WO2022074033A1 - Polythérapie - Google Patents

Polythérapie Download PDF

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Publication number
WO2022074033A1
WO2022074033A1 PCT/EP2021/077504 EP2021077504W WO2022074033A1 WO 2022074033 A1 WO2022074033 A1 WO 2022074033A1 EP 2021077504 W EP2021077504 W EP 2021077504W WO 2022074033 A1 WO2022074033 A1 WO 2022074033A1
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WIPO (PCT)
Prior art keywords
adc
treatment
individual
cancer
cells
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PCT/EP2021/077504
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English (en)
Inventor
Francesca ZAMMARCHI
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Adc Therapeutics Sa
Medimmune Limited
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Publication of WO2022074033A1 publication Critical patent/WO2022074033A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present disclosure relates to combination therapies for the treatment of pathological conditions, such as cancer.
  • the present disclosure relates to combination therapies comprising treatment with an anti-CD25 Antibody Drug Conjugate (anti-CD25 ADC) and an IL-2.
  • anti-CD25 ADC anti-CD25 Antibody Drug Conjugate
  • IL-2 an IL-2
  • ADC antibody-drug conjugates
  • cytotoxic or cytostatic agents i.e. drugs to kill or inhibit tumour cells in the treatment of cancer
  • cytotoxic or cytostatic agents i.e. drugs to kill or inhibit tumour cells in the treatment of cancer
  • systemic administration of these unconjugated drug agents may result in unacceptable levels of toxicity to normal cells
  • the type I transmembrane protein CD25 is present on activated T- and B- cells, some thymocytes, myeloid precursors, and oligodendrocytes. On activated T-cells, it forms heterodimers with the beta- and gamma subunits (CD122 and CD132), thus comprising the high-affinity receptor for IL-2. This ligand represents a survival factor for activated T- cells, as removal of IL-2 leads to immediate death of these cells.
  • CD25 is physiologically expressed in early developmental stages of late pro-B and pre-B cells. Malignancies arising from this stage of B-cell differentiation may thus also express CD25. Mast cell lesions are also positive for CD25 which is thus considered as a key diagnostic criterion for determination of systemic mastocytosis.
  • Hodgkin lymphomas CD25 is reported to be not expressed in Hodgkin-/Reed-Sternberg cells in nodular lymphocyte predominance Hodgkin lymphoma (NLPHL), whereas the same cell type expresses CD25 at varying levels in classical Hodgkin’ lymphomas of mixed cellularity type. The general expression levels are reported to be lower than in tumor infiltrating lymphocytes (TILs), which may result in problems demonstrating CD25 tumor cells in these cases (Levi et al., Merz et al, 1995).
  • TILs tumor infiltrating lymphocytes
  • B- and T-cell-derived subtypes of non-Hodgkin-lymphomas i.e. B-cell chronic lymphatic leukemia, hairy cell leukemia, small cell lymphocytic lymphoma/chronic lymphocytic leukemia as well as adult T-cell leukemia/lymphoma and anaplastic large cell lymphoma.
  • CD25 may be localised to the membrane, with some expression observed in the cytoplasm. Soluble CD25 may also be observed outside of cells, such as in serum.
  • an Antibody Drug Conjugate comprising an anti-CD25 antibody (an anti CD25-ADC) in the treatment of, for example, cancer has been established - see, for example, W02014/057119, WO2016/083468, and WO2016/166341.
  • the present authors have determined that the administration of a combination of an anti-CD25 ADC and IL-2 to an individual leads to unexpected clinical advantages.
  • the present authors have further determined that administration of an anti-CD25 ADC to an individual that has either been treated with, or is being treated with, and IL-2 leads to a synergistic increase in treatment efficacy.
  • the present disclosure provides a method of selecting an individual as suitable for treatment with an anti-CD25 ADC, wherein the individual is selected for treatment with the anti-CD25 ADC if the individual has been treated, or is being treated, with an IL-2.
  • the individual may be selected for treatment if the individual is refractory to treatment, or further treatment, with the IL-2.
  • the present disclosure provides a method for treating a disorder in an individual, the method comprising selecting an individual as suitable for treatment by a method of the first aspect, and then administering to the individual an effective amount of the anti-CD25 ADC.
  • the method of treatment may further comprise administering an IL-2 in combination with the anti-CD25 ADC.
  • the disclosure provides a method for treating a disorder in an individual, the method comprising administering to the individual an effective amount of an anti-CD25 ADC and IL-2.
  • the individual may be selected for treatment according to a method according of the first aspect.
  • the disorder may be a proliferative disease, for example a cancer such as Hodgkin’s and non-Hodgkin’s Lymphoma, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, (FL), Mantle Cell lymphoma (MCL), chronic lymphatic lymphoma (CLL), Marginal Zone B-cell lymphoma (MZBL) and leukemias such as Hairy cell leukemia (HCL), Hairy cell leukemia variant (HCL-v), Acute Myeloid Leukaemia (AML), anaplastic large cell lymphoma (ALCL), and Acute Lymphoblastic Leukaemia (ALL) such as Philadelphia chromosome-positive ALL (Ph+ALL) or
  • the proliferative disease may be characterised by the presence of a neoplasm comprising both CD25+ve and CD25-ve cells.
  • the proliferative disease may be characterised by the presence of a neoplasm composed of CD25-ve neoplastic cells, optionally wherein the CD25-ve neoplastic cells are associated with CD25+ve non-neoplastic cells such as CD25+ve T-cells.
  • the target neoplasm or neoplastic cells may be all or part of a solid tumour.
  • Solid tumor herein will be understood to include solid haematological cancers such as lymphomas (Hodgkin’s lymphoma or non-Hodgkin’s lymphoma) which are discussed in more detail herein.
  • lymphomas Hodgkin’s lymphoma or non-Hodgkin’s lymphoma
  • Solid tumors may be neoplasms, including non-haematological cancers, comprising or composed of CD25+ve neoplastic cells.
  • Solid tumors may be neoplasms, including non- haematological cancers, infiltrated with CD25+ve cells, such as CD25+ve T-cells; such solid tumours may lack expression of CD25 (that is, comprise or be composed of CD25- ve neoplastic cells).
  • the solid tumour may be a tumour with high levels of infiltrating T-cells, such as infiltrating regulatory T-cells (Treg; Menetrier-Caux, C., et al., Targ Oncol (2012) 7:15- 28; Arce Vargas et al., 2017, Immunity 46, 1-10; Tanaka, A., et al., Cell Res. 2017 Jan;27(1):109-118).
  • the solid tumour may be pancreatic cancer, breast cancer, colorectal cancer, gastric and oesophageal cancer, leukemia and lymphoma, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular carcinoma, renal cell carcinoma, and head and neck cancer.
  • the anti-CD25-ADC may be ADCX25 described herein.
  • the anti-CD25-ADC may be ADCT-301 or Camidanlumab Tesirine.
  • the IL-2 may be, or comprise, a polypeptide having at least 70% sequence identity to SEQ ID NO.12, such as 90% sequence identity to SEQ ID NO.12.
  • the IL-2 specifically binds IL-2R and/or activates IL-2 signalling.
  • the individual may be human.
  • the individual may have cancer, or may have been determined to have cancer.
  • the individual may have, or have been determined to have, a CD25+ cancer or CD25+ tumour-associated non-tumour cells, such as CD25+ infiltrating T-cells.
  • the anti-CD25 ADC may be administered before the IL-2, simultaneous with the IL-2, or after the IL-2.
  • the disclosed methods may comprise administering a further chemotherapeutic agent to the individual.
  • the present disclosure provides an anti-CD25 ADC, or a composition comprising an anti-CD25 ADC, for use in a method of treatment as described herein.
  • the present disclosure provides an IL-2, or a composition comprising an IL- 2, for use in a method of treatment as described herein.
  • the present disclosure provides for the use of an anti-CD25 ADC or an IL-2 in the manufacture of a medicament for treating a disorder in an individual, wherein the treatment comprises a method of treatment as described herein.
  • the disclosure provides a first composition comprising an anti-CD25 ADC for use in a method of treating a disorder in an individual, wherein the treatment comprises administration of the first composition in combination with a second composition comprising a IL-2.
  • a first composition comprising a IL-2 for use in a method of treating a disorder in an individual, wherein the treatment comprises administration of the first composition in combination with a second composition comprising an anti-CD25 ADC.
  • the disorder may be a proliferative disease, for example a cancer such as non-Hodgkin’s Lymphoma, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, (FL), Mantle Cell lymphoma (MCL), chronic lymphatic lymphoma (CLL), and Marginal Zone B- cell lymphoma (MZBL), and leukemias such as Hairy cell leukemia (HCL), Hairy cell leukemia variant (HCL-v), anaplastic large cell lymphoma (ALCL), and Acute Lymphoblastic Leukaemia (ALL) such as Philadelphia chromosome-positive ALL (Ph+ALL) or Philadelphia chromosome-negative ALL (Ph-ALL).
  • a cancer such as non-Hodgkin’s Lymphoma, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, (FL), Mantle Cell lymphoma (MCL), chronic lymphatic lymphoma (
  • the anti-CD25-ADC may be ADCX25 described herein.
  • the anti-CD25-ADC may be ADCT-301 or Camidanlumab Tesirine.
  • the IL-2 may be, or comprise, a polypeptide having at least 70% sequence identity to SEQ ID NO.12, such as 90% sequence identity to SEQ ID NO.12.
  • the IL-2 specifically binds IL-2R and/or activates IL-2 signalling.
  • the individual may be human.
  • the individual may have cancer, or may have been determined to have cancer.
  • the individual may have, or have been determined to have, a CD25+ cancer or CD25+ tumour-associated non-tumour cells, such as CD25+ infiltrating T-cells.
  • the first composition may be administered before the second composition, simultaneous with the second composition, or after the second composition.
  • the treatment may comprise administering a further chemotherapeutic agent to the individual.
  • the disclosure provides the use of an anti-CD25 ADC in the manufacture of a medicament for treating a disorder in an individual, wherein the medicament comprises an anti-CD25 ADC, and wherein the treatment comprises administration of the medicament in combination with a composition comprising IL-2.
  • IL-2 in the manufacture of a medicament for treating a disorder in an individual, wherein the medicament comprises a IL-2, and wherein the treatment comprises administration of the medicament in combination with a composition comprising an anti-CD25 ADC.
  • the disorder may be a proliferative disease, for example a cancer such as Hodgkin’s and non-Hodgkin’s Lymphoma, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, (FL), Mantle Cell lymphoma (MCL), chronic lymphatic lymphoma (CLL), Marginal Zone B-cell lymphoma (MZBL) and leukemias such as Hairy cell leukemia (HCL), Hairy cell leukemia variant (HCL-v), Acute Myeloid Leukaemia (AML), anaplastic large cell lymphoma (ALCL), and Acute Lymphoblastic Leukaemia (ALL) such as Philadelphia chromosome-positive ALL (Ph+ALL) or Philadelphia chromosome-negative ALL (Ph-ALL).
  • DLBCL diffuse large B-cell lymphoma
  • FL follicular lymphoma
  • MCL Mantle Cell lymphoma
  • CLL chronic lymphatic lymphom
  • the proliferative disease may be characterised by the presence of a neoplasm comprising both CD25+ve and CD25-ve cells.
  • the proliferative disease may be characterised by the presence of a neoplasm composed of CD25-ve neoplastic cells, optionally wherein the CD25-ve neoplastic cells are associated with CD25+ve non-neoplastic cells such as CD25+ve T-cells.
  • Solid tumor herein will be understood to include solid haematological cancers such as lymphomas (Hodgkin’s lymphoma or non-Hodgkin’s lymphoma) which are discussed in more detail herein.
  • Solid tumors may be neoplasms, including non-haematological cancers, comprising or composed of CD25+ve neoplastic cells.
  • Solid tumors may be neoplasms, including non- haematological cancers, infiltrated with CD25+ve cells, such as CD25+ve T-cells; such solid tumours may lack expression of CD25 (that is, comprise or be composed of CD25- ve neoplastic cells).
  • the solid tumour may be a tumour with high levels of infiltrating T-cells, such as infiltrating regulatory T-cells (Treg; Menetrier-Caux, C., et al., Targ Oncol (2012) 7:15- 28; Arce Vargas et al., 2017, Immunity 46, 1-10; Tanaka, A., et al., Cell Res. 2017 Jan;27(1):109-118).
  • the solid tumour may be pancreatic cancer, breast cancer, colorectal cancer, gastric and oesophageal cancer, leukemia and lymphoma, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular carcinoma, renal cell carcinoma, and head and neck cancer.
  • the anti-CD25 ADC may be ADCX25 as described herein.
  • the anti-CD25-ADC may be ADCT-301 or Camidanlumab Tesirine.
  • the IL-2 may be, or comprise, a polypeptide having at least 70% sequence identity to SEQ ID NO.12, such as 90% sequence identity to SEQ ID NO.12.
  • the IL-2 specifically binds IL-2R and/or activates IL-2 signalling.
  • the individual may be human.
  • the individual may have cancer, or may have been determined to have cancer.
  • the individual may have, or have been determined to have, a CD25+ cancer or CD25+ tumour-associated non-tumour cells, such as CD25+ infiltrating T-cells.
  • the medicament may be administered before the composition, simultaneous with the composition, or after the composition.
  • the treatment may comprise administering a further chemotherapeutic agent to the individual.
  • kits comprising: a first medicament comprising an anti-CD25 ADC; a package insert comprising instructions for administration of the first medicament according to a method of treatment as disclosed herein.
  • the kit may further comprise a second medicament comprising an IL-2.
  • kits comprising: a first medicament comprising an anti-CD25 ADC; a second medicament comprising an IL-2; and, optionally, a package insert comprising instructions for administration of the first medicament to an individual in combination with the second medicament for the treatment of a disorder.
  • kits comprising a medicament comprising an anti-CD25 ADC and a package insert comprising instructions for administration of the medicament to an individual in combination with a composition comprising an IL-2 for the treatment of a disorder.
  • kits comprising a medicament comprising an IL-2 and a package insert comprising instructions for administration of the medicament to an individual in combination with a composition comprising an anti-CD25 ADC for the treatment of a disorder.
  • the disorder may be a proliferative disease, for example a cancer such as Hodgkin’s and non-Hodgkin’s Lymphoma, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, (FL), Mantle Cell lymphoma (MCL), chronic lymphatic lymphoma (CLL), Marginal Zone B-cell lymphoma (MZBL) and leukemias such as Hairy cell leukemia (HCL), Hairy cell leukemia variant (HCL-v), Acute Myeloid Leukaemia (AML), anaplastic large cell lymphoma (ALCL), and Acute Lymphoblastic Leukaemia (ALL) such as Philadelphia chromosome-positive ALL (Ph+ALL) or Philadelphia chromosome-negative ALL (Ph-ALL).
  • DLBCL diffuse large B-cell lymphoma
  • FL follicular lymphoma
  • MCL Mantle Cell lymphoma
  • CLL chronic lymphatic lymphom
  • the proliferative disease may be characterised by the presence of a neoplasm comprising both CD25+ve and CD25-ve cells.
  • the proliferative disease may be characterised by the presence of a neoplasm composed of CD25-ve neoplastic cells, optionally wherein the CD25-ve neoplastic cells are associated with CD25+ve non-neoplastic cells such as CD25+ve T-cells.
  • the target neoplasm or neoplastic cells may be all or part of a solid tumour.
  • Solid tumor herein will be understood to include solid haematological cancers such as lymphomas (Hodgkin’s lymphoma or non-Hodgkin’s lymphoma) which are discussed in more detail herein.
  • lymphomas Hodgkin’s lymphoma or non-Hodgkin’s lymphoma
  • Solid tumors may be neoplasms, including non-haematological cancers, comprising or composed of CD25+ve neoplastic cells.
  • Solid tumors may be neoplasms, including non- haematological cancers, infiltrated with CD25+ve cells, such as CD25+ve T-cells; such solid tumours may lack expression of CD25 (that is, comprise or be composed of CD25- ve neoplastic cells).
  • the solid tumour may be a tumour with high levels of infiltrating T-cells, such as infiltrating regulatory T-cells (Treg; Menetrier-Caux, C., et al., Targ Oncol (2012) 7:15- 28; Arce Vargas et al., 2017, Immunity 46, 1-10; Tanaka, A., et al., Cell Res. 2017 Jan;27(1):109-118).
  • the solid tumour may be pancreatic cancer, breast cancer, colorectal cancer, gastric and oesophageal cancer, leukemia and lymphoma, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular carcinoma, renal cell carcinoma, and head and neck cancer.
  • the anti-CD25 ADC may be ADCX25 as described herein.
  • the anti-CD25-ADC may be ADCT-301 or Camidanlumab Tesirine.
  • the IL-2 may be, or comprise, a polypeptide having at least 70% sequence identity to SEQ ID NO.12, such as 90% sequence identity to SEQ ID NO.12.
  • the IL-2 specifically binds IL-2R and/or activates IL-2 signalling.
  • the individual may be human.
  • the individual may have cancer, or may have been determined to have cancer.
  • the individual may have, or have been determined to have, a CD25+ cancer or CD25+ tumour-associated non-tumour cells, such as CD25+ infiltrating T-cells.
  • the medicament or composition comprising the anti-CD25 ADC may be administered before the medicament or composition comprising the IL-2, simultaneous with the medicament or composition comprising the IL-2, or after the medicament or composition comprising the IL-2.
  • the treatment may comprise administering a further chemotherapeutic agent to the individual.
  • the disclosure provides a composition comprising an anti-CD25 ADC and an IL-2.
  • Also provided in this aspect of the disclosure is a method of treating a disorder in an individual, the method comprising administering to the individual an effective amount of the composition comprising an anti-CD25 ADC and an IL-2.
  • composition comprising an anti-CD25 ADC and an IL-2 for use in a method of treating a disorder in an individual.
  • composition comprising an anti-CD25 ADC and an IL-2 in the manufacture of a medicament for treating a disorder in an individual.
  • kit comprising composition comprising an anti-CD25 ADC and an IL-2 and a set of instructions for administration of the medicament to an individual for the treatment of a disorder.
  • the disorder may be a proliferative disease, for example a cancer such as Hodgkin’s and non-Hodgkin’s Lymphoma, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, (FL), Mantle Cell lymphoma (MCL), chronic lymphatic lymphoma (CLL), Marginal Zone B-cell lymphoma (MZBL) and leukemias such as Hairy cell leukemia (HCL), Hairy cell leukemia variant (HCL-v), Acute Myeloid Leukaemia (AML), anaplastic large cell lymphoma (ALCL), and Acute Lymphoblastic Leukaemia (ALL) such as Philadelphia chromosome-positive ALL (Ph+ALL) or Philadelphia chromosome-negative ALL (Ph-ALL).
  • DLBCL diffuse large B-cell lymphoma
  • FL follicular lymphoma
  • MCL Mantle Cell lymphoma
  • CLL chronic lymphatic lymphom
  • the proliferative disease may be characterised by the presence of a neoplasm comprising both CD25+ve and CD25-ve cells.
  • the proliferative disease may be characterised by the presence of a neoplasm composed of CD25-ve neoplastic cells, optionally wherein the CD25-ve neoplastic cells are associated with CD25+ve non-neoplastic cells such as CD25+ve T-cells.
  • the target neoplasm or neoplastic cells may be all or part of a solid tumour.
  • Solid tumor herein will be understood to include solid haematological cancers such as lymphomas (Hodgkin’s lymphoma or non-Hodgkin’s lymphoma) which are discussed in more detail herein.
  • lymphomas Hodgkin’s lymphoma or non-Hodgkin’s lymphoma
  • Solid tumors may be neoplasms, including non-haematological cancers, comprising or composed of CD25+ve neoplastic cells.
  • Solid tumors may be neoplasms, including non- haematological cancers, infiltrated with CD25+ve cells, such as CD25+ve T-cells; such solid tumours may lack expression of CD25 (that is, comprise or be composed of CD25- ve neoplastic cells).
  • the solid tumour may be a tumour with high levels of infiltrating T-cells, such as infiltrating regulatory T-cells (Treg; Menetrier-Caux, C., et al., Targ Oncol (2012) 7:15- 28; Arce Vargas et al., 2017, Immunity 46, 1-10; Tanaka, A., et al., Cell Res. 2017 Jan;27(1):109-118).
  • the solid tumour may be pancreatic cancer, breast cancer, colorectal cancer, gastric and oesophageal cancer, leukemia and lymphoma, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular carcinoma, renal cell carcinoma, and head and neck cancer.
  • the anti-CD25 ADC may be ADCX25 as described herein.
  • the anti-CD25-ADC may be ADCT-301 or Camidanlumab Tesirine.
  • the IL-2 may be, or comprise, a polypeptide having at least 70% sequence identity to SEQ ID NO.12, such as 90% sequence identity to SEQ ID NO.12.
  • the IL-2 specifically binds IL-2R and/or activates IL-2 signalling.
  • the individual may be human.
  • the individual may have cancer, or may have been determined to have cancer.
  • the individual may have, or have been determined to have, a CD25+ cancer or CD25+ tumour-associated non-tumour cells, such as CD25+ infiltrating T-cells.
  • the treatment may comprise administering a further chemotherapeutic agent to the individual.
  • ADCs Antibody Drug Conjugates
  • the present disclosure relates to the improved efficacy of combinations of an ADC and an IL-2.
  • the ADC can deliver a drug to a target location.
  • the target location is preferably a proliferative cell population.
  • the antibody is an antibody for an antigen present on a Proliferative cell population.
  • the antigen is absent or present at a reduced level in a non-proliferative cell population compared to the amount of antigen present in the proliferative cell population, for example a tumour cell population.
  • the ADC may comprise a linker which may be cleaved so as to release the drug at the target location.
  • the drug may be a compound selected from RelA, RelB, RelC, RelD or RelE.
  • the conjugate may be used to selectively provide a compound RelA, RelB, Rel C, RelD or RelE to the target location.
  • the linker may be cleaved by an enzyme present at the target location.
  • the disclosure particularly relates treatment with an anti-CD25 ADC disclosed in WO2014/057119, and as herein described.
  • anti-CD25 ADCs disclosed in WO2014/057119, and as herein described.
  • the term “anti-CD25-ADC” refers to an ADC in which the antibody component is an anti-CD25 antibody and the drug component comprises a pyrrolobenzodiazepine (PBD), such as a PBD dimer.
  • PBD dimers have been shown to form sequence selective, non-distorting and potently cytotoxic DNA interstrand cross-links in the minor groove of DNA. Typically therefore the PBD is able to bind to, and form interstrand cross-links in the minor groove of target cell DNA.
  • the anti-CD25-ADC may be an antibody drug conjugate (ADC) comprising an anti-CD25 antibody linked to a pyrrolobenzodiazepine (PBD) dimer warhead.
  • the ADC may comprise a conjugate of formula L - (D L ) P wherein:
  • L is an antibody that binds to CD25
  • D L is a pyrrolobenzodiazepine (PBD), such as a PBD dimer; and p is preferably from 1 to 8.
  • PBD pyrrolobenzodiazepine
  • Li may be absent, or simply a covalent bond between the antibody and the PBD.
  • Li is a cleavable linker where - for example - the linker incorporates a sequence that is readily cleaved by enzyme action.
  • a known class of cleavable linkers incorporate a peptide sequence that can be readily cleaved by proteases such as cathepsin.
  • An example of a cleavable drug-linker is the drug-linker of ADCx25 described herein.
  • the ADC may comprise a conjugate of formula L - (D L ) P , where D L is of formula I or II: wherein:
  • L is an antibody (Ab) which is an antibody that binds to CD25; when there is a double bond present between C2’ and C3’, R 12 is selected from the group consisting of:
  • R 25a and R 25b are H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and
  • R 24 is selected from: H; C1.3 saturated alkyl; C2-3 alkenyl; C2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; when there is a single bond present between C2’ and C3’,
  • R 12 is , where R 26a and R 26b are independently selected from H, F, C1.4 saturated alkyl, C2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C1.4 alkyl amido and C1.4 alkyl ester; or, when one of R 26a and R 26b is H, the other is selected from nitrile and a C1.4 alkyl ester;
  • R 6 and R 9 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR’, nitro, MesSn and halo; where R and R’ are independently selected from optionally substituted C1.12 alkyl, C3-20 heterocyclyl and C5-20 aryl groups;
  • R 7 is selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NHRR’, nitro, Me 3 Sn and halo;
  • R" is a C3-12 alkylene group, which chain may be interrupted by one or more heteroatoms, e.g. O, S, NR N2 (where R N2 is H or C1.4 alkyl), and/or aromatic rings, e.g. benzene or pyridine;
  • Y and Y’ are selected from O, S, or NH;
  • R 6 ’, R 7 ’, R 9 ’ are selected from the same groups as R 6 , R 7 and R 9 respectively;
  • R L1 ’ is a linker for connection to the antibody (Ab);
  • R 11a is selected from OH, OR A , where R A is C1.4 alkyl, and SO Z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;
  • R 20 and R 21 either together form a double bond between the nitrogen and carbon atoms to which they are bound or;
  • R 20 is selected from H and R c , where R c is a capping group
  • R 21 is selected from OH, OR A and SO Z M; when there is a double bond present between C2 and C3, R 2 is selected from the group consisting of:
  • R 11 , R 12 and R 13 are independently selected from H, C1.3 saturated alkyl, C2-3 alkenyl, C2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R 2 group is no more than 5;
  • R 15a and R 15b are H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and
  • R 14 is selected from: H; C1.3 saturated alkyl; C2-3 alkenyl; C2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; when there is a single bond present between C2 and C3,
  • R 2 is R , where R 16a and R 16b are independently selected from H, F, C1.4 saturated alkyl, C2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C1.4 alkyl amido and C1.4 alkyl ester; or, when one of R 16a and R 16b is H, the other is selected from nitrile and a C1.4 alkyl ester;
  • R 22 is of formula Illa, formula lllb or formula lllc:
  • Q 1 is a single bond
  • Q 2 is selected from a single bond and -Z-(CH2)n-, where Z is selected from a single bond, O, S and NH and n is from 1 to 3; or Q 2 is a single bond; lllb dependently selected from H and unsubstituted C1.2 alkyl; lllc where Q is selected from O-R L2 ’, S-R L2 ’ and NR N -R L2 ’, and R N is selected from H, methyl and ethyl
  • R L2 ’ is a linker for connection to the antibody (Ab);
  • R 10 and R 11 either together form a double bond between the nitrogen and carbon atoms to which they are bound or;
  • R 10 is H and R 11 is selected from OH, OR A and SO Z M;
  • R 30 and R 31 either together form a double bond between the nitrogen and carbon atoms to which they are bound or;
  • R 30 is H and R 31 is selected from OH, OR A and SO Z M.
  • L 1 is enzyme cleavable, such as cathepsin cleavable.
  • anti-CD25-ADC may include any embodiment described in WO 2014/057119.
  • the ADC may have the chemical structure: , where the Ab is a CD25 antibody, and the
  • the antibody may comprise a VH domain comprising a VH CDR1 with the amino acid sequence of SEQ ID NO.3, a VH CDR2 with the amino acid sequence of SEQ ID NO.4, and a VH CDR3 with the amino acid sequence of SEQ ID NO.5.
  • the antibody component of the anti-CD25-ADC is an antibody comprising: a VH domain comprising a VH CDR1 with the amino acid sequence of SEQ ID NO.3, a VH CDR2 with the amino acid sequence of SEQ ID NO.4, and a VH CDR3 with the amino acid sequence of SEQ ID NO.5.
  • the antibody comprises a VH domain having the sequence according to SEQ ID NO. 1.
  • the antibody may further comprise: a VL domain comprising a VL CDR1 with the amino acid sequence of SEQ ID NO.6, a VL CDR2 with the amino acid sequence of SEQ ID NO.7, and a VL CDR3 with the amino acid sequence of SEQ ID NO.8.
  • the antibody further comprises a VL domain having the sequence according to SEQ ID NO. 2.
  • the antibody has a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3, wherein the antibody comprises the CDR sequences of the VH domain having the sequence according to SEQ ID NO: 1.
  • the antibody has a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3, wherein the antibody comprises the CDR sequences of the VL domain having the sequence according to SEQ ID NO: 2.
  • the antibody comprises a VH domain and a VL domain, the VH and VL domains having the sequences of SEQ ID NO. 1 paired with SEQ ID NO. 2.
  • the VH and VL domain(s) may pair so as to form an antibody antigen binding site that binds CD25.
  • the antibody is an intact antibody comprising a VH domain and a VL domain, the VH and VL domains having sequences of SEQ ID NO. 1 and SEQ ID NO. 2.
  • the antibody is a fully human monoclonal lgG1 antibody, preferably lgG1 ,K.
  • the antibody is the AB12 antibody described in WO 2004/045512 (Genmab A/S).
  • the antibody is an antibody as described herein which has been modified (or further modified) as described below.
  • the antibody is a humanised, deimmunised or resurfaced version of an antibody disclosed herein.
  • a preferred anti-CD25-ADC for use with the aspects of the present disclosure is ADCX25, as described herein below.
  • Another preferred anti-CD25-ADC for use with the aspects of the present disclosure is ADCT-301.
  • ADCx25 is an antibody drug conjugate composed of a human antibody against human CD25 attached to a pyrrolobenzodiazepine (PBD) warhead via a cleavable linker.
  • the mechanism of action of ADCX25 depends on CD25 binding.
  • the CD25 specific antibody targets the antibody drug conjugate (ADC) to cells expressing CD25.
  • ADC antibody drug conjugate
  • the ADC internalizes and is transported to the lysosome, where the protease sensitive linker is cleaved and free PBD dimer is released inside the target cell.
  • the released PBD dimer inhibits transcription in a sequence-selective manner, due either to direct inhibition of RNA polymerase or inhibition of the interaction of associated transcription factors.
  • the PBD dimer produces covalent crosslinks that do not distort the DNA double helix and which are not recognized by nucleotide excision repair factors, allowing for a longer effective period (Hartley 2011).
  • Antibody AB12 (fully human monoclonal lgG1 , K antibody with the VH and VL sequences SEQ ID NO. 1 and SEQ ID NO. 2, respectively, also known as HuMax- TAC). It is synthesised as described in WO 2014/057119 (Conj AB12-E) and typically has a DAR (Drug to Antibody Ratio) of 2.0+/-0.3.
  • the “first target protein” (FTP) as used herein is preferably CD25.
  • binds CD25 is used to mean the antibody binds CD25 with a higher affinity than a non-specific partner such as Bovine Serum Albumin (BSA, Genbank accession no. CAA76847, version no. CAA76847.1 Gl:3336842, record update date: Jan 7, 2011 02:30 PM).
  • BSA Bovine Serum Albumin
  • the antibody binds CD25 with an association constant (Ka) at least 2, 3, 4, 5, 10, 20, 50, 100, 200, 500, 1000, 2000, 5000, 10 4 , 10 5 or 10 6 -fold higher than the antibody’s association constant for BSA, when measured at physiological conditions.
  • the antibodies of the disclosure can bind CD25 with a high affinity.
  • the antibody can bind CD25 with a KD equal to or less than about 10' 6 M, such as equal to or less than one of 1 x 10' 6 , 10' 7 , 10' 8 , 10' 9 ,10' 10 , 10' 11 , 10' 12 , 10- 13 or 10' 14 .
  • CD25 polypeptide corresponds to Genbank accession no. NP_000408, version no. NP_000408.1 Gl:4557667, record update date: Sep 09, 2012 04:59 PM.
  • the nucleic acid encoding CD25 polypeptide corresponds to Genbank accession no. NM_000417, version no. NM_000417.2 GI:269973860, record update date: Sep 09, 2012 04:59 PM.
  • CD25 polypeptide corresponds to Uniprot/Swiss-Prot accession No. P01589.
  • IL-2 is a member of a cytokine family, each member of which has a four alpha helix bundle; the family also includes IL-4, IL-7, IL-9, IL-15 and IL-21.
  • IL-2 signals through the IL-2 receptor a complex consisting of three chains, termed alpha (CD25), beta (CD122) and gamma (CD132).
  • the subunits are able to bind IL-1 in a number of different combinations [Arenas-Ramirez N. et al. 2015, Trends in Immunology. 36 (12): 763-7777 // Wang X. et al., 2005, Science. 310 (5751): 1159-63 ]: the a subunit (CD25) can bind IL-2 with low affinity (Kd ⁇ 10 -8 M).
  • the IL- 2/CD25 complex alone does not allow signal transduction due to CD25’s short intracellular chain.
  • the p and y subunits form an intermediate-affinity (Kd ⁇ 10" 9 M) heterodimer that is expressed by memory CD8+ T-cells and NK cells, and is the minimal structure required for signalling.
  • a, p, and y subunits together form a high-affinity (K d ⁇ 10 -11 M) heterotrimer that is expressed by regulatory T-cells and activated T-cells.
  • IL-2 Signalling through IL-2 is transduced through three different signalling pathways; JAK- STAT, PI3K/Akt/mTOR and MAPK/ERK pathway. These in turn ultimately lead to activation and/or repression of a number of different expression factors [Friedmann MC, wt al. 1996, PNAS 93 (5): 2077-82], For example, one of IL-2’s checkpoints is through the activated T-cell receptor (TCR) post-MHC binding. Signalling from the TCR goes via a phospholipase-C (PLC) dependent pathway, which in turn activates the NFAT, NFkB and AP-1 transcription factors.
  • TCR T-cell receptor
  • PLC phospholipase-C
  • IL-2 has been reported to have a number of important roles in the immune system, tolerance and immunity, primarily via its direct effects on T-cells. In the thymus it acts to prevent autoimmune diseases by promoting the differentiation of regulatory T cells, IL-2 also promotes the differentiation of T cells into effector T cells and into memory T cells when the initial T cell is also stimulated by an antigen. Together with other polarizing cytokines, IL-2 stimulates naive CD4+ T cell differentiation into Th1 and Th2 lymphocytes while it impedes differentiation into Th17 and folicular Th lymphocytes [Liao W., et al. 2011, Current Opinion in Immunology. 23 (5): 598-604 // Liao W., et al., 2013, Immunity.
  • IL-2 IL-2’s expression and secretion is tightly regulated and functions as part of both transient positive and negative feedback loops in mounting and dampening immune responses.
  • T cell immunologic memory which depends upon the expansion of the number and function of antigen-selected T cell clones, it plays a key role in enduring cell-mediated immunity.
  • IL-2 as defined herein is the murine IL-2 disclosed herein as SEQ ID NO.9, preferably the mature form (ie. SEQ ID NO.10) thereof.
  • IL-2 as defined herein is the human IL-2 disclosed herein as SEQ ID NO.11 , preferably the mature form (ie. SEQ ID NO.12) thereof.
  • IL-2 as defined herein is the polypeptide that corresponds to Genbank accession no. CAA23827, version no. CAA23827.1 , record update date: Feb 2, 2011 10:13 AM.
  • IL-2 as defined herein is the polypeptide encoded by the nucleic acid encoding IL-2 polypeptide corresponds to Genbank accession no V00564, version no. V00564.1, record update date: Feb 2, 2011 10:13 AM.
  • IL-2 as defined herein is the polypeptide corresponds to Uniprot/Swiss-Prot accession No. P60568-1.
  • IL-2 as defined herein also includes functional variants or analogs of IL-2. In some embodiments an analog is considered functional if specifically binds IL-2R and/or activate IL-2 signalling (preferably both).
  • “specifically binds IL-2R” is used to mean the variant or analog of IL-2 binds IL-2R with a higher affinity than a non-specific partner such as Bovine Serum Albumin (BSA, Genbank accession no. CAA76847, version no. CAA76847.1 Gl:3336842, record update date: Jan 7, 2011 02:30 PM).
  • BSA Bovine Serum Albumin
  • the variant or analog of IL-2 binds IL-2R with an association constant (K a ) at least 2, 3, 4, 5, 10, 20, 50, 100, 200, 500, 1000, 2000, 5000, 10 4 , 10 5 or 10 6 -fold higher than the variant or analog of IL-2’s association constant for BSA, when measured at physiological conditions.
  • the variant or analog of IL-2 may bind IL-2R with a high affinity.
  • the variant or analog of IL-2 can bind IL-2R with a KD equal to or less than about 10' 6 M, such as 1 x 10 -6 , 10 -7 , 10 -8 , 10' 9 ,10' 10 , or 10’ 11 .
  • the ‘IL-2R’ against which binding is assayed is the beta/gamma heterodimer (ie. without the alpha subunit).
  • activate IL-2 signalling is used to mean that the variant or analog of IL-2 activates the JAK-STAT, PI3K/Akt/mTOR and/or MAPK/ERK pathway.
  • the activation is measured by assessing the phosphorylation levels of a STAT (eg. STAT5), PI3K, and/or MAPK.
  • STAT eg. STAT5
  • PI3K e.g. MAPK
  • the pathway is considered activated if phosphorylation levels are at least 10% of the level stimulated by the same concentration of ‘wild-type’ IL-2 (ie. mature, unmodified IL-2).
  • the pathway is considered activated if phosphorylation levels are at least 20%, such as at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the level stimulated by the same concentration of ‘wild-type’ IL-2.
  • the IL-2 analog or variant is, or comprises, a polypeptide having at least 60% sequence identity to SEQ ID NO.10 or, preferably, SEQ ID NO.12 as disclosed herein. In some embodiments the IL-2 analog or variant is, or comprises, a polypeptide having at least 70%, such as at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO.10 or , preferably, SEQ ID NO.12 as disclosed herein.
  • the cysteine corresponding to position 140 of SEQ ID NO.10 or positon 125 of SEQ ID NO. 12 may be substituted with another amino acid, such as serine.
  • the IL-2 analog or variant is, or comprises, a polypeptide having a substitution at the cysteine corresponding to position 140 of SEQ ID NO.10.
  • the IL-2 analog or variant is, or comprises, a polypeptide having at the sequence of SEQ ID NO.10 with a substitution of the cysteine at position 140.
  • the IL-2 analog or variant is, or comprises, a polypeptide having a substitution at the cysteine corresponding to position 125 of SEQ ID NO.12.
  • the IL-2 analog or variant is, or comprises, a polypeptide having at the sequence of SEQ ID NO.12 with a substitution of the cysteine at position 125.
  • the substitution is with serine.
  • the IL-2 analog or variant is, or comprises, a polypeptide in which the alanine at position 1 of SEQ ID NO.10 has been deleted.
  • the IL-2 analog or variant is, or comprises, a polypeptide having at the sequence of SEQ ID NO.10 with a deletion of the alanine at position 1.
  • the IL-2 analog or variant is, or comprises, a polypeptide in which the alanine at position 1 of SEQ ID NO.12 has been deleted.
  • the IL-2 analog or variant is, or comprises, a polypeptide having at the sequence of SEQ ID NO.10 with a deletion of the alanine at position 1.
  • the IL-2 analog or variant is aglycosylated.
  • Examples of pharmaceutical agents that are suitable for use as IL-2 in the present disclosure include: a) Aldesleukin (aka Proleukin) i. CAS Number -> 110942-02-4
  • Neoleukin 2/15 i. aka NL-201 ii. See Silva DA. Et al., 2019, Nature, Jan;565(7738):186-191
  • Bempegaldesleukin (NKTR-214) i. CAS Number 1939126-74-5
  • Pulmoleukin/lmmunservice i) De-lmmunized Anti-CD20-IL-2 Immunocytokine (DI-Leu16-IL-2) i. See www.clinicaltrials.gov, NCT01874288 and NCT02151903 ii. See Gillies et al. 2005, Blood, May 15;105(10):3972-8 j) Simlukafusp alfa i. CAS Number -> 1776942-10-9
  • both the anti-CD25 ADC and IL-2 when used as a single agent in isolation have demonstrated clinical utility - for example, in the treatment of cancer.
  • combination of the anti-CD25 ADC and IL-2 is expected to provide one or more of the following advantages over treatment with either anti-CD25 ADC or IL-2 alone:
  • Effective treatment of a broader range of cancers as used herein means that following treatment with the combination a complete response is observed with a greater range of recognised cancer types. That is, a complete response is seen from cancer types not previously reported to completely respond to either anti-CD25 ADC or IL-2 alone.
  • Effective treatment of a resistant, refractory, or relapsed forms as used herein means that following treatment with the combination a complete response is observed in individuals that are either partially or completely resistant or refractory to treatment with either anti-CD25 ADC or IL-2 alone (for example, individuals who show no response or only partial response following treatment with either agent alone, or those with relapsed disorder).
  • a complete response following treatment with the anti-CD25 ADC I IL-2 combination is observed at least 10% of individuals that are either partially or completely resistant or refractory to treatment with either anti-CD25 ADC or IL- 2 alone.
  • a complete response following treatment with the anti-CD25 ADC I IL-2 combination is observed at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% of individuals that are either partially or completely resistant or refractory to treatment with either anti-CD25 ADC or IL-2 alone.
  • Increased response rate to treatment as used herein means that following treatment with the combination a complete response is observed in a greater proportion of individuals than is observed following treatment with either anti-CD25 ADC or IL-2 alone.
  • a complete response following treatment with the anti-CD25 ADC I IL-2 combination is observed at least 10% of treated individuals.
  • a complete response following treatment with the anti-CD25 ADC I IL-2 combination is observed at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% of treated individuals.
  • Increased durability of treatment means that average duration of complete response in individuals treated with the combination is longer than in individuals who achieve complete response following treatment with either anti-CD25 ADC or IL-2 alone.
  • the average duration of a complete response following treatment with the anti-CD25 ADC I IL-2 combination is at least 6 months.
  • the average duration of a complete response following treatment with the anti-CD25 ADC I IL-2 combination is at least 12 months, at least 18 months, at least 24 months, at least 3 years, at least 4 years, at least 5 years, at least 6 years, at least 7 years, at least 8 years, at least 9 years, at least 10 years, at least 15 years, or at least 20 years.
  • Compplete response is used herein to mean the absence of any clinical evidence of disease in an individual. Evidence may be assessed using the appropriate methodology in the art, for example CT or PET scanning, or biopsy where appropriate.
  • the number of doses required to achieve complete response may be one, two, three, four, five, ten or more. In some embodiments the individuals achieve complete response no more than a year after administration of the first dose, such as no more than 6 months, no more than 3 months, no more than a month, no more than a fortnight, or no more than a week after administration of the first dose.
  • the therapies described herein include those with utility for anticancer activity.
  • the therapies include an antibody conjugated, i.e. covalently attached by a linker, to a PBD drug moiety, i.e. toxin.
  • a linker i.e. covalently attached by a linker
  • the PBD drug has a cytotoxic effect.
  • the biological activity of the PBD drug moiety is thus modulated by conjugation to an antibody.
  • the antibody-drug conjugates (ADC) of the disclosure selectively deliver an effective dose of a cytotoxic agent to tumor tissue whereby greater selectivity, i.e. a lower efficacious dose, may be achieved.
  • the present disclosure provides combined therapies comprising administering an anti-CD25 ADC which binds CD25 for use in therapy, wherein the method comprises selecting a subject based on expression of the target protein.
  • the present disclosure provides a combined therapy with a label that specifies that the therapy is suitable for use with a subject determined to be suitable for such use.
  • the label may specify that the therapy is suitable for use in a subject has expression of CD25, such as overexpression of CD25.
  • the label may specify that the subject has a particular type of cancer.
  • a combined therapy as described herein for use in the treatment of a proliferative disease provides the use of a conjugate compound in the manufacture of a medicament for treating a proliferative disease.
  • proliferative disease pertains to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo.
  • proliferative conditions include, but are not limited to, benign, pre-malignant, and malignant cellular proliferation, including but not limited to, neoplasms and tumours (e.g. histocytoma, glioma, astrocyoma, osteoma), cancers (e.g.
  • lung cancer small cell lung cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carinoma, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreas cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, melanoma), lymphomas, leukemias, psoriasis, bone diseases, fibroproliferative disorders (e.g. of connective tissues), and atherosclerosis.
  • Cancers of interest include, but are not limited to, leukemias and ovarian cancers.
  • Any type of cell may be treated, including but not limited to, lung, gastrointestinal (including, e.g. bowel, colon), breast (mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin.
  • gastrointestinal including, e.g. bowel, colon
  • breast mammary
  • ovarian prostate
  • liver hepatic
  • kidney renal
  • bladder pancreas
  • brain and skin.
  • Non-Hodgkin’s Lymphoma including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, (FL), Mantle Cell lymphoma (MCL), chronic lymphatic lymphoma (CLL), and Marginal Zone B- cell lymphoma (MZBL), and leukemias such as Hairy cell leukemia (HCL), Hairy cell leukemia variant (HCL-v), anaplastic large cell lymphoma (ALCL), and Acute Lymphoblastic Leukaemia (ALL) such as Philadelphia chromosome-positive ALL (Ph+ALL) or Philadelphia chromosome-negative ALL (Ph-ALL).
  • DLBCL diffuse large B-cell lymphoma
  • FL Mantle Cell lymphoma
  • CLL chronic lymphatic lymphoma
  • MZBL Marginal Zone B- cell lymphoma
  • leukemias such as Hairy cell leukemia (HCL), Hairy cell leukemia variant (HCL-v), anaplastic large cell
  • the proliferative disease may be characterised by the presence of a neoplasm comprising both CD25+ve and CD25-ve cells.
  • the proliferative disease may be characterised by the presence of a neoplasm composed of CD25-ve neoplastic cells, optionally wherein the CD25-ve neoplastic cells are associated with CD25+ve non-neoplastic cells such as CD25+ve T-cells.
  • the target neoplasm or neoplastic cells may be all or part of a solid tumour.
  • Solid tumor herein will be understood to include solid haematological cancers such as lymphomas (Hodgkin’s lymphoma or non-Hodgkin’s lymphoma) which are discussed in more detail herein.
  • lymphomas Hodgkin’s lymphoma or non-Hodgkin’s lymphoma
  • Solid tumors may be neoplasms, including non-haematological cancers, comprising or composed of CD25+ve neoplastic cells.
  • Solid tumors may be neoplasms, including non- haematological cancers, infiltrated with CD25+ve cells, such as CD25+ve T-cells; such solid tumours may lack expression of CD25 (that is, comprise or be composed of CD25- ve neoplastic cells).
  • the solid tumour may be a tumour with high levels of infiltrating T-cells, such as infiltrating regulatory T-cells (Treg; Menetrier-Caux, C., et al., Targ Oncol (2012) 7:15- 28; Arce Vargas et al., 2017, Immunity 46, 1-10; Tanaka, A., et al., Cell Res. 2017 Jan;27(1):109-118).
  • the solid tumour may be pancreatic cancer, breast cancer, colorectal cancer, gastric and oesophageal cancer, leukemia and lymphoma, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular carcinoma, renal cell carcinoma, and head and neck cancer.
  • the proliferative disorder is a T-cell lymphoma.
  • the disorder is anaplastic large cell lymphoma (ALCL), such as ALK-pos or ALK-neg ALCL.
  • ALCL anaplastic large cell lymphoma
  • the combined therapies of the present disclosure may be used to treat various diseases or disorders, e.g. characterized by the overexpression of a tumor antigen.
  • exemplary conditions or hyperproliferative disorders include benign or malignant tumors; leukemia, haematological, and lymphoid malignancies.
  • Others include neuronal, glial, astrocytal, hypothalamic, glandular, macrophagal, epithelial, stromal, blastocoelic, inflammatory, angiogenic and immunologic, including autoimmune disorders and graft- versus-host disease (GVHD).
  • GVHD graft- versus-host disease
  • the disease or disorder to be treated is a hyperproliferative disease such as cancer.
  • cancer to be treated herein include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g.
  • lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer.
  • lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer,
  • Autoimmune diseases for which the combined therapies may be used in treatment include rheumatologic disorders (such as, for example, rheumatoid arthritis, Sjogren's syndrome, scleroderma, lupus such as SLE and lupus nephritis, polymyositis/dermatomyositis, cryoglobulinemia, anti-phospholipid antibody syndrome, and psoriatic arthritis), osteoarthritis, autoimmune gastrointestinal and liver disorders (such as, for example, inflammatory bowel diseases (e.g.
  • autoimmune gastritis and pernicious anemia autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, and celiac disease
  • vasculitis such as, for example, ANCA-associated vasculitis, including Churg-Strauss vasculitis, Wegener's granulomatosis, and polyarteriitis
  • autoimmune neurological disorders such as, for example, multiple sclerosis, opsoclonus myoclonus syndrome, myasthenia gravis, neuromyelitis optica, Parkinson’s disease, Alzheimer’s disease, and autoimmune polyneuropathies
  • renal disorders such as, for example, glomerulonephritis, Goodpasture’s syndrome, and Berger’s disease
  • autoimmune dermatologic disorders such as, for example, psoriasis, urticaria, hives, pemphigus vulgaris, bullous pemphigoid,
  • Graves’ disease and thyroiditis More preferred such diseases include, for example, rheumatoid arthritis, ulcerative colitis, ANCA-associated vasculitis, lupus, multiple sclerosis, Sjogren's syndrome, Graves’ disease, IDDM, pernicious anemia, thyroiditis, and glomerulonephritis.
  • the subject has a proliferative disorder selected from (classical) Hodgkin lymphomas, with mixed cellularity type (Hodgkin-/Reed-Sternbert-Cells: CD25 +/-), or non-Hodgkin lymphoma, including B-cell chronic lymphatic leukemaia, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, (FL), Mantle Cell lymphoma (MCL), chronic lymphatic lymphoma (CLL), Marginal Zone B-cell lymphoma (MZBL) and leukemias such as Hairy cell leukemia (HCL), Hairy cell leukemia variant (HCL-v), Acute Myeloid Leukaemia (AML), anaplastic large cell lymphoma (ALCL), Acute Lymphoblastic Leukaemia (ALL) such as Philadelphia chromosome-positive ALL (Ph+ALL) or Philadelphia chromosome-negative ALL (Ph-ALL) [Fielding A.,
  • the subject has a proliferative disease characterised by the presence of a neoplasm comprising both CD25+ve and CD25-ve cells.
  • the proliferative disease may be characterised by the presence of a neoplasm composed of CD25-ve neoplastic cells, optionally wherein the CD25-ve neoplastic cells are associated with CD25+ve non-neoplastic cells such as CD25+ve T-cells.
  • the target neoplasm or neoplastic cells may be all or part of a solid tumour.
  • Solid tumors may be neoplasms, including non-haematological cancers, comprising or composed of CD25+ve neoplastic cells.
  • Solid tumors may be neoplasms, including non- haematological cancers, infiltrated with CD25+ve cells, such as CD25+ve T-cells; such solid tumours may lack expression of CD25 (that is, comprise or be composed of CD25- ve neoplastic cells).
  • the solid tumour may be a tumour with high levels of infiltrating T-cells, such as infiltrating regulatory T-cells (Treg; Menetrier-Caux, C., et al., Targ Oncol (2012) 7:15- 28; Arce Vargas et al., 2017, Immunity 46, 1-10; Tanaka, A., et al., Cell Res. 2017 Jan;27(1):109-118).
  • the solid tumour may be pancreatic cancer, breast cancer, colorectal cancer, gastric and oesophageal cancer, leukemia and lymphoma, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular carcinoma, renal cell carcinoma, and head and neck cancer.
  • Classical Hodgkins lymphoma includes the subtypes nodular sclerosing, lymphocyte predominant, lymphocyte depleted and mixed cellularity.
  • the Hodgkins lymphoma subtype may not be defined.
  • the patients tested according to the methods here have Hodgkins lymphoma of the nodular sclerosing and mixed cellularity subtypes.
  • the subject has diffuse large B cell lymphoma or peripheral T cell lymphoma, including the anaplastic large cell lymphoma and angioimmunoblastic T cell lymphoma subtypes.
  • the individuals are selected as suitable for treatment with the combined treatments before the treatments are administered.
  • individuals who are considered suitable for treatment are those individuals who are expected to benefit from, or respond to, the treatment.
  • Individuals may have, or be suspected of having, or be at risk of having cancer.
  • Individuals may have received a diagnosis of cancer.
  • individuals may have, or be suspected of having, or be at risk of having, lymphoma.
  • individuals may have, or be suspected of having, or be at risk of having, a solid cancer that has tumour associated non-tumor cells that express CD25, such as infiltrating cells that express CD25.
  • subjects are selected on the basis of the amount or pattern of expression of CD25. In some aspects, the selection is based on expression of CD25 at the cell surface in a tissue or structure of interest. So, in some cases, subjects are selected on the basis they have, or are suspected of having, are at risk of having, or have received a diagnosis of a proliferative disease characterized by the presence of a neoplasm comprising or associated with cells having surface expression of CD25.
  • the neoplasm may be composed of cells having surface expression of CD25.
  • subjects are selected on the basis they have a neoplasm comprising both CD25+ve and CD25-ve cells.
  • the neoplasm may be composed of CD25-ve neoplastic cells, optionally wherein the CD25-ve neoplastic cells are associated with CD25+ve non-neoplastic cells such as CD25+ve Tregs.
  • the neoplasm or neoplastic cells may be all or part of a solid tumour.
  • the solid tumour may be partially or wholly CD25-ve, and may be infiltrated with CD25+ve cells, such as CD25+ve Tregs.
  • the solid tumour is associated with high-levels of CD25+ve infiltrating cells, such as Treg cells.
  • the solid tumour is associated with low-levels of CD25+ve infiltrating cells, such as Treg cells. In some aspects, the solid tumour is not associated with CD25+ve infiltrating cells, such as Treg cells; for example, the levels of CD25+ve cells may be below the detection limit.
  • expression of CD25 in a particular tissue of interest is determined. For example, in a sample of tumor tissue. In some cases, systemic expression of CD25 is determined. For example, in a sample of circulating fluid such as blood, plasma, serum or lymph.
  • the subject is selected as suitable for treatment due to the presence of CD25 expression in a sample. In those cases, subjects without CD25 expression may be considered not suitable for treatment.
  • the level of CD25 expression is used to select a subject as suitable for treatment. Where the level of expression of the target is above a threshold level, the subject is determined to be suitable for treatment.
  • an subject is indicated as suitable for treatment if cells obtained from the tumour react with antibodies against CD25 as determined by IHC.
  • a subject is determined to be suitable for treatment if at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or more of all cells in the sample express CD25. In some aspects disclosed herein, a subject is determined to be suitable for treatment if at least at least 5% of the cells in the sample express CD25.
  • the presence of CD25 and/or in cells in the sample indicates that the individual is suitable for treatment with a combination comprising an anti-CD25 ADC and an IL-2.
  • the amount of CD25 and/or expression must be above a threshold level to indicate that the individual is suitable for treatment.
  • the observation that CD25 and/or localisation is altered in the sample as compared to a control indicates that the individual is suitable for treatment.
  • an individual is indicated as suitable for treatment if cells obtained from lymph node or extra nodal sites react with antibodies against CD25 and/or as determined by IHC.
  • a patient is determined to be suitable for treatment if at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or more of all cells in the sample express CD25. In some aspects disclosed herein, a patient is determined to be suitable for treatment if at least at least 10% of the cells in the sample express CD25.
  • a patient is determined to be suitable for treatment if at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or more of all cells in the sample express. In some aspects disclosed herein, a patient is determined to be suitable for treatment if at least at least 10% of the cells in the sample express.
  • the individual is selected as suitable for treatment based on their current or previous treatment regime. In some embodiments the individual is selected for treatment with the anti-CD25 ADC if the individual has been treated with an IL-2. In some embodiments the individual is selected for treatment with the anti-CD25 ADC if the individual is being treated with an IL-2. In some cases the individual is selected for treatment if they are refractory to treatment (or further treatment) with the IL-2. In some cases the IL-2 may be, or comprise, a polypeptide having at least 70% sequence identity to SEQ ID NO.12, such as 90% sequence identity to SEQ ID NO.12. Preferably, the IL-2 specifically binds IL-2R and/or activates IL-2 signalling.
  • the anti-CD25 ADC may be administered in combination with an IL-2, or without continued administration of the IL-2.
  • the anti-CD25 ADC is administered to the selected individual in combination with an IL-2. In some embodiments the anti-CD25 ADC is administered to the selected individual without continued administration of an IL-2.
  • refractory to treatment (or further treatment) with the IL-2 is used herein to mean that the disorder (such as cancer) does not respond, or has ceased to respond, to administration of the IL-2 when administered as a monotherapy.
  • individuals with refractory NHL are identified using the response criteria disclosed in Cheson at al., 2014 (South Asian J Cancer. 2014 Jan-Mar; 3(1): 66-70).
  • non-responders are defined as individuals where there is either (i) a >50% increase from nadir in the sum product of diameters of any previously identified abnormal node, or (ii) an appearance of any new lesion during or at the end of therapy.
  • individuals with refractory leukaemia are identified as individuals with either stable or progressive disease who have completed one complete treatment cycle, or individual achieving partial response after two or more complete treatment cycles.
  • the sample may comprise or may be derived from: a quantity of blood; a quantity of serum derived from the individual’s blood which may comprise the fluid portion of the blood obtained after removal of the fibrin clot and blood cells; a quantity of pancreatic juice; a tissue sample or biopsy; or cells isolated from said individual.
  • a sample may be taken from any tissue or bodily fluid.
  • the sample may include or may be derived from a tissue sample, biopsy, resection or isolated cells from said individual.
  • the sample is a tissue sample.
  • the sample may be a sample of tumor tissue, such as cancerous tumor tissue.
  • the sample may have been obtained by a tumor biopsy.
  • the sample is a lymphoid tissue sample, such as a lymphoid lesion sample or lymph node biopsy.
  • the sample is a skin biopsy.
  • the sample is taken from a bodily fluid, more preferably one that circulates through the body. Accordingly, the sample may be a blood sample or lymph sample. In some cases, the sample is a urine sample or a saliva sample.
  • the sample is a blood sample or blood-derived sample.
  • the blood derived sample may be a selected fraction of a individual’s blood, e.g. a selected cellcontaining fraction or a plasma or serum fraction.
  • a selected cell-containing fraction may contain cell types of interest which may include white blood cells (WBC), particularly peripheral blood mononuclear cells (PBC) and/or granulocytes, and/or red blood cells (RBC).
  • WBC white blood cells
  • PBC peripheral blood mononuclear cells
  • RBC red blood cells
  • methods according to the present disclosure may involve detection of a first target polypeptide or nucleic acid in the blood, in white blood cells, peripheral blood mononuclear cells, granulocytes and/or red blood cells.
  • the sample may be fresh or archival.
  • archival tissue may be from the first diagnosis of an individual, or a biopsy at a relapse.
  • the sample is a fresh biopsy.
  • the first target polypeptide may be CD25.
  • the individual may be an animal, mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a monotreme (e.g., duckbilled platypus), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), an a
  • the individual may be any of its forms of development, for example, a foetus.
  • the individual is a human.
  • the terms “subject”, “patient” and “individual” are used interchangeably herein.
  • an individual has, or is suspected as having, or has been identified as being at risk of, cancer.
  • the individual has already received a diagnosis of cancer.
  • the individual may have received a diagnosis of a proliferative disease characterised by the presence of a neoplasm comprising both CD25+ve and CD25-ve cells.
  • the proliferative disease may be characterised by the presence of a neoplasm composed of CD25-ve neoplastic cells, optionally wherein the CD25-ve neoplastic cells are associated with CD25+ve non-neoplastic cells such as CD25+ve T-cells.
  • the individual has received a diagnosis of a solid tumour containing CD25+ expressing infiltrating cells.
  • Solid tumors may be neoplasms, including non-haematological cancers, comprising or composed of CD25+ve neoplastic cells.
  • Solid tumors may be neoplasms, including non- haematological cancers, infiltrated with CD25+ve cells, such as CD25+ve T-cells; such solid tumours may lack expression of CD25 (that is, comprise or be composed of CD25- ve neoplastic cells).
  • the solid tumour may be a tumour with high levels of infiltrating T-cells, such as infiltrating regulatory T-cells (Treg; Menetrier-Caux, C., et al., Targ Oncol (2012) 7:15- 28; Arce Vargas et al., 2017, Immunity 46, 1-10; Tanaka, A., et al., Cell Res. 2017 Jan;27(1):109-118).
  • the solid tumour may be pancreatic cancer, breast cancer, colorectal cancer, gastric and oesophageal cancer, leukemia and lymphoma, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular carcinoma, renal cell carcinoma, and head and neck cancer.
  • the Individual may be undergoing, or have undergone, a therapeutic treatment for that cancer.
  • the subject may, or may not, have previously received ADCX25.
  • the cancer is lymphoma, including non-Hodgkins lymphoma.
  • the Individual may be undergoing, or have undergone, treatment with an IL-2.
  • the individual may be refractory to treatment (or further treatment) with the IL-2.
  • the IL-2 may be, or comprise, a polypeptide having at least 70% sequence identity to SEQ ID NO.12, such as 90% sequence identity to SEQ ID NO.12.
  • the IL-2 specifically binds IL-2R and/or activates IL-2 signalling.
  • the anti-CD25 ADC may be administered in combination with an IL-2, or without continued administration of the IL-2.
  • target expression in the individual is compared to target expression in a control.
  • Controls are useful to support the validity of staining, and to identify experimental artefacts.
  • control may be a reference sample or reference dataset.
  • the reference may be a sample that has been previously obtained from a individual with a known degree of suitability.
  • the reference may be a dataset obtained from analyzing a reference sample.
  • Controls may be positive controls in which the target molecule is known to be present, or expressed at high level, or negative controls in which the target molecule is known to be absent or expressed at low level.
  • Controls may be samples of tissue that are from individuals who are known to benefit from the treatment.
  • the tissue may be of the same type as the sample being tested.
  • a sample of tumor tissue from a individual may be compared to a control sample of tumor tissue from a individual who is known to be suitable for the treatment, such as a individual who has previously responded to the treatment.
  • control may be a sample obtained from the same individual as the test sample, but from a tissue known to be healthy.
  • a sample of cancerous tissue from a individual may be compared to a non-cancerous tissue sample.
  • control is a cell culture sample.
  • test sample is analyzed prior to incubation with an antibody to determine the level of background staining inherent to that sample.
  • Isotype controls use an antibody of the same class as the target specific antibody, but are not immunoreactive with the sample. Such controls are useful for distinguishing non-specific interactions of the target specific antibody.
  • the methods may include hematopathologist interpretation of morphology and immunohistochemistry, to ensure accurate interpretation of test results.
  • the method may involve confirmation that the pattern of expression correlates with the expected pattern. For example, where the amount of CD25 expression is analyzed, the method may involve confirmation that in the test sample the expression is observed as membrane staining, with a cytoplasmic component. The method may involve confirmation that the ratio of target signal to noise is above a threshold level, thereby allowing clear discrimination between specific and non-specific background signals.
  • treatment pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, regression of the condition, amelioration of the condition, and cure of the condition.
  • Treatment as a prophylactic measure i.e., prophylaxis, prevention is also included.
  • terapéuticaally-effective amount or “effective amount” as used herein, pertains to that amount of an active compound, or a material, composition or dosage from comprising an active compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
  • prophylactically-effective amount refers to that amount of an active compound, or a material, composition or dosage from comprising an active compound, which is effective for producing some desired prophylactic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
  • a method of treatment comprising administering to a subject in need of treatment a therapeutically-effective amount of an anti-CD25 ADC and an IL-2.
  • therapeutically effective amount is an amount sufficient to show benefit to a subject. Such benefit may be at least amelioration of at least one symptom.
  • the actual amount administered, and rate and time-course of administration, will depend on the nature and severity of what is being treated. Prescription of treatment, e.g. decisions on dosage, is within the responsibility of general practitioners and other medical doctors.
  • the subject may have been tested to determine their eligibility to receive the treatment according to the methods disclosed herein.
  • the method of treatment may comprise a step of determining whether a subject is eligible for treatment, using a method disclosed herein.
  • the anti-CD25 ADC comprises an anti-CD25 antibody.
  • the anti-CD25 antibody may be HuMax-TACTM.
  • the ADC may comprise a drug which is a PBD dimer.
  • the ADC may be an anti-CD25-ADC, and in particular, ADCX25 or ADCT-301.
  • the ADC may be an ADC disclosed in WO2014/057119.
  • the IL-2 may be, or comprise, a polypeptide having at least 70% sequence identity to SEQ ID NO.12, such as 90% sequence identity to SEQ ID NO.12.
  • the IL-2 specifically binds IL-2R and/or activates IL-2 signalling.
  • the treatment may involve administration of the anti-CD25 ADC I IL-2 combination alone or in further combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated.
  • An example method of treatment involves:
  • treatments and therapies include, but are not limited to, chemotherapy (the administration of active agents, including, e.g. drugs, such as chemotherapeutics); surgery; and radiation therapy.
  • a “chemotherapeutic agent” is a chemical compound useful in the treatment of cancer, regardless of mechanism of action.
  • Classes of chemotherapeutic agents include, but are not limited to: alkylating agents, antimetabolites, spindle poison plant alkaloids, cytotoxic/antitumor antibiotics, topoisomerase inhibitors, antibodies, photosensitizers, and kinase inhibitors.
  • Chemotherapeutic agents include compounds used in “targeted therapy” and conventional chemotherapy.
  • chemotherapeutic agents include: Lenalidomide (REVLIMID®, Celgene), Vorinostat (ZOLINZA®, Merck), Panobinostat (FARYDAK®, Novartis), Mocetinostat (MGCD0103), Everolimus (ZORTRESS®, CERTICAN®, Novartis), Bendamustine (TREAKISYM®, RIBOMUSTIN®, LEVACT®, TREANDA®, Mundipharma International), erlotinib (TARCEVA®, Genentech/OSI Pharm.), docetaxel (TAXOTERE®, Sanofi- Aventis), 5-FU (fluorouracil, 5-fluorouracil, CAS No.
  • gemcitabine Lilly
  • PD-0325901 CAS No. 391210-10-9, Pfizer
  • cisplatin cis-diamine, dichloroplatinum(ll), CAS No. 15663-27-1
  • carboplatin CAS No. 41575-94-4
  • paclitaxel TAXOL®, Bristol-Myers Squibb Oncology, Princeton, N.J.
  • trastuzumab HERCEPTIN®, Genentech
  • temozolomide 4-methyl-5-oxo- 2,3,4,6,8-pentazabicyclo [4.3.0] nona-2,7,9- triene- 9-carboxamide, CAS No.
  • tamoxifen (Z)-2-[4-(1 ,2-diphenylbut-1-enyl)phenoxy]-/V,/ ⁇ /-dimethylethanamine, NOLVADEX®, ISTUBAL®, VALODEX®), and doxorubicin (ADRIAMYCIN®), Akti-1/2, HPPD, and rapamycin.
  • chemotherapeutic agents include: oxaliplatin (ELOXATIN®, Sanofi), bortezomib (VELCADE®, Millennium Pharm.), sutent (SUNITINIB®, SU11248, Pfizer), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), XL-518 (Mek inhibitor, Exelixis, WO 2007/044515), ARRY-886 (Mek inhibitor, AZD6244, Array BioPharma, Astra Zeneca), SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ- 235 (PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis), PTK787/ZK 222584 (Novartis), fulvestrant (FASLODEX®, AstraZeneca), leucovorin (folinic acid), rapamycin (sirol
  • calicheamicin calicheamicin gammall, calicheamicin omegall (Angew Chem. Inti. Ed. Engl. (1994) 33:183-186); dynemicin, dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, morpholinodoxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and
  • chemotherapeutic agent include: (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole),
  • SERMs
  • chemotherapeutic agent therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), pertuzumab (PERJETATM, OMNITARGTM, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), MDX-060 (Medarex) and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).
  • therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), pertuzumab (PERJETATM, OMNITARGTM, 2C4, Genentech), trastuzumab
  • Humanized monoclonal antibodies with therapeutic potential as chemotherapeutic agents in combination with the conjugates of the disclosure include: alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab,
  • compositions according to the present disclosure are preferably pharmaceutical compositions.
  • Pharmaceutical compositions according to the present disclosure, and for use in accordance with the present disclosure may comprise, in addition to the active ingredient, i.e. a conjugate compound, a pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • the precise nature of the carrier or other material will depend on the route of administration, which may be oral, or by injection, e.g. cutaneous, subcutaneous, or intravenous.
  • compositions for oral administration may be in tablet, capsule, powder or liquid form.
  • a tablet may comprise a solid carrier or an adjuvant.
  • Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included.
  • a capsule may comprise a solid carrier such a gelatin.
  • the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
  • a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
  • isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection.
  • Preservatives, stabilisers, buffers, antioxidants and/or other additives may be included, as required.
  • appropriate dosages of the anti-CD25 ADC and/or the IL-2, and compositions comprising these active elements can vary from subject to subject. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects.
  • the selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and prior medical history of the subject.
  • the amount of compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
  • the dosage of anti-CD25 ADC is determined by the expression of CD25 observed in a sample obtained from the subject.
  • the level or localisation of expression of CD25 in the sample may be indicative that a higher or lower dose of anti-CD25 ADC is required.
  • a high expression level of CD25 may indicate that a higher dose of anti-CD25 ADC would be suitable.
  • a high expression level of CD25 may indicate the need for administration of another agent in addition to the anti-CD25 ADC.
  • a high expression level of CD25 may indicate a more aggressive therapy.
  • Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.
  • a suitable dose of each active compound is in the range of about 100 ng to about 25 mg (more typically about 1 pg to about 10 mg) per kilogram body weight of the subject per day.
  • the active compound is a salt, an ester, an amide, a prodrug, or the like
  • the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.
  • each active compound is administered to a human subject according to the following dosage regime: about 100 mg, 3 times daily.
  • each active compound is administered to a human subject according to the following dosage regime: about 150 mg, 2 times daily.
  • each active compound is administered to a human subject according to the following dosage regime: about 200 mg, 2 times daily.
  • each conjugate compound is administered to a human subject according to the following dosage regime: about 50 or about 75 mg, 3 or 4 times daily.
  • each conjugate compound is administered to a human subject according to the following dosage regime: about 100 or about 125 mg, 2 times daily.
  • the dosage amounts described above may apply to the conjugate (including the PBD moiety and the linker to the antibody) or to the effective amount of PBD compound provided, for example the amount of compound that is releasable after cleavage of the linker.
  • the anti-CD25 ADC comprises an anti-CD25 antibody.
  • the anti-CD25 antibody may be HuMax-TAC.
  • the ADC may comprise a drug which is a PBD dimer.
  • the ADC may be an anti-CD25-ADC, and in particular, ADCX25 or ADCT-301.
  • the ADC may be an ADC disclosed in WO2014/057119.
  • the IL-2 may be, or comprise, a polypeptide having at least 70% sequence identity to SEQ ID NO.12, such as 90% sequence identity to SEQ ID NO.12.
  • the IL-2 specifically binds IL-2R and/or activates IL-2 signalling.
  • antibody herein is used in the broadest sense and specifically covers monoclonal antibodies, polyclonal antibodies, dimers, multimers, multispecific antibodies ⁇ e.g., bispecific antibodies), intact antibodies (also described as “full-length” antibodies) and antibody fragments, so long as they exhibit the desired biological activity, for example, the ability to bind CD25 (Miller et al (2003) Jour, of Immunology 170:4854- 4861).
  • Antibodies may be murine, human, humanized, chimeric, or derived from other species such as rabbit, goat, sheep, horse or camel.
  • An antibody is a protein generated by the immune system that is capable of recognizing and binding to a specific antigen.
  • a target antigen generally has numerous binding sites, also called epitopes, recognized by Complementarity Determining Regions (CDRs) on multiple antibodies.
  • CDRs Complementarity Determining Regions
  • An antibody may comprise a full- length immunoglobulin molecule or an immunologically active portion of a full-length immunoglobulin molecule, i.e., a molecule that contains an antigen binding site that immunospecifically binds an antigen of a target of interest or part thereof, such targets including but not limited to, cancer cell or cells that produce autoimmune antibodies associated with an autoimmune disease.
  • the immunoglobulin can be of any type (e.g. IgG, IgE, IgM, IgD, and IgA), class (e.g. lgG1 , lgG2, lgG3, lgG4, lgA1 and lgA2) or subclass, or allotype (e.g.
  • human G1m1, G1m2, G1m3, non-G1m1 [that, is any allotype other than G1m1], G1m17, G2m23, G3m21 , G3m28, G3m11, G3m5, G3m13, G3m14, G3m10, G3m15, G3m16, G3m6, G3m24, G3m26, G3m27, A2m1, A2m2, Km1, Km2 and Km3) of immunoglobulin molecule.
  • the immunoglobulins can be derived from any species, including human, murine, or rabbit origin.
  • Antibody fragments comprise a portion of a full length antibody, generally the antigen binding or variable region thereof.
  • Examples of antibody fragments include Fab, Fab', F(ab')2, and scFv fragments; diabodies; linear antibodies; fragments produced by a Fab expression library, anti-idiotypic (anti-ld) antibodies, CDR (complementary determining region), and epitope-binding fragments of any of the above which immunospecifically bind to cancer cell antigens, viral antigens or microbial antigens, single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.
  • the term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e. the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to polyclonal antibody preparations which include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, the monoclonal antibodies are advantageous in that they may be synthesized uncontaminated by other antibodies.
  • the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
  • the monoclonal antibodies to be used in accordance with the present disclosure may be made by the hybridoma method first described by Kohler et al (1975) Nature 256:495, or may be made by recombinant DNA methods (see, US 4816567).
  • the monoclonal antibodies may also be isolated from phage antibody libraries using the techniques described in Clackson et al (1991) Nature, 352:624-628; Marks et al (1991) J. Mol. Biol., 222:581-597 or from transgenic mice carrying a fully human immunoglobulin system (Lonberg (2008) Curr. Opinion 20(4):450-459).
  • the monoclonal antibodies herein specifically include “chimeric” antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (US 4816567; and Morrison et al (1984) Proc. Natl. Acad. Sci. USA, 81 :6851-6855).
  • Chimeric antibodies include “primatized” antibodies comprising variable domain antigen-binding sequences derived from a non-human primate (e.g. Old World Monkey or Ape) and human constant region sequences.
  • an “intact antibody” herein is one comprising VL and VH domains, as well as a light chain constant domain (CL) and heavy chain constant domains, CH1, CH2 and CH3.
  • the constant domains may be native sequence constant domains (e.g. human native sequence constant domains) or amino acid sequence variant thereof.
  • the intact antibody may have one or more “effector functions” which refer to those biological activities attributable to the Fc region (a native sequence Fc region or amino acid sequence variant Fc region) of an antibody. Examples of antibody effector functions include C1q binding; complement dependent cytotoxicity; Fc receptor binding; antibody-dependent cell- mediated cytotoxicity (ADCC); phagocytosis; and down regulation of cell surface receptors such as B cell receptor and BCR.
  • intact antibodies can be assigned to different “classes.” There are five major classes of intact antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into “subclasses” (isotypes), e.g., lgG1, lgG2, lgG3, lgG4, IgA, and lgA2.
  • the heavychain constant domains that correspond to the different classes of antibodies are called a, 5, E, y, and p, respectively.
  • the subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.
  • Each line on a graph represents the tumour model of an individual animal.
  • the disclosure includes the combination of the aspects and preferred features described except where such a combination is clearly impermissible or expressly avoided.
  • a method of selecting an individual as suitable for treatment with an anti-CD25 ADC wherein the individual is selected for treatment with the anti-CD25 ADC if the individual has been treated with an IL-2.
  • a method of selecting an individual as suitable for treatment with an anti-CD25 ADC wherein the individual is selected for treatment with the anti-CD25 ADC if the individual is being treated with an IL-2.
  • a method for treating a disorder in an individual comprising:
  • a method for treating a disorder in an individual comprising administering to the individual an effective amount of an anti-CD25 ADC and IL-2.
  • the treatment further comprises administering a chemotherapeutic agent.
  • the anti-CD25 ADC comprises a conjugate of formula L - (D L ) P , wherein L is an antibody that binds to CD25, D L is a pyrrolobenzodiazepine (PBD) dimer, and p is preferably from 1 to 8.
  • the conjugate comprises a cleavable linker (Li) connecting L to D L .
  • the anti-CD25 ADC has the chemical structure: wherein Ab is antibody comprising a VH domain having the sequence of SEQ ID NO. 1 and a VL domain having the sequence of SEQ ID NO. 2.
  • the anti-CD25 ADC is ADCx25, ADCT-301 , or Camidanlumab Tesirine.
  • composition, method, use, or kit according any previous paragraph, wherein the individual has, or has been has been determined to have, a disorder characterised by the presence of a neoplasm comprising both CD25+ve and CD25-ve cells.
  • composition, method, use, or kit according any previous paragraph, wherein the individual has, or has been has been determined to have, a disorder characterised by the presence of a neoplasm comprising, or composed of, CD25-ve neoplastic cells.
  • composition, method, use, or kit according to either of paragraphs 24 or 25, wherein the neoplasm is all or part of a solid tumour.
  • the solid tumour is selected from the group consisting of pancreatic cancer, breast cancer (including triple negative breast cancer), colorectal cancer, gastric and oesophageal cancer, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular carcinoma, renal cell carcinoma, bladder, and head and neck cancer.
  • composition, method, use, or kit of any previous paragraph, wherein the disorder is selected from the group comprising:
  • Hodgkin’s and non-Hodgkin’s Lymphoma including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, (FL), Mantle Cell lymphoma (MCL), chronic lymphatic lymphoma (CLL), Marginal Zone B-cell lymphoma (MZBL); leukemias such as Hairy cell leukemia (HCL), Hairy cell leukemia variant (HCL-v), Acute Myeloid Leukaemia (AML), anaplastic large cell lymphoma (ALCL), and Acute Lymphoblastic Leukaemia (ALL) such as Philadelphia chromosome-positive ALL (Ph+ALL) or Philadelphia chromosome-negative ALL (Ph-ALL); pancreatic cancer, breast cancer, colorectal cancer, gastric and oesophageal cancer, leukemia and lymphoma, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular carcinoma, renal cell carcinoma, and head and neck cancer
  • IL-2 is, or comprises, a polypeptide having at least 90% sequence identity to SEQ ID NO.12.
  • IL-2 is, or comprises, a polypeptide having the sequence of SEQ ID NO.12.
  • IL-2 is selected from the group consisting of: Aldesleukin, Interking, NL-201 ,Bempegaldesleukin, ALKS 4230, HQR-707, MDNA109, Pulmoleukin, DI-Leu16-IL-2, Simlukafusp alfa, Bifikafusp alfa, Teleukin, Cergutuzumab amunaleukin, and NHS-IL2-LT.
  • composition comprising an anti-CD25 ADC, for use in a method of treatment according to any one of paragraphs 4 to 40.
  • a kit comprising: a first medicament comprising an anti-CD25 ADC; a package insert comprising instructions for administration of the first medicament according to the method of any one or paragraphs 4 to 40.
  • kit according to paragraph 47 further comprising: a second medicament comprising an IL-2.
  • Example 1 in vivo study of anti-CD25 ADC and IL-2 combination
  • Camidanlumab tesirine is an anti-CD25 antibody-drug conjugate (ADC) conjugated via a protease cleavable linker to SG3199, a highly cytotoxic DNA minor groove crosslinking pyrrolobenzodiazepine dimer (Flynn et al. Mol Cancer Ther 2016, and as described herein).
  • ADC anti-CD25 antibody-drug conjugate
  • MC38 is a CD25-ve mouse colon cancer-derived model used pre-clinically in immunotherapy-type studies which is known to have infiltration of Treg and Teff cells.
  • Surrogate-ADCx25 was studied as monotherapy or in combination with human IL-2 IS (“improved sequence” - single, non-glycosylated polypeptide chain without N-terminal Met and a Cys to Ser substitution at amino acid position 125 // 133 amino acids, 15.4kDa) in the MC38 syngeneic mouse model.
  • mice Female C57BL/6 mice (C57BL/6NCrl, Envigo) were 9-12 weeks old (part A) on Day 0 of the study and had a body weight (BW) range of 17 to 24 g.
  • BW body weight
  • TFS tumor-free survivors
  • the TFS from part A were 17-20 weeks old on Day 0 of the rechallenge study.
  • All ADC doses were administered intravenously on Day 0 as single dose; IL-2 was administered intraperitoneally (i.p.) 48h after the ADC QDx5 on, QDx2 off, for 2 cycles.
  • the dosing volume was 0.2 mL per 20 grams of body weight (10 mL/kg), and was scaled to the body weight of each individual animal.
  • Tumors were measured twice per week until the study was ended on Day 53. Each single mouse was euthanized when its tumor volume reached 2,000 mm 3 and each group was euthanized when the mean tumor volume reached 1500 mm 3 .
  • part B 5 x 10 5 MC38 cells (0.1 mL suspension) were subcutaneously implanted into the right flank (contralateral to the original cell implant) and tumor growth was monitored for 27 days. No treatment was administered in part B of the study.
  • Tumors were measured in two dimensions using calipers, and volume was calculated using the formula:
  • Tumor weight may be estimated with the assumption that 1 mg is equivalent to 1 mm3 of tumor volume.
  • This primary purpose of this study is to explore whether these agents can be safely combined, and if so, will identify the dose(s) and regimens appropriate for further study. The study will also assess whether each combination induces pharmacologic changes in tumor that would suggest potential clinical benefit.
  • Each disease group may include a subset of patients previously treated with the IL-2 to explore whether combination therapy might overcome resistance to IL-2 therapy.
  • it is not intended to apply specific molecular selection as the data available at present generally do not support excluding patients on the basis of approved molecular diagnostic tests.
  • the RDE for already established fo r ADC (in ug/kg administered every three weeks) will be used for all patients in this study.
  • a starting dose below the RDE will be used; the starting dose level will be one where patient benefit could still be demonstrated in study ADC1 , suggesting that patients enrolled at such dose level will gain at least some benefit by taking part.
  • the RDE for already established f o r the IL-2 (in ug/kg administered every three weeks) will be used for all patients in this study.
  • a starting dose below the RDE will be used; the starting dose level will be one where patient benefit could still be demonstrated in study SA1 , suggesting that patients enrolled at such dose level will gain at least some benefit by taking part.
  • the study is comprised of a dose escalation part followed by a dose expansion part.
  • Dose escalation will start with reduced starting doses (compared to their respective recommended phase 2 or licensed dose levels), for both ADC and the IL-2, to guarantee patient safety. Starting doses will be 33% (or 50%) of the RDE for each compound. Subsequently, doses will be first escalated for the IL-2 until the RDE or licensed dose has been reached, or a lower dose if necessary for tolerability reasons. Then, the dose for ADC will be escalated, until the RDE for combination treatment is reached.
  • a perceived safe starting dose of 33% of the intended efficacious dose is proposed for both compounds, but this may need adaptation to lower or higher, as the individual risk profile for the combination may be.
  • Compound 1 should be the compound for which an efficatious clinical dose has been firmly established (at 100%), and which is therefore aimed to be reached quickly in the trial patients by first escalating the dose of this compound.
  • the dose combination is determined to be safe, it may be tested in additional patients to confirm the safety and tolerability at that dose level. Further tailoring of the dose of each compound may be conducted, and/or the regimen may be modified.
  • the dose escalation of the combination will be guided by a Bayesian Logistic Regression Model (BLRM) based on any Dose Limiting Toxicities (DLTs) observed in the first (or first two, TBC) cycles of therapy.
  • BLRM Bayesian Logistic Regression Model
  • DLTs Dose Limiting Toxicities
  • MTD maximum tolerated dose
  • RDE recommended dose for expansion
  • EWOC Escalation With Overdose Control
  • the decisions on new dose combinations are made by the Investigators and sponsor study personnel in a dose escalation safety call (DESC) based upon the review of patient tolerability and safety information (including the BLRM summaries of DLT risk, if applicable) along with PK, PD and preliminary activity information available at the time of the decision.
  • DSC dose escalation safety call
  • the expansion part of the study may be initiated to further assess the safety, tolerability and preliminary efficacy.
  • Dose Level 1 There will be a 24-hour observation before enrolling the second patient at Dose Level 1.
  • the DLT observation period at each dose level is either 1 cycle (3 weeks) or 2 cycles (6 weeks) as mandated by the appropriate authorities for IO therapies, after which it will be determined whether to escalate to the next dose level, stay at the current dose level, or de-escalate to the previous dose level for the next cohort. There will be no de-escalation from Dose Level 1. Intrapatient dose escalation is not permitted.
  • Dose escalation is not permitted unless 2 or more patients have complete DLT information through the first cycle in any given dose level. Dose escalation will be determined by using a mCRM with a target DLT rate of 30% and an equivalence interval of 20% to 35%, and with dose escalation-with-overdose-control (EWOC) and no dose skipping.
  • EWOC dose escalation-with-overdose-control
  • AEs adverse events
  • laboratory values will be closely monitored for all enrolled patients in order to identify any DLTs.
  • a single MTD/RDE will be defined; a disease-specific MTD/RDE will not be established.
  • the mCRM will be implemented for DE under the oversight of a Dose Escalation Steering Committee (DESC).
  • the DESC will confirm each escalating dose level after reviewing all available safety data. PK data from patients in that dose level and prior dose levels may also inform decision making.
  • the DESC may halt dose escalation prior to determining the MTD based on emerging PK, PD, toxicity or response data.
  • Additional patients may be included at any dose level to further assess the safety and tolerability if at least 1 patient in the study has achieved a partial response or better, or if further evaluation of PK or PD data is deemed necessary by the DESC to determine the RDE.
  • Dose Escalation will be stopped after 3 cohorts (or at least 6 patients) are consecutively assigned to the same dose level. If the MTD is not reached, the recommended dose for expansion (RDE) will be determined. Prior to the determination of the MTD/RDE a minimum of 6 patients must have been treated with the combination.
  • paired tumor biopsies will be obtained from patients during dose escalation. Analysis of these biopsies will contribute to a better understanding of the relationship between the dose and the pharmacodynamic activity of the combination.
  • a DESC comprised of ADC Therapeutics and the investigators will review patient safety on an ongoing basis during the DE to determine if the dose escalation schedule prescribed by the mCRM warrants modification.
  • PK and/or PD data may also inform decision making.
  • Intermediate doses may be assigned after agreement between ADC Therapeutics and investigators.
  • the DESC may continue to provide oversight during Part 2. No formal Data Safety Monitoring Board (DSMB) will be used.
  • DSMB Data Safety Monitoring Board
  • dose expansion part may begin.
  • the main objective of the expansion part is to further assess the safety and tolerability of the study treatment at the MTD/RDE and to gain a preliminary understanding of the efficacy of the combination compared to historical single agent efficacy data.
  • An important exploratory objective is to assess changes in the immune infiltrate in tumor in response to treatment. This will be assessed in paired tumor biopsies collected from patients, with a minimum of ten evaluable biopsy pairs (biopsy specimens must contain sufficient tumor for analysis) in patients treated at the MTD/RDE. If this is not feasible, collection of these biopsies may be stopped. A minimum of 10 to 20 patients are planned to be treated in each investigational arm,
  • investigational arms will open, one per disease. A total of nine investigational arms may be run in the dose expansion. Should enrollment for any of these groups not be feasible, then enrollment to that group may be closed before the 10 to 20 patients target is met.
  • IL-2 therapy In each treatment group a maximum of approximately six patients who have received and progressed on prior single administration (i.e. not in combination) IL-2 therapy will be allowed to be treated. This number may be increased if a combination shows promise of overcoming resistance to prior treatment with single administration IL-2.
  • TBC Patient must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating institution's guidelines. Patient must be willing to undergo a new tumor biopsy at baseline, and again during therapy on this study.
  • Serum creatinine ⁇ 1.5 x ULN. If serum creatinine > 1.5, the creatinine clearance (calculated using Cockcroft-Gault formula, or measured) must be
  • Total bilirubin > 1.5 x ULN except for patients with Gilbert's syndrome who are excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN
  • ALT Alanine aminotransferase
  • AST Aspartate aminotransferase
  • Impaired cardiac function or clinically significant cardiac disease including any of the following:
  • LVEF Left Ventricular Ejection Fraction
  • HCV Human Immunodeficiency Virus
  • HBV active Hepatitis B
  • HCV Hepatitis C virus infection Testing
  • Malignant disease other than that being treated in this study. Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 2 years prior to study treatment; completely resected basal cell and squamous cell skin cancers; any malignancy considered to be indolent and that has never required therapy; and completely resected carcinoma in situ of any type.
  • hematopoietic colony-stimulating growth factors e.g. G-CSF, GMCSF, M- CSF
  • An erythroid stimulating agent is allowed as long as it was initiated at least 2 weeks prior to the first dose of study treatment.
  • a limited field such as for the treatment of bone pain or a focally painful tunlor mass.
  • Women of child-bearing potential defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during study treatment and for 90 days after the last any dose of study treatment.
  • Highly effective contraception methods include:
  • a dose-limiting toxicity is defined as any of the following events thought to be at least possibly related to ADC per investigator judgment that occurs during the 21 -day DLT evaluation period. Toxicity that is clearly and directly related to the primary disease or to another etiology is excluded from this definition. DLT Definitions
  • a hematologic DLT is defined as:
  • a non-hematologic DLT is defined as:
  • Grade 3 or higher hypersensitivity/infusion-related reaction (regardless of premedication).
  • a grade 3 hypersensitivity I infusion-related reaction that resolves within 8 hours after onset with appropriate clinical management does not qualify as a DLT.
  • ⁇ LVEF decrease to ⁇ 40% or >20% decrease from baseline
  • Grade 3 diarrhea nausea, or vomiting in the absence of premedication that responds to therapy and improves by at least 1 grade within 3 days for Grade 3 events or to ⁇ Grade 1 within 7 days.
  • Patients who experience a DLT that resolves or stabilizes with appropriate medical management may continue treatment at the discretion of the investigator in consultation with the sponsor.
  • VDFLRRWIAFCQSIISTSPQ SEQ ID NO. 11 (human IL-2, immature*):
  • SEQ ID NO. 12 (human IL-2, mature):
  • IL-2 polypeptides of SEQ ID Nos. 9 and 11 are the immature polypeptides comprising a 20 amino-acid leader sequence (underlined) before the start of the mature sequence.

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Abstract

La présente divulgation concerne des polythérapies destinées au traitement d'états pathologiques, tels que le cancer. En particulier, la présente divulgation concerne des polythérapies comprenant un traitement faisant appel à un conjugué anticorps anti-CD25-médicament (ADC anti-CD25) et à un second agent.
PCT/EP2021/077504 2020-10-07 2021-10-06 Polythérapie WO2022074033A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
WO2004045512A2 (fr) 2002-11-15 2004-06-03 Genmab A/S Anticorps monoclonaux humains contre cd25
WO2007044515A1 (fr) 2005-10-07 2007-04-19 Exelixis, Inc. Inhibiteurs de mek et procedes pour les utiliser
WO2014057119A1 (fr) 2012-10-12 2014-04-17 Adc Therapeutics Sàrl Conjugués anticorps - pyrrolobenzodiazépine
WO2016083468A1 (fr) 2014-11-25 2016-06-02 Adc Therapeutics Sa Conjugués anticorps-pyrrolobenzodiazépine
WO2016166341A1 (fr) 2015-04-15 2016-10-20 Van Berkel Patricius Hendrikus Cornelis Conjugués anticorps-médicament spécifiques à un site
WO2020011724A1 (fr) * 2018-07-11 2020-01-16 Adc Therapeutics Sa Polythérapie

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
WO2004045512A2 (fr) 2002-11-15 2004-06-03 Genmab A/S Anticorps monoclonaux humains contre cd25
WO2007044515A1 (fr) 2005-10-07 2007-04-19 Exelixis, Inc. Inhibiteurs de mek et procedes pour les utiliser
WO2014057119A1 (fr) 2012-10-12 2014-04-17 Adc Therapeutics Sàrl Conjugués anticorps - pyrrolobenzodiazépine
WO2016083468A1 (fr) 2014-11-25 2016-06-02 Adc Therapeutics Sa Conjugués anticorps-pyrrolobenzodiazépine
WO2016166341A1 (fr) 2015-04-15 2016-10-20 Van Berkel Patricius Hendrikus Cornelis Conjugués anticorps-médicament spécifiques à un site
WO2020011724A1 (fr) * 2018-07-11 2020-01-16 Adc Therapeutics Sa Polythérapie

Non-Patent Citations (41)

* Cited by examiner, † Cited by third party
Title
"Genbank", Database accession no. NM_000417.2
"Uniprot", Database accession no. P60568-1
ANGEW CHEM. INTL. ED. ENGL., vol. 33, 1994, pages 183 - 186
ARCE VARGAS ET AL., IMMUNITY, vol. 46, 18 April 2017 (2017-04-18), pages 1 - 10, Retrieved from the Internet <URL:http://dx.doi.Org/10.1016/j.immuni.2017.03.013>
ARCE VARGAS ET AL., IMMUNITY, vol. 46, 2017, pages 1 - 10
CARTER, P., NATURE REVIEWS IMMUNOLOGY, vol. 6, 2006, pages 343 - 357
CAS , no. 1957239-90-5
CATANIA ET AL., CELL MIGR. ADHES., vol. 9
CHESON, SOUTH ASIAN J CANCER, vol. 3, no. 1, 2014, pages 66 - 70
CLACKSON ET AL., NATURE, vol. 352, 1991, pages 624 - 628
COLLINS GRAHAM P. ET AL: "Adct-301 (Camidanlumab Tesirine), a Novel PyrrolobenzodiazepineBased CD25-Targeting Antibody Drug Conjugate, in aPhase 1 Study of Relapsed/Refractory Non-HodgkinLymphoma Shows Activity in T-Cell Lymphoma", vol. 132, no. Supplement 1, 29 November 2018 (2018-11-29), US, pages 1658 - 1658, XP055812663, ISSN: 0006-4971, Retrieved from the Internet <URL:https://ashpublications.org/blood/article/132/Supplement%201/1658/273195/Adct301-Camidanlumab-Tesirine-a-Novel> DOI: 10.1182/blood-2018-99-115986 *
EXPERT OPIN. THER. PATENTS, vol. 15, no. 9, 2005, pages 1087 - 1103
F SPRIANO ET AL: "THE ANTI-CD25 ANTIBODY-DRUG CONJUGATE CAMIDANLUMAB TESIRINE (ADCT-301) PRESENTS A STRONG PRECLINICAL ACTIVITY BOTH AS SINGLE AGENT AND IN COMBINATION IN LYMPHOMA CELL LINES", HEMATOLOGICAL ONCOLOGY, 15TH INTERNATIONAL CONFERENCE ON MALIGNANT LYMPHOMA, 2019, LUGANO, 12 June 2019 (2019-06-12), XP055721611, DOI: 10.1002/hon.134_2630 *
FDAEMEA, GUIDELINE ON CLINICAL TRIALS IN SMALL POPULATIONS, 1 February 2007 (2007-02-01)
FIELDING A., HAEMATOLOGICA, vol. 95, no. 1, January 2010 (2010-01-01), pages 8 - 12
FLYNN ET AL., MOL CANCER THER, 2016
GILLESSESN ET AL., EUR J CANCER, vol. 49, no. 1, January 2013 (2013-01-01), pages 35 - 44
GILLIES ET AL., BLOOD, vol. 105, no. 10, 2005, pages 3972 - 8
GISSELBRECHT C ET AL: "Interleukin-2 treatment in lymphoma: A phase II multicenter study", BLOOD, AMERICAN SOCIETY OF HEMATOLOGY, US, vol. 83, no. 8, 1 January 1994 (1994-01-01), pages 2081 - 2085, XP002327659, ISSN: 0006-4971 *
GOLDBERG AARON D ET AL: "Camidanlumab tesirine, an antibody-drug conjugate, in relapsed/refractory CD25-positive acute myeloid leukemia or acute lymphoblastic leukemia: A phase I study", LEUKEMIA RESEARCH, NEW YORK,NY, US, vol. 95, 7 June 2020 (2020-06-07), XP086208177, ISSN: 0145-2126, [retrieved on 20200607], DOI: 10.1016/J.LEUKRES.2020.106385 *
HOLMBERG L A ET AL: "RITUXIMAB AND INTERLEUKIN 2 FOR CD20 POSITIVE NON-HODGKIN'S LYMPHOMA FOLLOWING AUTOLOGOUS TRANSPLANT", BLOOD, AMERICAN SOCIETY OF HEMATOLOGY, US, vol. 100, no. 11, 10 December 2002 (2002-12-10), XP009058800, ISSN: 0006-4971 *
JOURNAL OF CLINICAL ONCOLOGY, vol. 37, pages e14220 - e14220
KLEIN ET AL., ONCOIMMUNOLOGY, vol. 6, no. 3, 11 January 2017 (2017-01-11), pages e1277306
KOHLER ET AL., NATURE, vol. 256, 1975, pages 495
KOVTUN ET AL., CANCER RES., vol. 66, no. 4, 2006, pages 2328 - 2337
KS PEGGS ET AL., CLINICAL AND EXPERIMENTAL IMMUNOLOGY, vol. 157, 2009, pages 9 - 19
LAMBERT J., CURRENT OPIN. IN PHARMACOL., vol. 5, 2005, pages 543 - 549
LONBERG, CURR. OPINION, vol. 20, no. 4, 2008, pages 450 - 459
LOPES, JE. ET AL., J IMMUNOTHER CANCER, vol. 8, no. 1, 2020, pages e000673
MARKS ET AL., J. MOL. BIOL., vol. 222, 1991, pages 581 - 597
MENETRIER-CAUX, C. ET AL., TARG ONCOL, vol. 7, 2012, pages 15 - 28
MORRISON ET AL., PROC. NATL. ACAD. SCI. USA, vol. 81, 1984, pages 6851 - 6855
PAYNE, G, CANCER CELL, vol. 3, 2003, pages 207 - 212
SCHLIEMANN ET AL., CANCER IMMUNOL. RES., vol. 3, 2015, pages 547 - 556
SILVA DA ET AL., NATURE, vol. 565, no. 7738, January 2019 (2019-01-01), pages 186 - 191
SYRIGOSEPENETOS, ANTICANCER RESEARCH, vol. 19, 1999, pages 605 - 614
TANAKA, A. ET AL., CELL RES, vol. 27, no. 1, January 2017 (2017-01-01), pages 109 - 118
TANAKA, A. ET AL., CELL RES., vol. 27, no. 1, January 2017 (2017-01-01), pages 109 - 118
TRAIL ET AL., CANCER IMMUNOL. IMMUNOTHER., vol. 52, 2003, pages 328 - 337
WU ET AL., NATURE BIOTECH., vol. 23, no. 9, 2005, pages 1137 - 1145
XIE ET AL., EXPERT. OPIN. BIOL. THER., vol. 6, no. 3, 2006, pages 281 - 291

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