EP2456790A1 - Combinaison d un anticorps anti-ctla-4 avec divers régimes de traitement pour le traitement synergique de maladies prolifératives - Google Patents

Combinaison d un anticorps anti-ctla-4 avec divers régimes de traitement pour le traitement synergique de maladies prolifératives

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Publication number
EP2456790A1
EP2456790A1 EP09749268.0A EP09749268A EP2456790A1 EP 2456790 A1 EP2456790 A1 EP 2456790A1 EP 09749268 A EP09749268 A EP 09749268A EP 2456790 A1 EP2456790 A1 EP 2456790A1
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EP
European Patent Office
Prior art keywords
ctla
cancer
agent
antibody
ctla4
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
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EP09749268.0A
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German (de)
English (en)
Inventor
Francis Y. Lee
Maria Jure-Kunkel
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Bristol Myers Squibb Co
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Bristol Myers Squibb Co
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Filing date
Publication date
Priority claimed from PCT/US2009/052209 external-priority patent/WO2010014784A2/fr
Application filed by Bristol Myers Squibb Co filed Critical Bristol Myers Squibb Co
Priority to EP15166232.7A priority Critical patent/EP2947098B1/fr
Priority to DK14162613.5T priority patent/DK2769737T3/en
Priority to EP19207926.7A priority patent/EP3659596A1/fr
Priority to EP14162613.5A priority patent/EP2769737B1/fr
Publication of EP2456790A1 publication Critical patent/EP2456790A1/fr
Priority to CY20171100694T priority patent/CY1119128T1/el
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • This invention relates to the fields of oncology and improved therapy regimens.
  • anticancer agents Due to the wide variety of cancers presently observed, numerous anticancer agents have been developed to destroy cancer within the body. These compounds are administered to cancer patients with the objective of destroying or otherwise inhibiting the growth of malignant cells while leaving normal, healthy cells undisturbed. Anticancer agents have been classified based upon their mechanism of action.
  • chemotherapeutic is referred to as a metal coordination complex. It is believed this type of chemotherapeutic forms predominantly inter- strand DNA cross links in the nuclei of cells, thereby preventing cellular replication. As a result, tumor growth is initially repressed, and then reversed.
  • Another type of chemotherapeutic is referred to as an alkylating agent. These compounds function by inserting foreign compositions or molecules into the DNA of dividing cancer cells. As a result of these foreign moieties, the normal functions of cancer cells are disrupted and proliferation is prevented.
  • Another type of chemotherapeutic is an antineoplastic agent. This type of agent prevents, kills, or blocks the growth and spread of cancer cells. Still other types of anticancer agents include nonsteroidal aromastase inhibitors, bifunctional alkylating agents, etc.
  • Chemoimmunotherapy the combination of chemotherapeutic and immunotherapeutic agents, is a novel approach for the treatment of cancer which combines the effects of agents that directly attack tumor cells producing tumor cell necrosis or apoptosis, and agents that modulate host immune responses to the tumor.
  • Chemotherapeutic agents could enhance the effect of immunotherapy by generating tumor antigens to be presented by antigen-presenting cells creating a "polyvalent" tumor cell vaccine, and by distorting the tumor architecture, thus facilitating the penetration of the immunotherapeutic agents as well as the expanded immune population.
  • Ipilimumab is a human anti-human CTLA-4 antibody which blocks the binding of CTLA-4 to CD80 and CD86 expressed on antigen presenting cells and thereby, blocking the negative downregulation of the immune responses elicited by the interaction of these molecules. Since ipilimumab does not recognize mouse CTLA-4, an anti-mouse CTLA-4 antibody (clone UC10-4F10) was used in the studies presented here to investigate the effect of CTLA-4 blockade with chemotherapeutic agents.
  • Dasatinib (SPRYCEL®) is commonly used for the treatment of many types of cancer and represent an attractive class of agents to combine with CTLA-4 blockade.
  • Microtubule-stabilizing agents such as ixabepilone (IXEMPRATM) and paclitaxel (TAXOL®), are commonly used for the treatment of many types of cancer and represent an attractive class of agents to combine with CTLA-4 blockade.
  • IXEMPRATM ixabepilone
  • TAXOL® paclitaxel
  • Nucleoside analogues such as gemcitabine are also commonly used for the treatment of many types of cancers.
  • Gemcitabine is an antimetabolite nucleoside analogue (2',2'-difluorodeoxycytidine) that becomes active after intracellular phosphorylation by deoxycytidine kinase as only its di- and tri-phosphate forms possess cytotoxic activity.
  • the triphosphate form competes with deoxycytidine triphosphate for incorporation into DNA as an inactive base, and the diphosphate form inhibits ribonucleotide reductase, an enzyme that is essential for normal DNA synthesis.
  • Gemcitabine has been studied in a wide variety of malignancies, both as single agent and in combination with other cytotoxic drugs. Moreover it is approved in many countries for the treatment of a variety of neoplasms in man, including pancreatic, ovarian, non-small cell lung, bladder and breast carcinoma. Its therapeutic use in these tumors is also supported by a favorable toxicity profile.
  • Etoposide is a cancer drug that induces strand breaks in cellular DNA by inhibiting topoisomerase II (topoll) religation of cleaved DNA molecules.
  • topoisomerase II topoisomerase II- linked DNA double-strand breaks
  • DSBs topoisomerase II- linked DNA double-strand breaks
  • SSBs single-strand breaks
  • the present inventors have discovered for the first time the synergistic benefit of combining a protein tyrosine kinase inhibitor, such as dasatinib, with an anti-CTLA-4 inhibitor for the treatment of proliferative diseases.
  • a protein tyrosine kinase inhibitor such as dasatinib
  • an anti-CTLA-4 inhibitor for the treatment of proliferative diseases.
  • the present inventors have discovered for the first time the synergistic benefit of combining a microtubuline-stabilizing agent, such as paclitaxel, with an anti-CTLA-4 inhibitor for the treatment of proliferative diseases.
  • the present inventors have discovered for the first time the synergistic benefit of combining a nucleoside analogue, such as gemcitabine, with an anti-CTLA-4 inhibitor for the treatment of proliferative diseases.
  • the present inventors have discovered for the first time the synergistic benefit of combining a DNA double strand inducing agent, such as etoposide, with an anti-CTLA-4 inhibitor for the treatment of proliferative diseases. It is an object of the invention to provide efficacious combination chemotherapeutic treatment regimens wherein one or more of the following: a protein tyrosine kinase inhibitor, a microtubuline-stabilizing agent, a nucleoside analogue, or a DNA double strand inducing agent is combined with one or more anti-CTLA4 agents for the treatment of proliferative diseases.
  • the present invention provides a synergistic method for the treatment of anti-proliferative diseases, including cancer, which comprises administering to a mammalian species in need thereof a synergistic, therapeutically effective amount of:
  • a co-stimulatory pathway modulator such as an anti-CTLA4 antagonist.
  • the proliferative disease is one or more cancerous solid tumors such as lung cancer, pancreatic cancer, colon cancer, prostate cancer, and/or CML or leukemia.
  • the proliferative disease is one or more refractory tumors.
  • the CTLA-4 antibody is ipilimumab or tremelimumab.
  • the protein tyrosine kinase inhibitor is SPRYCEL®, GLEEVEC®, or nilotinib.
  • the microtubulin- stabilizing agent is paclitaxel, TAXOL®, epothilone A, epothilone B, epothilone C, epothilone D, or ixabepilone.
  • the nucleoside analogue is gembitabine.
  • the DNA double strand inducing agent is etoposide, calicheamicin, bleomycin, neocarzinostatin, sulforaphane, or idarubicin.
  • a nucleoside analogue is gemcitabine, BCH-4556, clofarabine, fludarabine, cladribine, cytarabine, puromycin, and fluorouracil.
  • Suitable anti-CTLA4 antagonist agents for use in the methods of the invention include, without limitation, anti-CTLA4 antibodies, human anti-CTLA4 antibodies, mouse anti-CTLA4 antibodies, mammalian anti-CTLA4 antibodies, humanized anti-CTLA4 antibodies, monoclonal anti-CTLA4 antibodies, polyclonal anti-CTLA4 antibodies, chimeric anti-CTLA4 antibodies, MDX-010 (ipilimumab), tremelimumab, anti-CD28 antibodies, anti-CTLA4 adnectins, anti-CTLA4 domain antibodies, single chain anti-CTLA4 fragments, heavy chain anti-CTLA4 fragments, light chain anti-CTLA4 fragments, inhibitors of CTLA4 that agonize the co- stimulatory pathway, the antibodies disclosed in PCT Publication No.
  • CTLA-4 antibodies are described in U.S. Patent Nos. 5,811,097, 5,855,887, 6,051,227, and 6,984,720; in PCT Publication Nos. WO 01/14424 and WO 00/37504; and in U.S. Publication Nos. 2002/0039581 and 2002/086014.
  • Other anti-CTLA-4 antibodies that can be used in a method of the present invention include, for example, those disclosed in: WO 98/42752; U.S. Patent Nos.
  • Additional anti-CTLA4 antagonists include, but are not limited to, the following: any inhibitor that is capable of disrupting the ability of CD28 antigen to bind to its cognate ligand, to inhibit the ability of CTLA4 to bind to its cognate ligand, to augment T cell responses via the co-stimulatory pathway, to disrupt the ability of B7 to bind to CD28 and/or CTLA4, to disrupt the ability of B7 to activate the co-stimulatory pathway, to disrupt the ability of CD80 to bind to CD28 and/or CTLA4, to disrupt the ability of CD80 to activate the co-stimulatory pathway, to disrupt the ability of CD86 to bind to CD28 and/or CTLA4, to disrupt the ability of CD86 to activate the co-stimulatory pathway, and to disrupt the co-stimulatory pathway, in general from being activated.
  • CTL A-4 antibodies are specifically incorporated herein by reference for purposes of description of CTL A-4 antibodies.
  • a preferred clinical CTL A-4 antibody is human monoclonal antibody 10Dl (also referred to as MDX-OlO and ipilimumab and available from Medarex, Inc., Bloomsbury, NJ) is disclosed in WO 01/14424.
  • FIG. 1A-1B illustrates results showing that concurrent treatment with CTLA-4 mAb and dasatinib produced synergistic effects in the SAlN fibrosarcoma tumor model. Dasatinib was administered daily for 11 days ("A") or for 15 days following an intermittent schedule (5 days on/2 days off) ("B").
  • FIG. 2 illustrates results showing that concurrent treatment with dasatinib and CTLA-4 mAb produced synergistic effects in the CT-26 tumor model.
  • FIG. 3A-3C illustrates results showing that treatment with dasatinib augments the cytolytic activity of CTLA-4 mAb.
  • Mice bearing subcutaneous CT26 colon tumors were treated with dasatinib (30 mg/kg, qldxl4, bid, days 4-18 after tumor cell implantation), CTLA-4 mAb (20 mg/kg, q4dx3, days 4, 8, 12 after tumor cell implantation) or the combination of both agents.
  • CTLA-4 mAb (20 mg/kg, q4dx3, days 4, 8, 12 after tumor cell implantation
  • FIG. 4A-4B illustrates results showing that combinatorial treatment with dasatinib and CTLA-4 mAb results in an increase in the ratio of CD8 activated T cells (CD8+CD69+, T effector cells) over A) T regulatory cells (CD4+CD25+FoxP3+, T suppressor cells) and B) Activated CD4+T cells in tumor-draining lymph nodes (TDLN).
  • Mice bearing subcutaneous CT26 colon tumors were treated with dasatinib (30 mg/kg, qldxl4, bid, days 4-18 after tumor cell implantation), CTLA-4 mAb (20 mg/kg, q4dx3, days 4, 8, 12 after tumor cell implantation) or the combination of both agents.
  • TDLN were collected 2 days after the final treatment, and subjected to immunophenotypic characterization by flow cytometry.
  • FIG. 5 illustrates that concurrent treatment with SPRYCEL® and CTLA-4 mAb produced enhanced effects in a P815 tumor model.
  • SPRYCEL® was administered P.O. on days 9-13, 16-20, 23-27 post tumor implantation where as anti-
  • CTLA-4 mAb was dosed IP on days 10, 14, 18.
  • FIG. 6 shows CTLA-4 blockade activity was not abolished by concurrent treatment with etoposide, paclitaxel, or gemcitabine.
  • FIG. 7 shows CTLA-4 blocking mAb in combination with gemcitabine produced synergistic effects. Mice that achieved complete response (“CR”) rejected a second rechallenge with live CT-26 cells, suggesting that this combination treatment elicited a memory immune response.
  • CR complete response
  • FIG. 8 shows CTLA-4 blocking mAb in combination with etoposide produced synergistic effects.
  • FIG. 9 shows CTLA-4 blocking mAb in combination with microtubule- stabilizing agent(s) produced synergistic effect.
  • FIG. 10 shows the order in which the combination CTLA-4 blocking mAB and chemotherapeutic agent are administered has relevance for inhibiting proliferation. As shown, co-administering gemcitabine concurrent with the CTLA-4 blocking mAb showed the greatest anti-proliferative effect as compared to sequential administration.
  • FIG. 11 shows expansion of cytotoxic CD8+ T-cells by treatment with
  • CTLA-4 mAb and ixabepilone produced expansion of cytotoxic T-cells (CD8+CD107+) in this model, but not in combination with paclitaxel.
  • FIG. 12 shows gemcitabine and etoposide promote in vivo cytotoxicity.
  • FIG. 13 shows gemcitabine modulates the composition of immune cells in tumor-draining lymph nodes.
  • FIG. 14 shows Gemcitabine + CTLA-4 blockade modulated expression of genes involved in immune regulation. DETAILED DESCRIPTION OF THE INVENTION
  • the present invention provides a synergistic method for the treatment of anti-proliferative diseases, including cancer, which comprises administering to a mammalian species in need thereof a synergistic, therapeutically effective amount of: (1) a member of the group consisting of : a protein tyrosine kinase inhibitor, such as dasatinib, a microtubuline-stabilizing agent, such as paclitaxel; a nucleoside analogue, such as gemcitabine; or a DNA double strand inducing agent, such as etoposide; and (2) a co-stimulatory pathway modulator, such as an anti-CTLA4 antagonist.
  • a protein tyrosine kinase inhibitor such as dasatinib
  • a microtubuline-stabilizing agent such as paclitaxel
  • a nucleoside analogue such as gemcitabine
  • a DNA double strand inducing agent such as etoposide
  • co-stimulatory pathway modulator
  • Optimal T cell activation requires interaction between the T cell receptor and specific antigen (Bretscher, P. et al, Science, 169:1042-1049 (1970)) (the first signal) and engagement of costimulatory receptors on the surface of the T cell with costimulatory ligands expressed by the antigen-presenting cell (APC) (the second signal). Failure of the T cell to receive a second signal can lead to clonal anergy (Schwartz, R.H., Science, 248:1349-1356 (1990)).
  • CD28 and CTLA-4 are cytotoxic T lymphocyte-associated antigen 4 (CTLA-4, CD152) whose ligands on APC are B7-1 and B7-2 (Linsley, P.S. et al., J. Exp. Med., 173:721-730 (1991); Linsley, P.S. et al., J. Exp. Med., 174:561-569 (1991)).
  • CTLA-4 cytotoxic T lymphocyte-associated antigen 4
  • CD28 and CTLA-4 are closely related members of the Ig superfamily (Brunet, J.F. et al., Nature, 328:267-270 (1987)), they function antagonistically.
  • CD28 is constitutively expressed on the surface of T cells (Gross, J.A.
  • CTLA-4 is not found on resting T cells but is up-regulated for 2-3 days after T cell activation (Lindsten, T. et al., J.
  • CTLA-4 also binds to B7-1 and B7-2 but with greater affinity than CD28 (Linsley, P.S. et al., Immunity, 1 :793-801 (1994)) and antagonizes T cell activation, interferes with IL-2 production and IL-2 receptor expression, and interrupts cell cycle progression of activated T cells (Walunas, T.L. et al., J. Exp. Med., 183:2541-2550 (1996); Krummel, M.F. et al., J. Exp.
  • the overall T cell response is determined by the integration of all signals, stimulatory and inhibitory.
  • CTLA-4 appears to undermine T cell activation, attempts have been made to block CTLA-4 activity in murine models of cancer immunotherapy.
  • administration of anti-CTLA-4 Ab enhanced tumor rejection (Leach, D. R. et al., Science, 271 :1734-1736 (1996)), although little effect was seen with poorly immunogenic tumors such as SMl mammary carcinoma or B16 melanoma.
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • Chemoimmunotherapy the combination of chemotherapeutic and immunotherapeutic agents, is a novel approach for the treatment of cancer which combines the effects of agents that directly attack tumor cells producing tumor cell necrosis or apoptosis, and agents that modulate host immune responses to the tumor.
  • Chemotherapeutic agents could enhance the effect of immunotherapy by generating tumor antigens to be presented by antigen-presenting cells creating a "polyvalent" tumor cell vaccine, and by distorting the tumor architecture, thus facilitating the penetration of the immunotherapeutic agents as well as the expanded immune population.
  • the present invention provides methods for the administration of a protein tyrosine kinase inhibitor in synergistic combination(s) with at least one anti- CTLA4 agent for the treatment of a variety of cancers, including, but not limited to, the following: carcinoma including that of the bladder (including accelerated and metastatic bladder cancer), breast, colon (including colorectal cancer), kidney, liver, lung (including small and non-small cell lung cancer and lung adenocarcinoma), ovary, prostate, testes, genitourinary tract, lymphatic system, rectum, larynx, pancreas (including exocrine pancreatic carcinoma), esophagus, stomach, gall bladder, cervix, thyroid, and skin (including squamous cell carcinoma); hematopoietic tumors of lymphoid lineage including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma,
  • disorders include urticaria pigmentosa, mastocytosises such as diffuse cutaneous mastocytosis, solitary mastocytoma in human, as well as dog mastocytoma and some rare subtypes like bullous, erythrodermic and teleangiectatic mastocytosis, mastocytosis with an associated hematological disorder, such as a myeloproliferative or myelodysplastic syndrome, or acute leukemia, myeloproliferative disorder associated with mastocytosis, mast cell leukemia, in addition to other cancers.
  • mastocytosises such as diffuse cutaneous mastocytosis, solitary mastocytoma in human, as well as dog mastocytoma and some rare subtypes like bullous, erythrodermic and teleangiectatic mastocytosis
  • mastocytosis with an associated hematological disorder such as a myeloproliferative or myelodysplastic syndrome, or acute leukemia,
  • carcinoma including that of the bladder, urothelial carcinoma, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid, testis, particularly testicular seminomas, and skin; including squamous cell carcinoma; gastrointestinal stromal tumors ("GIST"); hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma and Burketts lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhab
  • the combination of a protein tyrosine kinase inhibitor with at least one co- stimulatory pathway modulator, preferably an anti-CTLA4 agent, may also include the addition of an anti-pro liferative cytotoxic agent.
  • Classes of compounds that may be used as anti-pro liferative cytotoxic agents include the following: [0040] Alkylating agents (including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes): Uracil mustard, Chlormethine, Cyclophosphamide (CYTOXAN®), Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, dacarbazine, and Temozolomide.
  • Alkylating agents including, without limitation, nitrogen mustards, ethylenimine derivatives, alky
  • Antimetabolites including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors: Methotrexate, 5-Fluorouracil, Floxuridine, Cytarabine, 6-Mercaptopurine, 6- Thioguanine, Fludarabine phosphate, Pentostatine, and Gemcitabine.
  • a co-stimulatory pathway modulator encompasses one or more of the following: an anti-CTLA4 agent, an anti- CTLA-4 antibody, ipilimumab, and tremelimumab.
  • co-stimulatory pathway modulators of the present invention that may be used in combination with a protein tyrosine kinase inhibitor, either alone or in further combination with other co-stimulatory pathway modulators disclosed herein, or in combination with other compounds disclosed herein include, but are not limited to, the following: agatolimod, belatacept, blinatumomab, CD40 ligand, anti-B7-l antibody, anti-B7-2 antibody, anti-B7-H4 antibody, AG4263, eritoran, anti-OX40 antibody, ISF-154, and SGN-70; B7-1, B7-2, ICAM-I, IC AM-2, ICAM-3, CD48, LFA-3, CD30 ligand, CD40 ligand, heat stable antigen, B7h, OX40 ligand, LIGHT, CD70 and CD24.
  • a method for the synergistic treatment of cancerous tumors is provided.
  • the synergistic method of this invention reduces the development of tumors, reduces tumor burden, or produces tumor regression in a mammalian host.
  • a protein tyrosine kinase inhibitor such as dasatinib
  • a microtubuline-stabilizing agent such as paclitaxel
  • a nucleoside analogue such as gemcitabine
  • a DNA double strand inducing agent such as etoposide
  • an anti-proliferative cytotoxic agent either alone or in combination with radiation therapy.
  • anti-pro liferative cytotoxic agents are navelbene, CPT-I l, anastrazole, letrazole, capecitabine, reloxafme, cyclophosphamide, ifosamide, and droloxafine.
  • Natural products and their derivatives for example, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins: Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Ara-C, paclitaxel (paclitaxel is commercially available as TAXOL®), Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Interferons (especially IFN-a), Etoposide, and Teniposide.
  • Vinblastine Vincristine
  • Vindesine Bleomycin
  • Dactinomycin Daunorubicin
  • Doxorubicin Doxorubicin
  • Epirubicin Idarubicin
  • Ara-C paclitaxel
  • Mitaxel is commercially available as TAXOL®
  • Mithramycin Deoxycoformycin
  • co-stimulatory pathway modulator may include a combination of a co- stimulatory pathway agonist (i.e., immunostimulant), a tubulin stabilizing agent (e.g., pacitaxol, epothilone, taxane, etc.), IXEMPRATM, dacarbazine, PARAPLATIN®, Docetaxel, one or more peptide vaccines, MDX- 1379 Melanoma Peptide Vaccine, one or more gplOO peptide vaccine, fowlpox-P SA-TRIC OMTM vaccine, vaccinia- PS A-TRICOMTM vaccine, MART-I antigen, sargramostim, tremelimumab, Combination Androgen Ablative Therapy; the combination of ipilimumab and another co-stimulatory pathway agonist; combination of ipilimumab and a tubulin stabilizing agent.
  • a co- stimulatory pathway agonist i.e., immuno
  • radiation therapy includes, but is not limited to, x-rays or gamma rays which are delivered from either an externally applied source such as a beam or by implantation of small radioactive sources.
  • dasatinib is also referred to as N-(2-chloro-6- methylphenyl)-2- [ [6- [4-(2-hydroxy ethyl)- 1 -piperazinyl] -2-methyl-4- pyrimidinyl]amino]-5-thiazolecarboxamide and describes a compound having the following structure (I):
  • Compound (I) can also be referred to as JV-(2-chloro-6-methylphenyl)-2- ((6-(4-(2-hydroxyethyl)-l-piperazinyl)-2-methyl-4-pyrimidinyl)amino)-l,3-thiazole- 5-carboxamide in accordance with IUPAC nomenclature.
  • N-(2- chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4- pyrimidinyl]amino]-5-thiazolecarboxamide encompasses (unless otherwise indicated) solvates (including hydrates) and polymorphic forms of the compound (I) or its salts (such as the monohydrate form of (I) described in USSN 11/051 ,208, filed February 4, 2005, incorporated herein by reference in its entirety and for all purposes).
  • compositions of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2- hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide include all pharmaceutically acceptable compositions comprising N-(2-chloro-6- methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l- ⁇ iperazinyl]-2-methyl-4- pyrimidinyl]amino]-5-thiazolecarboxamide and one or more diluents, vehicles and/or excipients, such as those compositions described in USSN 11/402,502, filed April 12, 2006, incorporated herein by reference in its entirety and for all purposes.
  • composition comprising N-(2-chloro-6-methylphenyl)-2- [[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5- thiazolecarboxamide is SPRYCEL® (Bristol-Myers Squibb Company).
  • SPRYCEL® comprises N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)- 1 -piperazinyl]-2- methyl-4-pyrimidinyl] amino]-5-thiazolecarboxamide as the active ingredient, also referred to as dasatinib, and as inactive ingredients or excipients, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate in a tablet comprising hypromellose, titanium dioxide, and polyethylene glycol.
  • Ipilimumab refers to an anti-CTLA-4 antibody, and is a fully human IgG i ⁇ antibody derived from transgenic mice having human genes encoding heavy and light chains to generate a functional human repertoire. Ipilimumab can also be referred to by its CAS Registry No. 477202-00-9, and is disclosed as antibody IODI in PCT Publication No. WO 01/14424, incorporated herein by reference in its entirety and for all purposes.
  • Ipilimumab describes a human monoclonal antibody or antigen-binding portion thereof that specifically binds to CTLA4, comprising a light chain variable region and a heavy chain variable region having a light chain variable region comprised of SEQ ID NO:1, and comprising a heavy chain region comprised of SEQ ID NO:2.
  • Pharmaceutical compositions of Ipilimumab include all pharmaceutically acceptable compositions comprising Ipilimumab and one or more diluents, vehicles and/or excipients. Examples of a pharmaceutical composition comprising Ipilimumab are provided in PCT Publication No. WO 2007/67959. Impilimumab may be administered by I. V. Light chain variable region for Impilimumab:
  • the administration of one or more anti-CTLA4 antagonists may be administered either alone or in combination with a peptide antigen (e.g., gplOO), in addition to an anti-proliferative agent disclosed herein.
  • a peptide antigen e.g., gplOO
  • a non- limiting example of a peptide antigen would be a gplOO peptide comprising, or alternatively consisting of, the sequence selected from the group consisting of: IMDQVPFSV (SEQ ID NO:3), and YLEPGPVTV (SEQ ID NO:4).
  • Such a peptide may be administered orally, or preferably by injection s.c. at 1 mg emulsified in incomplete Freund's adjuvant (IFA) injected s.c. in one extremity, and 1 mg of either the same or a different peptide emulsified in IFA may be injected in another extremity.
  • IFA incomplete Freund's adjuvant
  • paclitaxel refers to a compound having the following structure (II):
  • Compound (II) can also be referred to as 5beta,20-Epoxy- l,2alpha,4,7beta,10beta,13alpha-hexahydroxytax-l l-en-9-one 4,10-diacetate 2- benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine in accordance with IUPAC nomenclature.
  • compositions of 5beta,20-Epoxy- l,2alpha,4,7beta,10beta,13alpha-hexahydroxytax-l l-en-9-one 4,10-diacetate 2- benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine include all pharmaceutically acceptable compositions comprising 5beta,20-Epoxy- l,2alpha,4,7beta,10beta,13alpha-hexahydroxytax-l l-en-9-one 4,10-diacetate 2- benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine and one or more diluents, vehicles and/or excipients.
  • composition comprising 5beta,20-Epoxy- 1 ,2alpha,4,7beta, 1 Obeta, 13alpha-hexahydroxytax- 11 -en- 9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine is TAXOL® (Bristol-Myers Squibb Company).
  • TAXOL® comprises 5beta,20- Epoxy- 1 ,2alpha,4,7beta, 1 Obeta, 13alpha-hexahydroxytax- 11 -en-9-one 4, 10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine as the active ingredient, also referred to as paclitaxel, for IV infusion including inactive ingredients in the form of a diluent consisting of a sterile 0.9% Sodium Chloride injection, USP, 5% Dextrose Injection, USP, 0.9% Sodium Chloride and 5% Dextrose Injection, USP, or 5% Dextrose in Ringer's Injection to a final concentration of 0.3 to 1.2 mg/ml.
  • gemcitabine refers to a compound having the following structure (III):
  • Compound (III) can also be referred to as 2'-deoxy-2',2'-difluorocytidine monohydrochloride ( ⁇ -isomer) in accordance with IUPAC nomenclature.
  • Use of the term "2'-deoxy-2',2'-difluorocytidine monohydrochloride ( ⁇ -isomer)" encompasses (unless otherwise indicated) solvates (including hydrates) and polymorphic forms of the compound (III) or its salts.
  • GEMZ AR® (gemcitabine HCl).
  • GEMZAR® comprises 2'-deoxy-2',2'-difluorocytidine monohydrochloride ( ⁇ -isomer) as the active ingredient, for IV infusion including inactive ingredients in a sterile form for intravenous use only.
  • Vials of GEMZAR® contain either 200 mg or 1 g of gemcitabine HCl (expressed as free base) formulated with mannitol (200 mg or 1 g, respectively) and sodium acetate (12.5 mg or 62.5 mg, respectively) as a sterile lyophilized powder. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment.
  • etoposide refers to a compound having the following structure (IV):
  • Compound (IV) can also be referred to as 4'-Demethylepipodophyllotoxin 9-[4,6-O- (R)-ethylidene- ⁇ -D-glucopyranoside], 4'-(dihydrogen phosphate) in accordance with IUPAC nomenclature.
  • Use of the term "4'-Demethylepipodophyllotoxin 9-[4,6-O- (R)-ethylidene- ⁇ -D-glucopyranoside], 4'-(dihydrogen phosphate)” encompasses (unless otherwise indicated) solvates (including hydrates) and polymorphic forms of the compound (IV) or its salts.
  • compositions of 4'- Demethylepipodophyllotoxin 9-[4,6-O-(R)-ethylidene- ⁇ -D-glucopyranoside], 4'- (dihydrogen phosphate) and one or more diluents, vehicles and/or excipients are included.
  • One example of a pharmaceutical composition comprising 4'-Demethylepipodophyllotoxin 9-[4,6-O-(R)-ethylidene- ⁇ -D-glucopyranoside], 4'-(dihydrogen phosphate) is ETOPOPHOS (etoposide phosphate).
  • ETOPOPHOS comprises 4'-
  • Suitable anti-proliferative agents for use in the methods of the invention include, without limitation, taxanes, paclitaxel (paclitaxel is commercially available as TAXOL®), docetaxel, discodermolide (DDM), dictyostatin (DCT), Peloruside A, epothilones, epothilone A, epothilone B, epothilone C, epothilone D, epothilone E, epothilone F, furanoepothilone D, desoxyepothilone Bl, [17]- dehydrodesoxyepothilone B, [18]dehydrodesoxyepothilones B, C12,13-cyclopropyl- epothilone A, C6-C8 bridged epothilone A, trans-9,10-dehydroepothilone D, cis-9,10- dehydroepothilone D,
  • protein tyrosine kinase inhibitor is meant to refer to agents that inhibit one or more members of the protein tyrosine kinase family.
  • Non- limiting examples of protein tyrosine kinase inhibitors include, but are not limited to, dasatinib, imatinib, nilotinib, PD 180970, GGP76030, AP23464, SKI 606, NS-187, and/or AZD0530.
  • Such protein tyrosine kinase inhibitors may be administered either alone or in combination with other molecules, such as T315I inhibitors.
  • microtubulin modulating agent is meant to refer to agents that either stabilize microtubulin or destabilize microtubulin synthesis and/or polymerization.
  • the at least one anti-proliferative agent may be a microtubule affecting agent.
  • a microtubule affecting agent interferes with cellular mitosis and are well known in the art for their anti-proliferative cytotoxic activity.
  • Microtubule affecting agents useful in the invention include, but are not limited to, allocolchicine (NSC 406042), Halichondrin B (NSC 609395), colchicine (NSC 757), colchicine derivatives (e.g., NSC 33410), dolastatin 10 (NSC 376128), maytansine (NSC 153858), rhizoxin (NSC 332598), paclitaxel (TAXOL®, NSC 125973), TAXOL® derivatives (e.g., derivatives (e.g., NSC 608832), thiocolchicine NSC 361792), trityl cysteine (NSC 83265), vinblastine sulfate (NSC 49842), vincristine sulfate (NSC 67574), natural and synthetic epothilones including but not limited to epothilone A, epothilone B, epothilone C, epothilone D, des
  • Additional antineoplastic agents include, discodermolide (see Service, Science, 274:2009 (1996)) estramustine, nocodazole, MAP4, and the like. Examples of such agents are also described in the scientific and patent literature, see, e.g., Bulinski, J. CeIl ScL, 110:3055-3064 (1997); Panda, Proc. Natl. Acad. ScL USA, 94:10560-10564 (1997); Muhlradt, Cancer Res., 57:3344-3346 (1997); Nicolaou, Nature, 387:268-272 (1997); Vasquez, MoI. Biol. Cell., 8:973-985 (1997); Panda, J. Biol. Chem., 271 :29807-29812 (1996).
  • hormones and steroids include synthetic analogs: 17a- Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyl-testosterone, Prednisolone, Triamcinolone, Chlorotrianisene,
  • Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, ZOLADEX® can also be administered to the patient.
  • antiangiogenics such as matrix metalloproteinase inhibitors, and other VEGF inhibitors, such as anti-VEGF antibodies and small molecules such as ZD6474 and SU6668 are also included.
  • Anti-Her2 antibodies from Genentech may also be utilized.
  • a suitable EGFR inhibitor is EKB-569 (an irreversible inhibitor).
  • CASODEX® also suitable for use as an antiproliferative cytostatic agent is CASODEX® which renders androgen-dependent carcinomas non-proliferative.
  • cytostatic agent is the antiestrogen Tamoxifen which inhibits the proliferation or growth of estrogen dependent breast cancer.
  • Inhibitors of the transduction of cellular proliferative signals are cytostatic agents. Examples are epidermal growth factor inhibitors, Her-2 inhibitors, MEK-I kinase inhibitors, MAPK kinase inhibitors, PB inhibitors, Src kinase inhibitors, and PDGF inhibitors.
  • certain anti-proliferative agents are anti-angiogenic and antivascular agents and, by interrupting blood flow to solid tumors, render cancer cells quiescent by depriving them of nutrition. Castration, which also renders androgen dependent carcinomas non-proliferative, may also be utilized. Starvation by means other than surgical disruption of blood flow is another example of a cytostatic agent.
  • a particularly preferred class of antivascular cytostatic agents is the combretastatins.
  • Other exemplary cytostatic agents include MET kinase inhibitors, MAP kinase inhibitors, inhibitors of non-receptor and receptor tyrosine kinases, inhibitors of integrin signaling, and inhibitors of insulin-like growth factor receptors.
  • the present invention also provides methods for the administration of a protein tyrosine kinase inhibitor, a microtubuline-stabilizing agent, such as paclitaxel; a nucleoside analogue, such as gemcitabine; or a DNA double strand inducing agent, such as etoposide, in synergistic combination(s) with at least one co-stimulatory pathway modulators, particularly an anti-CTLA4 agent, for the treatment and prevention of a proliferative disorder, in addition to a BCR-ABL associated disorder, a mutant BCR-ABL associated disorder, and/or a protein tyrosine kinase-associated disorder, an a disorder associated with the presence of an imatinib-resistant BCR- ABL mutation, a dasatinib-resistant BCR-ABL mutation, CML, imatinib-resistant CML, and/or Imatinib-intolerant CML.
  • a protein tyrosine kinase inhibitor such as
  • BCR-ABL is inclusive of both wild-type and mutant BCR-ABL.
  • BCR-ABL associated disorders are those disorders which result from BCR-ABL activity, including mutant BCR-ABL activity, and/or which are alleviated by the inhibition of BCR-ABL, including mutant BCR-ABL, expression and/or activity.
  • a reciprocal translocation between chromosomes 9 and 22 produces the oncogenic BCR-ABL fusion protein.
  • BCR-ABL associated disorders is inclusive of "mutant BCR-ABL associated disorders”.
  • disorders included in the scope of the present invention include, for example, leukemias, including, for example, chronic myeloid leukemia, acute lymphoblastic leukemia, and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL), squamous cell carcinoma, small-cell lung cancer, non-small cell lung cancer, glioma, gastrointestinal cancer, renal cancer, ovarian cancer, liver cancer, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, neuroblastoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, stomach cancer, bladder cancer, hepatoma, breast cancer, colon carcinoma, and head and neck cancer, gastric cancer, germ cell tumor, pediatric sarcoma, sinonasal natural killer, multiple myeloma, acute myelogenous leukemia, chronic lymphocytic leukemia, mastocytosis and any symptom associated with mastocytosis.
  • leukemias including, for example, chronic
  • disorders include urticaria pigmentosa, mastocytosises such as diffuse cutaneous mastocytosis, solitary mastocytoma in human, as well as dog mastocytoma and some rare subtypes like bullous, erythrodermic and teleangiectatic mastocytosis, mastocytosis with an associated hematological disorder, such as a myeloproliferative or myelodysplastic syndrome, or acute leukemia, myeloproliferative disorder associated with mastocytosis, and mast cell leukemia.
  • Various additional cancers are also included within the scope of protein tyrosine kinase-associated disorders including, for example, the following: carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid, testis, particularly testicular seminomas, and skin; including squamous cell carcinoma; gastrointestinal stromal tumors ("GIST"); hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B- cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma and Burketts lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosar
  • the disorder is leukemia, breast cancer, prostate cancer, lung cancer, colon cancer, melanoma, or solid tumors.
  • the leukemia is chronic myeloid leukemia (CML), Ph+ ALL, AML, imatinib-resistant CML, imatinib-intolerant CML, accelerated CML, lymphoid blast phase CML.
  • a "solid tumor” includes, for example, sarcoma, melanoma, carcinoma, prostate carcinoma, lung carcinoma, colon carcinoma, or other solid tumor cancer.
  • cancer refers to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • cancer include, for example, leukemia, lymphoma, blastoma, carcinoma and sarcoma.
  • cancers include chronic myeloid leukemia, acute lymphoblastic leukemia, Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL), squamous cell carcinoma, small-cell lung cancer, non-small cell lung cancer, glioma, gastrointestinal cancer, renal cancer, ovarian cancer, liver cancer, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, neuroblastoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, stomach cancer, bladder cancer, hepatoma, breast cancer, colon carcinoma, and head and neck cancer, gastric cancer, germ cell tumor, pediatric sarcoma, sinonasal natural killer, multiple myeloma, acute myelogenous leukemia (AML), and chronic lymphocytic leukemia (CML).
  • CML chronic lymphocytic leukemia
  • Leukemia refers to progressive, malignant diseases of the blood-forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease—acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number of abnormal cells in the blood— leukemic or aleukemic (subleukemic).
  • Leukemia includes, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell le
  • a "mutant BCR-ABL” encompasses a BCR-ABL tyrosine kinase with an amino acid sequence that differs from wild type BCR-ABL tyrosine kinase by one or more amino acid substitutions, additions or deletions. For example a substitution of the amino acid at position 507 of SEQ ID NO:2 with another amino acid would result in a mutant BCR-ABL tyrosine kinase.
  • a kinase inhibitor compound can be used to treat a cancerous condition, which compound inhibits the activity of wild type BCR- ABL which will inhibit proliferation and/or induce apoptosis of cancerous cells.
  • a mutation can be introduced into the gene encoding BCR-ABL kinase, which can alter the amino acid sequence of the BCR-ABL kinase and cause the cancer cells to become resistant, or at least partially resistant, to treatment with the compound.
  • a mutation can already be present within the gene encoding BCR-ABL kinase, either genetically or as a consequence of an oncogenic event, independent of treatment with a protein tyrosine kinase inhibitor, which can be one factor resulting in these cells propensity to differentiate into a cancerous or proliferative state, and also result in these cells being less sensitive to treatment with a protein tyrosine kinase inhibitor.
  • mutant BCR-ABL kinase associated disorder Such situations are expected to result, either directly or indirectly, in a "mutant BCR-ABL kinase associated disorder" and treatment of such condition will require a compound that is at least partially effective against the mutant BCR-ABL, preferably against both wild type BCR-ABL and the mutant BCR-ABL.
  • the mutant BCR-ABL associated disorder is one that results from an imatinib-resistant BCR-ABL mutation, or a protein tyrosine kinase inhibitor resistant BCR-ABL mutation.
  • the mutant BCR-ABL associated disorder is one that results from an N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2- hydroxyethyl)- 1 -piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide resistant BCR-ABL mutation, or a protein tyrosine kinase inhibitor resistant BCR- ABL mutation.
  • the present inventors discovered that after treatment with N-(2- chloro-6-methylphenyl)-2-[[6-[4-(2 -hydroxyethyl)- l-piperazinyl]-2-methyl-4- pyrimidinyl]amino]-5-thiazolecarboxamide, certain individuals developed E507G mutations.
  • the present invention provides, among other things, methods of treating mutant BCR-ABL associated disorders and methods of identifying if an individual has a mutant BCR-ABL associated disorder.
  • Protein tyrosine kinase-associated disorders of particular interest herein are those disorders which result, at least in part, from aberrant SRC or BCR-ABL (WT or mutant) activity and/or which are alleviated by the inhibition of SRC or BCR- ABL (WT or mutant) referred to herein as "SRC associated disorders", “SRC associated cancer”, or "BCR-ABL associated disorders", "BCR-ABL associated cancer”
  • Imatinib-resistant BCR-ABL mutation refers to a specific mutation in the amino acid sequence of BCR-ABL that confers upon cells that express said mutation resistance to treatment with imatinib. As discussed herein such mutations can include mutations at the T315I position of BCR-ABL.
  • Additional mutations that may render a BCR-ABL protein at least partially imatinib resistant can include, for example, E279K, F359C, F359I, L364I, L387M, F486S, D233H, T243S, M244V, G249D, G250E, G251S, Q252H, Y253F, Y253H, E255K, E255V, V256L, Y257F, Y257R, F259S, K262E, D263G, K264R, S265R, V268A, V270A, T272A, Y274C, Y274R, D276N, T277P, M278K, E279K, E282G, F283S, A288T, A288V, M290T, K291R, E292G, I293T, P296S, L298M, L298P, V299
  • Dasatinib-resistant BCR-ABL mutation refers to a specific mutation in the amino acid sequence of BCR-ABL that confers upon cells that express said mutation at least partial resistance to treatment with dasatinib. As discussed herein such mutations can include mutations at the T315I, T315A, F317A, F317I, and E507G position of BCR-ABL. Additional dasatinib -resistant BCR-ABL mutations may also include other BCR-ABL mutations disclosed elsewhere herein.
  • Imatinib-resistant CML refers to a CML in which the cells involved in CML are resistant to treatment with imatinib. Generally it is a result of a mutation in BCR-ABL.
  • Imatinib-intolerant CML refers to a CML in which the individual having the CML is intolerant to treatment with imatinib, i.e., the toxic and/or detrimental side effects of imatinib outweigh any therapeutically beneficial effects.
  • the synergistic combination of a protein tyrosine kinase inhibitor, microtubuline-stabilizing agent, such as paclitaxel; a nucleoside analogue, such as gemcitabine; or a DNA double strand inducing agent, such as etoposide with a co- stimulatory pathway modulator may also including the addition of one or more additional compounds, which include but are not limited to the following: a tubulin stabilizing agent (e.g., pacitaxol, epothilone, taxane, etc.); a farnysyl transferase inhibitor (e.g., (R)-2,3,4,5-tetrahydro-l-(lH-imidazol-4-ylmethyl)-3-(phenylmethyl)- 4-(2-thienylsulfonyl)- IH-1 ,4-benzodiazepine-7-carbonitrile, hydrochloride salt); another protein tyrosine kinase inhibitor
  • a "farnysyl transferase inhibitor” can be any compound or molecule that inhibits farnysyl transferase.
  • the farnysyl transferase inhibitor can have formula (II), (R)-2,3,4,5-tetrahydro-l-(lH-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2- thienylsulfonyl)-lH-l,4-benzodiazepine-7-carbonitrile, hydrochloride salt.
  • the compound of formula (V) is a cytotoxic FT inhibitor which is known to kill non- proliferating cancer cells preferentially.
  • the compound of formula (V) can further be useful in killing stem cells.
  • Non-limiting examples of tyrosine kinases include receptor tyrosine kinases such as EGFR (e.g., EGFR/HERl/ErbBl, HER2/Neu/ErbB2, HER3/ErbB3, HER4/ErbB4), INSR (insulin receptor), IGF-IR, IGF-IIlR, IRR (insulin receptor-related receptor), PDGFR (e.g., PDGFRA, PDGFRB), c-KIT/SCFR, VEGFR-I /FLT-I, VEGFR-2/FLK-l/KDR, VEGFR-3/FLT- 4, FLT-3/FLK-2, CSF-IR, FGFR 1-4, CCK4, TRK A-C, MET, RON, EPHA 1-8, EPHB 1-6, AXL, MER, TYR03, TIE, TEK, RYK, DDR 1-2, RET, c-ROS, LTK (leukocyte t
  • tyrosine kinase inhibitor includes any of a variety of therapeutic agents or drugs that act as selective or non-selective inhibitors of receptor and/or non-receptor tyrosine kinases. Without being bound to any particular theory, tyrosine kinase inhibitors generally inhibit target tyrosine kinases by binding to the ATP-binding site of the enzyme.
  • tyrosine kinase inhibitors suitable for use in the methods of the present invention include, but are not limited to, gefitinib (IRESSA®), sunitinib (SUTENT®; SUl 1248), erlotinib (TARCEVA®; OSI-1774), lapatinib (GW572016; GW2016), canertinib (CI 1033), semaxinib (SU5416), vatalanib (PTK787/ZK222584), sorafenib (BAY 43-9006), imatinib (GLEEVEC®; STI571), dasatinib (BMS-354825), lefiunomide (SUlOl), vandetanib (ZACTIMA®; ZD6474), nilotinib, derivatives thereof, analogs thereof, and combinations thereof.
  • gefitinib IRESSA®
  • sunitinib SUTENT®
  • SUl 1248 sunitinib
  • compositions of the present invention may further comprise one or more pharmaceutically acceptable additional ingredient(s) such as alum, stabilizers, antimicrobial agents, buffers, coloring agents, flavoring agents, adjuvants, and the like.
  • additional ingredient(s) such as alum, stabilizers, antimicrobial agents, buffers, coloring agents, flavoring agents, adjuvants, and the like.
  • the pharmaceutical compositions of the present invention may be administered orally or parenterally including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
  • the pharmaceutical compositions of the present invention may be administered, for example, in the form of tablets or capsules, powders, dispersible granules, or cachets, or as aqueous solutions or suspensions.
  • carriers which are commonly used include lactose, corn starch, magnesium carbonate, talc, and sugar, and lubricating agents such as magnesium stearate are commonly added.
  • useful carriers include lactose, corn starch, magnesium carbonate, talc, and sugar.
  • emulsifying and/or suspending agents are commonly added.
  • sweetening and/or flavoring agents may be added to the oral compositions.
  • sterile solutions of the active ingredient(s) are usually employed, and the pH of the solutions should be suitably adjusted and buffered.
  • the total concentration of the solute(s) should be controlled in order to render the preparation isotonic.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously in the wax, for example by stirring. The molten homogeneous mixture is then poured into conveniently sized molds and allowed to cool and thereby solidify.
  • Liquid preparations include solutions, suspensions and emulsions. Such preparations are exemplified by water or water/propylene glycol solutions for parenteral injection. Liquid preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas.
  • a pharmaceutically acceptable carrier such as an inert compressed gas.
  • solid preparations which are intended for conversion, shortly before use, to liquid preparations for either oral or parenteral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • the co-stimulatory pathway modulator preferably an anti-CTLA4 agent, described herein may also be delivered transdermally.
  • the transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • the active ingredients of the pharmaceutical combination compositions of the present invention are employed within the dosage ranges described below.
  • the co-stimulatory pathway modulator and the protein tyrosine kinase inhibitor may be administered separately in the dosage ranges described below.
  • the co- stimulatory pathway modulator is administered in the dosage range described below following or simultaneously with administration of the protein tyrosine kinase inhibitor in the dosage range described below.
  • this table provides exemplary dosage ranges of the protein tyrosine kinase inhibitor, preferably SPRYCEL®, a co-stimulator pathway modulator, preferably anti-CTLA4 antibody, and/or anti-cancer vaccine agents
  • the clinician may utilize preferred dosages as warranted by the condition of the patient being treated.
  • the anti-CTLA4 antibody may preferably be administered at about 0.3 - 10 mg/kg, or the maximum tolerated dose.
  • a dosage of CTLA- 4 antibody is administered about every three weeks.
  • the CTL A-4 antibody may be administered by an escalating dosage regimen including administering a first dosage of CTLA-4 antibody at about 3 mg/kg, a second dosage of CTLA-4 antibody at about 5 mg/kg, and a third dosage of CTLA-4 antibody at about 9 mg/kg.
  • the protein tyrosine kinase inhibitor may preferably be administered at about 2 times per day at 70 mg. Alternatively, it can be dosed at, for example, about 50, about 70, about 90, about 100, 110, or 120 BID, or 100, 140, or 180 once daily, or the maximum tolerated dose.
  • the dose of a protein tyrosine kinase inhibitor may depend upon a number of factors, including
  • Each combination listed herein optionally includes the administration of an anticancer vaccine from about 0.001-100 mg. stage of disease, the presence of one or more mutations in the targeted protein tyrosine kinase, BCR-ABL mutations, etc.
  • the specific dose that should be administered based upon the presence of one or more of such factors is within the skill of the artisan.
  • etoposide may preferably be administered at about 50 mg to about 900 mg per day.
  • Etoposide is available for intravenous infusion as a sterile lyophile in single-dose vials containing etoposide phosphate equivalent to 100 mg etoposide, 32.7 mg sodium citrate USP, and 300 mg dextran 40.
  • it can be dosed at, for example, about 50, about 70, about 90, about 100, about 200, about 300, about 400, about 500, about 600, about 700, about 800 or about 900 daily, or the maximum tolerated dose.
  • gemcitabine may preferably be administered at about 200 mg/m to about 1250 mg/m per day by IV over 30 to 90 minute infusion.
  • Gemcitabine is available for intravenous infusion containing from about 200 mg to about 1250 mg of gemcitabine HCl (expressed as free base) formulated with mannitol (200 mg or 1 g, respectively) and sodium acetate (12.5 mg or 62.5 mg, respectively) as a sterile lyophilized powder.
  • it can be dosed at, for example, about 50, about 100, about 200, about 300, about 400, about 500, about 600, about 700, about 800, about 900, about 1000, about 1100, about 1200 or about 1250 daily, or the maximum tolerated dose.
  • combinations of the present invention may also be used in conjunction with other well known therapies that are selected for their particular usefulness against the condition that is being treated.
  • the anti-CTLA4 antibody may preferably be administered at about 0.3 - 10 mg/kg, or the maximum tolerated dose.
  • a dosage of CTLA-4 antibody is administered about every three weeks.
  • the CTLA-4 antibody may be administered by an escalating dosage regimen including administering a first dosage of CTLA-4 antibody at about 3 mg/kg, a second dosage of CTLA-4 antibody at about 5 mg/kg, and a third dosage of CTLA-4 antibody at about 9 mg/kg.
  • the escalating dosage regimen includes administering a first dosage of CTLA-4 antibody at about 5 mg/kg and a second dosage of CTLA-4 antibody at about 9 mg/kg.
  • the present invention provides an escalating dosage regimen, which includes administering an increasing dosage of CTLA-4 antibody about every six weeks.
  • a stepwise escalating dosage regimen which includes administering a first CTLA-4 antibody dosage of about 3 mg/kg, a second CTLA-4 antibody dosage of about 3 mg/kg, a third CTLA-4 antibody dosage of about 5 mg/kg, a fourth CTLA-4 antibody dosage of about 5 mg/kg, and a fifth CTLA-4 antibody dosage of about 9 mg/kg.
  • a stepwise escalating dosage regimen is provided, which includes administering a first dosage of 5 mg/kg, a second dosage of 5 mg/kg, and a third dosage of 9 mg/kg.
  • the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small amounts until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired. Intermittent therapy (e.g. , one week out of three weeks or three out of four weeks) may also be used.
  • the combinations of the instant invention may also be co-administered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated. Combinations of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a multiple combination formulation is inappropriate.
  • the chemotherapeutic agent(s) and/or radiation therapy can be administered according to therapeutic protocols well known in the art. It will be apparent to those skilled in the art that the administration of the chemotherapeutic agent(s) and/or radiation therapy can be varied depending on the disease being treated and the known effects of the chemotherapeutic agent(s) and/or radiation therapy on that disease. Also, in accordance with the knowledge of the skilled clinician, the therapeutic protocols (e.g.
  • dosage amounts and times of administration can be varied in view of the observed effects of the administered therapeutic agents (i.e., anti- CTLA4 agent(s) and protein tyrosine kinase inhibitor) on the patient, and in view of the observed responses of the disease to the administered therapeutic agents.
  • the administered therapeutic agents i.e., anti- CTLA4 agent(s) and protein tyrosine kinase inhibitor
  • a protein tyrosine kinase inhibitor such as dasatinib
  • a microtubuline-stabilizing agent such as paclitaxel
  • a nucleoside analogue such as gemcitabine
  • a DNA double strand inducing agent such as etoposide
  • an anti-CTLA4 agent it is not necessary that the anti-CTLA4 therapeutic agent(s) and a microtubuline-stabilizing agent, such as paclitaxel; a nucleoside analogue, such as gemcitabine; or a DNA double strand inducing agent, such as etoposide be administered simultaneously or essentially simultaneously.
  • the advantage of a simultaneous or essentially simultaneous or a sequential (before or after) administration is well within the determination of the skilled clinician.
  • Additional combinations include, but are not limited to the following: Gemcitabine + cisplatin + ipilimumab; ipilimumab + carboplatini + paclitaxel; ipilimumab + etoposide + cisplatin or carboplatin; ipilimumab + pern (cisPlatin, Etoposide and Mitomycin) + cisplatin.
  • These combinations may either be administered sequentially (before or after one another), concurrently, or in any order recommended by a skilled clinician.
  • a microtubuline-stabilizing agent such as paclitaxel; a nucleoside analogue, such as gemcitabine; or a DNA double strand inducing agent, such as etoposide and anti-CTLA4 agent(s) do not have to be administered in the same pharmaceutical composition, and may, because of different physical and chemical characteristics, have to be administered by different routes.
  • a microtubuline-stabilizing agent such as paclitaxel; a nucleoside analogue, such as gemcitabine; or a DNA double strand inducing agent, such as etoposide and the anti-CTLA4 agent(s) are not administered simultaneously or essentially simultaneously, then the initial order of administration of a protein tyrosine kinase inhibitor, such as dasatinib, a microtubuline-stabilizing agent, such as paclitaxel; a nucleoside analogue, such as gemcitabine; or a DNA double strand inducing agent, such as etoposide and the anti-CTLA4 agent(s) may be varied.
  • a protein tyrosine kinase inhibitor such as dasatinib
  • a microtubuline-stabilizing agent such as paclitaxel
  • a nucleoside analogue such as gemcitabine
  • a DNA double strand inducing agent such as etoposide and the anti-CT
  • a microtubuline-stabilizing agent such as paclitaxel; a nucleoside analogue, such as gemcitabine; or a DNA double strand inducing agent, such as etoposide
  • a microtubuline-stabilizing agent such as paclitaxel
  • a nucleoside analogue such as gemcitabine
  • a DNA double strand inducing agent such as etoposide
  • This alternate administration may be repeated during a single treatment protocol. The determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the disease being treated and the condition of the patient.
  • the practicing physician can modify each protocol for the administration of a component (therapeutic agent - i.e., a protein tyrosine kinase inhibitor, such as dasatinib, a microtubuline-stabilizing agent, such as paclitaxel; a nucleoside analogue, such as gemcitabine; or a DNA double strand inducing agent, such as etoposide, anti-CTLA4 agent(s),) of the treatment according to the individual patient's needs, as the treatment proceeds.
  • a component i.e., a protein tyrosine kinase inhibitor, such as dasatinib, a microtubuline-stabilizing agent, such as paclitaxel; a nucleoside analogue, such as gemcitabine; or a DNA double strand inducing agent, such as etoposide, anti-CTLA4 agent(s),
  • the attending clinician in judging whether treatment is effective at the dosage administered, will consider the general well-being of the patient as well as more definite signs such as relief of disease-related symptoms, inhibition of tumor growth, actual shrinkage of the tumor, or inhibition of metastasis. Size of the tumor can be measured by standard methods such as radiological studies, e.g., CAT or MRI scan, and successive measurements can be used to judge whether or not growth of the tumor has been retarded or even reversed. Relief of disease-related symptoms such as pain, and improvement in overall condition can also be used to help judge effectiveness of treatment.
  • the optimal dose for the protein tyrosine kinase inhibitor may depend upon a number of factors, including but limited to the presence of one or more mutations in the targeted protein tyrosine kinase inhibitor and/or in BCR-ABL.
  • a "therapeutically effective amount" of an inhibitor of a mutant BCR- ABL kinase can be a function of the mutation present.
  • Shah et al. disclose that cell lines with certain mutations in BCR-ABL kinase are more sensitive to N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl- 4-pyrimidinyl]amino]-5-thiazolecarboxamide than cell lines with different BCR-ABL kinase mutations.
  • cells comprising a F317L mutation in BCR-ABL kinase may require three to five-fold higher concentration of N-(2-chloro-6- methylphenyl)-2- [ [6- [4-(2-hydroxy ethyl)- 1 -piperazinyl] -2-methyl-4- pyrimidinyl]amino]-5-thiazolecarboxamide than cell lines expressing a F317I mutation.
  • One skilled in the art will appreciate the difference in sensitivity of the mutant BCR-ABL kinase cells and determine a therapeutically effective dose accordingly.
  • a therapeutically relevant dose of N-(2-chloro-6- methylphenyl)-2- [ [6- [4-(2-hydroxy ethyl)- 1 -piperazinyl] -2-methyl-4- pyrimidinyl]amino]-5-thiazolecarboxamide for patients harboring this mutation could range, for example, anywhere from 1 to 14 fold higher than the typical dose.
  • therapeutically relevant doses of N-(2-chloro-6-methylphenyl)-2-[[6-[4- (2 -hydroxy ethyl)- 1 -piperazinyl] -2-methyl-4-pyrimidinyl] amino] -5 - thiazolecarboxamide for any of the BCR-ABL kinase mutants can be, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 225, 250, or 300 folder higher than the prescribed dose.
  • therapeutically relevant doses of N-(2-chloro-6-methylphenyl)- 2-[[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5- thiazolecarboxamide can be, for example, 0.9x, 0.8x, 0.7x, 0.6x, 0.5x, 0.4x, 0.3x, 0.2x, O.lx, 0.09x, 0.08x, 0.07x, 0.06x, 0.05x, 0.04x, 0.03x, 0.02x, or O.Olx of the prescribed dose.
  • the M244V mutant had a fold change of "1.3" in the GST-AbI kinase assay, a fold change of "1.1” in the autophosphorylation assay, and a fold change of "2" in the cellular proliferation assay;
  • the G250E mutant had a fold change of "0.5” in the GST-AbI kinase assay, a fold change of "3” in the autophosphorylation assay, and a fold change of "2” in the cellular proliferation assay;
  • the Q252H mutant had a fold change of "4" in the cellular proliferation assay;
  • the Y253F mutant had a fold change of "0.6” in the GST-AbI kinase assay, a fold change of "4" in the autophosphorylation assay, and a fold change of "4" in the cellular proliferation assay;
  • the Y253H mutant had a fold change of "3" in the GST- AbI kinase assay,
  • the present invention also encompasses additional anti-CTLA-4 agents including, but not limited to, an anti-CTLA-4 antibody, an anti-CTLA-4 adnectin, an anti-CTLA-4 RNAi, single chain anti-CTLA-4 antibody fragments, domain anti- CTLA-4 antibody fragments, and an anti-CTLA-4 antisense molecule.
  • additional anti-CTLA-4 agents including, but not limited to, an anti-CTLA-4 antibody, an anti-CTLA-4 adnectin, an anti-CTLA-4 RNAi, single chain anti-CTLA-4 antibody fragments, domain anti- CTLA-4 antibody fragments, and an anti-CTLA-4 antisense molecule.
  • a preferred anti-CTLA4 agent of the present invention is the anti-CTLA4 antibody ipilimumab.
  • Other anti-CTLA4 antibodies and fragments are encompassed by the present invention which immunospecif ⁇ cally bind a polypeptide, polypeptide fragment, or variant of CTLA4, and/or an epitope of CTLA4 (as determined by immunoassays well known in the art for assaying specific antibody-antigen binding).
  • Antibodies include, but are not limited to, polyclonal, monoclonal, monovalent, bispecific, heteroconjugate, multispecific, human, humanized or chimeric antibodies, single chain antibodies, Fab fragments, F(ab') fragments, fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies (including, e.g., anti-Id antibodies to antibodies of the invention), and epitope-binding fragments of any of the above.
  • antibody refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that immunospecif ⁇ cally binds an antigen.
  • the immunoglobulin molecules of the invention can be of any type ⁇ e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2) or subclass of immunoglobulin molecule.
  • antibody or “monoclonal antibody” (Mab) is meant to include intact molecules, as well as, antibody fragments (such as, for example, Fab and F(ab')2 fragments) which are capable of specifically binding to protein.
  • Fab and F(ab')2 fragments lack the Fc fragment of intact antibody, clear more rapidly from the circulation of the animal or plant, and may have less non-specific tissue binding than an intact antibody (Wahl et al., J. Nucl. Med., 24:316-325 (1983)). Thus, these fragments are preferred, as well as the products of a FAB or other immunoglobulin expression library.
  • anti-CTLA4 antibodies include chimeric, single chain, and humanized antibodies.
  • the anti-CTLA4 antibodies can be produced by any method known in the art for the synthesis of antibodies, in particular, by chemical synthesis or preferably, by recombinant expression techniques.
  • adnectins of the present invention may be made according to the methods outlined in co-owned U.S. Publication Nos. 2007/0082365 and 2008/0139791.
  • an anti-CTLA4 antibody, or fragment, derivative or analog thereof ⁇ e.g., a heavy or light chain of an antibody of the invention or a single chain antibody of the invention
  • an expression vector containing a polynucleotide that encodes the antibody Once a polynucleotide encoding an anti-CTLA4 antibody molecule or a heavy or light chain of an antibody, or portion thereof (preferably containing the heavy or light chain variable domain), has been obtained, the vector for the production of the anti-CTLA4 antibody molecule may be produced by recombinant DNA technology using techniques well known in the art.
  • a protein by expressing a polynucleotide containing an antibody encoding nucleotide sequence are described herein. Methods which are well known to those skilled in the art can be used to construct expression vectors containing antibody coding sequences and appropriate transcriptional and translational control signals. These methods include, for example, in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination.
  • the invention thus, provides replicable vectors comprising a nucleotide sequence encoding an anti-CTLA4 antibody, or a heavy or light chain thereof, or a heavy or light chain variable domain, operably linked to a promoter.
  • Such vectors may include the nucleotide sequence encoding the constant region of the antibody molecule (see, e.g., PCT Publication Nos. WO 86/05807 and WO 89/01036; and U.S. Patent No. 5,122,464) and the variable domain of the antibody may be cloned into such a vector for expression of the entire heavy or light chain.
  • the expression vector is transferred to a host cell by conventional techniques and the transfected cells are then cultured by conventional techniques to produce an anti-CTLA4 antibody.
  • the invention includes host cells containing a polynucleotide encoding an anti-CTLA4 antibody, or a heavy or light chain thereof, or a single chain antibody of the invention, operably linked to a heterologous promoter.
  • vectors encoding both the heavy and light chains may be co-expressed in the host cell for expression of the entire immunoglobulin molecule, as detailed below.
  • host-expression vector systems may be utilized to express the anti-CTLA4 antibody molecules.
  • Such host-expression systems represent vehicles by which the coding sequences of interest may be produced and subsequently purified, but also represent cells which may, when transformed or transfected with the appropriate nucleotide coding sequences, express an antibody molecule of the invention in situ.
  • These include but are not limited to microorganisms such as bacteria ⁇ e.g., E. coli, B.
  • subtilis transformed with recombinant bacteriophage DNA, plasmid DNA or cosmid DNA expression vectors containing antibody coding sequences; yeast ⁇ e.g., Saccharomyces, Pichia) transformed with recombinant yeast expression vectors containing antibody coding sequences; insect cell systems infected with recombinant virus expression vectors ⁇ e.g., baculovirus) containing antibody coding sequences; plant cell systems infected with recombinant virus expression vectors ⁇ e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with recombinant plasmid expression vectors (e.g., Ti plasmid) containing antibody coding sequences; or mammalian cell systems (e.g., COS, CHO, BHK, 293, 3T3 cells) harboring recombinant expression constructs containing promoters derived from the genome of mammalian cells (e.g., metallothionein promoter) or
  • bacterial cells such as Escherichia coli, and more preferably, eukaryotic cells, especially for the expression of whole recombinant antibody molecule, are used for the expression of a recombinant antibody molecule.
  • mammalian cells such as Chinese hamster ovary cells (CHO), in conjunction with a vector such as the major intermediate early gene promoter element from human cytomegalovirus is an effective expression system for antibodies (Foecking et al, Gene, 45:101 (1986); Cockett et al, Bio/Technology, 8:2 (1990)).
  • a number of expression vectors may be advantageously selected depending upon the use intended for the antibody molecule being expressed. For example, when a large quantity of such a protein is to be produced, for the generation of pharmaceutical compositions of an antibody molecule, vectors which direct the expression of high levels of fusion protein products that are readily purified may be desirable. Such vectors include, but are not limited, to the E.
  • coli expression vector pUR278 (Ruther et al., EMBO J, 2:1791 (1983)), in which the antibody coding sequence may be ligated individually into the vector in frame with the lac Z coding region so that a fusion protein is produced; pIN vectors (Inouye et al., Nucleic Acids Res., 13:3101-3109 (1985); Van Heeke et al., J. Biol. Chem., 24:5503-5509 (1989)); and the like.
  • pGEX vectors may also be used to express foreign polypeptides as fusion proteins with glutathione S-transferase (GST).
  • fusion proteins are soluble and can easily be purified from lysed cells by adsorption and binding to matrix glutathione-agarose beads followed by elution in the presence of free glutathione.
  • the pGEX vectors are designed to include thrombin or factor Xa protease cleavage sites so that the cloned target gene product can be released from the GST moiety.
  • AcNPV Autographa californica nuclear polyhedrosis virus
  • the virus grows in Spodoptera frugiperda cells.
  • the antibody coding sequence may be cloned individually into non- essential regions (for example the polyhedrin gene) of the virus and placed under control of an AcNPV promoter (for example the polyhedrin promoter).
  • the anti- CTLA4 antibody coding sequence may be ligated to an adenovirus transcription/translation control complex, e.g., the late promoter and tripartite leader sequence.
  • This chimeric gene may then be inserted in the adenovirus genome by in vitro or in vivo recombination. Insertion in a non- essential region of the viral genome (e.g., region El or E3) will result in a recombinant virus that is viable and capable of expressing the antibody molecule in infected hosts, (e.g., see Logan et al., Proc.
  • Specific initiation signals may also be required for efficient translation of inserted antibody coding sequences. These signals include the ATG initiation codon and adjacent sequences. Furthermore, the initiation codon must be in phase with the reading frame of the desired coding sequence to ensure translation of the entire insert. These exogenous translational control signals and initiation codons can be of a variety of origins, both natural and synthetic. The efficiency of expression may be enhanced by the inclusion of appropriate transcription enhancer elements, transcription terminators, etc. (see Bitter et al., Meth. Enzymol, 153:516-544 (1987)).
  • a host cell strain may be chosen which modulates the expression of the inserted sequences, or modifies and processes the gene product in the specific fashion desired. Such modifications (e.g., glycosylation) and processing (e.g. , cleavage) of protein products may be important for the function of the protein.
  • Different host cells have characteristic and specific mechanisms for the post- translational processing and modification of proteins and gene products. Appropriate cell lines or host systems can be chosen to ensure the correct modification and processing of the foreign protein expressed.
  • eukaryotic host cells which possess the cellular machinery for proper processing of the primary transcript, glycosylation, and phosphorylation of the gene product may be used.
  • Such mammalian host cells include but are not limited to CHO, VERY, BHK, HeIa, COS, MDCK, 293, 3T3, WI38, and in particular, breast cancer cell lines such as, for example, BT483, Hs578T, HTB2, BT20 and T47D, and normal mammary gland cell line such as, for example, CRL7030 and Hs578Bst.
  • cell lines which stably express the anti-CTLA4 antibody molecule may be engineered.
  • host cells can be transformed with DNA controlled by appropriate expression control elements (e.g., promoter, enhancer, sequences, transcription terminators, polyadenylation sites, etc.), and a selectable marker.
  • appropriate expression control elements e.g., promoter, enhancer, sequences, transcription terminators, polyadenylation sites, etc.
  • engineered cells may be allowed to grow for 1-2 days in an enriched media, and then are switched to a selective media.
  • the selectable marker in the recombinant plasmid confers resistance to the selection and allows cells to stably integrate the plasmid into their chromosomes and grow to form foci which in turn can be cloned and expanded into cell lines.
  • This method may advantageously be used to engineer cell lines which express the antibody molecule.
  • Such engineered cell lines may be particularly useful in screening and evaluation of compounds that interact directly or indirectly with the anti-CTLA4 antibody molecule.
  • a number of selection systems may be used, including but not limited to the herpes simplex virus thymidine kinase (Wigler et al., Cell, 11 :223 (1977)), hypoxanthine-guanine phosphoribosyltransferase (Szybalska et al., Proc. Natl. Acad. Sci. USA, 48:202 (1992)), and adenine phosphoribosyltransferase (Lowy et al., Cell, 22:817 (1980)) genes can be employed in tk-, hgprt- or aprt- cells, respectively.
  • antimetabolite resistance can be used as the basis of selection for the following genes: dhfr, which confers resistance to methotrexate (Wigler et al., Proc. Natl. Acad. Sci. USA, 77:357 (1980); O'Hare et al., Proc. Natl. Acad. Sci. USA, 78:1527 (1981)); gpt, which confers resistance to mycophenolic acid (Mulligan et al., Proc. Natl. Acad. Sci.
  • the expression levels of an anti-CTLA4 antibody molecule can be increased by vector amplification (for a review, see Bebbington et al., "The use of vectors based on gene amplification for the expression of cloned genes in mammalian cells” in DNA Cloning, Vol. 3, Academic Press, NY (1987)).
  • vector amplification for a review, see Bebbington et al., "The use of vectors based on gene amplification for the expression of cloned genes in mammalian cells” in DNA Cloning, Vol. 3, Academic Press, NY (1987)).
  • a marker in the vector system expressing antibody is amplifiable
  • increase in the level of inhibitor present in culture of host cell will increase the number of copies of the marker gene. Since the amplified region is associated with the antibody gene, production of the antibody will also increase (Crouse et al., MoI. Cell. Biol, 3:257 (1983)).
  • the host cell may be co-transfected with two expression vectors, the first vector encoding a heavy chain derived polypeptide and the second vector encoding a light chain derived polypeptide.
  • the two vectors may contain identical selectable markers which enable equal expression of heavy and light chain polypeptides.
  • a single vector may be used which encodes, and is capable of expressing, both heavy and light chain polypeptides. In such situations, the light chain should be placed before the heavy chain to avoid an excess of toxic free heavy chain (Proudfoot, Nature, 322:52 (1986); Kohler, Proc. Natl. Acad. Sci. USA, 77:2197 (1980)).
  • the coding sequences for the heavy and light chains may comprise cDNA or genomic DNA.
  • an antibody molecule of the invention may be purified by any method known in the art for purification of an immunoglobulin molecule, for example, by chromatography (e.g. , ion exchange, affinity, particularly by affinity for the specific antigen after Protein A, and sizing column chromatography), centrifugation, differential solubility, or by any other standard technique for the purification of proteins.
  • chromatography e.g. , ion exchange, affinity, particularly by affinity for the specific antigen after Protein A, and sizing column chromatography
  • centrifugation e.g., ion exchange, affinity, particularly by affinity for the specific antigen after Protein A, and sizing column chromatography
  • differential solubility e.g., differential solubility
  • the anti-CTLA4 antibodies or fragments thereof can be fused to heterologous polypeptide sequences described herein or otherwise known in the art, to facilitate purification.
  • the present invention further includes compositions comprising polypeptides or conjugated to anti-CTLA4 antibody domains other than the variable regions.
  • the polypeptides may be fused or conjugated to an antibody Fc region, or portion thereof.
  • the anti-CTLA4 antibody portion fused to a polypeptide may comprise the constant region, hinge region, CHl domain, CH2 domain, and CH3 domain or any combination of whole domains or portions thereof.
  • the polypeptides may also be fused or conjugated to the above antibody portions to form multimers.
  • Fc portions fused to the polypeptides of the present invention can form dimers through disulfide bonding between the Fc portions.
  • an anti-CTLA4 antibody or fragment thereof may be conjugated to a therapeutic moiety such as a cytotoxin, e.g., a cytostatic or cytocidal agent, a therapeutic agent or a radioactive metal ion, e.g., alpha-emitters such as, for example, 213Bi.
  • a cytotoxin or cytotoxic agent includes any agent that is detrimental to cells.
  • Examples include paclitaxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologues thereof.
  • Therapeutic agents include, but are not limited to, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g., mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU) and lomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP) cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents (e.g.
  • the conjugates of the invention can be used for modifying a given biological response, the therapeutic agent or drug moiety is not to be construed as limited to classical chemical therapeutic agents.
  • the drug moiety may be a protein or polypeptide possessing a desired biological activity.
  • Such proteins may include, for example, a toxin such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin; a protein such as tumor necrosis factor, a-interferon, ⁇ -interferon, nerve growth factor, platelet derived growth factor, tissue plasminogen activator, an apoptotic agent, e.g., TNF-alpha, TNF-beta, AIM I (See PCT Publication No. WO 97/33899), AIM II (See PCT Publication No. WO 97/34911), Fas Ligand (Takahashi et al, Int.
  • a toxin such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin
  • a protein such as tumor necrosis factor, a-interferon, ⁇ -interferon, nerve growth factor, platelet derived growth factor, tissue plasminogen activator, an a
  • VEGI See PCT Publication No. WO 99/23105
  • a thrombotic agent or an anti-angiogenic agent e.g., angiostatin or endostatin
  • biological response modifiers such as, for example, lymphokines, interleukin-1 ("IL-I”), interleukin-2 (“IL-2”), interleukin-6 (“IL-6”), granulocyte macrophage colony stimulating factor (“GM-CSF”), granulocyte colony stimulating factor (“G-CSF”), or other growth factors.
  • IL-I interleukin-1
  • IL-2 interleukin-2
  • IL-6 interleukin-6
  • GM-CSF granulocyte macrophage colony stimulating factor
  • G-CSF granulocyte colony stimulating factor
  • an anti-CTLA4 antibody can be conjugated to a second antibody to form an antibody heteroconjugate as described by Segal in U.S. Patent No. 4,676,980, which is incorporated herein by reference in its entirety.
  • An anti-CTLA4 antibody with or without a therapeutic moiety conjugated to it, administered alone or in combination with cytotoxic factor(s) and/or cytokine(s) can be used as a therapeutic.
  • the present invention also encompasses the creation of synthetic antibodies directed against the polypeptides of the present invention.
  • synthetic antibodies is described in Radrizzani, M., et al., Medicina (Aires), 59(6):753-758, (1999)).
  • MIPs molecularly imprinted polymers
  • Antibodies, peptides, and enzymes are often used as molecular recognition elements in chemical and biological sensors. However, their lack of stability and signal transduction mechanisms limits their use as sensing devices.
  • Molecularly imprinted polymers (MIPs) are capable of mimicking the function of biological receptors but with less stability constraints.
  • MIPs have the ability to bind to small molecules and to target molecules such as organics and proteins' with equal or greater potency than that of natural antibodies. These "super" MIPs have higher affinities for their target and thus require lower concentrations for efficacious binding.
  • the MIPs are imprinted so as to have complementary size, shape, charge and functional groups of the selected target by using the target molecule itself (such as a polypeptide, antibody, etc.), or a substance having a very similar structure, as its "print” or “template.”
  • MIPs can be derivatized with the same reagents afforded to antibodies.
  • fluorescent 'super' MIPs can be coated onto beads or wells for use in highly sensitive separations or assays, or for use in high throughput screening of proteins.
  • a number of methods may be employed to create MIPs to a specific receptor, ligand, polypeptide, peptide, organic molecule.
  • Several preferred methods are described by Esteban et al. in J. Analytical Chem., 370(7):795-802 (2001), which is hereby incorporated herein by reference in its entirety in addition to any references cited therein. Additional methods are known in the art and are encompassed by the present invention, such as for example, Hart, B. R. et al., J. Am. Chem. Soc, 123(9):2072-2073 (2001); and Quaglia, M. et al., J. Am. Chem. Soc, 123(10):2146- 2154 (2001); which are hereby incorporated by reference in their entirety herein.
  • Antisense oligonucleotides may be single or double stranded. Double stranded RNA' s may be designed based upon the teachings of Paddison et al., Proc. Nat. Acad. ScL, 99:1443-1448 (2002); and PCT Publication Nos. WO 01/29058, and WO 99/32619; which are hereby incorporated herein by reference.
  • Double stranded RNA may also take the form of an RNA inhibitor ("RNAi") such that they are competent for RNA interference.
  • RNAi RNA inhibitor
  • anti- CTLA4 RNAi molecules may take the form of the molecules described by Mello and Fire in PCT Publication Nos. WO 1999/032619 and WO 2001/029058; U.S. Publication Nos. 2003/0051263, 2003/0055020, 2003/0056235, 2004/265839, 2005/0100913, 2006/0024798, 2008/0050342, 2008/0081373, 2008/0248576, and 2008/055443; and/or U.S. Patent Nos. 6,506,559, 7,282,564, 7,538,095, and 7,560,438.
  • the teachings of these patent and patent applications are hereby incorporated herein by reference in their entirety.
  • the anti-CTLA4 RNAi molecules may be double stranded RNA, and between about 25 to 400 nucleotides in length, and complementary to the encoding nucleotide sequence of CTLA4.
  • Such RNAi molecules may be about 20, about 25, about 30, about 35, about 45, and about 50 nucleotides in length.
  • the term "about” is construed to be about 1, 2, 3, 4, 5, or 6 nucleotides longer in either the 5 ' or 3' direction, or both.
  • the anti-CTLA4 RNAi molecules of the present invention may take the form be double stranded RNAi molecules described by Kreutzer in European Patent Nos. EP 1144639, and EP 1214945. The teachings of these patent and patent applications are hereby incorporated herein by reference in their entirety.
  • the anti-CTLA4 RNAi molecules of the present invention may be double stranded RNA that is complementary to the coding region of CTLA4, and is between about 15 to about 49 nucleotides in length, and preferably between about 15 to about 21 nucleotides in length.
  • anti-CTLA-4 molecules can be stabilized by chemical linkage of the single RNA strands.
  • the anti-CTLA4 RNAi molecules of the present invention may take the form be double stranded RNAi molecules described by Tuschl in European Patent No. EP 1309726.
  • the teachings of these patent and patent applications are hereby incorporated herein by reference in their entirety.
  • the anti-CTLA4 RNAi molecules of the present invention may be double stranded RNA that is complementary to the coding region of CTLA4, and is between about 21 to about 23 nucleotides in length, and are either blunt ended or contain either one or more overhangs on the 5' end or 3' end of one or both of the strands with each overhang being about 1, 2, 3, 4, 5, 6, or more nucleotides in length.
  • each strand may be modified by phosphorylation, hydroxylation, or other modifications.
  • the internucleotide linkages of one or more of the nucleotides may be modified, and may contain 2'-OH.
  • the term "about” is construed to be about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides longer in either the 5' or 3' direction, or both.
  • Such anti-CTLA-4 molecules can be stabilized by chemical linkage of the single RNA strands.
  • the anti-CTLA4 RNAi molecules of the present invention may take the form be double stranded RNAi molecules described by Tuschl in U.S. Patent Nos. 7,056,704 and 7,078,196. The teachings of these patent and patent applications are hereby incorporated herein by reference in their entirety.
  • the anti-CTLA4 RNAi molecules of the present invention may be double stranded RNA that is complementary to the coding region of CTLA4, and is between about 19 to about 25 nucleotides in length, and are either blunt ended or contain either one or more overhangs on the 5' end or 3' end of one or both of the strands with each overhang being about 1, 2, 3, 4, or 5 or more nucleotides in length.
  • each strand may be modified by phosphorylation, hydroxylation, or other modifications.
  • the internucleotide linkages of one or more of the nucleotides may be modified, and may contain 2'-OH.
  • the term "about” is construed to be about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides longer in either the 5' or 3' direction, or both.
  • Such anti-CTLA-4 molecules can be stabilized by chemical linkage of the single RNA strands.
  • the anti-CTLA4 RNAi molecules of the present invention may take the form be RNA molecules described by Crooke in U.S. Patent Nos.
  • the anti-CTLA4 molecules may be single stranded RNA, containing a first segment having at least one ribofuranosyl nucleoside subunit which is modified to improve the binding affinity of said compound to the preselected RNA target when compared to the binding affinity of an unmodified oligoribonucleotide to the RNA target; and a second segment comprising at least four consecutive ribofuranosyl nucleoside subunits having T- hydroxyl moieties thereon; said nucleoside subunits of said oligomeric compound being connected by internucleoside linkages which are modified to stabilize said linkages from degradation as compared to phosphodiester linkages.
  • RNA molecules are about 15 to 25 nucleotides in length, or about 17 to about 20 nucleotides in length.
  • such molecules are competent to activate a double- stranded RNAse enzyme to effect cleavage of CTLA4 RNA.
  • the term "about” is construed to be about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides longer in either the 5' or 3' direction, or both.
  • Such anti-CTLA-4 molecules can be stabilized by chemical linkage of the single RNA strands.
  • SiRNA reagents are specifically contemplated by the present invention. Such reagents are useful for inhibiting expression of the polynucleotides of the present invention and may have therapeutic efficacy.
  • Several methods are known in the art for the therapeutic treatment of disorders by the administration of siRNA reagents.
  • One such method is described by Tiscornia et al. (Proc. Natl. Acad. Sci., 100(4): 1844- 1848 (2003)); WO 04/09769, filed July 18, 2003; and Reich, S.J. et al., MoI. Vis., 9:210-216 (May 30, 2003), which are incorporated by reference herein in its entirety.
  • dasatinib The effect of dasatinib on immune function has been the subject of recent investigations. Some reports demonstrated that in vitro, dasatinib (concentrations of 10-50 nM), inhibits T-cell function, as measured by inhibition of cytokine secretion and degranulation (Weischel et al., 2008) which was postulated to be the result of Lck inhibition. Other reports demonstrated that dasatinib produced blockade of T-cell activation (Schade et al., 2007). However, treatment with dasatinib might also have immunomodulatory effects based on its potent inhibition of STAT3, which may result in maturation of dendritic cells and modulation of T-cell responses (Yu, H.
  • SPRYCEL® showed modest antitumor activity in the P815 model. As shown in Figure 5, concurrent treatment with CTLA-4 mAb + SPRYCEL® resulted in synergistic effects. Synergy was observed when SPRYCEL® was administered at 30 mg/kg either on a daily dosing regimen or following an intermittent schedule (5 days on/2 days off).
  • CTLA-4 mAb an anti-CTLA-4 monoclonal antibody
  • CTLA-4 mAb was initiated one day after the first dose of chemotherapy. Percent tumor growth inhibition and number of days to reach target tumor size were used to evaluate efficacy. Antitumor activity was scored as: complete regression (CR; non-palpable tumor for > 2 assessments) or partial regression (PR; 50% reduction in tumor volume for > 2 assessments). Synergy was defined as antitumor activity significantly superior (p ⁇ 0.05) to the activity of monotherapy with each agent.
  • Ml 09 tumors are insensitive to CTLA-4 blockade and modestly sensitive to Paclitaxel, Etoposide and Gemcitabine.
  • Combination of CTLA-4 + Paclitaxel produced enhanced antitumor activity compared to each agent alone, while no enhancement was seen with Etoposide.
  • Gemcitabine as single agent did not produce significant antitumor activity, Gemcitabine plus CTLA-4 mAb produced synergistic effects (Table 1).
  • SAlN is an immunogenic tumor line sensitive to CTLA-4 mAb and chemotherapy. While the 3 chemotherapeutic agents tested enhanced the activity of CTLA-4 mAb, synergy was only observed with Etoposide (Table 3). TABLE 3
  • CTLA-4 mAb Antitumor Activity of CTLA-4 mAb in Combination with Paclitaxel, Etoposide and Gemcitabine in the SAlN Fibrosarcoma Subcutaneous Tumor Model
  • CTLA-4 and Paclitaxel are ineffective therapies against CT26 colon carcinoma tumors; their combination was ineffective against established tumors, but synergistic against minimal tumor burden.
  • Etoposide and Gemcitabine were effective as single agents, but their activity was significantly potentiated by the addition of CTL-4 mAb.
  • CTLA-4 mAb to chemotherapeutic agents such as Etoposide, Gemcitabine, Paclitaxel, and Ixabepilone
  • chemotherapeutic agents such as Etoposide, Gemcitabine, Paclitaxel, and Ixabepilone
  • All the combination regimens were well tolerated.
  • synergy was observed in tumors that did not respond to CTLA-4 alone suggesting that the chemotherapeutic agents might have induced immunogenic cell death.
  • Gemcitabine, etoposide, paclitaxel, and ixabepilone as monotherapy appear to induce an immunogenic signature and modulation of the immune response.
  • the results suggest, that, due to their short half- life, these agents will not affect effector T- cell function.

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Abstract

La présente invention a pour objet des compositions et des méthodes qui sont utiles pour le traitement et la prévention de troubles prolifératifs. De telles compositions comprennent entre autres un agent anti-CTLA-4, par exemple l’ipilimumab ou le trémélimumab en combinaison avec d’autres agents chimiothérapeutiques tels que le dasatinib, l’imatinib, le paclitaxel, la gemcitabine, le cisplatine ou l’étoposide.
EP09749268.0A 2009-07-20 2009-10-29 Combinaison d un anticorps anti-ctla-4 avec divers régimes de traitement pour le traitement synergique de maladies prolifératives Withdrawn EP2456790A1 (fr)

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EP15166232.7A EP2947098B1 (fr) 2009-07-20 2009-10-29 Combinaison d'anticorps anti-ctla4 avec gemcitabine pour le traitement synergique de prolifération
DK14162613.5T DK2769737T3 (en) 2009-07-20 2009-10-29 COMBINATION OF ANTI-CTLA4 ANTIBODY WITH ETOPOSIDE FOR SYNERGISTIC TREATMENT OF PROLIFERATIVE DISEASES
EP19207926.7A EP3659596A1 (fr) 2009-07-20 2009-10-29 Combinaison d'anticorps anti-ctla4 avec paclitaxel pour le traitement synergique de prolifération
EP14162613.5A EP2769737B1 (fr) 2009-07-20 2009-10-29 Combinaison d'anticorps anti-ctla4 avec etoposide pour le traitement synergique de prolifération
CY20171100694T CY1119128T1 (el) 2009-07-20 2017-06-29 Συνδυασμος αντισωματος ctla4 με ετοποσιδη για την συνεργιστικη αγωγη πολλαπλασιαστικων νοσηματων

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US12/462,168 US8119129B2 (en) 2008-08-01 2009-07-30 Combination of anti-CTLA4 antibody with dasatinib for the treatment of proliferative diseases
PCT/US2009/062519 WO2011011027A1 (fr) 2009-07-20 2009-10-29 Combinaison d’un anticorps anti-ctla-4 avec divers régimes de traitement pour le traitement synergique de maladies prolifératives

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MX2012000851A (es) 2012-06-08
SI2769737T1 (sl) 2017-06-30
KR20120048564A (ko) 2012-05-15
EP2947098A1 (fr) 2015-11-25
DK2769737T3 (en) 2017-07-24
JP2014198737A (ja) 2014-10-23
EP2769737A1 (fr) 2014-08-27
JP5957043B2 (ja) 2016-07-27
JP5957036B2 (ja) 2016-07-27
JP2012533619A (ja) 2012-12-27
CY1119128T1 (el) 2018-02-14
EP2947098B1 (fr) 2019-11-20
CN102822200A (zh) 2012-12-12
AU2009350151B2 (en) 2015-07-16
EP3659596A1 (fr) 2020-06-03
AU2009350151A1 (en) 2012-02-09
ES2768990T3 (es) 2020-06-24
EP2769737B1 (fr) 2017-04-05
PT2769737T (pt) 2017-06-29
LT2769737T (lt) 2017-06-26
JP5589077B2 (ja) 2014-09-10
ES2629167T3 (es) 2017-08-07
HUE033312T2 (en) 2017-11-28
HRP20170785T1 (hr) 2017-08-11
KR101733255B1 (ko) 2017-05-08
JP2014167029A (ja) 2014-09-11
WO2011011027A1 (fr) 2011-01-27
PL2769737T3 (pl) 2017-08-31

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