EP3645566A1 - Procédé de traitement à l'aide d'un anticorps dirigé contre il-13r - Google Patents

Procédé de traitement à l'aide d'un anticorps dirigé contre il-13r

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Publication number
EP3645566A1
EP3645566A1 EP18743109.3A EP18743109A EP3645566A1 EP 3645566 A1 EP3645566 A1 EP 3645566A1 EP 18743109 A EP18743109 A EP 18743109A EP 3645566 A1 EP3645566 A1 EP 3645566A1
Authority
EP
European Patent Office
Prior art keywords
antibody
seq
binding fragment
sequence
variable domain
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP18743109.3A
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German (de)
English (en)
Inventor
Bertil Lindmark
Ann Gee Lisa OOI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
CSL Ltd
Aslan Pharmaceuticals Pte Ltd
Original Assignee
CSL Ltd
Aslan Pharmaceuticals Pte Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by CSL Ltd, Aslan Pharmaceuticals Pte Ltd filed Critical CSL Ltd
Priority claimed from PCT/SG2018/050319 external-priority patent/WO2019004943A1/fr
Publication of EP3645566A1 publication Critical patent/EP3645566A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present disclosure relates to a therapy for the treatment of cutaneous T cell lymphoma, in particular mycosis fungoides and/or Sezary syndrome.
  • Cutaneous T cell lymphoma is a subclass of non-Hodgkin lymphoma. Unlike most non-Hodgkin lymphomas (which are generally B cell related), CTCL is caused by a mutation of T cells. The cancerous T cells in the body initially migrate to the skin, causing various lesions to appear. These lesions change shape as the disease progresses, typically beginning as what appears to be a rash, which can be very itchy, and eventually forming plaques and tumors before spreading to other parts of the body.
  • CTCL can be subdivided into mycosis fungoides and Sezary Syndrome.
  • Sezary syndrome is a rare, aggressive subtype of CTCL, a distinct form, but closely related to mycosis fungoides (MF).
  • Sezary syndrome is characterized by exfoliative erythroderma and significant numbers of circulating malignant T cells (Sezary cells). Sezary syndrome can also involve lymph nodes and visceral organs in some patients.
  • Mycosis fungoides also known as Alibert-Bazin syndrome or granuloma fungoides, is the most common form of cutaneous T-cell lymphoma. It generally affects the skin, but may progress internally over time. Symptoms include rash, tumors, skin lesions, and itchy skin. While the cause remains unclear, most cases are not hereditary. Most cases are in people over 20 years of age, and it is more common in men than women.
  • Mycosis fungoides can be treated in a variety of ways. Common treatments include simple sunlight, ultraviolet light, topical steroids, topical and systemic chemotherapies, local superficial radiotherapy, the histone deacetylase inhibitor vorinostat, total skin electron beam radiation, photopheresis and systemic therapies (e.g. interferons, retinoids, rexinoids) or biological therapies. Treatments are often used in combination.
  • Common treatments include simple sunlight, ultraviolet light, topical steroids, topical and systemic chemotherapies, local superficial radiotherapy, the histone deacetylase inhibitor vorinostat, total skin electron beam radiation, photopheresis and systemic therapies (e.g. interferons, retinoids, rexinoids) or biological therapies. Treatments are often used in combination.
  • Treatments may halt disease progression, and this is called stable disease. Stable disease may also last indefinitely but is a less satisfactory situation.
  • naloxone lotion a topical opioid receptor competitive antagonist used as a treatment for pruritus in cutaneous T-cell lymphoma.
  • a method of treating cutaneous T cell lymphoma comprising administering a therapeutically effective amount of an antagonist antibody or a binding fragment thereof specific to the IL-13 receptor to a patient in need thereof.
  • the antibody heavy chain has the sequence shown in SEQ ID NO: 10 or a sequence at least 95% identical thereto, in particular SEQ ID NO: 10.
  • lymphoma is mycosis fungoides.
  • lymphoma is Sezary syndrome
  • the further therapeutic agent is an anticancer agent, for example a chemotherapeutic agent or combination of chemotherapeutic agents, such as selected from the group comprising of a platin (such as cisplatin or oxaliplatin), gemcitabine, capecitabine, 5-FU, FOLFOX, FOLFIRI, FLOFIRINOX and a combination of two or more of the same.
  • a chemotherapeutic agent or combination of chemotherapeutic agents such as selected from the group comprising of a platin (such as cisplatin or oxaliplatin), gemcitabine, capecitabine, 5-FU, FOLFOX, FOLFIRI, FLOFIRINOX and a combination of two or more of the same.
  • the therapeutic agent is an immune modifying agent such as a cytokine, for example selected from the group comprising: IL-13, IL-12 and IL-2.
  • an immune modifying agent such as a cytokine, for example selected from the group comprising: IL-13, IL-12 and IL-2.
  • An antagonist antibody or binding fragment thereof specific to the IL-13 receptor for use in treating cutaneous T cell lymphoma.
  • an antagonist antibody or binding fragment for use according to any one of paragraph 28 to 32 wherein the antibody has a light chain variable domain comprising a CDR LI, CDR L2 and a CDR L3 with a sequence shown in SEQ ID NO: 5, 6 and 7 (or any one of sequences 39 to 52) respectively or a variable domain wherein one, two or three amino acids in the CDRs are independently added substituted or deleted.
  • an antagonist antibody or binding fragment for use according to any one of paragraphs 28 to 35 wherein the antibody has a heavy chain variable domain comprising a sequence shown in SEQ ID NO: 8 or a sequence at least 95% percent identical thereto (which retains specificity for IL-13 receptor, in particular IL-13 Ral).
  • an antagonist antibody or binding fragment for use according to paragraph 40 wherein the antibody heavy chain has the sequence shown in SEQ ID NO: 10 or a sequence at least 95% identical thereto, such as SEQ ID NO: 10.
  • lymphoma is mycosis fungoides.
  • an anti-cancer agent for example a chemotherapeutic agent or combination of chemotherapeutic agents, such as selected from the group comprising of a platin (such as cisplatin or oxaliplatin), gemcitabine, capecitabine, 5-FU, FOLFOX, FOLFIRI, FLOFIRINOX and a combination of two or more of the same.
  • a chemotherapeutic agent or combination of chemotherapeutic agents such as selected from the group comprising of a platin (such as cisplatin or oxaliplatin), gemcitabine, capecitabine, 5-FU, FOLFOX, FOLFIRI, FLOFIRINOX and a combination of two or more of the same.
  • an immune modifying agent such as a cytokine, for example selected from the group comprising: IL-13, IL-12 and IL-2.
  • an antagonist antibody or binding fragment according to any one of paragraphs 55 to 58, wherein the antibody or binding fragment has a heavy chain variable domain comprising a CDR HI, CDR H2 and a CDR H3 with a sequence shown in SEQ ID NO: 1, 2 and 3 or 4 (or any one of sequences 12 to 38) respectively or a variable domain where one, two or three amino acids in the CDRs are independently added, deleted or substituted.
  • an antagonist antibody or binding fragment according to any one of paragraphs 55 to 59, wherein the antibody has a heavy chain variable domain comprising a CDR LI, CDR L2 and a CDR L3 with a sequence shown in SEQ ID NO: 5, 6 and 7 (or any one of sequence 39 to 52) respectively or a sequence where one, two or three amino acids in the CDRs are independently added, deleted or substituted.
  • an antagonist antibody or binding fragment according to any one of paragraphs 55 to 60, wherein the antibody has a light chain variable domain comprising a sequence shown in SEQ ID NO: 9 or a sequence at least 95% percent identical thereto (which retains specificity for IL-13 receptor, in particular IL-13 Ral).
  • an antagonist antibody or binding fragment according to any one of paragraphs 55 to 62, wherein the antibody has a heavy chain variable domain comprising a sequence shown in SEQ ID NO: 8 or a sequence at least 95% percent identical thereto (which retains specificity for IL-13 receptor, in particular IL-13 Ral).
  • an antagonist antibody or binding fragment according to any one of paragraphs 55 to 64, wherein the antibody is human or humanized.
  • 66 Use of an antagonist antibody or binding fragment according to any one of paragraphs 55 to 65, wherein the antibody binding fragment is selected from the group comprises an Fv, dsFv, scFv, Fab, Fab' or F(ab') 2 fragment.
  • an antagonist antibody or binding fragment according to paragraph 77 wherein the further therapeutic agent is an anti-cancer agent, for example a chemotherapeutic agent or combination of chemotherapeutic agents, such as selected from the group comprising of a platin (such as cisplatin or oxaliplatin), gemcitabine, capecitabine, 5-FU, FOLFOX, FOLFIRI, FLOFIRINOX and a combination of two or more of the same.
  • a chemotherapeutic agent or combination of chemotherapeutic agents such as selected from the group comprising of a platin (such as cisplatin or oxaliplatin), gemcitabine, capecitabine, 5-FU, FOLFOX, FOLFIRI, FLOFIRINOX and a combination of two or more of the same.
  • the IL13-Rlal antibody or binding fragment employed in the f the present disclosure comprises a CDRH3 independently selected from a sequence comprising SEQ ID NO: 13 to 38.
  • the anti-IL13R antibody or binding fragment employed in the present disclosure comprises a VH CDR1 comprising an amino acid sequence as set forth in SEQ ID NO: 1
  • VH CDR2 comprising an amino acid sequence as set forth in SEQ ID NO: 2
  • VH VH CDR2 comprising an amino acid sequence as set forth in SEQ ID NO: 2
  • CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 3 or 12.
  • the anti-IL13R antibody or binding fragment employed in the present disclosure comprises a CDRH1 comprising an amino acid sequence as set forth in SEQ ID NO: 1, a CDRH2 comprising an amino acid sequence as set forth in SEQ ID NO: 2, and a CDRH3 comprising an amino acid sequence as set forth in SEQ ID NO: 4, 13, 14, 15, 16, 17, 18, 19, 20,
  • the anti-IL13R antibody or binding fragment employed in the present disclosure comprises a CDRH1 comprising an amino acid sequence as set forth in SEQ ID NO: 1, a CDRH2 comprising an amino acid sequence as set forth in SEQ ID NO: 2, and a CDRH3 comprising an amino acid sequence as set forth in SEQ ID NO: 4.
  • CDRLl is an amino acid sequence comprising SEQ ID NO: 5.
  • CDRL2 is an amino acid sequence comprising SEQ ID NO: 6.
  • CDL3 comprises SEQ ID NO: 39
  • the IL-13Ral antibody employed in the formulation of the present disclosure comprises a CDRL3 independently selected from a sequence comprising SEQ ID NO:
  • the anti-IL-13 Ra antibody or binding fragment employed in the present disclosure comprises a CDRLl comprising an amino acid sequence SEQ ID NO: 5, a CDRL2 comprising an amino acid sequence SEQ ID NO: 6, and a CDRL3 comprising an amino acid sequence as set forth in SEQ ID NO:39.
  • the anti-IL-13Ra antibody of the present disclosure comprises a VL CDRLl comprising an amino acid sequence SEQ ID NO: 5, CDRL2 comprising an amino acid sequence SEQ ID NO: 6, and a CDRL3 comprising an amino acid sequence as set forth in SEQ ID NO: 7, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52.
  • the anti-IL-13Ra antibody of the present disclosure comprises a CDRLl comprising an amino acid sequence SEQ ID NO: 31, a CDRL2 comprising an amino acid sequence SEQ ID NO: 6, and a CDRL3 comprising an amino acid sequence as set forth in SEQ ID NO: 7.
  • the anti-IL13R antibody of the present disclosure comprises a CDRH1 comprising an amino acid sequence as set forth in SEQ ID NO: 1, a CDRH2 comprising an amino acid sequence as set forth in SEQ ID NO: 2, and a CDRH3 comprising an amino acid sequence as set forth in SEQ ID NO: or 3 or 12, a CDRLl comprising an amino acid sequence SEQ ID NO: 5, a CDRL2 comprising an amino acid sequence SEQ ID NO: 6, and a CDRL3 comprising an amino acid sequence as set forth in SEQ ID NO: 39.
  • the anti-IL13R antibody of the present disclosure comprises a CDRH1 comprising an amino acid sequence as set forth in SEQ ID NO: 1, a CDRH2 comprising an amino acid sequence as set forth in SEQ ID NO: 2, and a CDRH3 comprising an amino acid sequence as set forth in SEQ ID NO: 3, 4 or 12, a CDRLl comprising an amino acid sequence SEQ ID NO: 5, a CDRL2 comprising an amino acid sequence SEQ ID NO: 6, and a CDRL3 comprising an amino acid sequence as set forth in SEQ ID NO: 7, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52.
  • the anti-IL13R antibody of the present disclosure comprises a CDRH1 comprising an amino acid sequence as set forth in SEQ ID NO: 1, a CDRH2 comprising an amino acid sequence as set forth in SEQ ID NO: 2, and a CDRH3 comprising an amino acid sequence as set forth in SEQ ID NO: 3, 4 or 12, a CDRLl comprising an amino acid sequence SEQ ID NO: 5, a CDRL2 comprising an amino acid sequence SEQ ID NO: 6, and a CDRL3 comprising an amino acid sequence as set forth in SEQ ID NO: 7.
  • the anti-IL13R antibody of the present disclosure comprises a CDRH1 comprising an amino acid sequence as set forth in SEQ ID NO: 1, a CDRH2 comprising an amino acid sequence as set forth in SEQ ID NO: 2, and a CDRH3 comprising an amino acid sequence as set forth in SEQ ID NO: 4, a CDRLl comprising an amino acid sequence SEQ ID NO: 5, a CDRL2 comprising an amino acid sequence SEQ ID NO: 6, and a CDRL3 comprising an amino acid sequence as set forth in SEQ ID NO: 7.
  • the VH region is independently selected from a sequence comprising SEQ ID NO: 8, 53, 54 or 55.
  • the VL is independently selected from a sequence comprising SEQ ID NO: 56, 57 or 58.
  • the VH sequence is SEQ ID NO: 53 (or a sequence at least 95% identical thereto) and the VL sequence is SEQ ID NO: 56, SEQ ID NO: 9 or 57, SEQ ID NO: 58 or SEQ ID NO: 55 (or a sequence at least 95% identical to any one of the same).
  • the VH sequence is SEQ ID NO: 54 (or a sequence at least 95% identical thereto) and the VL sequence is SEQ ID NO: 9; SEQ ID NO: 56, SEQ ID NO: 57, or SEQ ID NO: 58 (or a sequence at least 95% identical to any one of the same).
  • the VH sequence is SEQ ID NO: 55 (or a sequence at least 95% identical thereto) and the VL sequence is SEQ ID NO: 9; SEQ ID NO: 56, SEQ ID NO: 57, or SEQ ID NO: 58 (or a sequence at least 95% identical to any one of the same).
  • the VH sequence is SEQ ID NO: 8 (or a sequence at least 95% identical thereto) and the VL sequence is SEQ ID NO: 9, SEQ ID NO: 56, SEQ ID NO: 57, or SEQ ID NO: 58 (or a sequence at least 95% identical to any one of the same).
  • the VL sequence is SEQ ID NO: 56 (or a sequence at least 95% identical thereto) and the VH sequence is SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55 or SEQ ID NO: 8. (or a sequence at least 95% identical to any one of the same)
  • the VL sequence is SEQ ID NO: 9 or 57 (or a sequence at least 95% identical thereto) and the VH sequence is SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55 or SEQ ID NO: 8 (or a sequence at least 95% identical to any one of the same).
  • the VL sequence is SEQ ID NO: 58 (or a sequence at least 95% identical thereto) and the VH sequence is SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55 or SEQ ID NO: 8 (or a sequence at least 95% identical to any one of the same).
  • the VH sequence is SEQ ID NO: 8 (or a sequence at least 95% identical thereto) and the VL sequence is SEQ ID NO: 9 or 57((or a sequence at least 95% identical thereto).
  • Variable region as employed herein refers to the region in an antibody chain comprising the CDRs and a suitable framework.
  • SEQ ID NO: 10 SEQ ID NO: 10, 59, 60, 61, 62, 63, 64 or a sequence at least 95% identical to any one of the same.
  • the light chain is independently selected from SEQ ID NO: 11, SEQ ID NO: 65, SEQ ID NO: 66 or a sequence at least 95% identical to any one of the same.
  • the heavy chain is independently selected from SEQ ID NO: 10, 59, 60, 61, 62, 63 and 64 (or a sequence at least 95% identical to any one of the same) and the light chain is independently selected from SEQ ID NO: 11, 65 and 66 (or a sequence at least 95% identical to any one of the same).
  • the heavy chain is SEQ ID NO: 10 (or a sequence at least 95% identical thereto) and the light chain is independently selected from SEQ ID NO: 11, 65 and 66 (or a sequence at least 95% identical to any one of the same).
  • the heavy chain is SEQ ID NO: 59 (or a sequence at least 95% identical thereto) and the light chain is independently selected from SEQ ID NO: 11, 65 and 66 (or a sequence at least 95% identical to any one of the same).
  • the heavy chain is SEQ ID NO: 60 (or a sequence at least 95% identical thereto) and the light chain is independently selected from SEQ ID NO: 11, 65 and 66 (or a sequence at least 95% identical to any one of the same).
  • the heavy chain is SEQ ID NO: 61 (or a sequence at least 95% identical thereto) and the light chain is independently selected from SEQ ID NO: 11, 65 and 66 (or a sequence at least 95% identical to any one of the same).
  • the heavy chain is SEQ ID NO: 62 (or a sequence at least 95% identical thereto) and the light chain is independently selected from SEQ ID NO: 11, 65 and 66 (or a sequence at least 95% identical to any one of the same). In one embodiment the heavy chain is SEQ ID NO: 63 (or a sequence at least 95% identical thereto) and the light chain is independently selected from SEQ ID NO: 11, 65 and 66 (or a sequence at least 95% identical to any one of the same).
  • the heavy chain is SEQ ID NO: 64 (or a sequence at least 95% identical thereto) and the light chain is independently selected from SEQ ID NO: 11, 65 and 66 (or a sequence at least 95% identical to any one of the same).
  • the heavy chain is SEQ ID NO: 62 or 64 (or a sequence at least 95% identical to any one of the same) and a light chain with the sequence shown in SEQ ID NO: 11 (or a sequence at least 95% identical thereto).
  • the heavy chain is SEQ ID NO: 62 (or a sequence at least 95% identical to any one of the same) and a light chain with the sequence shown in SEQ ID NO: 11 (or a sequence at least 95% identical thereto).
  • the heavy chain is SEQ ID NO: 64 (or a sequence at least 95% identical to any one of the same) and a light chain with the sequence shown in SEQ ID NO: 11 (or a sequence at least 95% identical thereto).
  • the heavy chain is SEQ ID NO: 10 (or a sequence at least 95% identical to any one of the same) and a light chain with the sequence shown in SEQ ID NO: 11 (or a sequence at least 95% identical thereto).
  • Figure 1 ASLAN004 anti-tumor activity in a sample from a patient with primary CTCL.
  • Figure 2 Shows expression of IL-13Ral as determined by flow cytometry in Hut-78 cells
  • Figure 3 Shows ASLAN004 Anti-tumour activity in HUT-78 cells
  • Xaa is: Phe or Leu
  • Xbb is: His, Tyr, Thr, or Ser
  • XI denotes Phe, Met, Gin, Leu or Val
  • X6 denotes Ser or Ala
  • X7 denotes Phe, Leu, Ala or Met
  • X9 denotes Tyr, Gin, Lys, Arg, Trp, His, Ala, Thr, Ser, Asn or Gly SEQ ID NO: 39 CDRL3 GI11 X2X3X4X5
  • X2 denotes Gin, Arg, Met, Ser, Thr or Val.
  • X3 denotes Tyr or Val.
  • X4 denotes Glu, Ala, Gly or Ser.
  • X5 denotes Thr, Ala or Ser.
  • Cutaneous T cell lymphoma refers to a rare type of non-Hodgkin lymphoma that affects the skin. It is caused by white blood cells, called T-cell lymphocytes, growing in an uncontrolled way, for example causing raised, rash-like or itchy patches of skin, lumps on the skin and/or swollen lymph nodes. As mentioned above it can be divided into mycosis fungoides, Sezary Syndrome, CD30+ cutaneous T-cell lymphoma and extranodal NK/T- cell lymphoma (nasal type).
  • Sezary Syndrome is a rare and aggressive type of cutaneous T cell lymphoma, which is closely related to mycosis fungoides. As mentioned above patients have exfoliative erythroderma and significant numbers of circulating malignant T cells (Sezary cells). The condition can also involve the lymph nodes and visceral organs.
  • Sezary Syndrome can develop from mycosis fungoides or the full symptoms may develop de novo.
  • Mycosis fungoides also known as Alibert-Bazin syndrome or granuloma fungoides, is the most common form of cutaneous T-cell lymphoma. It generally affects the skin but may progress internally over time. Symptoms include rash, tumors, skin lesions, and itchy skin. Pagetoid reticulosis (also known as “acral mycoses fungoides”, “localized epidermotropic reticulosis”, “mycosis fungoides palmaris et plantaris”, “unilesional mycosis fungoides", and "Woringer-Kolopp disease”) can be considered to be a form of mycosis fungoides.
  • the disease is an unusual expression of CD4 T cells. These T cells are skin-associated, meaning that they biochemically and biologically are most related to the skin, in a dynamic manner. Diagnosis is sometimes difficult because the early phases of the disease often resemble eczema or even psoriasis. Diagnosis is generally accomplished through a skin biopsy. Several biopsies are recommended, to be more certain of the diagnosis. The diagnosis is made through a combination of the clinical picture and examination and is confirmed by biopsy.
  • Premycotic is a phase of mycosis fungoides in which a patient has areas of red, scaly, itchy skin on areas of the body that are not usually exposed to sun. This early-phase mycosis fungoides is hard to diagnose. The premycotic phase may last from months to decades.
  • Secondary cutaneous CD30+ large-cell lymphoma is a cutaneous condition that may arise in cases of mycosis fungoides, and in patients with lymphomatoid papulosis.
  • T describes how much of the skin is affected by the lymphoma (tumor).
  • N describes the extent of the lymphoma in the lymph nodes.
  • M is for the spread (metastasis) of the lymphoma to other organs.
  • B is for lymphoma cells in the blood.
  • Skin lesions can be small patches (flat lesions), papules (small bumps), and/or plaques (raised or lowered, flat lesions), but the lesions cover less than 10% of the skin surface.
  • T2 The patches, papules, and/or plaques cover 10% or more of the skin surface.
  • T3 At least one of the skin lesions is a tumor that is at least 1 centimeter (cm) across (a cm is a little less than 1/2 inch).
  • T4 The skin lesions have spread, grown larger, and grown together to cover at least 80% of the skin surface.
  • Lymph nodes are not enlarged and a lymph node biopsy is not needed.
  • Nl Lymph nodes are enlarged, but the patterns of cells look normal or close to normal under the microscope.
  • N2 Lymph nodes are enlarged, and the patterns of cells look more abnormal under the microscope.
  • N3 Lymph nodes are enlarged, and the patterns of cells look very abnormal under the microscope.
  • NX Lymph nodes are enlarged but haven't been removed (biopsied) to be looked at under the microscope.
  • MO The lymphoma cells have not spread outside the skin or lymph nodes.
  • Ml Lymphoma cells have spread to other organs or tissues, such as the liver or spleen.
  • B categories
  • Bl Low numbers of Sezary cells in the blood (more than in B0 but less than in B2).
  • stage grouping Once the values for T, N, M, and B are known, they are combined to determine the overall stage of the lymphoma. This process is called stage grouping.
  • Stage IA Tl, NO, M0, B0 or Bl.
  • Skin lesions cover less than 10% of the skin surface (Tl), the lymph nodes are not enlarged (NO), lymphoma cells have not spread to other organs or tissues (M0), and the number of Sezary cells in the blood is not high (B0 or Bl).
  • Stage IB T2, NO, MO, BO or Bl. There are skin lesions but no tumors. Skin lesions cover at least 10% of the skin surface (T2), the lymph nodes are not enlarged (NO), lymphoma cells have not spread to other organs or tissues (MO), and the number of Sezary cells in the blood is not high (BO or Bl).
  • Stage IIA Tl or T2, Nl or N2, MO, BO or Bl.
  • Skin lesions can cover up to 80% of the skin surface (Tl or T2). Lymph nodes are enlarged but the patterns of cells do not look very abnormal under the microscope (Nl or N2). Lymphoma cells have not spread to other organs or tissues (M0), and the number of Sezary cells in the blood is not high (B0 or Bl).
  • Stage IIB T3, NO to N2, MO, BO or Bl.
  • At least one of the skin lesions is a tumor that is 1 cm across or larger (T3).
  • the lymph nodes are either normal (NO) or are enlarged but the patterns of cells do not look very abnormal under the microscope (Nl or N2). Lymphoma cells have not spread to other organs or tissues (M0), and the number of Sezary cells in the blood is not high (B0 or Bl).
  • Stage IIIA T4, NO to N2, MO, BO.
  • Skin lesions cover at least 80% of the skin surface (T4).
  • the lymph nodes are either normal
  • Lymphoma cells have not spread to other organs or tissues (M0), and there are few
  • Stage IIIB T4, NO to N2, MO, Bl
  • Skin lesions cover at least 80% of the skin surface (T4).
  • the lymph nodes are either normal
  • Lymphoma cells have not spread to other organs or tissues (M0), and the number of Sezary cells in the blood is low (Bl).
  • Stage IVA1 any T, NO to N2, MO, B2.
  • Skin lesions can cover any amount of the skin surface (any T).
  • the lymph nodes are either normal (NO) or are enlarged, but the patterns of cells do not look very abnormal under the microscope (Nl or N2). Lymphoma cells have not spread to other organs or tissues (M0), and the number of Sezary cells in the blood is high (B2).
  • Stage IVA2 any T, N3, MO, any B.
  • Skin lesions can cover any amount of the skin surface (any T). Some lymph nodes are enlarged and the patterns of cells look very abnormal under the microscope (N3). Lymphoma cells have not spread to other organs or tissues (M0). Sezary cells may or may not be in the blood (any B).
  • Stage IVB any T, any N, Ml, any B
  • Skin lesions can cover any amount of the skin surface (any T).
  • the lymph nodes may be normal or abnormal (any N), and Sezary cells may or may not be in the blood (any B). Lymphoma cells have spread to other organs or tissues, such as the liver or spleen (Ml).
  • T describes how much of the skin is affected by the lymphoma (tumor).
  • ⁇ N describes the extent of the lymphoma in the lymph nodes.
  • M is for the spread (metastasis) of the lymphoma to other organs.
  • lymphomas only the T category is used at the time of diagnosis. If sites besides the skin (such as lymph nodes) are involved at the time of diagnosis, these lymphomas are no longer considered skin lymphomas and are staged like regular non-Hodgkin lymphoma.
  • the N and M categories are only used if the lymphoma progresses (continues to grow) during treatment or comes back after treatment.
  • Tl There is only a single skin lesion.
  • Tla The skin lesion is less than 5 cm (about 2 inches) across.
  • Tib The skin lesion is larger than 5 cm across.
  • T2 There are 2 or more lesions on the skin. These may be in a single body region or in 2 body regions that are next to each other.
  • T2a All of the skin lesions could be placed within a circle that is 15 cm (about 6 inches) across.
  • T2b The circle needed to surround all of the skin lesions is larger than 15 cm across, but smaller than 30 cm (about 1 foot) across.
  • T2c The circle needed to surround all of the skin lesions is larger than 30 cm across.
  • T3 There are skin lesions in body regions that aren't next to each other, or in at least 3 different body regions.
  • T3a There are many lesions involving 2 body regions that aren't next to each other.
  • T3b There are many lesions involving 3 or more body regions.
  • lymph node is enlarged or contains lymphoma cells.
  • lymphoma cells There are lymphoma cells in the lymph nodes that drain an area where skin contained lymphoma.
  • lymphoma cells At least 2 sets of lymph nodes from different areas contain lymphoma cells.
  • lymphoma cells in lymph nodes that do not drain areas where the skin contained lymphoma.
  • N3 Lymph nodes deep inside the chest or abdomen contain lymphoma cells.
  • M0 No signs of lymphoma outside of the skin or lymph nodes.
  • Ml Lymphoma has spread to other organs or tissues. This system does not assign an overall stage to the lymphoma, as the system for mycosis fungoides/Sezary syndrome does. Because this system is still fairly new, it's not yet clear how well it can help predict a person's prognosis (outlook).
  • IL-13 receptor as employed herein is a type I cytokine receptor with two subunit IL-13Ral (Uniprot number P78552) and IL4Ra (Q9H186). These form a dimer with IL-13.
  • the signal ly occurs via activation of the JAK/Signal Transducer and Activator of Transcription (STAT) pathway.
  • the IL-13 receptor can also instigate IL-4 signalling.
  • Antagonist refers to the reduction or inhibition of a biological activity or function, such as a physiological antagonist, in particular blocking or reducing actions of the JAK/signal Transducer and Activator of Transcription pathway.
  • Antibody as employed herein includes substantially intact antibody molecules, as well as chimeric antibodies, humanised antibodies, human antibodies (wherein at least one amino acid is mutated relative to the naturally occurring human antibodies), single chain antibodies (such as antibody heavy chains, antibody light chains), multispecific antibodies (such as bispecific antibodies), homodimers and heterodimers of antibody heavy and/or light chains, and may also include antigen binding fragments and derivatives of the same, unless the context indicates otherwise.
  • the antibody or binding fragment thereof is monoclonal.
  • Antigen-binding fragment is employed herein to refer to a functional fragment of an antibody that is capable of binding to the antigen to which it is specific.
  • Antibody binding fragment, antigen binding fragment and binding fragment are employed interchangeably herein unless the context indicates otherwise.
  • antibody binding fragments include to Fab, modified Fab, Fab', modified Fab', F(ab') 2 , Fv, Fab-Fv, Fab-dsFv, single domain antibodies (e.g. VH or VL or VHH), scFv, bi, tri or tetra-valent antibodies, Bis-scFv, diabodies, triabodies, tetrabodies and epitope-binding fragments of any of the above (see for example Holliger and Hudson, 2005, Nature Biotech. 23(9):1126-1136; Adair and Lawson, 2005, Drug Design Reviews - Online 2(3), 209-217).
  • antibody fragments for use in the present invention include the Fab and Fab' fragments described in International patent applications WO2005/003169, WO2005/003170 and WO2005/003171.
  • Examples of a multispecific antibody comprising a full-length antibody include a DVD-Ig, IgG- scFv, scFv-IgG, and IgG-V.
  • IgG-scFv as employed herein is a full-length antibody with a scFv on the C-terminal of each of the heavy chains or each of the light chains.
  • scFv-IgG as employed herein is a full-length antibody with a scFv on the N-terminal of each of the heavy chains or each of the light chains.
  • V-IgG as employed herein is a full-length antibody with a variable domain on the N- terminal of each of the heavy chains or each of the light chains.
  • IgG-V as employed herein is a full- length antibody with a variable domain on the C- terminal of each of the heavy chains or each of the light chains
  • DVD-Ig (also known as dual V domain IgG) is a fulllength antibody with 4 additional variable domains, one on the N-terminus of each heavy and each light chain.
  • the antibody binding fragment is or comprises a Fab or Fab' fragment.
  • Antibody binding fragments that comprise a Fab or Fab' fragment include Fabdab, Fab'dab, FabFv, Fab'Fv, FabdsFv, Fab-scFv, Fab'-scFv, Fab-(scFv)2, Fab'-(scFv)2, DiFab, DiFab'.
  • Fabdab as employed herein refers to a Fab fragment with a domain antibody appended to the heavy or light chain thereof, optionally via a linker.
  • Fab'dab as employed herein refers to a Fab' fragment with a domain antibody appended to the heavy or light chain thereof, optionally via a linker.
  • FabFv refers to a Fab fragment with an additional variable region appended to the C-terminal of each of the following, the CHI of the heavy chain and CL of the light chain see for example WO2009/040562.
  • the format may be provided as a PEGylated version thereof see for example WO2011/061492,
  • Fab'Fv as employed herein is similar to FabFv, wherein the Fab portion is replaced by a
  • the format may be provided as a PEGylated version thereof.
  • FabdsFv refers to a FabFv wherein an intra-Fv disulfide bond stabilises the appended C-terminal variable regions, see for example WO2010/035012.
  • the format may be provided as a PEGylated version thereof Fab-scFv (also referred to as a bibody) as employed herein is a Fab molecule with a scFv appended on the C-terminal of the light or heavy chain, optionally via a linker.
  • Fab'-scFv as employed herein is a Fab' molecule with a scFv appended on the C-terminal of the light or heavy chain, optionally via a linker.
  • DiFab as employed herein refers to two Fab molecules linked via their C-terminus of the heavy chains.
  • DiFab' as employed herein refers to two Fab' molecules linked via one or more disulfide bonds in the hinge region thereof.
  • DiFab and DiFab' molecules include chemically conjugated forms thereof.
  • Antibodies and binding fragments according to the present disclosure refers to modified antibodies which retain the specificity to the antigen (target-antigen), i.e. which are specificity for the IL-13 receptor, in particular the IL-13Ral receptor.
  • target-antigen i.e. which are specificity for the IL-13 receptor, in particular the IL-13Ral receptor.
  • One, two, three amino acids changed in the CDRs refers to no more than a total of three amino acids changed in the CDRs of a variable domain. It does not refer to up to three amino acids changes in each of the CDRs of a given variable domain.
  • Modified variable domains with at least 95% (such as 96, 97, 98, 99%) identity to a sequence explicitly disclosed herein form an aspect of the present disclosure. These modified variable domains retain specificity to the antigen (target-antigen), i.e. which are specific for the IL-13 receptor, in particular the IL-13Ral receptor.
  • Specific to a target antigen as employed herein refers to the fact that the antibody or binding fragment only binds the antigen to which it is specific or binds the antigen to which it is specific with greater affinity, for 2, 3, 4, 5 times greater affinity or more in comparison to the affinity to a substance or antigen to which it is non-specific.
  • the binding affinity (KD) of the antibody or bindings fragments of the present disclosure is 1 nM or less, such as 0.5 nM, 0.3 nM or 0.2 nM. In one embodiment, the binding affinity is ⁇ 254 pM.
  • Antibodies and binding fragments may be referred to herein as "active".
  • 'pharmaceutical formulation refers to a therapeutically effective formulation comprising an antibody or binding fragment thereof and pharmaceutically acceptable diluent, excipient and/or carrier.
  • a 'therapeutically effective amount', or 'effective amount', or 'therapeutically effective', as used herein, refers to that amount which provides a therapeutic effect for a given condition and administration regimen. This is a predetermined quantity of active material calculated to produce a desired therapeutic effect in association with the required additive and diluent, i.e. a carrier or administration vehicle. Further, it is intended to mean an amount sufficient to reduce and/or prevent, a clinically significant deficit in the activity, function and response of the host/patient. Alternatively, a therapeutically effective amount is sufficient to cause an improvement in a clinically significant condition in a host/patient.
  • an active agent such as an antibody or binding fragment according to the present disclosure
  • Suitable dosage amounts may contain a predetermined quantity of active composition calculated to produce the desired therapeutic effect in association with the required diluent.
  • a therapeutically effective amount of the active component is provided, for example as a unit dose.
  • a therapeutically effective amount can be determined by the ordinary skilled medical or veterinary worker based on patient characteristics, such as age, weight, sex, condition, complications, other diseases, etc., as is well known in the art.
  • the patient is a human.
  • payloads as used herein includes, for example, biologically active proteins, such as enzymes, other antibody or antibody binding fragments, synthetic or naturally occurring polymers, nucleic acids and fragments thereof e.g. DNA, RNA and fragments thereof, radionuclides, particularly radioiodide, radioisotopes, chelated metals, nanoparticles and reporter groups such as fluorescent compounds or compounds which may be detected by NMR or ESR spectroscopy.
  • biologically active proteins such as enzymes, other antibody or antibody binding fragments, synthetic or naturally occurring polymers
  • nucleic acids and fragments thereof e.g. DNA, RNA and fragments thereof
  • radionuclides particularly radioiodide, radioisotopes, chelated metals, nanoparticles and reporter groups
  • fluorescent compounds or compounds which may be detected by NMR or ESR spectroscopy such as fluorescent compounds or compounds which may be detected by NMR or ESR spectroscopy.
  • the payload is a toxin, for example elected from calicheamicin, aplidin, anastrozole, azacytidine, bortezomib, bryostatin-1, busulfan, combrestatins, carmustine, dolastatins, epothilones, staurosporin, maytansinoids, spongistatins, rhizoxin, halichondrins, roridins, hemiasterlins, taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1- dehydrotestosterone, glucocorticoids, procaine,
  • the payload is a drug, for example selected from nitrogen mustard, ethylenimine derivative, alkyl sulfonates, nitrosourea, gemcitabine, triazene, folic acid analog, anthracycline, taxane, COX-2 inhibitor, pyrimidine analog, purine analog, antibiotic, enzyme inhibitor, epipodophyllotoxin, platinum coordination complex, vinca alkaloid, substituted urea, methyl hydrazine derivative, adrenocortical suppressant, hormone antagonist, endostatin, taxol, camptothecin, doxorubicin, doxorubicin analog, antimetabolite, alkylating agent, antimitotic, anti-angiogenic agent, tyrosine kinase inhibitor, mTOR inhibitor, heat shock protein (HSP90) inhibitor, proteosome inhibitor, HDAC inhibitor, pro-apoptotic agent, methotrexate, CPT-11, amifostine, cisplatin, daca
  • methotrexate 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine
  • alkylating agents e.g. mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU) and lomustine (CCNU)
  • cyclothosphamide busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP) cisplatin
  • carboplatin anthracyclines [e.g.
  • daunorubicin (formerly daunomycin) and doxorubicin or doxorubicin glucuronide), antibiotics [e.g. dactinomycin (formerly actinomycin), bleomycin, mithramycin, anthramycin (AMC), calicheamicins or duocarmycins), and anti-mitotic agents [e.g. vincristine and vinblastine), an auristatin (US5,635,483; US5,780,588), for example, MMAE (monomethyl auristatin E) or MMAF (monomethyl auristatin F).
  • antibiotics e.g. dactinomycin (formerly actinomycin), bleomycin, mithramycin, anthramycin (AMC), calicheamicins or duocarmycins
  • anti-mitotic agents e.g. vincristine and vinblastine
  • an auristatin (US5,635,483; US5,780
  • the drug is a dolastatin or dolastatin peptidic analog or derivative, a maytansinoid.
  • the maytansinoid is N 2'-deacetyl-N 2'-(3-mercapto-l-oxopropyl)-maytansine (DM1), N 2'-deacetyl-N2'-(4- mercapto-l-oxopentyl)-maytansine (DM3) or N 2'-deacetyl-N 2'(4-methyl-4-mercapto-l- oxopentyl)-maytansine (DM4).
  • Maytansinoids are mitotic inhibitors which act by inhibiting tubulin polymerization. Maytansine was first isolated from the east African shrub Maytenus serrata (U.S. Pat. No. 3,896,111), tubulysin
  • payloads may include chelated radionuclides such as lllln and 90Y, Lul77, Bismuth213, Californium252, Iridiuml92 and Tungstenl88/Rheniuml88; or drugs such as but not limited to, alkylphosphocholines, topoisomerase I inhibitors, taxoids and suramin.
  • chelated radionuclides such as lllln and 90Y, Lul77, Bismuth213, Californium252, Iridiuml92 and Tungstenl88/Rheniuml88
  • drugs such as but not limited to, alkylphosphocholines, topoisomerase I inhibitors, taxoids and suramin.
  • proteins, peptides and enzymes include proteins, peptides and enzymes.
  • Enzymes of interest include, but are not limited to, proteolytic enzymes, hydrolases, lyases, isomerases, transferases.
  • Proteins, polypeptides and peptides of interest include, but are not limited to, immunoglobulins, toxins such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin, a protein such as insulin, tumour necrosis factor, a-interferon, ⁇ -interferon, nerve growth factor, platelet derived growth factor or tissue plasminogen activator, a thrombotic agent or an anti-angiogenic agent, e.g.
  • angiostatin or endostatin or, a biological response modifier such as a lymphokine, interleukin- 1 (IL-1), interleukin-2 (IL-2), granulocyte macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), nerve growth factor (NGF) or other growth factor and immunoglobulins.
  • IL-1 interleukin- 1
  • IL-2 interleukin-2
  • GM-CSF granulocyte macrophage colony stimulating factor
  • G-CSF granulocyte colony stimulating factor
  • NGF nerve growth factor
  • Other payloads may include detectable substances useful for example in diagnosis.
  • detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, radioactive nuclides, positron emitting metals (for use in positron emission tomography), and nonradioactive paramagnetic metal ions. See generally U.S. Patent No. 4,741,900 for metal ions which can be conjugated to antibodies for use as diagnostics.
  • Suitable enzymes include horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase; suitable prosthetic groups include streptavidin, avidin and biotin; suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride and phycoerythrin; suitable luminescent materials include luminol; suitable bioluminescent materials include luciferase, luciferin, and aequorin; and suitable radioactive nuclides include 1251, 1311, lllln and 99Tc.
  • the payload may increase the half-life of the antibody in vivo, and/or reduce immunogenicity of the antibody and/or enhance the delivery of an antibody across an epithelial barrier to the immune system.
  • suitable effector molecules of this type include polymers, albumin, albumin binding proteins or albumin binding compounds such as those described in WO05/117984.
  • the effector molecule is a polymer it may, in general, be a synthetic or a naturally occurring polymer, for example an optionally substituted straight or branched chain polyalkylene, polyalkenylene or polyoxyalkylene polymer or a branched or unbranched polysaccharide, e.g. a homo- or hetero- polysaccharide.
  • Specific optional substituents which may be present on the above-mentioned synthetic polymers include one or more hydroxy, methyl or methoxy groups.
  • Specific examples of synthetic polymers include optionally substituted straight or branched chain poly(ethyleneglycol), poly(propyleneglycol) poly(vinylalcohol) or derivatives thereof, especially optionally substituted poly(ethyleneglycol) such as methoxypoly(ethyleneglycol) or derivatives thereof.
  • Specific naturally occurring polymers include lactose, amylose, dextran, glycogen or derivatives thereof.
  • Derivatives as used herein is intended to refer to modified molecules (such as polymbers) which retain the essential characteristics of the original molecule including reactive derivatives, for example thiol-selective reactive groups such as maleimides and the like.
  • the reactive group may be linked directly or through a linker segment to the polymer. It will be appreciated that the residue of such a group will in some instances form part of the product as the linking group between the antibody fragment and the polymer.
  • the size of the polymer may be varied as desired but will generally be in an average molecular weight range from 500Da to 50000Da, for example from 5000 to 40000Da such as from 20000 to 40000Da.
  • the polymer size may in particular be selected on the basis of the intended use of the product, for example ability to localize to certain tissues such as tumors or extend circulating half-life (for review see Chapman, 2002, Advanced Drug Delivery Reviews, 54, 531-545).
  • the product is intended to leave the circulation and penetrate tissue, for example for use in the treatment of a tumour
  • a small molecular weight polymer for example with a molecular weight of around 5000Da
  • a higher molecular weight polymer for example having a molecular weight in the range from 20000Da to 40000Da.
  • Suitable polymers include a polyalkylene polymer, such as a poly(ethyleneglycol) or, especially, a methoxypoly(ethyleneglycol) or a derivative thereof, and especially with a molecular weight in the range from about 15000Da to about 40000Da.
  • antibodies for use in the present invention are attached to poly(ethyleneglycol) (PEG) moieties.
  • the antibody is an antibody fragment and the PEG molecules may be attached through any available amino acid side-chain or terminal amino acid functional group located in the antibody fragment, for example any free amino, imino, thiol, hydroxyl or carboxyl group.
  • Such amino acids may occur naturally in the antibody fragment or may be engineered into the fragment using recombinant DNA methods (see for example US 5,219,996; US 5,667,425; W098/25971, WO2008/038024).
  • the antibody molecule of the present invention is a modified Fab fragment wherein the modification is the addition to the C-terminal end of its heavy chain one or more amino acids to allow the attachment of an effector molecule.
  • the additional amino acids form a modified hinge region containing one or more cysteine residues to which the effector molecule may be attached.
  • Multiple sites can be used to attach two or more PEG molecules.
  • PEG molecules are covalently linked through a thiol group of at least one cysteine residue located in the antibody fragment.
  • Each polymer molecule attached to the modified antibody fragment may be covalently linked to the sulphur atom of a cysteine residue located in the fragment.
  • the covalent linkage will generally be a disulphide bond or, in particular, a sulphur-carbon bond.
  • a thiol group is used as the point of attachment
  • appropriately activated effector molecules for example thiol selective derivatives such as maleimides and cysteine derivatives may be used.
  • An activated polymer may be used as the starting material in the preparation of polymer-modified antibody fragments as described above.
  • the activated polymer may be any polymer containing a thiol reactive group such as an a-halocarboxylic acid or ester, e.g. iodoacetamide, an imide, e.g. maleimide, a vinyl sulphone or a disulphide.
  • Such starting materials may be obtained commercially (for example from Nektar, formerly Shearwater Polymers Inc., Huntsville, AL, USA) or may be prepared from commercially available starting materials using conventional chemical procedures.
  • Particular PEG molecules include 20K methoxy-PEG-amine (obtainable from Nektar, formerly Shearwater; Rapp Polymere; and SunBio) and M-PEG-SPA (obtainable from Nektar, formerly Shearwater).
  • the antibody is a modified Fab fragment or diFab which is PEGylated, i.e. has PEG (poly(ethyleneglycol)) covalently attached thereto, e.g. according to the method disclosed in EP 0948544 or EP1090037 [see also “Poly(ethyleneglycol) Chemistry, Biotechnical and Biomedical Applications", 1992, J. Milton Harris (ed), Plenum Press, New York, “Poly(ethyleneglycol) Chemistry and Biological Applications", 1997, J. Milton Harris and S. Zalipsky (eds), American Chemical Society, Washington DC and "Bioconjugation Protein Coupling Techniques for the Biomedical Sciences", 1998, M. Aslam and A.
  • PEG poly(ethyleneglycol)
  • PEG is attached to a cysteine in the hinge region.
  • a PEG modified Fab fragment has a maleimide group covalently linked to a single thiol group in a modified hinge region.
  • a lysine residue may be covalently linked to the maleimide group and to each of the amine groups on the lysine residue may be attached a methoxypoly(ethyleneglycol) polymer having a molecular weight of approximately 20,000Da.
  • the total molecular weight of the PEG attached to the Fab fragment may therefore be approximately 40,000Da.
  • PEG molecules include 2-[3-(N-maleimido)propionamido]ethyl amide of N,N'-bis(methoxypoly(ethylene glycol) MW 20,000) modified lysine, also known as PEG2MAL40K (obtainable from Nektar, formerly Shearwater).
  • PEG linkers include NOF who supply GL2-400MA2 (wherein m in the structure below is 5) and GL2-400MA (where m is 2) and n is approximately 450:
  • m 2 or 5
  • each PEG is about 20,000Da.
  • an antibody which is PEGylated (for example with a PEG described herein), attached through a cysteine amino acid residue at or about amino acid 226 in the chain, for example amino acid 226 of the heavy chain (by sequential numbering).
  • the antibody or binding fragment is provided as a pharmaceutical formulation comprising one or more excipients, diluents and/or carriers. Accordingly, there is provided a pharmaceutical composition comprising an antibody or binding fragment as described above.
  • the antibody or antigen-binding fragment, derivative or variant thereof of the invention will generally be administered in admixture with a suitable pharmaceutical excipient diluent or carrier, selected with regard to the intended route of administration and standard pharmaceutical practice (for example, see Remington: The Science and Practice of Pharmacy, 19 th edition, 1995, Ed. Alfonso Gennaro, Mack Publishing Company, Pennsylvania, USA).
  • the antibody or antigen-binding fragment, derivative or variant thereof of the invention can be administered orally, buccally or sublingually in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed- or controlled-release applications.
  • Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxy-propylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
  • compositions of a similar type may also be employed as fillers in gelatin capsules.
  • Suitable excipients in this regard include lactose, starch, cellulose, milk sugar or high molecular weight polyethylene glycols.
  • the compounds of the invention may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
  • capsules may be filled with a liquid formulation.
  • the antibody or antigen-binding fragment, derivative or variant thereof of the invention can also be administered parenterally, for example, intravenously, intra-articularly, intra- arterially, intraperitoneally, intrathecally, intraventricularly, intrasternally, intracranially, intra-muscularly or subcutaneously, by intracavernosal injection, or they may be administered by infusion techniques.
  • parenterally for example, intravenously, intra-articularly, intra- arterially, intraperitoneally, intrathecally, intraventricularly, intrasternally, intracranially, intra-muscularly or subcutaneously, by intracavernosal injection, or they may be administered by infusion techniques.
  • They are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • the aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti- oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • Example approaches 1) Excipients such as buffers and detergents (usually Tween) are added to inhibit aggregation in aqueous formulations; 2) Freeze drying with appropriate excipients to provide bulk, stability and cosmetic appeal to the cake; 3) Formation of a glassy sugar using compounds such as trehalose.
  • Excipients such as buffers and detergents (usually Tween) are added to inhibit aggregation in aqueous formulations.
  • Freeze drying with appropriate excipients to provide bulk, stability and cosmetic appeal to the cake 3) Formation of a glassy sugar using compounds such as trehalose.
  • the daily dosage level of the antibody or antigen-binding fragment, derivative or variant thereof of the invention will usually be from l ⁇ g to 1000 mg per adult [i.e. from about 0.015 to 15 mg/kg), administered in single or divided doses.
  • the dosage level may be from about 0.5mg/kg to about 10 mg/kg
  • the administration regimen may be twice or three times weekly
  • the administration may, for example be intravenous or subcutaneous.
  • the dosing regimen may be in the range once a week to once a month delivered intravenously or by subcutaneous injection.
  • the antibody or antigen-binding fragment, derivative or variant thereof of the invention can also be administered intranasally or by inhalation and are conveniently delivered, for example in the form of a dry powder inhaler, pump, spray or nebuliser an aerosol spray presentation from a pressurised container with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoro-methane, dichlorotetrafluoro-ethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A3 or 1,1,1,2,3,3,3- heptafluoropropane (HFA 227EA3), carbon dioxide or other suitable gas.
  • a suitable propellant such as dichlorodifluoromethane, trichlorofluoro-methane, dichlorotetrafluoro-ethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluor
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurised container, pump, spray or nebuliser may contain a solution or suspension of the active antibody or antigen-binding fragment, derivative or variant the re of, such as using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, such as sorbitan trioleate.
  • Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of an antibody or binding fragment of the invention and a suitable powder base such as lactose or starch.
  • Aerosol or dry powder formulations are suitably arranged so that each dose (or metered dose or 'puff) contains at least 1 ⁇ g of an antibody or antigen-binding fragment, derivative or variantthereof ofthe invention for delivery to the patient. Itwill be appreciated thatthe overall daily dose with an aerosol will vary from patient to patient, and maybe administered in a single dose or, more usually, in divided doses throughout the day.
  • the antibody or antigen-binding fragment, derivative or variant thereof of the invention can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
  • the compounds of the invention may also be transdermally administered, for example, by the use of a skin patch. They may also be administered by the ocular route.
  • the antibody or antigen-binding fragment, derivative or variant thereof of the invention can be formulated as a suspension in isotonic, pH adjusted, sterile saline, or, suitably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride.
  • a preservative such as a benzylalkonium chloride.
  • they may be formulated in an ointment such as petrolatum.
  • the antibody or antigen-binding fragment, derivative or variant thereof of the invention can be formulated as a suitable ointment suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
  • the antibody or binding fragment can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouth-washes comprising the active ingredient in a suitable liquid carrier.
  • a sustained-release drug delivery system such as microspheres. These are designed specifically to reduce the frequency of injections.
  • An example of such a system is Nutropin Depot which encapsulates recombinant human growth hormone (rhGH) in biodegradable microspheres that, once injected, release rhGH slowly over a sustained period.
  • the antibody or antigen-binding fragment, derivative or variant thereof of the present invention can be administered by a surgically implanted device that releases the active, for example directly to the required site.
  • Electroporation therapy (EPT) systems can also be employed for the administration of the antibody or antigen-binding fragment, derivative or variant thereof.
  • EPT Electroporation therapy
  • a device which delivers a pulsed electric field to cells increases the permeability of the cell membranes to the drug, resulting in a significant enhancement of intracellular drug delivery.
  • the antibody or antigen-binding fragment, derivative or variant thereof can also be delivered by electroincorporation (EI).
  • EI occurs when small particles of up to 30 microns in diameter on the surface of the skin experience electrical pulses identical or similar to those used in electroporation. In EI, these particles are driven through the stratum corneum and into deeper layers of the skin.
  • the particles can be loaded or coated with drugs or genes or can simply act as "bullets" that generate pores in the skin through which the drugs can enter.
  • thermo-sensitive ReGel injectable An alternative method of antibody or antigen-binding fragment, derivative or variant thereof delivery is the thermo-sensitive ReGel injectable. Below body temperature, ReGel is an injectable liquid while at body temperature it immediately forms a gel reservoir that slowly erodes and dissolves into known, safe, biodegradable polymers. The active drug is delivered over time as the biopolymers dissolve.
  • Antibody or antigen-binding fragment, derivative or variant thereof, or pharmaceuticals can also be delivered orally.
  • One such system employs a natural process for oral uptake of vitamin B12 in the body to co-deliver proteins and polypeptides.
  • the protein or polypeptide can move through the intestinal wall.
  • Complexes are produced between vitamin B12 analogues and the drug that retain both significant affinity for intrinsic factor (IF) in the vitamin B12 portion of the complex and significant bioactivity of the
  • the monoclonal antibody AS LANO 04 (an anti-IL-13Ral antibody) was tested on leukemic cells from a patient with Sezary Syndrome. In vitro the antibody concentration employed was 0.01 ⁇ g/ml. The results are shown in Figure 1, which shows that the antibody has anti-tumor activity in the absence and also in the presence of IL-13.
  • HUT-78 have surface expression of IL-13Ral, which can be measured by flow cytometry.
  • Expression of IL-13Ral was determined by flow cytometry in Hut-78 cells treated with/without IL-13 (100 ng/ml) (dark grey histograms).
  • results show that HUT-78 cells expressed IL13Ral on their cell surfaces. Also, IL-13Ral expression does not change with or without addition of IL-13. Lastly, the results indicate a greater dynamic range with the anti-IL13Ral antibody from Sigma (B) vs the antibody from R&D (A).
  • ASLAN004 was a potent inhibitor of HUT-78 cell proliferation in the presence and also in the absence of IL-13.

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  • Health & Medical Sciences (AREA)
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  • Medicinal Chemistry (AREA)
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  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
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  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne un procédé de traitement d'un lymphome cutané T (CTCL), en particulier la mycose fongoïde et/ou le syndrome de Sézary, ce procédé consistant à administrer, à un patient qui en a besoin, une quantité thérapeutiquement efficace d'un anticorps antagoniste ou fragment de liaison de celui-ci, spécifique du récepteur d'IL -13.
EP18743109.3A 2017-06-30 2018-06-29 Procédé de traitement à l'aide d'un anticorps dirigé contre il-13r Withdrawn EP3645566A1 (fr)

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WO2024041650A1 (fr) * 2022-08-25 2024-02-29 Nanjing Legend Biotech Co., Ltd. Récepteurs antigéniques chimériques ciblant la sous-unité alpha 2 du récepteur de l'interleukine 13 et leurs procédés d'utilisation

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CA2480059C (fr) * 2002-03-22 2015-11-24 Amrad Operations Pty. Ltd. Anticorps monoclonal contre le recepteur alpha1 de l'interleukine 13 (il-13ra1)
JP2007031414A (ja) * 2005-06-24 2007-02-08 International Medical Center Of Japan Ｉｌ−１３シグナリング阻害をメカニズムとする消化管粘膜傷害治療剤及び薬物スクリーニング方法
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US10308719B2 (en) * 2015-01-26 2019-06-04 The University Of Chicago IL13Rα2 binding agents and use thereof in cancer treatment

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