralizing antibody. Furthermore, the terms first, second, third or (a), (b), (c) and the like in the description and in the claims are used for distinguishing between similar elements and not necessarily for describing a sequential or chronological order. It is to be understood that the terms so used are interchangeable under appropriate
circumstances and that the embodiments of the invention described herein are capable of operation in other sequences than described or illustrated herein.
However, in a specific embodiment of the invention, the method steps (a), (b) and (c), optionally including any intermediate steps defined herein, are performed in chronological order. In the context of the present invention any numerical value indicated is typically associated with an interval of accuracy that the person skilled in the art will understand to still ensure the technical effect of the feature in question. As used herein, the deviation from the indicated numerical value is in the range of ± 10%, and preferably of ± 5%. The aforementioned deviation from the indicated numerical interval of ± 10%, and preferably of ± 5% is also indicated by the terms "about" and "approximately" used herein with respect to a numerical value.
As used herein, the conjunctive term "and/or" between multiple recited elements is understood as encompassing both individual and combined options. For instance, where two elements are conjoined by "and/or", a first option refers to the
applicability of the first element without the second. A second option refers to the applicability of the second element without the first. A third option refers to the applicability of the first and second elements together. Any one of these options is understood to fall within the meaning, and therefore satisfy the requirement of the term "and/or" as used herein. Concurrent applicability of more than one of the options is also understood to fall within the meaning, and therefore satisfy the requirement of the term "and/or" as used herein. Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.), whether supra or infra, are hereby incorporated by reference in their entirety. To the extent the material incorporated by reference contradicts or is inconsistent with this
specification, the specification will supersede any such material. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.
As already discussed above, there still remains a need for further medicaments suitable for the treatment of psoriasis, since presently available treatments are often accompanied with unwanted side effects or provide unsatisfactory treatment results. It now has been found that a neutralizing antibody or a fragment thereof specifically binding to primate granulocyte macrophage colony stimulating factor (GM-CSF) is useful in the treatment of psoriasis. Thus, in one aspect, the present invention relates to a neutralizing antibody or a fragment thereof specifically binding primate granulocyte macrophage colony stimulating factor (GM-CSF) for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to a dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration,
(b) a second dose of the neutralizing antibody or a fragment thereof 7-21 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof 21-35 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of 21-35 days. In a further aspect, the present invention relates to a neutralizing antibody or a fragment thereof specifically binding primate granulocyte macrophage colony stimulating factor (GM-CSF) for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to a dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration,
(b) a second dose of the neutralizing antibody or a fragment thereof 21-35 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof 21-35 days after administration of the second dose and
(d) optionally, further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of 21-35 days.
In one embodiment, the doses of the neutralizing antibody or a fragment thereof according to (b) and (c) and optionally (d) are independently in the range of about 10 - 200 mg, optionally of about 20 - 150 mg. In another embodiment, the doses of the neutralizing antibody or a fragment thereof according to (b) and (c) and optionally (d) are independently selected from about 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg 190 mg or 200 mg, optionally independently selected from about 20 mg, 50 mg, 80 mg or 150 mg.
As used herein, the term "loading dose" denotes the first dose of the neutralizing antibody or a fragment thereof which is administered at the beginning of the treatment, i.e. at day 1 of the treatment. This includes the first dose of the anti-GM- CSF antibody or a fragment thereof as described herein administered to a patient, who has never before been treated with a neutralizing antibody. However, the term also relates to the first dose of the anti-GM-CSF antibody or a fragment thereof as described herein which is administered to a patient, who has been treated with the neutralizing antibody or fragment thereof as described herein before, but who has interrupted taking of the neutralizing antibody or a fragment thereof, thus showing insufficient blood serum levels of the neutralizing antibody or a fragment thereof. Insufficient blood serum levels of the neutralizing antibody or a fragment thereof as used herein includes any blood serum levels measured in a patient not sufficient for treatment and/or prevention of psoriasis. This also includes no measurable levels of the neutralizing antibody or a fragment thereof in the blood serum at all.
Interruptions in the taking of the neutralizing antibody or a fragment thereof may, for example, be due to a remission of the symptoms of psoriasis or a drug holiday.
Typically, the loading dose is used to achieve optimal blood serum levels of the neutralizing antibody or a fragment thereof as described herein right at the beginning of the treatment. Optimal blood serum levels denote any blood serum levels of the neutralizing antibody or a fragment useful in the treatment and/or prevention of psoriasis. This may include any blood serum levels able to obtain any of the effects defined herein with respect to the definition of the terms "treatment" and/or
"prevention". According to one embodiment of the present invention, the loading dose may be the same dose as the doses according to (b), (c) or (d) or the double dose as the doses according to (b), (c) or (d). In one embodiment, the loading dose of the neutralizing antibody or a fragment thereof as described herein is in the range of 20 - 400 mg. The loading dose of the neutralizing antibody or a fragment thereof may also be in the range of 40 - 300 mg. In one embodiment, the loading dose of the neutralizing antibody or a fragment thereof as described herein is selected from 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg,
300 mg, 320 mg, 340 mg, 380 mg or 400 mg. The loading dose of the neutralizing antibody or a fragment thereof as described herein may also be selected from 20 mg, 40 mg, 50 mg, 80 mg, 100 mg, 150 mg, 160 mg or 300 mg. In one embodiment, the loading dose of the neutralizing antibody or a fragment thereof as described herein is 20 mg. In one embodiment, the loading dose of the neutralizing antibody or a fragment thereof as described herein is 40 mg. In a further embodiment, the loading dose of the neutralizing antibody or a fragment thereof as described herein is 50 mg. In yet another embodiment, the loading dose of the neutralizing antibody or a fragment thereof as described herein is 80 mg. In another embodiment, the loading dose of the neutralizing antibody or a fragment thereof as described herein is 100 mg. In one embodiment, the loading dose of the neutralizing antibody or a fragment thereof as described herein is 150 mg. In yet another embodiment, the loading dose of the neutralizing antibody or a fragment thereof as described herein is 160 mg. In a further embodiment, the loading dose of the neutralizing antibody or a fragment thereof as described herein is 300 mg.
As described above, the loading dose is used to obtain optimal blood levels of the neutralizing antibody or a fragment thereof as described herein at the beginning of the treatment. Thus, the loading dose may be chosen in accordance with the further doses to be administered, such as doses (b), (c) and/or (d). The loading dose, thus may be the double dose of the doses according to (b), (c) and/or (d) of the dosage regimen as described herein. If doses (b), (c) and optionally (d) of the dosage regimen as described herein are the same, the loading dose may be a double dose of doses (b), (c) and, optionally (d) of the dosage regimen as described herein.
However, if doses (b), (c) and (d) of the dosage regimen as described herein differ from each other, the loading dose may be a double dose of dose (b). In another embodiment, the loading dose may be a double dose of dose (c). In a further embodiment, the loading dose may be a double dose of the further doses (d).
Thus, in an embodiment, wherein doses (b), (c) and optionally (d) are 20 mg, the loading dose (a) is 40 mg. In another embodiment, wherein doses (b), (c) and optionally (d) are 50 mg, the loading dose (a) is 100 mg. In yet another embodiment, wherein doses (b), (c) and optionally (d) are 80 mg, the loading dose (a) is 160 mg. In a further embodiment, wherein doses (b), (c) and optionally (d) are 150 mg, the loading dose (a) is 300 mg.
In one of its embodiments, the present invention relates to a neutralizing antibody or a fragment thereof specifically binding primate granulocyte macrophage colony stimulating factor (GM-CSF) for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to a dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment on the first day of administration , which is the double dose of the second dose (b),
(b) a second dose of the neutralizing antibody or a fragment 7-21 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof 21-35 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of 21-35 days. In a further aspect, the present invention relates to neutralizing antibody or a fragment thereof specifically binding primate granulocyte macrophage colony stimulating factor (GM-CSF) for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to a dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment on the first day of administration, which is the double dose of the second dose (b),
(b) a second dose of the neutralizing antibody or a fragment 21-35 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof 21-35 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of 21-35 days.
The loading dose may also be the same dose as any of the doses according to (b), (c) and/or (d) of the dosage regimen as described herein. If doses (b), (c) and, optionally (d), of the dosage regimen as described herein are the same, accordingly the loading dose may correspond to said doses (b), (c) and, optionally (d) of the dosage regimen as described herein. In one embodiment, doses (a), (b), (c) and (d) are 20 mg. In another embodiment, doses (a), (b), (c) and (d) are 50 mg. In yet another embodiment, doses (a), (b), (c) and (d) are 80 mg. In a further embodiment, doses (a), (b), (c) and (d) are 150 mg. However, if doses (b), (c) and, optionally (d) of the dosage regimen as described herein differ from each other, the loading dose may be the same dose as dose (b). In another embodiment, the loading dose may be the same dose as dose (c). In a further embodiment, the loading dose may be the same dose as the further doses (d).
In one of its embodiments, the present invention relates to a neutralizing antibody or a fragment thereof specifically binding primate granulocyte macrophage colony stimulating factor (GM-CSF) for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to a dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment on the first day of administration, which is the same as the second dose (b),
(b) a second dose of the neutralizing antibody or a fragment 7-21 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof 21-35 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of 21-35 days.
In a further aspect, the present invention relates to neutralizing antibody or a fragment thereof specifically binding primate granulocyte macrophage colony stimulating factor (GM-CSF) for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to a dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment on the first day of administration, which is the same as the second dose (b),
(b) a second dose of the neutralizing antibody or a fragment 21-35 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof 21-35 days after administration of the second dose and
(d) optionally, further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of 21-35 days.
It is to be understood that the loading dose may be administered to the patient as a single dose, for example as a single injection of 40 mg of the neutralizing antibody or a fragment thereof as described herein or in the form of two doses, for example as two separate injections of 20 mg of the neutralizing antibody or a fragment thereof as described herein. In the latter case, both injections should be administered in a short interval of time on day 1, such as in an interval of 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours or 5 hours. However, it may also be possible to administer the loading dose as two separate injections in intervals of 12 hours on day 1. The second dose (b) of the neutralizing antibody or a fragment thereof of the dosage regimen described herein may be administered 7-21 days after administration of the loading dose, optionally 10 -15 days after administration of the loading dose. In one embodiment, the second dose is administered on day 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 after administration of the loading dose, in particular on day 14 after administration of the loading dose.
The second dose (b) of the neutralizing antibody or a fragment thereof of the dosage regimen described herein may also be administered 21-35 days after administration of the loading dose, optionally 25 -20 days after administration of the loading dose. In one embodiment, the second dose is administered on day 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 after administration of the loading dose, in particular on day 28 after administration of the loading dose.
The second dose (b) of the neutralizing antibody or a fragment thereof of the dosage regimen described herein may be in the range of 10-200 mg of the neutralizing antibody or a fragment thereof, optionally in the range of 20-150 mg of the neutralizing antibody or a fragment thereof. In one embodiment, the second dose (b) is selected from 10 mg, 20mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, l lO mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg or 200 mg, optionally selected from 20 mg, 50 mg, 80 mg or 150 mg of the neutralizing antibody or a fragment thereof. In one embodiment, the second dose (b) is 20 mg of the neutralizing antibody or a fragment thereof. In another embodiment, the second dose (b) is 50 mg of the neutralizing antibody or a fragment thereof. In yet another embodiment, the second dose (b) is 80 mg of the neutralizing antibody or a fragment thereof. In a further embodiment, the second dose (b) is 150 mg of the neutralizing antibody or a fragment thereof. The third dose (c) of the neutralizing antibody or a fragment thereof of the dosage regimen described herein may be in the range of 10-200 mg of the neutralizing antibody or a fragment thereof, optionally in the range of 20-150 mg of the neutralizing antibody or a fragment thereof. In one embodiment, the third dose (c) is selected from 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, l lO mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg or 200 mg, optionally selected from 20 mg, 50 mg, 80 mg or 150 mg of the neutralizing antibody or a fragment thereof. In one embodiment, the third dose (c) is 20 mg of the neutralizing antibody or a fragment thereof. In another embodiment, the third dose (c) is 50 mg of the neutralizing antibody or a fragment thereof. In yet another embodiment, the third dose (c) is 80 mg of the neutralizing antibody or a fragment thereof. In a further embodiment, the third dose (c) is 150 mg of the neutralizing antibody or a fragment thereof.
The third dose (c) of the neutralizing antibody or a fragment thereof of the dosage regimen as described herein may be administered 21-35 days after administration of the second dose, optionally 25-30 days after administration of the second dose. In one embodiment, the third dose is administered on day 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or 35 after administration of the second, in particular on day 28 after administration of the second dose. After administration of the third dose, further doses (d) may be administered to the patient in order to maintain the desired blood serum levels of the neutralizing antibody or a fragment thereof as described herein. These further doses (d) may be administered to the patient in certain intervals, which are chosen according to the half-life of the neutralizing antibody or a fragment thereof in the blood of the patient. It is to be understood, that the intervals described herein relate to the interval between dose (c) and the first of the further doses (d) as well as the intervals between each of doses (d). In accordance with the present invention, the serum may contain 50% of the anti-primate GM-CSF antibody of fragment thereof at least 7 days, at least 14 days, at least 21 days, e.g., at least 28 days after the last administration of the neutralizing antibody or fragment thereof according to the invention. Generally, the serum may contain about 50% of the anti-primate GM-CSF antibody of fragment thereof at 28 days after the last administration. However, in one embodiment the serum may contain about 50% of the anti-primate GM-CSF antibody of fragment thereof at 21 days after the last administration. In one embodiment, the half life of the anti-primate GM-CSF antibody or fragment thereof in the blood serum is at least 17, at least 21 or at least 25 days. Accordingly, intervals in which doses (d) are administered may be in the range of 21-35 days between each of the doses, in particular in the range of 25-30 days between each of the doses. In one embodiment, the interval between doses (d) is selected from 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or 35 days. In another embodiment, the interval between doses (d) is 28 days.
The further doses (d) of the neutralizing antibody or a fragment thereof of the dosage regimen described herein may be in the range of 10-200 mg of the neutralizing antibody or a fragment thereof, optionally in the range of 20-150 mg of the neutralizing antibody or a fragment thereof. In one embodiment, the further doses (d) are selected from 10 mg, 20mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg or 200 mg, optionally selected from 20 mg, 50 mg, 80 mg or 150 mg of the neutralizing antibody or a fragment thereof. In one embodiment, the further doses (d) are 20 mg of the neutralizing antibody or a fragment thereof. In another embodiment, the further doses (d) are 50 mg of the neutralizing antibody or a fragment thereof. In yet another embodiment, the further doses (d) are 80 mg of the neutralizing antibody or a fragment thereof. In a further embodiment, the further doses (d) are 150 mg of the neutralizing antibody or a fragment thereof.
The further doses (d) may be administered to the patient as long he is in need of a treatment and/or prevention of psoriasis. Thus, the further doses (d) may be administered to the patient until a full or partial remission and/or alleviation symptoms of the psoriasis as described herein, a reduction of the body surface area affected by psoriasis, a reduction of the PASI score or a downscaling of the severity of the psoriasis on the EMEA's severity scale for psoriasis is achieved such as the reductions and downscaling described herein with respect to the definition of the term "treatment". Thus, further doses (d) may be administered to the patient over a period of at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9 or at least 10 weeks, in particular over a period of at least 8 weeks.
Accordingly, the neutralizing antibody or a fragment thereof may be administered to the patient over a period of at least 10, at least 14, at least 18, at least 22, at least 24, at least 26, at least 30, at least 34, at least 38 or at least 42 weeks, in particular over a period of at least 18 weeks.
If the neutralizing antibody or a fragment thereof is used for the prevention of psoriasis, further doses (d) may be administered to the patient to the patient as long as full or partial prevention of psoriasis and/or any of its symptoms is desired. It is to be understood that the administration of the neutralizing antibody or a fragment thereof may also be stopped after a certain period of treatment with the neutralizing antibody or fragment thereof after which the desired effects (such as a reduction of the PASI score, a reduction of the PGA, a reduction of the BSA or a change of the grade of the severity of the psoriasis) have been achieved. This is due to the fact that the effects of the antibody or fragment thereof last for a certain period of time after the administration has been stopped. Such a "drug holiday" (or "drug vacation", "medication vacation", "structured treatment interruption" or "strategic treatment interruption") may reduce the risk of side effects and may maintain the sensitivity to the neutralizing antibody or fragment thereof, may lead to the recovery of some normal physiologic functions in the patient or may improve patient compliance. The time point for a drug holiday may vary from patient to patient and may be chosen based on the basis of the clinical assessment by the treating physician. This clinical assessment may be based on biomarkers or on the basis of the effect achieved by the administration of the neutralizing antibody or fragment thereof. Any effect defined herein with respect to the term "treatment" may be indicative that a drug holiday may be made. In one embodiment of the invention, a drug holiday is made when the patient shows a reduction of the initial PASI score of about 75% or about 90%. In another embodiment, a drug holiday is made when the patient shows a reduction of the initial BSA of about 50%, about 75% or about 90%. In another embodiment of the invention, a drug holiday is made when the patient shows a downscaling of the EMEA's severity grade of at least one grade (e.g. from severe to moderate to severe).
In another embodiment, a drug holiday may be made at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months or at least 12 months after administration of the loading dose (a). In yet another embodiment, a drug holiday may be made at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months or at least 12 months after administration of the second dose (b). During the drug holiday the clinical parameters of the patient (such as the PASI score, the PGA, the BSA or the grade of the psoriasis on the EMEA's severity scale) have to be monitored in regular intervals, such as monthly. If the clinical parameters worsen, e.g. if the PASI score, the PGA, the BSA or the grade of psoriasis increases, the neutralizing antibody or a fragment thereof should again be administered to the patient. In one embodiment such a worsening of the clinical parameters may be an increase of the PASI score measured at the beginning of the drug holidays of about 25%, about 35%, about 45% or about 50% or more. In another embodiment such a worsening of the clinical parameters may be an increase of the PSA at the beginning of the drug holidays of about 5%, about 7%, about 10%> or about 15% or more. In yet another embodiment such a worsening of the clinical parameters may be an increase of the BSA measured at the beginning of the drug holidays of about 5%, about 7%, about 10% or about 15% or more. In a further embodiment, the worsening of the clinical parameter is an upscaling of the EMEA's severity grade for at least one grade. After a drug holiday, the neutralizing antibody or a fragment thereof may again be used according to any the dosage regimen described herein.
One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration ,
(b) a second dose of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days.
One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration , which is a double dose of the doses administered according to (b) and/or (c) and/or optionally (d),
(b) a second dose of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days.
Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising: (a) a loading dose of 40 mg of the neutralizing antibody or a fragment thereof on the first day of administration ,
(b) a second dose of 20 mg of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of 20 mg of the neutralizing antibody or a fragment thereof about 28 days after administration of the loading dose and
(d) optionally further doses of 20 mg of the neutralizing antibody or a fragment thereof after the third dose in intervals of about 28 days.
Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of 100 mg of the neutralizing antibody or a fragment thereof on the first day of administration ,
(b) a second dose of 50 mg of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of 50 mg of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of 50 mg of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days.
Yet another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising: (a) a loading dose of 160 mg of the neutralizing antibody or a fragment thereof on the first day of administration ,
(b) a second dose of 80 mg of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of 80 mg of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and (d) optionally further doses of 80 mg of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days .
Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of 300 mg of the neutralizing antibody or a fragment thereof on the first day of administration ,
(b) a second dose of 150 mg of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of 150 mg of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of 150 mg of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days.
Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration ,
(b) a second dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days.
The dose of the antibody or a fragment thereof for use according to the invention may be administered as a single dose or as multiple doses per day, e.g. two separate injections of 150 mg, one in the morning and one in the evening in order to administer a daily dose of 300 mg of the antibody or a fragment thereof according to the invention.
In a further embodiment, the present invention relates to a neutralizing antibody or a fragment thereof specifically binding primate GM-CSF for use in the treatment and/or prevention of psoriasis, wherein said antibody comprises a light chain variable region selected from the group consisting of SEQ ID NOs: 19, 34, 54 or 55 and a heavy chain variable region selected from the group consisting of SEQ ID NOs: 20- 33, 35-48, 52 or 53.
In the context of the present invention, the term "antibody" or its grammatically related variations relate to full length antibodies, human antibodies, humanized antibodies, fully human antibodies, genetically engineered antibodies (e.g.
monoclonal antibodies, polyclonal antibodies, chimeric antibodies, recombinant antibodies) and multispecific antibodies, as well as to fragments of such antibodies retaining the characteristic binding properties of the full length antibody. In one specific embodiment, the antibody used in the present invention is a human antibody, in particular a human monoclonal antibody. It is particularly difficult to prepare human antibodies which are monoclonal. In contrast to fusions of murine B cells with immortalized cell lines, fusions of human B cells with immortalized cell lines are not viable. Thus, the human monoclonal antibody of the invention is the result of overcoming significant technical hurdles generally acknowledged to exist in the field of antibody technology. The
monoclonal nature of the antibody makes it particularly well suited for use as a therapeutic agent, since such antibody will exist as a single, homogeneous molecular species which can be well-characterized and reproducibly made and purified. These factors result in a product whose biological activity can be predicted with a high level of precision. This is very important if such a molecule is going to gain regulatory approval for therapeutic administration in humans. It is especially desirable that the monoclonal antibody (or the corresponding fragment) according to the invention be a human antibody (or the corresponding fragment). In contemplating an antibody agent intended for therapeutic
administration to humans, it is advantageous if this antibody is of human origin. Following administration to a human patient, a human antibody or fragment thereof will most probably not elicit a strong immunogenic response by the patient's immune system, i.e. will not be recognized as being a "foreign", that is a non-human protein. This means that no patient antibodies will be generated against the therapeutic antibody which would otherwise block the therapeutic antibody's activity and/or accelerate the therapeutic antibody's elimination from the body of the patient, thus preventing it from exerting its desired therapeutic effect.
The term "human" antibody as used herein is to be understood as meaning that the antibody of the invention, or its fragment, comprises (an) amino acid sequence(s) contained in the human germ line antibody repertoire. For the purposes of definition herein, an antibody, or its fragment, may therefore be considered human if it consists of such (a) human germ line amino acid sequence(s), i.e. if the amino acid sequence(s) of the antibody in question or fragment thereof is (are) identical to (an) expressed human germ line amino acid sequence(s). An antibody or fragment thereof may also be regarded as human if it consists of (a) sequence(s) that deviate(s) from its (their) closest human germ line sequence(s) by no more than would be expected due to the imprint of somatic hyper mutation. Additionally, the antibodies of many non-human mammals, for example rodents such as mice and rats, comprise VH CDR3 amino acid sequences which one may expect to exist in the expressed human antibody repertoire as well. Any such sequence(s) of human or non-human origin which may be expected to exist in the expressed human repertoire would also be considered "human" for the purposes of the present invention.
According to a further embodiment of the invention, the human monoclonal antibody may be an IgG antibody. According to the present invention "IgG antibody" relates to a therapeutically useful antibody or fragment thereof falling within the IgG class (isotype) of antibodies and having a gamma-type (γ) heavy chain. This includes an antibody of any subtype of the IgG class known in the art, i.e. IgGl, IgG2, IgG3 or IgG4. As is well known in the art, an IgG antibody comprises not only the variable antibody regions responsible for the highly discriminative antigen recognition and binding, but also the constant regions of the heavy and light antibody polypeptide chains normally present in endogenously produced antibodies and, in some cases, even decoration at one or more sites with carbohydrates. Such glycosylation is generally a hallmark of the IgG format, and portions of these constant regions make up the so-called Fc region of a full antibody which is known to elicit various effector functions in vivo. In addition, the Fc region mediates binding of IgG to Fc receptor, hence prolonging half life in vivo as well as facilitating homing of the IgG to locations with increased Fc receptor presence. Particularly, the IgG antibody is an IgGl antibody or an IgG4 antibody, formats which are particulary desirable in the context of the present invention since their mechanism of action in vivo is
particularly well understood and characterized. This is especially the case for IgGl antibodies. Hence, in one specific embodiment, the antibody according to the present invention is an IgGl antibody.
The terms "antibody fragment" or "fragment thereof or its grammatically related variations relate to a part of a full length antibody specifically binding with the same antigen, i.e. primate GM-CSF as the full length antibody. In particular, it relates to a pharmaceutically active fragment of an antibody, i.e. having the same pharmaceutical effects as the full length anti-GM-CSF antibody. This part of a full length antibody may be at least the antigen binding portion or at least the variable region thereof. Genetically engineered proteins acting like an antibody are also included within the meaning of antibody fragment as used herein. Such genetically engineered antibodies may be scFv, i.e. fusion proteins of a heavy and a light chain variable region connected by a peptide linker. Further exemplary antibody fragments according to the present invention are Fab, Fab', F(ab')2, VHH antibodies, diabodies, tandem antibodies, single domain antibodies and Fv. These formats may generally be divided into two subclasses, namely those which consist of a single polypeptide chain, and those which comprise at least two polypeptide chains. Members of the former subclass include an scFv (comprising one VH region and one VL region joined into a single polypeptide chain via a polypeptide linker); a single domain antibody (comprising a single antibody variable region) such as a VHH antibody (comprising a single VH region). Members of the latter subclass include an Fv (comprising one VH region and one VL region as separate polypeptide chains which are non-covalently associated with one another); a diabody (comprising two non-covalently associated polypeptide chains, each of which comprises two antibody variable regions - normally one VH and one VL per polypeptide chain - the two polypeptide chains being arranged in a head-to-tail conformation so that a bivalent antibody molecule results); a tandem diabody (bispecific single-chain Fv antibodies comprising four covalently linked
immunoglobulin variable - VH and VL -regions of two different specificities, forming a homodimer that is twice as large as the diabody described above); a Fab (comprising as one polypeptide chain an entire antibody light chain, itself comprising a VL region and the entire light chain constant region and, as another polypeptide chain, a part of an antibody heavy chain comprising a complete VH region and part of the heavy chain constant region, said two polypeptide chains being
intermolecularly connected via an interchain disulfide bond); a Fab' (as a Fab, above, except with additional reduced disulfide bonds comprised on the antibody heavy chain); and a F(ab)2 (comprising two Fab' molecules, each Fab' molecule being linked to the respective other Fab' molecule via interchain disulfide bonds). In general, antibody fragments of the type described herein allow great flexibility in tailoring, for example, the pharmacokinetic properties of an antibody desired for therapeutic administration to the particular exigencies at hand. For example, it may be desirable to reduce the size of the antibody administered in order to increase the degree of tissue penetration when treating tissues known to be poorly vascularized (for example, joints). Under some circumstances, it may also be desirable to increase the rate at which the therapeutic antibody is eliminated from the body, said rate generally being accelerable by decreasing the size of the antibody administered. The antibody according to the present invention or the fragment thereof neutralize the activity of primate GM-CSF. As used herein, "neutralization," "neutralizer," "neutralizing" and grammatically related variants thereof refer to partial or complete attenuation of the biological effect(s) of GM-CSF. Such partial or complete attenuation of the biological effect(s) of GM-CSF results from modification, interruption and/or abrogation of GM-CSF-mediated signal transduction, as manifested, for example, in altering activation of cells, e.g. neurons, in particular nociceptive neurons, intracellular signaling, cellular proliferation or release of soluble substances, up- or down-regulation of intracellular gene activation, for example that resulting in expression of surface receptors for ligands other than GM- CSF. As one of skill in the art understands, there exist multiple modes of
determining whether an agent, for example an antibody in question or a fragment thereof is to be classified as a neutralizer. As an example, this may be accomplished by a standard in vitro test performed generally as follows: In a first proliferation experiment, a cell line, the degree of proliferation of which is known to depend on the activity of GM-CSF, is incubated in a series of samples with varying
concentrations of GM-CSF, following which incubation the degree of proliferation of the cell line is measured. From this measurement, the concentration of GM-CSF allowing half-maximal proliferation of the cells is determined. A second
proliferation experiment is then performed employing in each of a series of samples the same number of cells as used in the first proliferation experiment, the above- determined concentration of GM-CSF and, this time, varying concentrations of an antibody or fragment thereof suspected of being a neutralizer of GM-CSF. Cell proliferation is again measured to determine the concentration of antibody or fragment thereof sufficient to effect half-maximal growth inhibition. If the resulting graph of growth inhibition vs. concentration of antibody (or fragment thereof) is sigmoid in shape, resulting in decreased cell proliferation with increasing
concentration of antibody (or fragment thereof), then some degree of antibody- dependent growth inhibition has been effected, i.e. the activity of GM-CSF has been neutralized to some extent. In such a case, the antibody or fragment thereof may be considered a "neutralizer" in the sense of the present invention. One example of a cell line, the degree of proliferation of which is known to depend on the activity of GM-CSF, is the TF-1 cell line, as described in Kitamura, T. et al. (1989). J Cell Physiol 140, 323-34. As one of ordinary skill in the art understands, the degree of cellular proliferation is not the only parameter by which neutralizing capacity may be established. For example, measurement of the level of signaling molecules (e.g. cytokines), the level of secretion of which depends on GM-CSF, may be used to identify a suspected GM-CSF neutralizer. Other examples of cell lines which can be used to determine whether an antibody in question or fragment thereof is a neutralizer of primate GM-CSF activity include AML-193 (Lange, B. et al. (1987). Blood 70, 192-9); GF-D8 (Rambaldi, A. et al. (1993). Blood 81 , 1376-83); GM/SO (Oez, S. et al. (1990). Experimental Hematology 18, 1 108-1 1); M07E (Avanzi, G. C. et al. (1990). Journal of Cellular Physiology 145, 458-64); TALL-103 (Valtieri, M. et al. (1987). Journal of Immunology 138, 4042-50); UT-7 (Komatsu, N. et al. (1991). Cancer Research 51 , 341-8).
It is understood that "binds specifically" or "specifically binding" or grammatically related variations thereof relate to an antibody having a binding affinity to primate GM-CSF as defined herein of <10~ 9 mol/1. In one embodiment of the invention, the antibody or a fragment thereof bind to primate GM-CSF with extremely high affinity. KD values of from about 4 x 10~9 M down to as low as about 0.04 x 10~9 M, the latter corresponding to about 40 pM, have been observed for molecules of this class. Since the kinetic on-rate of such molecules in aqueous media is largely diffusion controlled and therefore cannot be improved beyond what the local diffusion conditions will allow under physiological conditions, the low KD arises primarily as a result of the kinetic off-rate, k0ff, which for the highest affinity antibody binder is approximately 10"5 "s. This means that once the complex between a human monoclonal antibody or fragment thereof according to the invention on the one hand and primate GM-CSF on the other hand is formed, it does not readily, or at least does not quickly separate. For binding molecules intended as neutralizers of biological activity, these characteristics are highly desirable since the neutralizing effect will normally last only as long as the molecule, the biological activity of which is to be neutralized (here primate GM-CSF) remains bound by the neutralizing binding molecule. So a neutralizing molecule which remains bound to its intended target for a long time will continue to neutralize for a correspondingly long time.
The high binding affinity of human monoclonal antibodies or fragments thereof to primate GM-CSF has an additional advantage. Normally, antibodies or fragments thereof will be eliminated from the bloodstream of a patient in a size-dependent fashion, with smaller molecules being excreted and eliminated before larger ones. Since the complex of the two polypeptides - antibody or antibody fragment and bound GM-CSF - is obviously larger than the antibody alone, the low k0s mentioned above has the effect that therapeutic neutralizer is excreted and eliminated from the patient's body more slowly than would be the case, were it not bound to GM-CSF. Thus, not only the magnitude of the neutralizing activity but also its duration in vivo is increased.
According to one embodiment of the invention, the primate GM-CSF to which the antibody or fragment thereof specifically binds is human GM-CSF (Homo sapiens, SEQ ID NO: 49) or non-human primate GM-CSF. Especially preferred variants of non-human primate GM-CSF include gibbon monkey GM-CSF (Nomascus concolor, also known as the western black crested gibbon, SEQ ID NO: 51) and GM-CSF of monkeys of the macaca family (SEQ ID NO: 50), for example rhesus monkey (Macaca mulatto) GM-CSF and cynomolgous monkey GM-CSF (Macaca
fascicularis). According to one embodiment of the invention, the human monoclonal antibody or fragment thereof exhibits cross reactivity between both human and at least one of the monkey species mentioned above. This is especially desirable for an antibody molecule which is intended for therapeutic administration in human subjects, since such an antibody will normally have to proceed through a multitude of tests prior to regulatory approval, of which certain early tests involve non-human animal species. In performing such tests, it is generally desirable to use as a non- human species a species bearing a high degree of genetic similarity to humans, since the results so obtained will generally be highly predictive of corresponding results which may be expected when administering the same molecule to humans.
However, such predictive power based on animal tests depends at least partially on the comparability of the molecule, and is very high when, due to cross-species reactivity, the same therapeutic molecule may be administered to humans and animal models. As in this embodiment of the invention, when an antibody molecule is cross reactive for the same antigen in humans as in another closely related species, tests may be performed using the same antibody molecule in humans as in this closely related species, for example in one of the monkey species mentioned above. This increases both the efficiency of the tests themselves as well as predictive power allowed by such tests regarding the behavior of such antibodies in humans, the ultimate species of interest from a therapeutic standpoint.
According to a further embodiment of the invention, the human monoclonal antibody or fragment thereof specifically binds to an epitope, in particular to a discontinuous epitope, of human or non-human primate GM-CSF comprising amino acids 23-27 (RRLLN) and/or amino acids 65-77 (GLR/QGSLTKLKGPL).
The variability at position 67 within the amino acid sequence stretch 65-77 depicted above reflects the heterogeneity in this portion of primate GM-CSF between, on the one hand, human and gibbon GM-CSF (in which position 67 is R) and, on the other hand, monkeys of the macaca family, for example cynomolgous and rhesus monkeys (in which position 67 is Q). As used herein, the numbering of human and non-human primate GM-CSF refers to that of mature GM-CSF, i.e. GM-CSF without its 17 amino acid signal sequence (the total length of mature GM-CSF in both human and non-human primate species described above is 127 amino acids). The sequence of human GM-CSF and gibbon GM-CSF is as follows: APARSPSPST QPWEHVNAIQ EARRLLNLST? DTAAEMNETV EVISEMFDLQ EPTCLQTRLE LYKQGLRGSL TKLKGPLTMM ASHYKQHCPP TPETSCATQl ITFESFKENL KDFLLVIPFD CWEPVQE. (SEQ ID NO: 49)
The sequence of GM-CSF in certain members of the macaca monkey family such as for example rhesus monkey and cynomolgous monkey is as follows:
APARSPSPGT QPWEHVNAIQ EARRLLNLSR DTAAEMNKTV EVVSEMFDLQ EPSCLQTRLE LYKQGLQGSL TKLKGPLTMM ASHYKQHCPP TPETSCATQl ITFQSFKENL KDFLLVIPFD CWEPVQE. (SEQ ID NO: 50) The minimum epitope, advantageously a discontinuous epitope, bound by the human monoclonal antibody of the invention (or fragment thereof) as described herein is indicated in the above GM-CSF sequence in boldface. As used herein, the term "discontinuous epitope" is to be understood as at least two non-adjacent amino acid sequence stretches within a given polypeptide chain, here mature human and non- human primate GM-CSF, which are simultaneously and specifically (as defined above) bound by an antibody. According to this definition, such simultaneous specific binding may be of the GM-CSF polypeptide in linear form. Here, one may imagine the mature GM-CSF polypeptide forming an extended loop, in one region of which the two sequences indicated in boldface above line up, for example more or less in parallel and in proximity of one another. In this state they are specifically and simultaneously bound by the antibody fragment of the invention. According to this definition, simultaneous specific binding of the two sequence stretches of mature GM-CSF indicated above may also take the form of antibody binding to a conformational epitope. Here, mature GM-CSF has already formed its tertiary conformation as it normally exists in vivo (Sun, H. W., J. Bernhagen, et al. (1996). Proc Natl Acad Sci USA 93, 5191-6). In this tertiary conformation, the polypeptide chain of mature GM-CSF is folded in such a manner as to bring the two sequence stretches indicated above into spatial proximity, for example on the outer surface of a particular region of mature, folded GM-CSF, where they are then recognized by virtue of their three-dimensional conformation in the context of the surrounding polypeptide sequences.
In one embodiment, the above (discontinuous) epitope to which the antibody or the fragment thereof specifically binds further comprises amino acids 28-31 (LSRD), italicized in the above sequences of human and non-human primate GM-CSF. In a specific embodiment, either of the above (discontinuous) epitopes further comprises amino acids 32-33 (TA) and/or amino acids 21-22 (EA), each of which stretch is underlined in the above sequences of human and non-human primate GM-CSF.
According to a further embodiment of the invention, the human monoclonal antibody or fragment thereof, or compositions or medicaments according to the invention comprising such antibodies or fragments, comprise in its heavy chain variable region a CDR3 comprising an amino acid sequence chosen from the group consisting of those set out in any of the SEQ ID NOs: 1-13 or 56, optionally SEQ ID NO: 2.
One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration ,
(b) a second dose of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days, wherein said antibody or a fragment thereof comprises a heavy chain variable region CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 1-13 or 56, optionally SEQ ID NO: 2, in combination with a heavy chain variable region CDR1 sequence having an amino acid sequence set out in SEQ ID NO: 14 and a heavy chain variable region sequence having an amino acid sequence set out in SEQ ID NO: 15.
Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising: (a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration, which is a double dose of the doses administered according to (b) and (c),
(b) a second dose of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days (t=d28) after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days, wherein the doses of the neutralizing antibody or a fragment thereof according to (b) and (c) and optionally (d) are in the range of 20-150 mg and wherein said antibody or a fragment thereof comprises a heavy chain variable region CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 1-13 or 56, optionally SEQ ID NO: 2, in combination with a heavy chain variable region CDR1 sequence having an amino acid sequence set out in SEQ ID NO: 14 and a heavy chain variable region sequence having an amino acid sequence set out in SEQ ID NO: 15.
One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration ,
(b) a second dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the loading dose, and (c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days, wherein said antibody or a fragment thereof comprises a heavy chain variable region CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 1-13 or 56, optionally SEQ ID NO: 2, in combination with a heavy chain variable region CDRl sequence having an amino acid sequence set out in SEQ ID NO: 14 and a heavy chain variable region sequence having an amino acid sequence set out in SEQ ID NO: 15.
Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising: (a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration, which is a double dose of the doses administered according to (b) and (c),
(b) a second dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days (t=d28) after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days, wherein the doses of the neutralizing antibody or a fragment thereof according to (b) and (c) and optionally (d) are in the range of 20-150 mg and wherein said antibody or a fragment thereof comprises a heavy chain variable region CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 1-13 or 56, optionally SEQ ID NO: 2, in combination with a heavy chain variable region CDRl sequence having an amino acid sequence set out in SEQ ID NO: 14 and a heavy chain variable region sequence having an amino acid sequence set out in SEQ ID NO: 15. One embodiment relates to a human monoclonal antibody or fragment thereof comprising a heavy chain variable region CDRl sequence as set out in SEQ ID NO: 14, a heavy chain variable region CDR2 sequence as set out in SEQ ID NO: 15 and a heavy chain variable region CDR3 sequence as set out in SEQ ID NO: 1; or comprising a heavy chain variable region CDRl sequence as set out in SEQ ID NO: 14, a heavy chain variable region CDR2 sequence as set out in SEQ ID NO: 15 and a heavy chain variable region CDR3 sequence as set out in SEQ ID NO: 2; or comprising a heavy chain variable region CDRl sequence as set out in SEQ ID NO: 14, a heavy chain variable region CDR2 sequence as set out in SEQ ID NO: 15 and a heavy chain variable region CDR3 sequence as set out in SEQ ID NO: 3; or comprising a heavy chain variable region CDRl sequence as set out in SEQ ID NO: 14, a heavy chain variable region CDR2 sequence as set out in SEQ ID NO: 15 and a heavy chain variable region CDR3 sequence as set out in SEQ ID NO: 4; or comprising a heavy chain variable region CDRl sequence as set out in SEQ ID NO: 14, a heavy chain variable region CDR2 sequence as set out in SEQ ID NO: 15 and a heavy chain variable region CDR3 sequence as set out in SEQ ID NO: 5; or comprising a heavy chain variable region CDRl sequence as set out in SEQ ID NO: 14, a heavy chain variable region CDR2 sequence as set out in SEQ ID NO: 15 and a heavy chain variable region CDR3 sequence as set out in SEQ ID NO: 6; or comprising a heavy chain variable region CDRl sequence as set out in SEQ ID NO: 14, a heavy chain variable region CDR2 sequence as set out in SEQ ID NO: 15 and a heavy chain variable region CDR3 sequence as set out in SEQ ID NO: 7; or comprising a heavy chain variable region CDRl sequence as set out in SEQ ID NO: 14, a heavy chain variable region CDR2 sequence as set out in SEQ ID NO: 15 and a heavy chain variable region CDR3 sequence as set out in SEQ ID NO: 8; or comprising a heavy chain variable region CDRl sequence as set out in SEQ ID NO: 14, a heavy chain variable region CDR2 sequence as set out in SEQ ID NO: 15 and a heavy chain variable region CDR3 sequence as set out in SEQ ID NO: 9; or comprising a heavy chain variable region CDRl sequence as set out in SEQ ID NO: 14, a heavy chain variable region CDR2 sequence as set out in SEQ ID NO: 15 and a heavy chain variable region CDR3 sequence as set out in SEQ ID NO: 10; or comprising a heavy chain variable region CDRl sequence as set out in SEQ ID NO: 14, a heavy chain variable region CDR2 sequence as set out in SEQ ID NO: 15 and a heavy chain variable region CDR3 sequence as set out in SEQ ID NO: 11; or comprising a heavy chain variable region CDRl sequence as set out in SEQ ID NO: 14, a heavy chain variable region CDR2 sequence as set out in SEQ ID NO: 15 and a heavy chain variable region CDR3 sequence as set out in SEQ ID NO: 12; or comprising a heavy chain variable region CDRl sequence as set out in SEQ ID NO: 14, a heavy chain variable region CDR2 sequence as set out in SEQ ID NO: 15 and a heavy chain variable region CDR3 sequence as set out in SEQ ID NO: 13; or comprising a heavy chain variable region CDRl sequence as set out in SEQ ID NO: 14, a heavy chain variable region CDR2 sequence as set out in SEQ ID NO: 15 and a heavy chain variable region CDR3 sequence as set out in SEQ ID NO: 56.
In another embodiment of the invention, any of the above 14 combinations of CDRl, CDR2 and CDR3 sequences exists in a human monoclonal antibody or fragment thereof further comprising in its light chain variable region a CDRl comprising the amino acid sequence set out in SEQ ID NO: 16, a CDR2 comprising the amino acid sequence set out in SEQ ID NO: 17, and a CDR3 comprising the amino acid sequence set out in SEQ ID NO: 18.
Thus, one embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration,
(b) a second dose of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days, and wherein any of the above 14 combinations of CDR1, CDR2 and CDR3 sequences exists in a human monoclonal antibody or fragment thereof further comprising in its light chain variable region a CDR1 comprising the amino acid sequence set out in SEQ ID NO: 16, a CDR2 comprising the amino acid sequence set out in SEQ ID NO: 17, and a CDR3 comprising the amino acid sequence set out in SEQ ID NO: 18.
Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising: (a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration, which is a double dose of the doses administered according to (b) and (c),
(b) a second dose of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days, wherein the doses of the neutralizing antibody or a fragment thereof according to (b) and (c) and optionally (d) are in the range of 20-150 mg and wherein any of the above 14 combinations of CDR1, CDR2 and CDR3 sequences exists in a human monoclonal antibody or fragment thereof further comprising in its light chain variable region a CDR1 comprising the amino acid sequence set out in SEQ ID NO: 16, a CDR2 comprising the amino acid sequence set out in SEQ ID NO: 17, and a CDR3 comprising the amino acid sequence set out in SEQ ID NO: 18.
Yet a further embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising: (a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration, (b) a second dose of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days, and wherein said antibody or a fragment thereof comprises a heavy chain variable region CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 1- 13 or 56, optionally SEQ ID NO: 2, in combination with a heavy chain variable region CDR1 having an amino acid sequence set out in SEQ ID NO: 14 and a heavy chain variable region CDR2 having an amino acid sequence set out in SEQ ID NO: 15 and further comprising in its light chain variable region a CDR1 comprising the amino acid sequence set out in SEQ ID NO: 16, a CDR2 comprising the amino acid sequence set out in SEQ ID NO: 17, and a CDR3 comprising the amino acid sequence set out in SEQ ID NO: 18.
Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising: (a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration, which is a double dose of the doses administered according to (b) and (c) and optionally (d),
(b) a second dose of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days, wherein the doses of the neutralizing antibody or a fragment thereof according to (b) and (c) and optionally (d) are in the range of about 20-150 mg and wherein said antibody or a fragment thereof comprises a heavy chain variable region CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 1-13 or 56, optionally SEQ ID NO: 2, in combination with a heavy chain variable region CDRl having an amino acid sequence set out in SEQ ID NO: 14 and a heavy chain variable region CDR2 having an amino acid sequence set out in SEQ ID NO: 15 and further comprising in its light chain variable region a CDRl comprising the amino acid sequence set out in SEQ ID NO: 16, a CDR2 comprising the amino acid sequence set out in SEQ ID NO: 17, and a CDR3 comprising the amino acid sequence set out in SEQ ID NO: 18. Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising: (a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration,
(b) a second dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days, and wherein any of the above 14 combinations of CDRl, CDR2 and CDR3 sequences exists in a human monoclonal antibody or fragment thereof further comprising in its light chain variable region a CDRl comprising the amino acid sequence set out in SEQ ID NO: 16, a CDR2 comprising the amino acid sequence set out in SEQ ID NO: 17, and a CDR3 comprising the amino acid sequence set out in SEQ ID NO: 18.
Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising: (a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration, which is a double dose of the doses administered according to (b) and (c),
(b) a second dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days, wherein the doses of the neutralizing antibody or a fragment thereof according to (b) and (c) and optionally (d) are in the range of 20-150 mg and wherein any of the above 14 combinations of CDR1, CDR2 and CDR3 sequences exists in a human monoclonal antibody or fragment thereof further comprising in its light chain variable region a CDR1 comprising the amino acid sequence set out in SEQ ID NO: 16, a CDR2 comprising the amino acid sequence set out in SEQ ID NO: 17, and a CDR3 comprising the amino acid sequence set out in SEQ ID NO: 18.
Yet a further embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration,
(b) a second dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days, and wherein said antibody or a fragment thereof comprises a heavy chain variable region CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 1- 13 or 56, optionally SEQ ID NO: 2, in combination with a heavy chain variable region CDRl having an amino acid sequence set out in SEQ ID NO: 14 and a heavy chain variable region CDR2 having an amino acid sequence set out in SEQ ID NO: 15 and further comprising in its light chain variable region a CDRl comprising the amino acid sequence set out in SEQ ID NO: 16, a CDR2 comprising the amino acid sequence set out in SEQ ID NO: 17, and a CDR3 comprising the amino acid sequence set out in SEQ ID NO: 18.
Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration, which is a double dose of the doses administered according to (b) and (c) and optionally (d),
(b) a second dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days, wherein the doses of the neutralizing antibody or a fragment thereof according to (b) and (c) and optionally (d) are in the range of about 20-150 mg and wherein said antibody or a fragment thereof comprises a heavy chain variable region CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 1-13 or 56, optionally SEQ ID NO: 2, in combination with a heavy chain variable region CDRl having an amino acid sequence set out in SEQ ID NO: 14 and a heavy chain variable region CDR2 having an amino acid sequence set out in SEQ ID NO: 15 and further comprising in its light chain variable region a CDRl comprising the amino acid sequence set out in SEQ ID NO: 16, a CDR2 comprising the amino acid sequence set out in SEQ ID NO: 17, and a CDR3 comprising the amino acid sequence set out in SEQ ID NO: 18. According to a further embodiment, the human monoclonal antibody of the invention or fragment thereof comprises in its light chain variable region an amino acid sequence as set out in SEQ ID NO: 19. Preferred is a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 19 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 20; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 19 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 21; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 19 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 22; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 19 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 23; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 19 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 24; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 19 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 25; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 19 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 26; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 19 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 27; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 19 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 28; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 19 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 29; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 19 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 30; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 19 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 31; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 19 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 32; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 19 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 33; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 19 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 52; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 19 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 53.
According to a further embodiment, the human monoclonal antibody of the invention or fragment thereof comprises in its light chain variable region an amino acid sequence as set out in SEQ ID NO: 54. One embodiment relates to a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 54 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 20; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 54 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 21; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 54 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 22; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 54 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 23; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 54 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 24; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 54 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 25; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 54 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 26; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 54 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 27; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 54 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 28; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 54 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 29; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 54 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 30; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 54 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 31; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 54 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 32; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 54 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 33; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 54 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 52; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 54 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 53.
According to a further embodiment, the human monoclonal antibody of the invention or fragment thereof comprises in its light chain variable region an amino acid sequence as set out in SEQ ID NO: 55. One embodiment relates to a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 55 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 20; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 55 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 21; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 55 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 22; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 55 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 23; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 55 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 24; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 55 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 25; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 55 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 26; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 55 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 27; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 55 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 28; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 55 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 29; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 55 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 30; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 55 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 31 ; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 55 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 32; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 55 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 33; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 55 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 52; or a human monoclonal antibody or fragment thereof, the light chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 55 and a heavy chain variable region comprising an amino acid sequence as set out in SEQ ID NO: 53. According to one embodiment of the invention, the human monoclonal antibody or a fragment thereof comprises in its light chain variable region an amino acid sequence as set out in SEQ ID NO: 19 and in its heavy chain variable region an amino acid sequence as set out in SEQ ID NO: 21.
One embodiment provides a human monoclonal antibody or fragment thereof comprising in its light chain a variable region a CDRl region comprising an amino acid sequence as set out in SEQ ID NO: 16, a CDR2 region having an amino acid sequence as set out in SEQ ID NO: 17 and a CDR3 having an amino acid sequence as set out in SEQ ID NO: 18 and comprising in its heavy chain variable region a CDRl region comprising an amino acid sequence as set out in SEQ ID NO: 14, a CDR2 region having an amino acid sequence as set out in SEQ ID NO: 15 and a CDR3 having an amino acid sequence as set out in any of SEQ ID NOs. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 56, optionally SEQ ID NO: 2.
In a further preferred embodiment the human monoclonal antibody comprises in its light chain an amino acid sequence as set out in SEQ ID NO: 34 and in its heavy chain an amino acid sequence as set out in SEQ ID NO: 35; or in its light chain an amino acid sequence as set out in SEQ ID NO: 34 and in its heavy chain an amino acid sequence as set out in SEQ ID NO: 36; or in its light chain an amino acid sequence as set out in SEQ ID NO: 34 and in its heavy chain an amino acid sequence as set out in SEQ ID NO: 37; or in its light chain an amino acid sequence as set out in SEQ ID NO: 34 and in its heavy chain an amino acid sequence as set out in SEQ ID NO: 38; or in its light chain an amino acid sequence as set out in SEQ ID NO: 34 and in its heavy chain an amino acid sequence as set out in SEQ ID NO: 39; or in its light chain an amino acid sequence as set out in SEQ ID NO: 34 and in its heavy chain an amino acid sequence as set out in SEQ ID NO: 40; or in its light chain an amino acid sequence as set out in SEQ ID NO: 34 and in its heavy chain an amino acid sequence as set out in SEQ ID NO: 41; or in its light chain an amino acid sequence as set out in SEQ ID NO: 34 and in its heavy chain an amino acid sequence as set out in SEQ ID NO: 42; or in its light chain an amino acid sequence as set out in SEQ ID NO: 34 and in its heavy chain an amino acid sequence as set out in SEQ ID NO: 43; or in its light chain an amino acid sequence as set out in SEQ ID NO: 34 and in its heavy chain an amino acid sequence as set out in SEQ ID NO: 44; or in its light chain an amino acid sequence as set out in SEQ ID NO: 34 and in its heavy chain an amino acid sequence as set out in SEQ ID NO: 45; or in its light chain an amino acid sequence as set out in SEQ ID NO: 34 and in its heavy chain an amino acid sequence as set out in SEQ ID NO: 46; or in its light chain an amino acid sequence as set out in SEQ ID NO: 34 and in its heavy chain an amino acid sequence as set out in SEQ ID NO: 47; or in its light chain an amino acid sequence as set out in SEQ ID NO: 34 and in its heavy chain an amino acid sequence as set out in SEQ ID NO: 48.
One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration,
(b) a second dose of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days, wherein said antibody or a fragment thereof comprises in its light chain an amino acid sequence as set out in SEQ ID NO: 34 and/or in its heavy chain an amino acid sequence as set out in SEQ ID NO: 35, optionally wherein said antibody or a fragment thereof comprises in its light chain an amino acid sequence as set out in SEQ ID NO: 34 and in its heavy chain an amino acid sequence as set out in SEQ ID NO: 35. Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration, which is a double dose of the doses administered according to (b) and (c) and optionally (d),
(b) a second dose of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days, wherein the doses of the neutralizing antibody or a fragment thereof according to (b) and (c) and optionally (d) are in the range of about 20-150 mg and wherein said antibody or a fragment thereof comprises in its light chain an amino acid sequence as set out in SEQ ID NO: 34 and/or in its heavy chain an amino acid sequence as set out in SEQ ID NO: 35, optionally wherein said antibody or a fragment thereof comprises in its light chain an amino acid sequence as set out in SEQ ID NO: 34 and in its heavy chain an amino acid sequence as set out in SEQ ID NO: 35.
One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration,
(b) a second dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days, wherein said antibody or a fragment thereof comprises in its light chain an amino acid sequence as set out in SEQ ID NO: 34 and/or in its heavy chain an amino acid sequence as set out in SEQ ID NO: 35, optionally wherein said antibody or a fragment thereof comprises in its light chain an amino acid sequence as set out in SEQ ID NO: 34 and in its heavy chain an amino acid sequence as set out in SEQ ID NO: 35.
Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising: (a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration, which is a double dose of the doses administered according to (b) and (c) and optionally (d),
(b) a second dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days, wherein the doses of the neutralizing antibody or a fragment thereof according to (b) and (c) and optionally (d) are in the range of about 20-150 mg and wherein said antibody or a fragment thereof comprises in its light chain an amino acid sequence as set out in SEQ ID NO: 34 and/or in its heavy chain an amino acid sequence as set out in SEQ ID NO: 35, optionally wherein said antibody or a fragment thereof comprises in its light chain an amino acid sequence as set out in SEQ ID NO: 34 and in its heavy chain an amino acid sequence as set out in SEQ ID NO: 35.
In one specific embodiment, the neutralizing antibody or a fragment thereof for use according to the present invention comprises in its light chain variable region a CDR1 sequence having an amino acid sequence as set out in SEQ ID NO: 16, a CDR2 sequence having an amino acid sequence set out in SEQ ID NO: 17 and a CDR3 sequence having an amino acid sequence set out in SEQ ID NO: 18 and comprising in its heavy chain variable region a CDR1 sequence having an amino acid sequence set out in SEQ ID NO: 14, a CDR2 sequence having an amino acid sequence set out in SEQ ID NO: 15 and a CDR3 sequence having an amino acid sequence set out in SEQ ID NO: 2.
A further embodiment of the invention relates to a human monoclonal antibody or fragment thereof comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 98% identity on the amino acid level with at least one amino acid as set out in any of SEQ ID NOs: 1- 48 and/or 52-56. A further embodiment of the invention relates to a human monoclonal antibody or fragment thereof comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 98% identity on the amino acid level with at least one, optionally with all amino acid as set out in SEQ ID NOs: 2, 14, 15, 16, 17 and 18. A further embodiment of the invention relates to a human monoclonal antibody or fragment thereof comprising an amino acid sequence having at least 70%>, at least 75%, at least 80%>, at least 85%, at least 90%, at least 95% or at least 98% identity on the amino acid level with at least one, optionally with all amino acid as set out in SEQ ID NOs: 19 and 21. A further embodiment of the invention relates to a human monoclonal antibody or fragment thereof comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 98% identity on the amino acid level with at least one, optionally with all amino acid as set out in SEQ ID NOs: 34 and 35. In one specific embodiment, the human monoclonal antibody or a fragment thereof specifically binding primate GM-CSF according to the present invention comprise an amino acid sequence having at least 70%>, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 98% identity on the amino acid level with an antibody or fragment thereof comprising in its light chain variable region a CDR1 sequence having an amino acid sequence as set out in SEQ ID NO: 16, a CDR2 sequence having an amino acid sequence set out in SEQ ID NO: 17 and a CDR3 sequence having an amino acid sequence set out in SEQ ID NO: 18 and comprising in its heavy chain variable region a CDR1 sequence having an amino acid sequence set out in SEQ ID NO: 14, a CDR2 sequence having an amino acid sequence set out in SEQ ID NO: 15 and a CDR3 sequence having an amino acid sequence set out in SEQ ID NOs: 1-13 or 56, optionally comprising a CDR3 sequence having an amino acid sequence set out in SEQ ID NO: 2. In another embodiment, the antibody or the fragment thereof according to the present invention specifically binding primate GM- CSF comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 98% identity on the amino acid level with an antibody or fragment thereof comprising a light chain variable region as set out in SEQ ID NO: 19 and/or a heavy chain variable region as set out in SEQ ID NO: 21, optionally comprising a light chain variable region as set out in SEQ ID NO: 19 and a heavy chain variable region as set out in SEQ ID NO: 21. The SEQ ID NOs used herein, denote the same sequences as disclosed in
WO 2006/111353 A2 for the corresponding SEQ ID NOs.
"Identity" and "sequence identity" are used interchangeably herein. Sequence identity may be determined by standard sequence alignment programs such as Vector NTI (InforMax(TM), Maryland, USA), BLAST
(http://blast.ncbi.nlm.nih.gov/Blast.cgi) or EMBOSS
(http://www.ebi.ac.uk/Tools/psa/). Such programs compare aligned sequences on an amino acid-by-amino acid basis, and can be set to various levels of stringency for the comparison (e.g. identical amino acid, conservative amino acid substitution, etc.). However, in one embodiment of the invention, the grade of identity is determined by using the standard parameters provided by the sequence alignment program, in particular the standard parameters provided by the sequence alignment programs specifically mentioned herein. As the term is used herein, two amino acids in question are considered as being "conservative substitutions" of one another if they each belong to the same chemical class, i.e. acidic, nonpolar, uncharged polar and basic. By way of non-limiting example, two different amino acids belonging to the class of nonpolar amino acids would be considered "conservative substitutions" of one another, even if these two amino acids were not identical, whereas a nonpolar amino acid on the one hand and a basic amino acid on the other hand would not be considered "conservative substitutions" of one another. Panel 3.1 of "Molecular Biology of the Cell", 4th Edition (2002), by Alberts, Johnson, Lewis, Raff, Roberts and Walter groups amino acids into four main groups: acidic, nonpolar, uncharged polar and basic. Such a grouping may be used for the purposes of determining, for the purposes of the present invention, whether or not a particular amino acid is a conservative substitution of another amino acid in question.
Determination of the "identity on the amino acid level" also includes comparison of a nucleotide sequence encoding an amino acid sequence with another nucleotide sequence, wherein a nucleotide in the sequence in question is considered identical on the amino acid level if it is either identical to the corresponding nucleotide in the nucleotide sequence to which it is compared, thus encoding a corresponding amino acid sequence or if one or more nucleotide deviation(s) in the sequence in question from the corresponding one or more nucleotide(s) in the nucleotide sequence to which it is compared encoding an amino acid sequence results in a nucleotide triplet which, when translated, results in an amino acid which is either identical to (due to a degenerate triplet) or a conservative substitution of the corresponding amino acid in the corresponding amino acid sequence to which it is compared. Thus, a further embodiment of the invention provides a polynucleotide molecule having a nucleotide sequence encoding an amino acid sequence as set out in any of SEQ ID NOs: 1-48 and/or 52 to 56 or a nucleotide sequence exhibiting at least 70% identity, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 98% identity therewith, wherein sequence identity may be determined by comparing a nucleotide sequence encoding an amino acid sequence of any of SEQ ID NOS: 1-48 and/or 52- 56 with a nucleotide sequence in question by sequence alignment (as described above for amino acid sequences), wherein a nucleotide in the sequence in question is considered identical on the amino acid level if it is either identical to the
corresponding nucleotide in the nucleotide sequence encoding a corresponding amino acid sequence of any of SEQ ID NOs: 1- 48 and/or 52-56 or if one or more nucleotide deviation(s) in the sequence in question from the corresponding one or more nucleotide(s) in the nucleotide sequence encoding an amino acid sequence of any of SEQ ID NOs: 1-48 and/or 52-56 results in a nucleotide triplet which, when translated, results in an amino acid which is either identical to (due to a degenerate triplet) or a conservative substitution of the corresponding amino acid in the corresponding amino acid sequence of any of SEQ ID NOs: 1-48 and/or 52-56. Here, the term "conservative substitution" is to be understood as described above. According to a further embodiment, the human monoclonal antibody or fragment thereof may be derivatized, for example with an organic polymer, for example with one or more molecules of polyethylene glycol ("PEG") and/or polyvinyl pyrrolidone ("PVP"). As is known in the art, such derivatization can be advantageous in modulating the pharmacodynamic properties of antibodies or fragments thereof. Especially preferred are PEG molecules derivatized as PEG-maleimide, enabling conjugation with the antibody or fragment thereof in a site-specific manner via the sulfhydryl group of a cysteine amino acid. Of these, especially preferred are 20 kD and/or 40 kD PEG-maleimide, in either branched or straight-chain form. It may be especially desirable to increase the effective molecular weight of smaller human anti- primate GM-CSF antibody fragments such as scFv fragments by coupling the latter to one or more molecules of PEG, especially PEG-maleimide.
The production of the neutralizing antibodies and fragments may be conducted through any method known in the art and is disclosed in detail in WO 2006/111353, the contents of which are incorporated herein in their entirety.
Another aspect of the present invention relates to a pharmaceutical composition for use in the treatment and/or prevention of psoriasis, comprising a neutralizing antibody or a fragment thereof specifically binding primate GM-CSF as defined herein to be administered according to the dosage regimen described herein. In one embodiment, the pharmaceutical composition for use according to the present invention may further comprise at least one pharmaceutically acceptable carriers.
In the context of the present invention "pharmaceutically acceptable" relates to any compound which may be used in a pharmaceutical composition without causing any undesired effects (such as negative side effects) in a patient to which the composition is administered.
Pharmaceutically acceptable carriers may be those well known in the art such as phosphate buffered saline solutions, water, emulsions, such as oil/water emulsions, various types of wetting agents, sterile solutions, liposomes, etc.. It is to be understood that the pharmaceutical composition for use according to the present invention may further include any compound considered suitable by the person skilled in the art, selected e.g. depending from the mode of administration for which the pharmaceutical composition is prepared. Preparations for parenteral
administration include e.g. sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present in the composition of the present invention such as, for example, antimicrobials, anti-oxidants, chelating agents, inert gases and the like. In addition, the pharmaceutical composition of the present invention might comprise proteinaceous carriers, like, e.g., serum albumin or immunoglobulin, preferably of human origin. The neutralizing antibodies and/or functional fragments thereof or the
pharmaceutical composition comprising the same should provide sufficient stability upon storage. It is possible to produce a wide variety of proteins for therapeutic applications. After their production, protein pharmaceuticals are usually stored prior to their use. Due to the fact that proteins are generally larger and more complex than "traditional" pharmaceuticals, formulation and processing of protein pharmaceuticals that are suitable for storage can be particularly challenging. For reviews of protein pharmaceutical formulation and process design, see Carpenter et al. (1997), Pharm. Res. 14: 969-975; Wang (2000), Int. J. Pharmaceutics 203: 1 -60; and Tang and Pikal (2004), Pharm. Res. 21 : 191-200. Several factors can be considered in designing formulations and processes for protein pharmaceutical production. Of primary concern is the stability of the protein through any or all steps of manufacture, shipping, and handling steps, which may include preparation of the composition, freezing, lyophilizing, drying, storage, shipping, reconstitution, freeze/thaw cycles, and post- reconstitution storage by the end user. Other potential considerations include ease and economy of manufacture, handling, and distribution, composition of the final product for patient administration, and ease of use by the end user, including solubility of the lyophilized formulation upon reconstitution.
Stable formulation comprising the neutralizing anti-GM-CSF antibody or fragments thereof according to the present invention may be an aqueous solution, wherein the antibody or fragments thereof are directly dissolved and/or dispersed therein. One embodiment of the present invention is a liquid formulation containing the antibody or fragments thereof which is stable and does not undergo the formation of conjugates/aggregates or fragments/degradation products when stored for a long period, and which formulation is suitable for subcutaneous administration.
Specifically, the neutralizing anti-GM-CSF antibody or fragments thereof could be stabilized if a tonicity modifier is added to the solution which is to be stored.
Examples for tonicity modifiers include, but are not limited to, sugars and sugar alcohols. Simple sugars are called monosaccharides and include glucose, fructose, galactose, xylose, ribose, mannose, lactulose, allose, altrose, gulose, idose, talose, arabinose and lyxose. According to the present invention disaccharides which include for example sucrose, maltose, lactose, isomaltose, trehalose and cellubiose may be used. Sugar alcohols include sorbitol, mannitol, glycerin, erythritol, maltitol, xylitol, polyglycitol. In one embodiment, the sugar is a non-reducing sugar such as sucrose or trehalose. Non-reducing sugars are characterized by the absence of an open chain structure, so they are not susceptible to oxidation-reduction reactions.
Therefore one or more of non-reducing sugars, such as sucrose or trehalose, or one or more of sugar alcohols, such as mannitol or sorbitol could be added to the formulation comprising a neutralizing antibody or a fragment thereof as described herein. Also combinations of non-reducing sugars and sugar alcohols could be added to the solution, such as sucrose and mannitol, sucrose and sorbitol, trehalose and mannitol, or trehalose and sorbitol. In one embodiment, the sugar alcohols mannitol and/or sorbitol are added, optionally in their D-form, more specifically sorbitol is added to the solution. The concentration of the tonicity modifier, optionally sorbitol, is between about 1% and about 15% (w/v), optionally between about 2% and about 10% (w/v), specifically between about 3% and about 7% (w/v), more specifically between about 4% and about 6% (w/v) and most preferably about 5% (w/v).
Another substance to stabilize the neutralizing anti-GM-CSF antibody or fragments thereof at a high concentration with regard to long-term storage is a buffer system with a pH of between about 4 and about 10, optionally between about 4 and about 7, specifically between about 4 and about 6 or between about 5 and about 7, more specifically between about 5.5 and about 6.5, or with a pH of about 5.8. The buffer may be selected from a histidine buffer, an acetate buffer and a citrate buffer. When referred herein, an amino acid is meant to be an L-amino acid or D-amino acid, wherein L-amino is preferred. In one embodiment, histidine or a salt thereof is used for the buffer system. In a specific embodiment, the salt is a chloride, phosphate, acetate or sulphate, optionally the salt is a chloride. The pH of the histidine buffer system is between about 5 and about 7, optionally between about 5.5 and about 6.5, specifically the pH is about or exactly 5.8. The pH may be adjusted by the use of conventionally used bases and acids, optionally NaOH. The concentration of the buffer system, optionally the histidine buffer system, is between about 10 mM and about 50 mM, optionally between about 20 mM and about 40 mM, specifically about 30mM.
According to one embodiment, a combination of the buffer system, optionally the histidine buffer, and the tonicity modifier, optionally the sugar alcohol, specifically mannitol or sorbitol, is used to stabilize the neutralizing anti-GM-CSF antibody or fragments thereof in the solution, in order to prevent aggregation and to render the formulation sufficiently stable for long-term storage and/or for one or more freeze/thaw cycles. It was shown that it is preferable in terms of stability to have about 6% (w/v) and higher of sugar alcohol, optionally sorbitol, in the formulation. However, the upper limit for osmolality of the formulation is set to be about
470 mOsm/kg which is still hyperosmotic. In one embodiment, the concentration of sugar alcohol, optionally sorbitol, is therefore between about 3% and about 7% (w/v), optionally between about 4% and about 6% (w/v) and specifically about 5% (w/v). In some embodiments of the present invention, the formulations or compositions of the invention comprising the neutralizing anti-GM-CSF antibody or fragments thereof do not require further excipients in addition to those disclosed above (i.e., a buffer and a tonicity modifier), such as, for example, surfactants and amino acids, which are used in traditional formulations to stabilize proteins in solution. In addition, the formulations described herein are preferred over standard formulations because they have decreased immunogenicity due to the lack of additional agents commonly needed for protein stabilization. It is known that amino acids are useful to stabilize proteins at a high concentration by, inter alia, mediating protein solubility and/or inhibiting protein aggregation. Although threonine (e.g. at 250mM) indicates a minor stabilizing effect, the liquid formulation comprising the neutralizing anti-GM-CSF antibody or fragments thereof is optionally free from further amino acids.
Furthermore, in one embodiment, the present formulation is free or essentially free of sodium chloride. By "essentially free" is meant that the concentration of sodium chloride is at or very near to 0 (zero) mM, e.g. less than about 50 mM, optionally less than about 20 mM, less than about 10 mM, less than about 5 mM, less than about 2 mM or even less than about 1 mM.
In biopharmaceutical products, the addition of surfactants can be useful to reduce protein degradation during storage. The polysorbates 20 and 80 (Tween 20 and Tween 80) are well established excipients for this purpose.
In a more preferred embodiment the polysorbate 20 to protein ratio is between about 0.01 : 1 to about 3 :1, preferably between about 0.05:1 to about 2: 1, more preferably between about 0.1 : 1 and about 1.5: 1, even more preferably between about 0.1 : 1 to about 0.8: l, and most preferably between about 0.1 : 1 to about 0.2: l . For a protein concentration of 80 mg/mL, the polysorbate 20 concentration is between about 0.001%(w/v) and about 0.2%(w/v), preferably between about 0.005%(w/v) and about 0.15%(w/v), more preferably between about 0.007%(w/v) and about 0.1%(w/v), even more preferably between about 0.007%(w/v) and about 0.06%(w/v) and most preferably about 0.01%(w/v). For a protein concentration of 150 mg/mL, the polysorbate 20 concentration is between about 0.001%(w/v) and about 0.4%(w/v), preferably between about 0.006%(w/v) and about 0.25%(w/v), more preferably between about 0.01%(w/v) and about 0.18%(w/v), even more preferably between about 0.01 %(w/v) and about 0.1 %(w/v) and most preferably about 0.02%(w/v).
In another more preferred embodiment, the polysorbate 80 to protein ratio is between about 0.01 : 1 to about 3: 1, preferably between about 0.05: 1 to about 2: 1, more preferably between about 0.1 : 1 and about 1.5: 1, even more preferably between about 0.1 : 1 to about 0.6: 1, and most preferably from about 0.3: 1 to about 0.6:1. For a protein concentration of 80 mg/mL, the polysorbate 80 concentration is between about 0.001%(w/v) and about 0.2%(w/v), preferably between about 0.004%(w/v) and about 0.14%(w/v), more preferably between about 0.007%(w/v) and about
0.1%(w/v), even more preferably between about 0.007%(w/v) and about
0.05%(w/v), and most preferably about 0.04%(w/v). For a protein concentration of 150 mg/mL, the polysorbate 80 concentration is between about 0.001%(w/v) and about 0.4%(w/v), preferably between about 0.007%(w/v) and about 0.26%(w/v), more preferably between about 0.01%(w/v) and about 0.2%(w/v), even more preferably between about 0.01%(w/v) and about 0.08%(w/v), most preferably about 0.04%(w/v).
The concentration of the neutralizing anti-GM-CSF antibody or functional fragments thereof used is at least about 20 mg/ml, preferably at least about 50 mg/ml, more preferably at least about 100 mg/ml in the liquid formulation which is to be stored, freeze/thawed and/or ready to use. Concentrations of about 20 mg/ml to about 200mg/mg, preferably about 50 mg/ml to about 200 mg/ml, more preferably about 100 mg/ml to about 180 mg/ml, even more preferably about 130 mg/ml to about 170 mg/ml, even more preferably about 135 mg/ml to about 165 mg/ml and most preferred about 150 mg/ml of the neutralizing antibody or a fragment thereof are used in the present invention. Another preferred concentration of the neutralizing anti-GM-CSF antibody or functional fragments thereof used is about 80 mg/ml.
Furthermore, in one embodiment, the present formulation of the neutralizing anti- GM-CSF antibody or a functional fragment thereof comprises from about 135 mg/ml to about 165 mg/ml of the neutralizing antibody, about 5% (w/v) sorbitol, about 30mM L-histidine and has a pH of about 5.8.
Furthermore, in one embodiment, the present formulation of the neutralizing anti- GM-CSF antibody or functional fragments thereof comprises from about 80 mg/ml to about 150 mg/ml of the neutralizing antibody, about 5% (w/v) sorbitol, about 30mM L-histidine, and from about 0.01% to about 0.08% (w/v) polysorbate 80 and has a pH of about 5.8.
Furthermore, in one embodiment, the present formulation of the neutralizing anti- GM-CSF antibody or functional fragments thereof comprises about 80 mg/ml of the neutralizing antibody, about 5% (w/v) sorbitol, about 30mM L-histidine, about 0.04%) (w/v) polysorbate 80 and has a pH of about 5.8. Furthermore, in one embodiment, the present formulation of the neutralizing anti- GM-CSF antibody or functional fragments thereof comprises about 150 mg/ml of the neutralizing antibody, about 5% (w/v) sorbitol, about 30mM L-histidine, about 0.04% (w/v) polysorbate 80 and has a pH of about 5.8.
The shelf life of the produced formulation may have a minimum requirement of 24 months at 2 to 8°C, 36 months at 2 to 8°C, 48 months at 2 to 8°C or at least 28 days at ambient temperature (25°C ± 2°C).
The neutralizing anti-GM-CSF antibody or fragments thereof may be provided in a stable formulation, optionally a stable liquid formulation that allows for long-term storage of compounds neutralizing GM-CSF. This formulation is useful, in part, because it is more convenient to use for the patient, as the neutralizing anti-GM-CSF antibody or fragments thereof of this formulation are highly concentrated so as to reduce side effects like pain due to high volume injection.
Accordingly, the formulations comprising a neutralizing anti-GM-CSF antibody or fragments thereof according to the invention comprise a buffer system optionally selected from a histidine buffer, an acetate buffer and/or a citrate buffer with a preferred pH of between 5 and 7, and a tonicity modifier optionally selected from non-reducing sugars, such as sucrose or trehalose, or sugar alcohols, such as mannitol or sorbitol are rendered sufficiently stable for long-term storage and/or freeze/thaw cycles. The formulation of the invention has many advantages over standard buffered formulations. In one aspect, the formulation shows minimal aggregation behaviour upon long-term storage without deleterious effects that might be expected with high protein formulations. Other advantages of the formulation according to the invention are: minimal fragmentation of neutralizing anti-GM-CSF antibody or fragments thereof and no significant impact on bioactivity of neutralizing anti-GM-CSF antibody or fragments thereof over long-term storage, and low viscosity of the composition. Finally, in one embodiment, the formulation is free of further excipients such as surfactants, additional amino acids and/or sodium chloride.
The neutralizing antibody or a fragment thereof or the pharmaceutical composition comprising the same according to the present invention is for use in the treatment and/or prevention of psoriasis. The neutralizing antibody or a fragment thereof as described herein may be used for the treatment and/or prevention of any type of psoriasis known in the art. Generally, psoriasis may be classified in the non-pustular and pustular type, whereby in the latter type pustules can be found on the patient's skin. Non-pustular psoriasis includes Psoriasis vulgaris or plaque -type psoriasis (i.e. the most common type of psoriasis) and Psoriasis erythroderma. Psoriasis vulgaris is characterized by the presence of red, raised scaly plaques that affect any surface of the body, however can be most often found on the scalp, knees, elbows and lower back of the patient. Different types of Psoriasis vulgaris may be distinguished, i.e. type I with an onset before the age of forty and type II with an onset after the age of forty. Psoriasis erythroderma is a generalized, inflammatory form of psoriasis affecting most of the body surface. Pustular psoriasis includes generalized pustular psoriasis (type Zumbusch), pustulosis palmaris et plantaris (Barber type), annular pustular psoriasis, Acrodermatits continua and Impetigo herpetiformis. Further types of psoriasis include drug-induced psoriasis, inverse psoriasis, napkin psoriasis, nail psoriasis, guttate psoriasis and seborrheic-like psoriasis. In one specific
embodiment, the neutralizing antibody or a fragment thereof according to the invention is for use in the treatment and/or prevention of pustular psoriasis, in particular selected from the group consisting of generalized pustular psoriasis (type Zumbusch), pustulosis palmaris et plantaris (Barber type), annular pustular psoriasis, Acrodermatits continua and Impetigo herpetiformis. In another specific
embodiment, the neutralizing antibody or a fragment thereof according to the invention is for use in the treatment and/or prevention of non-pustular psoriasis, in particular for use in the treatment and/or prevention of Psoriasis vulgaris and/or Psoriasis erythroderma. In a specific embodiment, the neutralizing antibody or a fragment thereof according to the invention is for use in the treatment and/or prevention of Psoriasis vulgaris, optionally type I or type II Psoriasis vulgaris. In a specific embodiment, the neutralizing antibody or a fragment thereof according to the invention is for use in the treatment of type I Psoriasis vulgaris. In another specific embodiment, the neutralizing antibody or a fragment thereof according to the invention is for use in the prevention of type II Psoriasis vulgaris. In another embodiment, the neutralizing antibody or a fragment thereof according to the invention is for use in the treatment and/or prevention of drug-induced psoriasis (e.g. induced by the use of beta blockers, lithium, antimalarials, terbinafme, calcium channel blockers, captopril, glyburide, granulocyte colony-stimulating factor, interleukins, interferons and/or lipid-lowering drugs), inverse psoriasis, napkin psoriasis, nail psoriasis, guttate psoriasis and/or seborrheic-like psoriasis.
In a specific embodiment, the neutralizing antibody or a fragment thereof according to the invention is for use in the treatment of psoriatic arthritis.
One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of non-pustular psoriasis, optionally Psoriasis vulgaris, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration,
(b) a second dose of the neutralizing antibody or a fragment thereof 7-21 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 21-35 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of 21-35 days.
One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of non-pustular psoriasis, optionally Psoriasis vulgaris, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising: (a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration, which is a double dose of the doses administered according to (b) and/or (c),
(b) a second dose of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and (d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days.
Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of non-pustular psoriasis, optionally Psoriasis vulgaris, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration, which is a double dose of the doses administered according to (b) and/or (c),
(b) a second dose of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and (d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days, wherein the doses according to (b) and (c) and optionally (d) of the neutralizing antibody or a fragment thereof are in the range of about 10-200 mg.
The psoriasis to be the treated with the neutralizing antibody or fragment thereof or composition comprising the same may be a clinically stable psoriasis or a relapse- remitting psoriasis. Clinically stable psoriasis as used herein relates to any course of disease that does not show any significant variations in e.g. the severity of the disease (i.e. no up-or downgrading in the EMEA's severity classification as described below), the PASI score (i.e. no change of PASI score of more than about 10% from the initial score), the PGA scale (i.e. no up-or downgrading of the PGA) or the BSA affected by psoriasis (i.e. no change of BSA affected of more than about 10% from the initial BSA). In one specific embodiment, the neutralizing antibody or a fragment thereof is for use in the treatment of clinically stable psoriasis. The clinically stable psoriasis to be treated with the neutralizing antibody or a fragment thereof may be clinically stable non-pustular psoriasis, optionally clinically stable Psoriasis vulgaris.
One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of clinically stable non-pustular psoriasis, optionally clinically stable Psoriasis vulgaris, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration,
(b) a second dose of the neutralizing antibody or a fragment thereof 7-21 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 21-35 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of 21-35 days.
One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of clinically stable non-pustular psoriasis, optionally clinically stable Psoriasis vulgaris, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration, which is a double dose of the doses administered according to (b) and/or (c) and optionally (d),
(b) a second dose of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days. Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of clinically stable non-pustular psoriasis, optionally clinically stable Psoriasis vulgaris, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration, which is a double dose of the doses administered according to (b) and/or (c) and optionally (d),
(b) a second dose of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days, wherein the doses according to (b) and (c) and optionally (d) of the neutralizing antibody or a fragment thereof are in the range of about 100-200 mg.
Relapse of psoriasis as used herein relates to any course of disease that involves a reduction of the maximal improvement from the baseline by >50%. Relapse may, however, also relate to any course of disease which necessitates re -initiation of the treatment (cf. EMEA, Guideline on clinical investigation of medicinal products indicated for the treatment of psoriasis (2004)). Hence, the neutralizing antibody or a fragment thereof may also be used for the treatment and/or prevention of relapse- remitting psoriasis. In one embodiment, the neutralizing antibody or a fragment thereof is for use in the treatment and/or prevention of a relapse-remitting non- pustular psoriasis, optionally of relapse-remitting Psoriasis vulgaris. However, the neutralizing antibody or a fragment thereof may also be used for the treatment and/or prevention of a rebound of psoriasis. A rebound of psoriasis may lead to a significant worsening of psoriasis (i.e. to a level worse than before the therapy was started) or a change of the character of the psoriasis. As used herein, the term "rebound" of psoriasis relates to worsening of psoriasis over a baseline, or a new pustular, erythrodermic or more inflammatory psoriasis occurring within two months after stopping therapy (cf. EMEA, Guideline on clinical investigation of medicinal products indicated for the treatment of psoriasis (2004)). Worsening of psoriasis over a baseline which was assessed before the start of the treatment may relate to an increase of the initial PASI score by at least 10%, at least 20%, at least 30%, at least 40% or at least 50%, to an increase of the initial BSA by at least 10%, at least 20%, at least 30% at least 40% or at least 50% and/or to an upscaling of the severity grade of the psoriasis according to the EMEA's classification described below. It is to be understood, that the neutralizing antibody or a fragment thereof may be used to treat a rebound of psoriasis in a patient currently treated with any active agent suitable for the treatment of psoriasis and/or any of its symptoms excluding the neutralizing antibody or a fragment thereof according to the invention.
Psoriasis severity may range from mild to severe. The European Medicines
Evaluation Agency (EMEA) has suggested the following classification of psoriasis severity based inter alia on the body surface area (BSA) involved and Psoriasis Area and Severity Index (PASI) score (cf. EMEA, Guideline on clinical investigation of medicinal products indicated for the treatment of psoriasis (2004),
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/ 09/WC500003329.pdf):
• Mild to moderate psoriasis:
Good control of lesions with topical therapy alone. BSA involvement <10% or PASI <10. Category "mild to moderate" on PGA. • Moderate psoriasis:
Topical therapy still possible to control the disease. BSA involvement >10% or PASI 10 or more. Category "moderate" on PGA.
• Moderate to severe psoriasis:
Topical therapies fail to control the disease. BSA involvement >10% or PASI 10 to 20. Very thick lesions located in "difficult to treat" regions (e.g. palmo-plantar) with BSA involvement <10% may also be considered.
Category "moderate to severe" on PGA.
• Severe psoriasis:
A justified need for systemic treatment to control the disease. BSA involvement > 20 % or PASI >20. Very important local signs with very thick lesions with BSA involvement >10% may also be considered. Category "severe" on PGA.
In the context of the present invention "mild psoriasis" and "mild to moderate psoriasis" are used interchangeably. Furthermore, it is to be understood, that any reference to severity grades of psoriasis as used herein (e.g. to moderate psoriasis), relates to the above defined severity grades according to the EMEA's guidelines, unless indicated otherwise. The Psoriasis Area and Severity Index (PASI) takes into account the severity of the lesions and the area affected on four body regions, i.e. the head, the trunk, the arms and the legs. For each of these body regions the percent of skin involved is assessed and transformed into a certain value from 1-6:
Surface involved (per body region) Value given
<10% 1
10-29% 2
30-49%
50-69% 4
70-89%
90-100% 6 Additionally, the severity of the lesions in each of the body regions is estimated, whereby three clinical signs, i.e. erythema, infiltration and desquamation are determined and associated with a value from 0-4:
Degree of severity (per body region) Value given
No symptoms 0
slight 1
moderate
marked 3
Very marked
Based on these values, the PASI score is calculated according to the following formula taking into account the percentage of each body region assessed to the overall body surface area (cf. Appendix of Guideline on clinical investigation of medicinal products indicated for the treatment of psoriasis (2004),
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/ 09/WC500003329.pdf for the corresponding formula):
PASI=0.1(Eh+Ih+Dh)Ah+0.2(Eu+Iu+Du)Au+0.3(E,+It+Dt)At+0.4(Ei+Ii+Di)Ai
E=erythema, I=infiltration, D=desquamation, h=head, t=trunk, u=upper extremities, Mower extremities
It is understood, that the antibody or fragment thereof or the pharmaceutical composition comprising the same may be used for treatment of patients having any PASI score >1. The clinical benefit of using the neutralizing antibody or functional fragment thereof according to the invention may be an improvement of at least 50 %, at least 55 %, at least 60 %, at least 65 %, at least 70 %, at least 75 % (PASI75) or at least 90 % (PASI90) of the initial PASI score of a patient before start of treatment. The clinical benefit may also comprise achieving PASI75 in at least 60, 65, 70, 75, 80 or 85 % of patients of a group of patients, in particular in at least 60% of patients of a group of patients. It may comprise achieving PASI90 in at least 40, 45, 50, 55, 60 or 65 % of patients of a group of patients. It is to be understood, that the group of patients in which PASI75 or PASI90 may be achieved relates to about 100, about 125, about 150, about 200, about 300 or about 400 patients, in particular about 125 patients. The antibody or fragment thereof or the pharmaceutical composition comprising the same may also be able to preserve the improved PASI score for at least about 50 weeks, at least about 55 weeks at least, about 60 weeks, at least about 65 weeks, at least about 70 weeks, or at least about 75 weeks.
Physican's global assessment (PGA) is another method for defining the severity of psoriasis, whereby there are two possible forms of PGA, i.e. the static form, wherein the physician assesses all lesions at a single time point and rates them on a six or seven point scale or the dynamic form, wherein the improvement of the disease from a baseline is assessed. The following exemplary scale for static PGA is provided in the Appendix of the EMEA's Guideline on clinical investigation of medicinal products indicated for the treatment of psoriasis (2004):
• Severe Very marked plaque elevation, scaling, and/or erythema
• Moderate to severe Marked plaque elevation, scaling, and/or erythema
• Moderate Moderate plaque elevation, scaling, and/or erythema
• Mild Slight plaque elevation, scaling, and/or erythema · Almost clear Intermediate between mild and clear
• Clear No signs of psoriasis (post-inflammatory
hyperpigmentation may be present)
Unless otherwise indicated, references to PGA as used herein, refer to the PGA according to the Appendix of the EMEA's guidelines shown above. Briefly, static PGA determines the severity of psoriasis at a single timepoint, whereby erythema, plaque elevation and scale of all involved lesions is taken into account. However, BSA involved is not considered in PGA assessment. It is understood, that the antibody or fragment thereof or the pharmaceutical composition comprising the same according to the invention may be used for treatment and/or prevention of psoriasis in patients having an almost clear, mild, moderate, moderate to severe or severe psoriasis according to PGA. In a specific embodiment, the neutralizing antibody or the fragment thereof or the pharmaceutical composition comprising the same is for use in the treatment and/or prevention of psoriasis in a patient having mild psoriasis, moderate psoriasis, moderate to severe psoriasis or severe psoriasis according to PGA.
The neutralizing antibody or a fragment thereof or the pharmaceutical composition comprising the same according to the invention is for use in the treatment of psoriasis of any severity, in particular any grade of severity according to the EMEA's guidelines described herein. However, it is to be understood that minimal or borderline psoriasis not defined by the EMEA, wherein the patient does not show any psoriatic lesions but only signs of psoriasis such as nail pitting and severe dandruff may also be treated with the antibody or fragment thereof or the
composition comprising the same according to the present invention. In one embodiment, the neutralizing antibody or a fragment thereof or the pharmaceutical composition comprising the same is for use in the treatment and/or prevention of moderate psoriasis, moderate to severe psoriasis and/or severe psoriasis. In one specific embodiment, the neutralizing antibody or a fragment thereof or the pharmaceutical composition comprising the same is for use in the treatment and/or prevention of moderate psoriasis. In another embodiment, the neutralizing antibody or a fragment thereof or the pharmaceutical composition comprising the same is for use in the treatment and/or prevention of moderate to severe psoriasis. In a further embodiment, the neutralizing antibody or a fragment thereof or the pharmaceutical composition comprising the same is for use in the treatment and/or prevention of severe psoriasis.
In a further specific embodiment, the neutralizing antibody or the fragment thereof or the pharmaceutical composition comprising the same according to the present invention is for use in the treatment of a patient having a PASI score of >1, >5 or >10, in particular >10. In a further specific embodiment, the neutralizing antibody or the fragment or the pharmaceutical composition comprising the same according to the present invention is for use in the treatment of a patient having a PASI score of >12, >15, or >20, in particular of >12. In another embodiment, the neutralizing antibody or a fragment thereof or the pharmaceutical composition comprising the same is used for treatment of a patient, wherein >1% body surface area , >5% body surface area, >10% body surface area, >15% body surface area, >20% body surface area, >30% body surface area, >40% body surface area or >50% body surface area, in particular >10% body surface area are affected by psoriasis. In an alternative embodiment, the neutralizing antibody or the fragment thereof or a pharmaceutical composition comprising the same according to the present invention is for use in the treatment of a patient having a PASI score of >12 and wherein >10% body surface area are affected by psoriasis.
One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of moderate to severe Psoriasis vulgaris, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration,
(b) a second dose of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days.
One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of moderate to severe Psoriasis vulgaris, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration, which is a double dose of the doses administered according to (b) and/or (c) and optionally (d),
(b) a second dose of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days.
Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of moderate to severe Psoriasis vulgaris, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration, which is a double dose of the doses administered according to (b) and/or (c) and optionally (d),
(b) a second dose of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days, wherein the doses according to (b) and (c) and optionally (d) of the neutralizing antibody or a fragment thereof are in the range of about 10-200 mg. One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of Psoriasis vulgaris in a patient having a PASI score of about 10-20, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration,
(b) a second dose of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days.
One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of moderate to severe Psoriasis vulgaris in a patient having a PASI score of about 10-20, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration, which is a double dose of the doses administered according to (b) and/or (c) and optionally (d),
(b) a second dose of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days.
Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of moderate to severe Psoriasis vulgaris in a patient having a PASI score of about 10-20, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration, which is a double dose of the doses administered according to (b) and/or (c) and optionally (d),
(b) a second dose of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and (d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days, wherein the doses according to (b) and (c) and optionally (d) of the neutralizing antibody or a fragment thereof are in the range of about 10-200 mg.
One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of Psoriasis vulgaris in a patient having a BSA of >10, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration,
(b) a second dose of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days.
One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of moderate to severe Psoriasis vulgaris in a patient having a BSA of >10, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration, which is a double dose of the doses administered according to (b) and/or (c) and optionally (d),
(b) a second dose of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and optionally further doses (d) of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days. Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of moderate to severe Psoriasis vulgaris in a patient having a BSA of >10, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration, which is a double dose of the doses administered according to (b) and/or (c) and optionally (d),
(b) a second dose of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days, wherein the doses according to (b) and (c) and optionally (d) of the neutralizing antibody or a fragment thereof are in the range of about 10-200 mg.
As used herein, "treatment" includes any treatment of an animal and/or human which leads to a full or partial remission and/or alleviation of the symptoms or the disease to be treated, i.e. psoriasis. Alleviation of the symptoms of psoriasis may include a reduction in dandruff, a reduction of itching, a reduction of plaques, a reduction of redness of the skin and/or a reduction of the discoloring of the nail plate. Treatment as used in the context of the present invention also includes any treatment with the antibody or a fragment thereof or the pharmaceutical composition comprising the same of the present invention leading to a reduction of the body surface area affected by psoriasis, a reduction of the PASI score, a reduction of the PGA score or a downscaling of the severity of the psoriasis on the EMEA's severity scale for psoriasis described herein. In one embodiment, treatment with the antibody or fragment thereof or a pharmaceutical composition comprising the same according to the invention leads to a downscaling of the EMEA's severity grade from severe to moderate to severe, from moderate to mild or from mild to minimal psoriasis. It is however to be understood that treatment may also lead to downscaling over more than one of the EMEA's severity grades, e.g. from severe psoriasis to moderate psoriasis. In another embodiment of the present invention, treatment includes any treatment with the antibody or fragment thereof or the pharmaceutical composition comprising the same according to the present invention, leading to a reduction of about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or about 95% of the initial PASI score. In another embodiment of the present invention, treatment includes any treatment with the antibody or fragment thereof or the pharmaceutical composition comprising the same according to the present invention, leading to a reduction of about 5%, about 10%>, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or about 95% of the initial BSA affected by psoriasis. The term "initial PASI score" or "initial BSA" relates to said PASI score or BSA determined for the patient before starting the treatment with the antibody or fragment thereof according to the present invention or a pharmaceutical composition comprising the same. In another embodiment, treatment as used herein relates to a treatment with the antibody or fragment thereof or a pharmaceutical composition comprising the same according to the present invention, leading to full remission of the psoriasis. In this context "full remission" relates to about 100% reduction of the initial PASI score or a reduction of psoriasis symptoms in the treated patient so that no psoriatic lesions and only signs of borderline psoriasis such as severe dandruff and/or nail pitting may be observed or a reduction to minimal psoriasis as defined herein or a PGA grade of clear psoriasis. It is to be understood that this full remission does not have to be permanently.
"Prevention" includes any treatment of an animal and/or human which fully or partially prevents the outbreak of a disease which should be prevented. This also includes treatment with the antibody or a fragment thereof or a pharmaceutical composition comprising the same according to the present invention which fully or partially prevents the development of any symptoms associated with psoriasis, such as the development of lesions, pustules, severe dandruff and/or nail pitting. Preventive treatment with the antibody or a fragment thereof or a pharmaceutical composition comprising the same may be in particular useful for treatment of patients suffering from relapse-remitting psoriasis. In this case it may be appropriate to administer the antibody or a fragment thereof or a pharmaceutical composition comprising the same during the remission phase in order to prevent and/or reduce the severity of the next relapse.
The antibody or a fragment thereof or the pharmaceutical composition comprising the same of the invention may be used for treatment of a patient who has been diagnosed with psoriasis, in particular non-pustular psoriasis such as Psoriasis vulgaris at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months, in particular at least 12 months before the beginning of the treatment. In one embodiment, the patient has been diagnosed with clinically stable Psoriasis vulgaris at least 12 months before the beginning of the treatment.
One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of clinically stable Psoriasis vulgaris diagnosed at least 12 months before the beginning of the treatment, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration,
(b) a second dose of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days. One embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of clinically stable Psoriasis vulgaris in a patient diagnosed at least 12 months before the beginning of the treatment, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration, which is a double dose of the doses administered according to (b) and/or (c) and optionally (d),
(b) a second dose of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and (d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days.
Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of clinically stable Psoriasis vulgaris in a patient diagnosed at least 12 months before the beginning of the treatment, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration, which is a double dose of the doses administered according to (b) and/or (c) and optionally (d),
(b) a second dose of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days, wherein the doses according to (b) and (c) and optionally (d) of the neutralizing antibody or a fragment thereof are in the range of about 10-200 mg. The antibody or fragment thereof or the pharmaceutical composition comprising the same of the invention may be administered to a patient either orally or parenteraly. In one embodiment, the antibody or fragment thereof or the pharmaceutical composition comprising the same is administered subcutaneously or by other parenteral routes. Other parenteral routes include administration by intravenous, intradermal, intramusclar, intramammary, intraperitoneal, intrathecal, retrobulbar, intrapulmonary injection and/or surgical implantation at a particular site and/or topical administration. Further the antibody or fragment thereof may be
administered intravesically, intranasally, intratumourally and/or intralesionally. In one embodiment, the antibody or fragment thereof or the pharmaceutical
composition comprising the same according to the present invention is administered parenteraly, in particular intravenously, subcutaneously or topically. Subcutaneous administration is particularly desirable. One advantage provided by subcutaneous injections is that they may be performed in short time, in particular when compared to intravenous injection (e.g. approximately 10 minutes for subcutaneous administration compared to about an hour for intravenous infusion). Another advantage is, that while intravenous administration requires an intravenous access which has to be established by trained personnel, subcutaneous injections may even performed by the patient himself, e.g. by using automatic injection devices, thus rendering the therapy more convenient for the patient.
Subcutaneous (SC) administration may be performed via a syringe, optionally a prefilled syringe, an injector pen, optionally an autoinjector pen, an injection device or an infusion pump or a suitable needleless device. Subcutaneous administration may be performed at a single site of the body or at different sites of the body, e.g. at sites adjacent to each other. Suitable sites for subcutaneous administration are known to the person skilled in the art and include, e.g. the thighs or the upper arms. However, another embodiment of the present invention relates to intravenous administration of the antibody or a fragment thereof or a pharmaceutical composition comprising the same according to the present invention. Intravenous administration may be in particular useful e.g. when higher concentrations of the antibody which may not be formulated for subcutaneous administration should be administered to the patient.
The antibody or the fragment thereof or a pharmaceutical composition comprising the same according to the present invention may also be administered topically. The antibody or fragment thereof or the pharmaceutical composition comprising the same according to the present invention may be administered in any therapeutically effective pharmaceutical dosage form for topical administration. Examples of such pharmaceutical dosage forms include inter alia solutions, suspensions, dispersions, tinctures, gels, topical sprays, topical foams, gels, water-in-oil emulsions such as ointments, and oil-in water emulsions such as creams, lotions, and balms. Within the scope of the present invention, it may be possible to apply the pharmaceutical dosage form comprising the antibody or fragment thereof or the pharmaceutical composition comprising the same according to the present invention to the skin by means of an applicator or dispenser device to ensure administration of a particular amount of the compound to a given skin area (that is to avoid overdosing of the dosage form).
However, the topical dosage forms may also be applied without such an applicator or dispenser device, e.g. by using a spatula or hands.
The neutralizing antibody or a fragment thereof for use according to the invention may be administered in combination with at least one further pharmaceutically active agent suitable for the treatment of psoriasis. Pharmaceutically active agents which may be administered in combination with the antibody or fragment thereof as described herein include in particular active agents labeled for use in the treatment of psoriasis and/or any of its symptoms, active agents currently studied in clinical trials for the treatment of psoriasis and/or any of its symptoms and/or any other active agent which is suitable for the treatment of psoriasis and/or any of its symptoms (e.g. use of known active agents not approved by the competent agencies for the treatment of psoriasis and/or any of its symptoms but which are used off-label). It is understood within the meaning of the present invention that each active agent mentioned herein may be used in combination with the antibody or fragment thereof for use as described herein either alone or in combination with (a) further active agents mentioned herein. Currently known therapies for psoriasis include topical agents, phototherapy, systemic agents, e.g. active agents which may be administered orally (e.g. as liquid or solid oral dosage forms), intravenously or subcutaneously and alternative therapies such as changes in diet and lifestyle. Thus, any active agent useful in any of the aforementioned therapies may be administered in combination with the antibody or fragment thereof according to the invention. The further active agent may be administered separately, concurrently or sequentially with the antibody or fragment thereof or the composition comprising the same according to the present invention.
A non-exhaustive list of topical agents currently used for treatment of psoriasis and/or any of its symptoms includes bath solutions, moisturizers, mineral oil, urea, salicylic acid, petroleum jelly, coal tar, dithranol, corticosteroids (e.g.
desoximetason), fluocinonide, vitamin D3 analogues (e.g. calcipotriol), vitamin Bi2, and retinoids. It is also to be understood that phototherapy is included in the definition of further therapeutic agent for topical treatment of psoriasis and/or any of its symptoms. Phototherapy includes narrow spectrum UVB therapy, selective ultraviolet phototherapy, PUVA therapy (i.e. psoralen in combination with ultraviolet A therapy) and laser therapy. Hence, in one embodiment of the invention, the antibody or fragment thereof is used in combination with phototherapy.
Exemplary systemic agents useful for the treatment of psoriasis and/or any of its symptoms are methotrexate, cyclosporine, retinoids, fumaric acid esters (e.g.
dimethyl fumarate), monoclonal antibodies (e.g. efalizumab), sulphasalazine, immunosupressants (e.g. alefacept, a recombinant LFA-3/IgGl fusion protein, tacrolimus and mycophenolat mofetil), azathioprine, TNF-alpha inhibitors (e.g. infliximab, adalimumab, golimumab, certolizumab pegol, etanercept), IL-12 and/or IL-23 inhibitors (e.g. ustekinumab) and IL-17 inhibitors (secukinumab, ixekizumab, brodalumab, RG7624, MK-3222) . In one embodiment, the neutralizing antibody or a fragment thereof for use as described herein is administered in combination with at least one non-biologic disease-modifying antirheumatic drug (DMARD). The at least one non-biologic DMARD may be selected from the group consisting of methotrexate, sulphasalazine, azathioprine, cyclosporine, retinoids, fumaric acid esters and immunosuppressants. Examples for immunosuppressants useful for the treatment of psoriasis are tacrolimus and mycophenolate mofetil.
In another embodiment, the neutralizing antibody or a fragment thereof for use as described herein is administered in combination with at least one biologic. As used herein, the term "biologies" designates drugs that have been produced using biotechnological methods, e.g. therapeutic antibodies such as adalimumab, etanercept, golimumab, infliximab, and others. The at least one biologic may be selected from the group consisting of recombinant LFA-3/IgGl human fusion proteins, anti-cytokine antibodies and cytokine receptor antagonists, such as TNF- alpha inhibitors, IL-12 and/or IL-23 inhibitors, and IL-17 inhibitors.
As used herein, the term "TNF-alpha inhibitor" designates a biological drug that specifically targets TNFa or a receptor of TNFa. Drugs targeting TNF are for example the above-mentioned adalimumab, etanercept, certoluzimab pegol, golimumab, or infliximab.
Hence, the neutralizing antibody or a fragment thereof may be administered in combination with at least one biologic selected from the group consisting of efalizumab, infliximab, adalimumab, golimumab, certolizumab pegol, etanercept, ustekinumab, secukinumab, ixekizumab, brodalumab, RG7624, MK-3222 and alefacept. In one embodiment, the neutralizing antibody or a fragment thereof for use as described herein is administered in combination with at least one non-biologic DMARD and at least one biologic. Thus, the neutralizing antibody or a fragment thereof for use as described herein may be administered in combination with at least one non-biologic DMARD selected from methotrexate, sulphasalazine, azathioprine, cyclosporine, retinoids, fumaric acid esters and immunosuppressants and with at least one biologic selected from recombinant LFA-3/lgGl human fusion proteins, anti-cytokine antibodies and cytokine receptor antagonists, such as TNF-alpha inhibitors, IL-12 and/or IL-23 inhibitors, IL-17 inhibitors or.
In one embodiment, the neutralizing antibody or a fragment thereof for use as described herein is administered in combination with at least one further active agent suitable for the treatment of psoriasis, optionally selected from the group comprising methotrexate, sulphasalazine, azathiopine, cyclosporine, retinoids, fumaric acid esters, efalizumab, alefacept, infliximab, adalimumab, golimumab, certolizumab pegol, ustekinumab, etanercept, secukinumab, ixekizumab, brodalumab, RG7624, MK-3222, mineral oil, urea, salicylic acid, petroleum jelly, coal tar, dithranol, corticosteroids, fluocinonide, vitamin D3 analogues, vitamin Bi2, and retinoids.
In a further embodiment of the invention, the antibody or fragment thereof or the pharmaceutical composition comprising the same for use as described herein, is used in combination with methotrexate. In a further embodiment of the invention, the antibody or fragment thereof or the pharmaceutical composition comprising the same for use as described herein, is used in combination with non-biologic DMARDS, optionally selected from the group consisting of methotrexate, sulphasalazine, azathioprine, cyclosporine, retinoids, fumaric acid esters and immunosuppressants. In a further embodiment of the invention, the antibody or fragment thereof or the pharmaceutical composition comprising the same for use as described herein, is used in combination with immunosuppressants, optionally in combination with tacrolimus and/or mycophenolate mofetil.
In a further embodiment of the invention, the antibody or fragment thereof or the pharmaceutical composition comprising the same for use as described herein, is used in combination with TNF-alpha inhibitors. In a further embodiment of the invention, the antibody or fragment thereof or the pharmaceutical composition comprising the same for use as described herein, is used in combination with IL-12 and/or IL-23 inhibitors.
In a further embodiment of the invention, the antibody or a fragment thereof or the pharmaceutical composition comprising the same for use as described herein is used in combination with IL-17 inhibitors.
In yet a further embodiment of the invention, the antibody or a fragment thereof or a pharmaceutical composition comprising the same for use as described herein is used in combination with LFA-3/IgGl human fusion proteins.
In a further embodiment of the invention, the antibody or fragment thereof or the pharmaceutical composition comprising the same for use as described herein, is used in combination with topical agents useful in the treatment of psoriasis.
In another embodiment of the invention, the antibody or fragment thereof or the pharmaceutical composition comprising the same for use as described herein, is used in combination with a biologic optionally selected from the group consisting of efalizumab, alefacept, infliximab, adalimumab, golimumab, certolizumab pegol, ustekinumab, infliximab, etanercept, secukinumab, ixekizumab, brodalumab, RG7624, MK-3222 and ustekinumab. In yet a further embodiment of the invention, the antibody or fragment thereof or the pharmaceutical composition comprising the same for use as described herein, is used in combination with a further active agent selected from the group consisting of moisturizers, mineral oil, urea, salicylic acid, petroleum jelly, coal tar, dithranol, corticosteroids, fluocinonide, vitamin D3 analogues, vitamin Bi2 and retinoids.
Such combination therapies are particularly useful when the patient suffering from psoriasis and/or any of its symptoms does not adequately respond to or whose psoriasis is insufficiently controlled by a therapy with any of the active agents suitable for the treatment of psoriasis and/or any of its symptoms. As used herein, the term "patients not adequately responding to" or "patients with insufficiently controlled psoriasis" and any variations thereof refers to patient not showing the expected treatment response to an active agent, e.g. not showing a reduction of the PASI of at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 70% or at least 75% of the initial PASI after treatment with the active agent for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks or 8 weeks, in particular to patients not showing a reduction of the PASI of at least 30% of the initial PASI after treatment with the active agent for 4 weeks. Patients not adequately responding to the treatment with an active agent or patients with insufficiently controlled psoriasis also relates to patients not showing a reduction of the BSA involved of at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 70% or at least 75% of the initial BSA involved after treatment with the active agent for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks or 8 weeks, in particular to patients not showing a reduction of the BSA involved of at least 30% of the initial BSA involved after treatment with the active agent for 4 weeks. However, it is also to be understood that patients not adequately responding to a therapy with an active agent suitable for the treatment of psoriasis do also include patients developing unwanted or severe side effects such as infections, headache, ulcerative stomatitis, pulmonary alveolar proteinosis (PAP), low white blood cell count, nausea, abdominal pain, fatigue or fever in response to the treatment with said active agent.
The active agent to which the patient does not adequately respond or which insufficiently controls the psoriasis may be any active agent useful in the treatment of psoriasis and/or any of its symptoms, e.g. any of the active agents mentioned specifically herein, thus necessitating a combined treatment with the antibody or fragment thereof according to the invention or a pharmaceutical composition comprising the same and the further active agent or the treatment with the antibody or fragment thereof or a pharmaceutical composition comprising the same without co-administration of the active agent to which the patient does not adequately respond, or which insufficiently controls psoriasis in said patient.
One embodiment of the present invention thus relates to the neutralizing antibody or a fragment thereof or a pharmaceutical composition comprising the same for use in the treatment of psoriasis in a patient not adequately responding to or having a psoriasis which is insufficiently controlled by the treatment with a non-biologic DMARD. In one embodiment of the present invention, the patient not adequately responding to or having a psoriasis which is insufficiently controlled by the treatment with a non-biologic DMARD, is a patient whose psoriasis has not been treated with a biologic, i.e. a patient who is biologic treatment naive. The non-biologic DMARD to which the patient does not adequately respond or which insufficiently controls the psoriasis of the patient may be selected from the group consisting of methotrexate, sulphasalazine, azathioprine, cyclosporine, retinoids, fumaric acid esters and immunosuppressants.
Hence, one embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis which is insufficiently controlled by the treatment with a non-biologic DMARD, and wherein optionally the patient is biologic treatment naive, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising: (a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration,
(b) a second dose of the neutralizing antibody or a fragment thereof 7-21 days after administration of the loading dose, and
(c) a third dose (c) of the neutralizing antibody or a fragment thereof 21-35 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of 21-35 days.
Another embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis which is insufficiently controlled by the treatment with a non-biologic DMARD, and wherein optionally the patient is biologic treatment naive, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration,
(b) a second dose of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days.
A further embodiment relates to the neutralizing antibody or a fragment thereof for use in the treatment and/or prevention of psoriasis which is insufficiently controlled by the treatment with a non-biologic DMARD, and wherein optionally the patient is biologic treatment naive, wherein said antibody or fragment thereof is used according to the following dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration, which is a double dose of the doses administered according to (b) and (c) and optionally (d), (b) a second dose of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days, wherein the doses of the neutralizing antibody or a fragment thereof according to (b) and (c) and optionally (d) are in the range of 20-150 mg. In one embodiment of the invention, the neutralizing antibody or fragment thereof or a composition comprising the same is for use in the treatment and/or prevention of psoriasis in a patient not adequately responding to or having a psoriasis which is insufficiently controlled by the treatment with the non-biologic DMARD
methotrexat, wherein optionally the patient is biologic treatment naive.
In another embodiment of the invention, the antibody or a fragment thereof or a composition comprising the same is for use in the treatment and/or prevention of psoriasis in a patient not adequately responding to or having a psoriasis which is insufficiently controlled by the treatment with immunosuppressants, wherein optionally the patient is biologic treatment naive. In this case, the immune- suppressant may be selected from tacrolimus and mycophenolat mofetil.
In a further embodiment of the invention, the antibody or a fragment thereof or a composition comprising the same is for use in the treatment and/or prevention of psoriasis in a patient not adequately responding to or having a psoriasis which is insuffciently controlled by the treatment with sulphasalazine, wherein optionally the patient is biologic treatment naive.
In a further embodiment of the invention, the antibody or a fragment thereof or a composition comprising the same is for use in the treatment and/or prevention of psoriasis in a patient not adequately responding to or having a psoriasis which is insuffciently controlled by the treatment with azathioprine, wherein optionally the patient is biologic treatment naive.
In a further embodiment of the invention, the antibody or a fragment thereof or a composition comprising the same is for use in the treatment and/or prevention of psoriasis in a patient not adequately responding to or having a psoriasis which is insuffciently controlled by the treatment with cyclosporine, wherein optionally the patient is biologic treatment naive. In a further embodiment of the invention, the antibody or a fragment thereof or a composition comprising the same is for use in the treatment and/or prevention of psoriasis in a patient not adequately responding to or having a psoriasis which is insuffciently controlled by the treatment with retinoids, wherein optionally the patient is biologic treatment naive.
In a further embodiment of the invention, the antibody or a fragment thereof or a composition comprising the same is for use in the treatment and/or prevention of psoriasis in a patient not adequately responding to or having a psoriasis which is insuffciently controlled by the treatment with fumaric acid esters, wherein optionally the patient is biologic treatment naive.
In another embodiment of the invention, the antibody or fragment thereof or a composition comprising the same is for use in the treatment and/or prevention of psoriasis in a patient not adequately responding to the treatment with or having a psoriasis which is insufficiently controlled by biologic treatment such as treatment with monoclonal antibodies. In particular, the antibody or fragment thereof or a composition comprising the same is for use in the treatment and/or prevention of psoriasis in patients having developed an immune response (e.g. antibodies) to biologies, such as monoclonal antibodies used in the treatment of psoriasis. This includes patients having developed anti-drug antibodies against anti-GM-CSF antibodies that are different from the neutralizing antibodies or fragments thereof as described herein.
In one embodiment of the invention, the antibody or a fragment thereof is for use in the treatment and/or prevention of psoriasis in a patient not adequately responding to or having a psoriasis which is insufficiently controlled by the treatment with a cytokine antibody or a cytokine receptor antagonist, optionally selected from the group consisting of TNF-alpha inhibitors, IL-12/IL-23 inhibitors and IL-17 inhibitors.
In another embodiment of the invention, the antibody or fragment thereof or a composition comprising the same is for use in the treatment and/or prevention of psoriasis in a patient not adequately responding to or having a psoriasis which is insufficiently controlled by the treatment with TNF-alpha inhibitors, optionally the treatment with infliximab, adalimumab, golumumab, certolizumab pegol and/or etanercept.
In another embodiment of the invention, the antibody or fragment thereof or a composition comprising the same is for use in the treatment and/or prevention of psoriasis in a patient not adequately responding to or having a psoriasis which is insufficiently controlled by the treatment with IL-12 and/or IL-23 inhibitors optionally the treatment with ustekinumab and/or MK-3222.
In another embodiment of the invention, the antibody or fragment thereof or a composition comprising the same is for use in the treatment and/or prevention of psoriasis in a patient not adequately responding to or having a psoriasis which is insufficiently controlled by the treatment with IL-17 inhibitors, optionally the treatment with brodalumab, ixekizumab, secukinumab and/or RG7624. In another embodiment of the invention, the antibody or fragment thereof or a composition comprising the same is for use in the treatment and/or prevention of psoriasis in a patient not adequately responding to or having a psoriasis which is insufficiently controlled by the treatment with recombinant LFA-3/lgGl human fusion proteins, optionally the treatment with alefacept. In a further embodiment of the invention, the antibody or a fragment thereof or a composition comprising the same is for use in the treatment and/or prevention of psoriasis in a patient not adequately responding to or having a psoriasis which is insufficiently controlled by biologic treatment, in particular the treatment with an active agent selected from the group consisting of efalizumab, alefacept, infliximab, adalimumab, golimumab, certolizumab pegol, etanercept, brodalumab, ixekizumab, secukinumab, RG7624, MK-3222 and ustekinumab.
In another embodiment of the invention, the antibody or a fragment thereof or a composition comprising the same is for use in the treatment and/or prevention of psoriasis in a patient not adequately responding to or having a psoriasis which is insufficiently controlled by a combination of a non-biologic DMARD and a biologic treatment. In particular, the patient is not adequately responding to or has a psoriasis which is insufficiently controlled by a treatment with a non-biologic DMARD selected from methotrexate, sulphasalazine, azathioprine, cyclosporine, retinoids, fumaric acid esters and immunosuppressants in combination with the treatment with a biologic selected from anti-cytokine antibodies and cytokine receptor antagonists, optionally selected from TNF-alpha neutralizing agents, IL-12 and/or IL-23 neutralizing agents, IL-17 neutralizing agents and recombinant LFA-3/lgGl human fusion proteins.
In one embodiment, the patient is not adequately responding to or has a psoriasis which is insufficiently controlled by a treatment with methotrexate in combination with the treatment with a biologic selected from anti-cytokine antibodies, cytokine receptor antagonists, optionally selected from TNF-alpha neutralizing agents, IL-12 and/or IL-23 neutralizing agents, IL-17 neutralizing agents and recombinant LFA- 3/lgGl human fusion proteins. In another embodiment of the invention, the patient is not adequately responding to or has a psoriasis which is insufficiently controlled by a treatment with
sulphasalazine in combination with the treatment with a biologic selected from anti- cytokine antibodies, cytokine receptor antagonists, optionally selected from TNF- alpha neutralizing agents, IL-12 and/or IL-23 neutralizing agents, IL-17 neutralizing agents and recombinant LFA-3/lgGl human fusion proteins.
In another embodiment of the invention, the patient is not adequately responding to or has a psoriasis which is insufficiently controlled by a treatment with azathioprine in combination with the treatment with a biologic selected from anti-cytokine antibodies, cytokine receptor antagonists, optionally selected from TNF-alpha neutralizing agents, IL-12 and/or IL-23 neutralizing agents, IL-17 neutralizing agents and recombinant LFA-3/lgGl human fusion proteins.
In a further embodiment, the patient is not adequately responding to or has a psoriasis which is insufficiently controlled by a treatment with cyclosporine in combination with the treatment with a biologic selected from anti-cytokine antibodies, cytokine receptor antagonists, optionally selected from TNF-alpha neutralizing agents, IL-12 and/or IL-23 neutralizing agents, IL-17 neutralizing agents and recombinant LFA-3/lgGl human fusion proteins.
In a further embodiment, the patient is not adequately responding to or has a psoriasis which is insufficiently controlled by a treatment with retinoids in combination with the treatment with a biologic selected from anti-cytokine antibodies, cytokine receptor antagonists, optionally selected from TNF-alpha neutralizing agents, IL-12 and/or IL-23 neutralizing agents, IL-17 neutralizing agents and recombinant LFA-3/lgGl human fusion proteins. In a further embodiment, the patient is not adequately responding to or has a psoriasis which is insufficiently controlled by a treatment with fumaric acid esters in combination with the treatment with a biologic selected from anti-cytokine antibodies, cytokine receptor antagonists, optionally selected from TNF-alpha neutralizing agents, IL-12 and/or IL-23 neutralizing agents, IL-17 neutralizing agents and recombinant LFA-3/lgGl human fusion proteins.
In a further embodiment, the patient is not adequately responding to or has a psoriasis which is insufficiently controlled by a treatment with immunosuppressants in combination with the treatment with a biologic selected from anti-cytokine antibodies, cytokine receptor antagonists, optionally selected from TNF-alpha neutralizing agents, IL-12 and/or IL-23 neutralizing agents, IL-17 neutralizing agents and recombinant LFA-3/lgGl human fusion proteins.
In yet a further embodiment, the patient is not adequately responding to or has a psoriasis which is insufficiently controlled by a treatment with a non-biologic DMARD selected from methotrexate, sulphasalazine, azathioprine, cyclosporine, retinoids, fumaric acid esters and immunosuppressants in combination with the treatment with anti-cytokine antibodies or cytokine receptor antagonists.
In another embodiment, the patient is not adequately responding to or has a psoriasis which is insufficiently controlled by a treatment with a non-biologic DMARD selected from methotrexate, sulphasalazine, azathioprine, cyclosporine, retinoids, fumaric acid esters and immunosuppressants in combination with the treatment with TNF-alpha inhibitors, optionally in combination with the treatment with infliximab, adalimumab, adumumab, certolizumab pegol and/or etanercept.
In another embodiment, the patient is not adequately responding to or has a psoriasis which is insufficiently controlled by a treatment with a non-biologic DMARD selected from methotrexate, sulphasalazine, azathioprine, cyclosporine, retinoids, fumaric acid esters and immunosuppressants in combination with the treatment with IL-12 and/or IL-23 inhibitors, optionally in combination with the treatment with ustekinumab and/or MK-3222. In another embodiment, the patient is not adequately responding to or has a psoriasis which is insufficiently controlled by a treatment with a non-biologic DMARD selected from methotrexate, sulphasalazine, azathioprine, cyclosporine, retinoids, fumaric acid esters and immunosuppressants in combination with the treatment with IL-17 inhibitors, optionally in combination with the treatment with brodalumab, ixekizumab, secukinumab and/or RG7624.
In another embodiment, the patient is not adequately responding to or has a psoriasis which is insufficiently controlled by a treatment with a non-biologic DMARD selected from methotrexate, sulphasalazine, azathioprine, cyclosporine, retinoids, fumaric acid esters and immunosuppressants in combination with the treatment with recombinant LFA-3/lgGl human fusion proteins, optionally in combination with the treatment with alefacept.
In a further embodiment of the invention, the antibody or fragment thereof or a composition comprising the same is for use in the treatment of psoriasis in a patient not adequately responding to or having a psoriasis which is insufficiently controlled by topical treatment, in particular the treatment with an active agent selected from the group consisting of moisturizers, mineral oil, urea, salicylic acid, petroleum jelly, coal tar, dithranol, corticosteroids, fluocinonide, vitamin D3 analogues, vitamin Bi2 and retinoids.
In another of its aspects, the present invention relates to a method of treatment of psoriasis in a patient, comprising administering a neutralizing antibody or a fragment thereof as defined herein to said patient according to the dosage regimen as described herein.
"Patient" as used herein relates to any mammalian, in particular a human, suffering from psoriasis in any of its forms mentioned herein, having been diagnosed with psoriasis in any of its forms mentioned herein, being predisposed to psoriasis in any of its forms mentioned herein or susceptible to psoriasis in any of its forms mentioned herein. In particular, the patient to be treated with the method according to the invention includes a patient suffering from any type of psoriasis specifically mentioned herein, such as pustular and non-pustular psoriasis. In one of its embodiments, the method of the invention relates to the treatment of patients suffering from non-pustular psoriasis, optionally selected from Psoriasis vulgaris and Psoriasis erythroderma. Furthermore, the patients to be treated with the method according to the invention include patients not adequately responding to or insufficiently controlled by a treatment with a further active agent useful in the treatment of psoriasis as described herein.
Within the scope of the method described herein the antibody or fragment thereof or a composition comprising the same may be administered in any form described herein, e.g. subcutaneously, intravenously or topically.
The method of the present invention also includes the administration of a further active agent suitable for the treatment of psoriasis to a patient suffering from psoriasis. These further active agents which may be administered in combination with the antibody or fragment thereof or a composition comprising the same include any active agents suitable for the treatment of psoriasis as defined herein. It is to be understood that within the context of the method of the invention, these active agents may be either administered simultaneously or subsequently with the antibody, the fragment thereof or a composition comprising the same. Another of its embodiments relates to the method of the present invention, wherein the administration of the antibody or fragment thereof or the composition comprising the same of the invention results in a reduction of about 20%, of about 25%, of about 30% , of about 35%, of about 40%, of about 45%, of about 50%, of about 55%, of about 60%, of about 65%, of about 70%, of about 75% , of about 80%, of about 85%, of about 90% or of about 95% of the initial PASI evaluated in said patient at the beginning of the treatment. In one specific embodiment, the administration of the antibody or a fragment thereof or the composition comprising the same according to the invention leads to a reduction of about 25% of the initial PASI evaluated in said patient at the beginning of the treatment. In one specific embodiment, the administration of the antibody or a fragment thereof or the composition comprising the same according to the invention leads to a reduction of about 50% of the initial PASI evaluated in said patient at the beginning of the treatment. In one specific embodiment, the administration of the antibody or a fragment thereof or the composition comprising the same according to the invention leads to a reduction of about 75% of the initial PASI evaluated in said patient at the beginning of the treatment. In one specific embodiment, the administration of the antibody or a fragment thereof or the composition comprising the same according to the invention leads to a reduction of about 90% of the initial PASI evaluated in said patient at the beginning of the treatment. The reduction of the initial PASI may be determined after 5 weeks from the beginning of the treatment, after 6 weeks from the beginning of the treatment, after 7 weeks from the beginning of the treatment, after 8 weeks from the beginning of the treatment, after 9 weeks from the beginning of the treatment, after 10 weeks from the beginning of the treatment, after 11 weeks from the beginning of the treatment or after 12 weeks from the beginning of the treatment. In one embodiment, the reduction of the initial PASI is determined after 10 weeks from the beginning of the treatment.
In another of its aspects, the present invention relates to a kit comprising the antibody or fragment thereof or a pharmaceutical composition comprising the same according to the invention. The kit may include the antibody or fragment thereof or a pharmaceutical composition comprising the same packed in single or multiple dosage forms. These dosage forms may be any dosage form suitable for e.g.
subcutaneous, intravenous or topical administration. The kit may also include a container comprising the antibody or a fragment thereof according to the invention in lyophilized form and, optionally, in another container liquid suitable for
reconstitution of the antibody, e.g. physiological saline.
The invention is further described in the following example which is solely for the purpose of illustrating specific embodiments of the invention, and is also not to be construed as limiting the scope of the invention in any way.
Examples Example 1 A phase 2 multicenter, randomised, double-blind, placebo-controlled, parallel group dose finding trial to compare four different dose levels of an antibody neutralizing GM-CSF (hereinafter referred to as "anti-GM-CSF-1") comprising a light chain CDR1 as depicted in SEQ ID NO: 16, a light chain CDR2 shown in SEQ ID NO: 17, a light chain CDR3 according to SEQ ID NO: 18, a heavy chain CDR1 shown in SEQ ID NO: 14, a heavy chain CDR2 shown in SEQ ID NO: 15, and a heavy chain CDR3 as depicted in SEQ ID NO: 2 (an antibody having a variable heavy chain and light chain as specified in SEQ ID Nos. 34 and 35). Preparation of this antibody is disclosed in WO 2006/111353. The antibody is used at doses of 20 mg, 50 mg, 80 mg or 150 mg and administered subcutaneously to subjects with clinically stable plaque psoriasis at week 0, 2, 6, and 10 versus placebo. The effects of the subcutaneous administration of anti-GM-CSF-1 on psoriasis manifestation is assessed using PASI score, PGA score and biopsies.
Study population
A total of about 100-125 subjects suffering from clinically stable plaque psoriasis involving >10% of their body surface area (BSA) and having a Psoriasis Area and Severity Index (PASI) score of >12. Study duration
The study comprises three different periods, i.e. the screening period, the treatment period and the follow-up period. The total trial duration being from at least 84 to up to 185 days or up to 448 days. It is noted that the duration of any drug holiday which may optionally be made is not included in the total trial duration.
Endpoint
The primary endpoint is a 75% reduction in the PASI score (PASI75) versus baseline at week 12. PASI50 and PASI90 will also be assessed.
Screening period
During the screening period from day -30 to day -1 the eligibility of the subjects for the study is assessed.
Eligibility criteria include inter alia:
• informed written consent
• clinically stable plaque psoriasis involving >10% of their body surface area (BSA) and having a Psoriasis Area and Severity Index (PASI) score of >12
• age from 6 to 70 years
• adequate contraception throughout the duration of the study and for 12 weeks after receiving the last dose of study medication
• candidate for or having received >1 phototherapy or systemic psoriasis
therapy Treatment period
The time points provided herein for the treatment period and the follow-up period are based on an overall study duration of 185 days. It is to be understood that when a shorter study duration is envisaged, the time points have to be adapted accordingly. Eligible subjects return to the clinic on day 1 when eligibility criteria including vital signs, lung function tests, blood sampling and pharmakokinetic evaluations are assessed. The subjects are randomly assigned to one of the five treatment groups (20 mg, 50 mg, 80 mg or 150 mg of anti-GM-CSF-1 or placebo) in a 1 : 1 : 1 :1 : 1 ratio. The subject has two subcutaneous injections ("loading dose") of 20 mg, 50 mg, 80 mg or 150 mg of anti-GM-CSF-1 or placebo, depending on which treatment group they have been assigned to in order to allow for optimal onset of efficacy of anti-GM- CSF-1. Furthermore, non-lesional biopsies as well as biopsies from one distinct plaque are taken from approximately 5 subjects per dosage group.
Before leaving the study site the subject has a follow-up evaluation and a blood specimen drawn for pharmacokinetic analysis.
At day 15, 43 and 71 subjects receives further subcutaneous injections of either 20 mg, 50 mg, 80 mg or 150 mg of anti-GM-CSF-1 or placebo, depending on the treatment group to which they have been assigned. Before dosing, vital signs, lung function test and an examination of the skin including the injection site are performed. Furthermore, efficacy and safety parameters and blood and urine collection for laboratory analyses are made. In week 2 and 12 additionally biopsies of one distinct plaque are taken from approximately 5 subjects in each dosing group.
Follow-up period
Follow-up visits are scheduled on days 85, 99, 127 and 155. During the follow-up period safety as well as efficacy assessments are performed.

Claims

A neutralizing antibody or a fragment thereof specifically binding primate granulocyte macrophage colony stimulating factor (GM-CSF) for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to a dosage regimen comprising:
(a) a loading dose on the first day of administration, which is a double dose of the doses administered according to (b) and/or (c) and/or optionally (d),
(b) a second dose 7-21 days after administration of the loading dose, and
(c) a third dose 21-35 days after administration of the second dose and
(d) optionally further doses after administration of the third dose in intervals of 21-35 days.
The neutralizing antibody or a fragment thereof for use according to claim 1 , wherein said antibody or fragment thereof is used according to a dosage regimen comprising:
(a) a loading dose of the neutralizing antibody or a fragment thereof on the first day of administration, which is a double dose of the doses administered according to (b) and/or (c) and/or optionally (d),
(b) a second dose of the neutralizing antibody or a fragment thereof about 14 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody of a fragment thereof about 28 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of about 28 days.
A neutralizing antibody or a fragment thereof specifically binding primate granulocyte macrophage colony stimulating factor (GM-CSF) for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to a dosage regimen comprising:
(a) a loading dose on the first day of administration, which is the same as the doses administered according to (b) and/or (c), and/or optionally (d) (b) a second dose 7-21 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof 21-35 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of 21-35 days.
A neutralizing antibody or a fragment thereof specifically binding primate granulocyte macrophage colony stimulating factor (GM-CSF) for use in the treatment and/or prevention of psoriasis, wherein said antibody or fragment thereof is used according to a dosage regimen comprising:
(a) a loading dose on the first day of administration, which is either the same or a double of the doses administered according to (b) and/or (c), and/or optionally (d)
(b) a second dose 21-35 days after administration of the loading dose, and
(c) a third dose of the neutralizing antibody or a fragment thereof 21-35 days after administration of the second dose and
(d) optionally further doses of the neutralizing antibody or a fragment thereof after administration of the third dose in intervals of 21-35 days.
The neutralizing antibody or a fragment thereof for use according to claim 1 to 4, wherein the doses of the neutralizing antibody or a fragment thereof according to (b) and (c) and optionally (d) are independently in the range of about 10 - 200 mg, optionally in the range of about 20 - 150 mg.
The neutralizing antibody or a fragment thereof for use according to any of the preceding claims, wherein the doses of the neutralizing antibody or a fragment thereof according to (b) and (c) and optionally (d) are independently selected from 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, l lO mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg 190 mg or 200 mg, optionally independently selected from 20 mg, 50 mg, 80 mg or 150 mg.
7. The neutralizing antibody or a fragment thereof for use according to any of the preceding claims, wherein the doses of the neutralizing antibody or a fragment thereof according to (b) and (c) and optionally (d) are 20 mg.
8. The neutralizing antibody or a fragment thereof for use according to any of claims 1 to 6, wherein the doses of the neutralizing antibody or a fragment thereof according to (b) and (c) and optionally (d) are 50 mg.
9. The neutralizing antibody or a fragment thereof for use according to any of claims 1 to 6, wherein the doses of the neutralizing antibody or a fragment thereof according to (b) and (c) and optionally (d) are 80 mg.
10. The neutralizing antibody or a fragment thereof for use according to any of claims 1 to 6, wherein the doses of the neutralizing antibody or a fragment thereof according to (b) and (c) and optionally (d) are 150 mg.
11. The neutralizing antibody or a fragment thereof for use according to any of the preceding claims, wherein the neutralizing antibody or fragment thereof is administered over a period of at least 10 weeks starting from the first day of administration.
12. The neutralizing antibody or a fragment thereof for use according to any of the preceding claims, wherein said antibody or fragment thereof comprises in its heavy chain variable region a CDR 3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-13 or 56.
13. The neutralizing antibody or a fragment thereof for use according to any of the preceding claims, wherein said antibody or a fragment thereof comprises a heavy chain variable region CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-13 or 56 in combination with a heavy chain variable region CDR1 having an amino acid sequence set out in SEQ ID NO: 14 and a heavy chain variable region CDR2 having an amino acid sequence set out in SEQ ID NO: 15.
14. The neutralizing antibody or a fragment thereof for use according to any of the preceding claims, wherein said antibody or a fragment thereof comprises a light chain variable region CDR1 having an amino acid sequence set out in SEQ ID NO: 16, a CDR2 having an amino acid sequence set out in SEQ ID NO: 17 and a CDR3 having an amino acid sequence set out in SEQ ID NO: 18.
15. The neutralizing antibody or a fragment thereof for use according to any of the preceding claims, wherein said antibody comprises a light chain variable region CDR1 having an amino acid sequence as set out in SEQ ID NO: 16, a CDR2 having an amino acid sequence set out in SEQ ID NO: 17 and a CDR3 having an amino acid sequence set out in SEQ ID NO: 18 and comprising a heavy chain variable region CDR1 having an amino acid sequence set out in SEQ ID NO: 14, a CDR2 having an amino acid sequence set out in SEQ ID NO: 15 and a CDR3 having an amino acid sequence set out in SEQ ID NO: 2.
16. The neutralizing antibody or a fragment thereof for use according to any of the preceding claims, wherein said antibody or a fragment thereof comprises a light chain variable region sequence set out in SEQ ID NO: 19 and/or a heavy chain variable region sequence set out in SEQ ID NO: 21.
17. The neutralizing antibody or a fragment thereof for use according to any of the preceding claims, wherein said antibody or a fragment thereof comprises a light chain sequence set out in SEQ ID NO: 34 and/or a heavy chain sequence set out in SEQ ID NO: 35.
18. The neutralizing antibody or a fragment thereof for use according to any of the preceding claims, wherein said neutralizing antibody or fragment thereof comprises at least one amino acid sequence having at least 70%, at least 80%, at least 90% or at least 95% identity to the amino acid sequence of any of SEQ ID
NO: 1-48 and/or 52-56.
19. The neutralizing antibody or a fragment thereof for use according to any of the preceding claims, wherein said fragment specifically binding primate GM-CSF is an scFv, a single domain antibody, an Fv, a VHH antibody, a diabody, a tandem antibody, a Fab, a Fab' or a F(ab)2.
20. The neutralizing antibody or a fragment thereof for use according to any of the preceding claims, wherein the psoriasis is a pustular or a non-pustular psoriasis.
21. The neutralizing antibody or a fragment thereof for use according to any of the preceding claims, wherein the psoriasis is a non-pustular psoriasis selected from the group consisting of Psoriasis vulgaris and Psoriasis erythroderma, optionally Psoriasis vulgaris.
22. The neutralizing antibody or a fragment thereof for use according to any of the preceding claims, wherein the psoriasis is a mild to moderate psoriasis, moderate psoriasis, moderate to severe psoriasis or severe psoriasis, optionally moderate to severe psoriasis.
23. The neutralizing antibody or a fragment thereof for use according to any of the preceding claims, wherein said antibody or said fragment thereof is administered parenterally.
24. The neutralizing antibody or a fragment thereof for use according to claim 23, wherein said antibody or a fragment thereof is administered subcutaneously, intravenously or topically, optionally subcutaneously.
25. The neutralizing antibody or a fragment thereof for use according to any of the preceding claims, wherein said antibody or fragment thereof is administered in combination with at least one further active agent suitable for the treatment of psoriasis, optionally selected from the group comprising methotrexate, sulphasalazine, azathioprine, cyclosporine, fumaric acid esters, efalizumab, alefacept, infliximab, adalimumab, golimumab, certolizumab pegol,
ustekinumab, etanercept, mineral oil, urea, salicylic acid, petroleum jelly, coal tar, dithranol, corticosteroids, fluocinonide, vitamin D3 analogues, vitamin Bi2, and retinoids.
26. The neutralizing antibody or a fragment thereof for use according to any of the preceding claims, wherein the patient in whom psoriasis is treated and/or prevented is a patient not previously treated for psoriasis or a patient with insufficiently controlled psoriasis.
27. The neutralizing antibody or a fragment thereof for us according to claim 26, wherein the patient with insufficiently controlled psoriasis is a patient treated with a non-biologic DMARD, optionally a biologic treatment naive patient treated with a non-biologic DMARD.
28. The neutralizing antibody or a fragment thereof for use according to claim 26, wherein the patient with insufficiently controlled psoriasis is a patient treated with a non-biologic DMARD in combination with a biologic.
29. The neutralizing antibody or a fragment thereof for use according to claim 27 or 28, wherein the non-biologic DMARD is selected from the group consisting of methotrexate, sulphasalazine, azathioprine, cyclosporine, retinoids, fumaric acid esters and immunosuppressants.
30. The neutralizing antibody or a fragment thereof for use according to claim 28, wherein the biologic is selected from the group consisting of recombinant LFA-3/IgGl human fusion protein, TNF-alpha inhibitors, IL-12 and/or IL-23 inhibitors or IL-17 inhibitors.
31. Method of treatment and/or prevention of psoriasis in a patient, comprising administering a neutralizing antibody or a fragment thereof to said patient according to the dosing scheme according to any of claims 1 to 11.
32. The method of treatment and/or prevention according to claim 31, wherein the antibody or a neutralizing fragment thereof is a neutralizing antibody or a fragment thereof according to any of claims 12 to 19.
33. The method of treatment and/or prevention according to any of claims 31 or 32, wherein said antibody or a said fragment thereof is administered subcutaneously, intravenously or topically, optionally subcutaneously.
34. The method of treatment and/or prevention according to any of claims 31 to 33, wherein the patient is suffering from pustular or non-pustular psoriasis.
35. The method of treatment and/or prevention according to claim 34, wherein the patient is suffering from non-pustular psoriasis selected from the group consisting of Psoriasis vulgaris and Psoriasis erythroderma, optionally
Psoriasis vulgaris.
36. The method of treatment and/or prevention according to any of claims 31 to 35, wherein the psoriasis to be treated and/or prevented is a mild to moderate psoriasis, moderate psoriasis, moderate to severe psoriasis or severe psoriasis, optionally moderate to severe psoriasis.
37. The method of treatment and/or prevention according to any of claims 31 to 36, wherein the patient in whom psoriasis is treated and/or prevented is a patient not previously treated for psoriasis or a patient with insufficiently controlled psoriasis.
38. The method of treatment and/or prevention according to any of claims 31 to 37, wherein additionally a further active agent suitable for the treatment of psoriasis, optionally selected from the group comprising methotrexate, sulphasalazine, azathioprine, cyclosporine, fumaric acid esters, efalizumab, alefacept, infliximab, adalimumab, golimumab, certolizumab pegol, ustekinumab, etanercept, mineral oil, urea, salicylic acid, petroleum jelly, coal tar, dithranol, corticosteroids, fluocinonide, vitamin D3 analogues, vitamin Bi2, and retinoids is administered to said patient.
39. The method of treatment and/or prevention according to any of claims 31 to 38, wherein the treatment with said neutralizing antibody or fragment thereof results - I l l - in a reduction of at least 75% of the initial Psoriasis Area and Severity Index (PASI) evaluated in said patient at the beginning of the treatment.
PCT/EP2014/068508 2013-08-30 2014-09-01 Neutralizing antibody or a fragment thereof specifically binding primate gm-csf for use in the treatment and/or prevention of psoriasis WO2015028666A1 (en)

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