WO2020242910A1 - Compositions et méthodes de traitement du cancer - Google Patents

Compositions et méthodes de traitement du cancer Download PDF

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WO2020242910A1
WO2020242910A1 PCT/US2020/034137 US2020034137W WO2020242910A1 WO 2020242910 A1 WO2020242910 A1 WO 2020242910A1 US 2020034137 W US2020034137 W US 2020034137W WO 2020242910 A1 WO2020242910 A1 WO 2020242910A1
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composition
inhibitor
phenyl
seq
antibody
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John P. Chute
Joshua SASINE
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The Regents Of The University Ofcalifornia
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering N.A.

Definitions

  • MM Multiple myeloma
  • plasma cell myeloma is a cancer of plasma cells, a type of white blood cell typically responsible for producing antibodies.
  • multiple myeloma affected 488,000 people and resulted in 101,100 deaths in 2015. In the United States, it develops in 6.5 per 100,000 people per year and 0.7% of people are affected at some point in their lives. Without treatment, typical survival is seven months. With current treatments, survival the five-year survival rate approximately 49%.
  • novel therapies such as those disclosed herein are needed.
  • the present disclosure provides methods of treating a cancer in a subject, the method comprising administering to the subject an inhibitor of Eph-ephrin signaling.
  • the present disclosure provides compositions comprising inhibitors of ephrin-Eph signaling.
  • FIG. 1A shows human endothelial cell (ec) promotion of MM is tissue-specific.
  • the MM cell line U266 is expanded > 10-fold in co-culture with bone marrow ECs (BMEC-60 cell line), umbilical vein (HUVEC), and aortic (HAEC) ECs, but not dermal (HDECs) ECs.
  • BMEC-60 cell line bone marrow ECs
  • UUVEC umbilical vein
  • HAEC aortic ECs
  • HDECs but not dermal
  • FIG. IB shows endothelial cell (ec) promotion of myeloma is tissue-specific.
  • ec endothelial cell
  • FIG. 2A shows loss of ephbl in ecs with sima reduces MM growth in co-culture.
  • FIG. 2B shows that loss of ephrinB2 in MM cells via shRNA reduces MM growth in vivo.
  • 5 million RPMI-8226 MM cells bearing non-targeting control or ephrinB2 shRNA were injected into the tail veins of NSG mice. After 5 weeks, bone marrow involvement was measured by flow cytometry. Results are mean ⁇ SD. Experiment was repeated with similar results. Statistical significance between groups was determined by Student’s t-test. **** pO.OOOl.
  • FIG. 3 shows that loss of ephrinB2 in MM cells via shRNA reduces MM growth in vivo. 5 million RPMI-8226 MM cells bearing non-targeting control or ephrinB2 shRNA were injected into the tail veins of NSG mice. After 5 weeks, bone marrow involvement was measured by flow cytometry. Representative flow cytometry plots and a histogram are shown.
  • FIG. 4A shows that endothelial cell (EC) promotion of MM is tissue-specific.
  • FIG. 4B shows that endothelial cell (EC) promotion of MM is tissue-specific.
  • FIG. 4C shows that endothelial cell (EC) promotion of MM is tissue-specific.
  • the MM cell line U266 was cultured alone (media), or co-cultured with dermal or aoritc ECs for 6 days, then injected via tail vein into NSG mice. At 8 weeks, bone marrow
  • FIG. 5A shows that the knockdown of EphBl in endothelial cells (ECs) impairs support of MM.
  • the MM cell line U266 was co-cultured with human aortic ECs bearing control siRNA or siRNA to EphBl for 4 days. Cells were then counted using flow cytometry with 123count eBeadsTM Counting Beads (ThermoFisher Scientific) and an antibody to human CD 138. Results are mean ⁇ SD in 2 independent experiments. **** p ⁇ 0.0001
  • FIG. 5B shows that the knockdown of ephbl in endothelial cells (ECs) impairs support of MM.
  • the MM cell line NCI-H929 was co-cultured with human aortic ECs bearing control siRNA or siRNA to EphBl for 4 days. Cells were then counted using flow cytometry with 123count eBeadsTM Counting Beads (ThermoFisher Scientific) and an antibody to human CD138. Results are mean ⁇ SD in 2 independent experiments. ** p ⁇ 0.01
  • FIG. 6A shows that the expression of EphBl and EphB4 are increased in bone marrow endothelial cells in response to multiple myeloma.
  • Bone marrow cells were extracted and FACS-sorted for Alexa Fluor® 647. We then used qRT-PCR for the EphB family genes.
  • FIG. 6B shows that EphBl expression is increased in human bone marrow endothelial cells in the setting of MM compared to healthy bone marrow ECs.
  • FIG. 6C shows that across three MM cell lines, ephrinB2 has the highest ephrinB family member expression.
  • FIG. 7A shows that high ephrinB2 expression is associated with gain of chromosome lq (a high-risk subtype) in multiple myeloma. Data mined from publicly available gene expression data from Zhan et al. Blood 2006.
  • FIG. 7B shows that high ephrinB2 expression is associated with t(4; 14) (a high-risk subtype) in multiple myeloma.
  • t(4; 14) a high-risk subtype
  • FIG. 7C shows that patient death at 5 years after diagnosis of MM is associated with high ephrinB2 expression.
  • FIG. 8 shows that knockdown of EphBl in human aortic ECs impairs MM support.
  • the MM cell line RPMI-8226 was cultured with media alone, or co-cultured with aoritc ECs harboring non-targeting control shRNA or EphBl shRNA for 6 days.
  • RPMI-8226 cells express luciferase. Radiance is quantified and representative micrographs of luciferase signals are shown to the right of each respective scatter plot with bar graph. Results are mean ⁇ SD. Experiment was repeated with similar results. Experiment was also repeated with shRNA to EphB4 with similar results. Statistical significance between groups was determined by Student’s t-test. **** pO.OOOl.
  • FIG. 9 shows that knockdown of ephrinB2 in human MM impairs growth.
  • the MM cell line RPMI-8226 harboring non-targeting control shRNA or ephrinB2 shRNA was cultured with media alone. Growth over time was measured. Results are mean ⁇ SD.
  • FIG. 10 shows that knockdown of ephrinB2 in human MM impairs ability to receive support from ECs.
  • the MM cell line RPMI-8226 harboring non-targeting control shRNA or ephrinB2 shRNA was co-cultured with bone marrow ECs for 5 days.
  • RPMI- 8226 cells express luciferase. Radiance is quantified and representative micrographs of luciferase signals are shown to the right of each respective scatter plot with bar graph. Results are mean ⁇ SD. Experiment was repeated with similar results. Statistical significance between groups was determined by Student’s t-test. *** p ⁇ 0.001.
  • FIG. 11 depicts an investigation wherein 5 million RPMI-8226 multiple myeloma cells were administered IV (tail vein) to 10-12 week-old NSG mice. Cells had either non targeting control (NT-Control) shRNA or shRNA specific to ephrinB2. Bone marrow was analyzed at 5 weeks post-injection for the presence of multiple myeloma (CD 138+ cells).
  • FIG. 12A loss of ephrinB2 in MM cells does not affect proliferation.
  • the MM cell line RPMI-8226 bearing non-targeting control shRNA or ephrinB2 shRNA was cultured in media containing BrdU overnight. BrdU incorporation was measured with flow cytometry.
  • FIG. 12B depicts loss of ephrinB2 in MM cells impairs cell migration.
  • Transwells were coated with bone marrow endothelial cells.
  • Multiple myeloma cells (200,000 RPMI- 8226 cell line) harboring non-targeting control shRNA or ephrinB2 shRNA were loaded in the top chamber. After 4 hours, cells migrating through the endothelial cells were counted. Statistical significance between groups was determined by Student’s t-test. ** p O.Ol.
  • FIG. 12C shows that loss of ephrinB2 in MM cells impairs steady-state cell survival.
  • the MM cell line RPMI-8226 bearing non-targeting control shRNA or ephrinB2 shRNA was cultured in media for 72 hours. Stain for 7AA and Annexin V was performed using flow cytometry.
  • FIG. 13A shows that inhibition of ephrinB2 via a single chain variable fragment of an antibody (scFv) impairs cell migration.
  • Transwells were coated with bone marrow endothelial cells.
  • Multiple myeloma cells (200,000 RPMI-8226 cell line) were loaded in the top chamber with an ephrinB2 scFv at the concentrations shown. After 4 hours, cells migrating through the endothelial cells were counted. Statistical significance between groups was determined by Student’s t-test. **** pO.OOOl .
  • FIG. 13B shows that inhibition of ephrinB2 via a single chain variable fragment of an antibody (scFv) impairs steady-state cell survival.
  • the MM cell line RPMI-8226 was cultured in media for 72 hours with an ephrinB2 scFv at the concentrations shown. Stain for 7AA and Annexin V was performed using flow cytometry. Statistical significance between groups was determined by Student’s t-test. * p ⁇ 0.05, *** p ⁇ 0.001
  • FIG. 14 shows that inhibition of ephrinB2 via a single chain variable fragment of an antibody (scFv) impairs MM growth in vivo.
  • 3 million RPMI-8226 MM cells were injected into the tail veins of NSG mice. Starting at day 4 after injection, scFv was administered IV every other day for 4 doses at 5mg/kg/dose. Bone marrow was analyzed at 4 weeks for the presence of multiple myeloma (CD 138+ cells) by flow cytometry. Statistical significance between groups was determined by Student’s t-test. ** p ⁇ 0.01
  • Angiogenesis and lymphangiogenesis are highly complex coordinated processes through which new blood and lymphatic vessels, respectively, arise from preexisting ones.
  • Angiogenesis occurs physiologically during embryonic development, tissue repair (ie, wound healing), and menstruation, but it is also important in the pathogenesis of many diseases such as tumor growth and metastasis. Because most tumors cannot grow and disseminate in the absence of new blood vessel formation, inhibition of the signaling pathways underlying pathologic angiogenesis is an important potential target for anticancer therapy.
  • Eph receptor tyrosine kinases and their ligands, ephrins control several cellular functions such as cell migration and cytoskeletal organization.
  • Ephrins are a family of cell- surface proteins linked to the cell membrane either by a GPI anchor (class A) or by a single transmembrane segment (class B).
  • An interesting feature of Eph-ephrin signaling is that both, receptors and ligands, are able to transduce a downstream signaling cascade on interaction, resulting in bidirectional cell-to-cell communication.
  • Eph-activated signaling is termed“forward” and ephrinactivated signaling is named“reverse.”
  • Eph receptors initiate forward signal transduction by autophosphorylation of several tyrosine residues located in the cytoplasmic part of the molecule in response to binding of clustered and membrane- attached ephrin ligands on adjacent cells.
  • ephrinB2 In the blood vasculature, ephrinB2 is expressed on arterial angioblasts, endothelial cells (ECs) and perivascular mesenchymal cells, whereas one of its binding partners, the receptor EphB4, is specific of venous ECs. Targeted inactivation of either 1yHB4 or EfiiB2 genes in mice leads to failure of embryonic vessel formation and early lethality, demonstrating their critical role during physiologic angiogenesis. This role of ephrinB2 also extends to tumor- derived angiogenesis and tumor growth. Moreover, ephrinB2 controls lymphangiogenesis o and it has been recently shown that an ephrinB2 blocking peptide was able to suppress VEGF -induced lymphatic endothelial sprouting.
  • EphB4/ephrinB2 signaling is important in angiogenesis, hampering this protein-protein interaction could have several potential medical applications in
  • angiogenesis-based diseases such as in tumor growth and metastasis.
  • EphB4 monomeric soluble extracellular domain of EphB4 is able to block ephrinB2 interaction with its receptor, leading to inhibition of angiogenesis and tumor growth.
  • the present disclosure provides methods of treating a cancer in a subject, the method comprising administering to the subject an inhibitor of Eph-ephrin signaling.
  • the inhibitor inhibits the interaction between ephrinB2 and EphB 1.
  • the inhibitor inhibits the interaction between ephrinB2 and EphB 4.
  • the inhibitor is an antibody or an antigen-binding fragment. In certain preferred embodiments, the antibody binds to ephrin B2, EphBl, or EphB4. In certain embodiments, the antibody is a single chain variable fragment. In certain embodiments, the inhibitor is an antibody comprising an amino acid sequence at least 76%, at least 80%, at least 90%, at least 95%, or at least 99% homologous to SEQ ID NO: 1.
  • the antibody comprises an amino acid sequence identical to SEQ ID NO: 1.
  • the antibody further comprises a signal peptide. In certain embodiments, the antibody further comprises a signal peptide comprising an amino acid sequence at least 76%, at least 80%, at least 90%, at least 95%, or at least 99% homologous to SEQ ID NO: 2.
  • the signal peptide comprises an amino acid sequence identical to SEQ ID NO: 2.
  • the antibody further comprises at least one marker.
  • the antibody further comprises a marker comprising an amino acid sequence at least 76%, at least 80%, at least 90%, at least 95%, or at least 99% homologous to SEQ ID NO: 3.
  • the marker comprises an amino acid sequence identical to SEQ ID NO: 3.
  • the inhibitor is an inhibitory protein.
  • the inhibitory protein is an inhibitory oligonucleotide.
  • the inhibitory oligonucleotide is an inhibitory RNA (RNAi) that binds to an mRNA that encodes ephrin B2, EphBl, or EphB4.
  • the inhibitor is a RNAi and the RNAi is a small inhibitory RNA (siRNA), a micro-RNA (miRNA), a short-hairpin RNA (shRNA), or an
  • oligonucleotide vectors that encodes the RNAi.
  • the inhibitor is a bioactive small molecule.
  • the bioactive small molecule is [2-[2,4-bis(2-methylbutan-2-yl)phenoxy]-5- methoxyphenyljmethanol, N-(4-fluorophenyl)-5-nitro-6-pyrrolidin-l-ylpyrimidin-4-amine, (N-(2-chloro-6-methylphenyl)-2-( ⁇ 6-[4-(2-hydroxyethyl)piperazin-l-yl]-2- methylpyrimidin-4-yl ⁇ amino)-l,3-thiazole-5-carboxamide (i.e., dasatinib), 6-(2,6- dichlorophenyl)-8-methyl-2- ⁇ [3-(methylsulfanyl)phenyl]amino ⁇ -7H,8H-pyrido[2,3- d]pyrimidin-7-one (PD- 173955), l-N'-[3-fluoro-4
  • Eph receptors from humans are provided below.
  • the cancer is a B-cell proliferative disorder.
  • the B-cell proliferative disorder is follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, Waldenstrom’s macroglobulinemia, multiple myeloma, marginal zone lymphoma, Burkitt’s lymphoma, non-Burkitt high grade B cell lymphoma, or extranodal marginal zone B cell lymphoma.
  • the cancer is relapsed or refractory.
  • the B-cell proliferative disorder is multiple myeloma.
  • the multiple myeloma is t(4; 14) multiple myeloma.
  • the multiple myeloma is gain of chromosome lq multiple myeloma.
  • the multiple myeloma is relapsed or refractory.
  • the subject does not experience a relapse of the cancer for about 6 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, or about 10 years.
  • the present disclosure provides a comprising an inhibitor of ephrin- Eph signaling and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical compositions of the invention are designed to deliver the inhibitors of ephrin-Eph signaling to specific tissues or specific cell types. In some such embodiments, pharmaceutical compositions are designed to deliver inhibitors of ephrin-Eph signaling to vascular endothelial cells. In other such embodiments,
  • compositions are designed to deliver inhibitors of ephrin- Eph receptor signaling to cancer cells.
  • compositions can be designed to deliver inhibitors of expression or activity of EphBl, such as, an antibody or an RNAi against EphBl to vascular endothelial cells.
  • Pharmaceutical compositions can also be designed to deliver inhibitors of expression or activity of EphBl, such as, an antibody or an RNAi against Eph receptor to cancer cells.
  • compositions of designing pharmaceutical compositions to deliver the inhibitors of EphBl -Eph receptor signaling to target cells are known in the art.
  • the inhibitors of EphBl -Eph receptor signaling can be conjugated with ligands that bind to the target cells.
  • the inhibitors of EphBl -Eph receptor signaling are encapsulated in liposomes comprising ligands that bind to the target cells.
  • the ligands can be embedded in the liposomal membranes.
  • the ligands that bind to target cells include antibodies binding to cell surface membrane proteins or peptides or proteins binding to receptors on the target cells.
  • the receptors on the target cells are chosen such that the receptors are exclusively present on the target cells, i.e., are absent from the non-target cells.
  • the receptors on the target cells are chosen such that the receptors are expressed at much higher levels in the target cells compared to the levels in the non-target cells.
  • the inhibitor is conjugated to a ligand that binds to a receptor on cancer cells or a receptor on vascular endothelial cells.
  • the inhibitor is encapsulated in liposomes comprising a ligand that binds to a receptor on cancer cells or a ligand that binds to the receptor on vascular endothelial cells.
  • the ligand is embedded in the liposomal membrane.
  • the composition comprises an inhibitor of this disclosure (e.g., an antibody, a inhibitory protein, or a bioactive small molecule).
  • agent is used herein to denote a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipid, a carbohydrate), or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues.
  • Agents include, for example, agents whose structure is known, and those whose structure is not known. The ability of such agents to inhibit AR or promote AR degradation may render them suitable as “therapeutic agents” in the methods and compositions of this disclosure.
  • A“patient,”“subject,” or“individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats).
  • Treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results.
  • treatment is an approach for obtaining beneficial or desired results, including clinical results.
  • Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.“Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • preventing is art-recognized, and when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition.
  • a condition such as a local recurrence (e.g., pain)
  • a disease such as cancer
  • a syndrome complex such as heart failure or any other medical condition
  • prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and/or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and/or clinically significant amount.
  • administering or“administration of’ a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art.
  • a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct).
  • a compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent.
  • Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.
  • a compound or an agent is administered orally, e.g., to a subject by ingestion.
  • the orally administered compound or agent is in an extended release or slow release formulation, or administered using a device for such slow or extended release.
  • the phrase“conjoint administration” refers to any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., the two agents are simultaneously effective in the patient, which may include synergistic effects of the two agents).
  • the different therapeutic compounds can be administered either in the same formulation or in separate formulations, either concomitantly or sequentially.
  • an individual who receives such treatment can benefit from a combined effect of different therapeutic agents.
  • A“therapeutically effective amount” or a“therapeutically effective dose” of a drug or agent is an amount of a drug or an agent that, when administered to a subject will have the intended therapeutic effect.
  • the full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
  • a therapeutically effective amount may be administered in one or more
  • the precise effective amount needed for a subject will depend upon, for example, the subject’s size, health and age, and the nature and extent of the condition being treated, such as cancer or MDS. The skilled worker can readily determine the effective amount for a given situation by routine experimentation.
  • “optional” or“optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not.
  • “optionally substituted alkyl” refers to the alkyl may be substituted as well as where the alkyl is not substituted.
  • module includes the inhibition or suppression of a function or activity (such as cell proliferation) as well as the enhancement of a function or activity.
  • phrases“pharmaceutically acceptable” is art-recognized.
  • the term includes compositions, excipients, adjuvants, polymers and other materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable salt” or“salt” is used herein to refer to an acid addition salt or a basic addition salt which is suitable for or compatible with the treatment of patients.
  • pharmaceutically acceptable acid addition salt means any non-toxic organic or inorganic salt of any base compounds represented by Formula I.
  • Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • Illustrative organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-toluene sulfonic and methanesulfonic acids. Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form.
  • mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sul
  • the acid addition salts of compounds of Formula I are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.
  • the selection of the appropriate salt will be known to one skilled in the art.
  • Other non-pharmaceutically acceptable salts e.g., oxalates, may be used, for example, in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
  • pharmaceutically acceptable basic addition salt means any non-toxic organic or inorganic base addition salt of any acid compounds represented by Formula I or any of their intermediates.
  • Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide.
  • Illustrative organic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia.
  • aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia.
  • aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia.
  • the selection of the appropriate salt will be known to a person skilled in the art.
  • Prodrug or“pharmaceutically acceptable prodrug” refers to a compound that is metabolized, for example hydrolyzed or oxidized, in the host after administration to form the compound of the present disclosure (e.g., compounds of formula I).
  • Typical examples of prodrugs include compounds that have biologically labile or cleavable (protecting) groups on a functional moiety of the active compound.
  • Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound.
  • prodrugs using ester or phosphoramidate as biologically labile or cleavable (protecting) groups are disclosed in U.S. Patents 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference.
  • the prodrugs of this disclosure are metabolized to produce a compound of Formula I.
  • the present disclosure includes within its scope, prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in“Design of Prodrugs” Ed. H. Bundgaard, Elsevier, 1985.
  • phrases“pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filter, diluent, excipient, solvent or encapsulating material useful for formulating a drug for medicinal or therapeutic use.
  • log of solubility is used in the art to quantify the aqueous solubility of a compound.
  • the aqueous solubility of a compound significantly affects its absorption and distribution characteristics. A low solubility often goes along with a poor absorption.
  • LogS value is a unit stripped logarithm (base 10) of the solubility measured in mol/liter.
  • compositions and methods of the present invention may be utilized to treat an individual in need thereof.
  • the individual is a mammal such as a human, or a non-human mammal.
  • the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
  • the aqueous solution is pyrogen-free, or substantially pyrogen-free.
  • the excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs.
  • the pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like.
  • the composition can also be present in a transdermal delivery system, e.g., a skin patch.
  • the composition can also be present in a solution suitable for topical administration, such as a lotion, cream, or ointment.
  • a pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the invention.
  • physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
  • the choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent depends, for example, on the route of administration of the composition.
  • the preparation or pharmaceutical composition can be a selfemulsifying drug delivery system or a selfmicroemulsifying drug delivery system.
  • the pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention.
  • Liposomes for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • phrases "pharmaceutically acceptable carrier” as used herein means a
  • composition or vehicle such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material.
  • a liquid or solid filler such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material.
  • pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and
  • oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil
  • glycols such as propylene glycol
  • polyols such as glycerin, sorbitol, mannitol and polyethylene glycol
  • esters such as ethyl oleate and ethyl laurate
  • (13) agar (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
  • alginic acid (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.
  • a pharmaceutical composition can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules
  • the compound may also be formulated for inhalation.
  • a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients.
  • an active compound such as a compound of the invention
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil- in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • Compositions or compounds may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents,
  • pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the
  • compositions that can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the active compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,
  • compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions.
  • prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
  • delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide.
  • active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • Methods of introduction may also be provided by rechargeable or biodegradable devices.
  • Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous
  • biopharmaceuticals A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • therapeutically effective amount is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention. A larger total dose can be delivered by multiple
  • a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • the active compound may be administered two or three times daily.
  • the active compound will be administered once daily.
  • the patient receiving this treatment is any animal in need, including primates, in particular humans; and other mammals such as equines, cattle, swine, sheep, cats, and dogs; poultry; and pets in general.
  • compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent.
  • contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. In certain embodiments,
  • contemplated salts of the invention include, but are not limited to, L-arginine,
  • contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts.
  • contemplated salts of the invention include, but are not limited to, 1- hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxy ethanesulfonic acid, 2- oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, 1- ascorbic acid, 1-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)- camphor- 10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gent
  • the pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared.
  • the source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabi sulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabi sulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (
  • ligands are selected that bind to the receptors on vascular endothelial cells, such as vascular cell adhesion molecule-1 (VCAM-1), P-selectin, E-selectin, platelet-endothelial adhesion molecule-1 (PEC AM), and intercellular adhesion molecule- 1 (ICAM).
  • VCAM-1 vascular cell adhesion molecule-1
  • PEC AM P-selectin
  • E-selectin E-selectin
  • IAM intercellular adhesion molecule- 1
  • vascular endothelial cell for example, a vascular endothelial cell or a cancer cells
  • a chosen target cell for example, a vascular endothelial cell or a cancer cells
  • ligands that bind to receptors on a chosen target cell for example, a vascular endothelial cell or a cancer cells are well known in the art and such embodiments are within the purview of the invention.
  • Example 1 Inhibition of EphBl in vascular endothelial cells inhibits MM growth
  • human aortic endothelial cells support the growth of human MM cells in culture was evaluated.
  • human dermal endothelial cells HDEC
  • human aortic endothelial cells HAEC
  • Comparison of gene expression in the HAEC versus HDEC revealed that EphBl was overexpressed in HAECs compared to non-supportive HDECs.
  • Gain of function and loss of function experiments were performed to test whether EphBl - Eph receptor signaling was responsible for MM growth in vitro. Addition of recombinant EphBl -Fc to cultures of human U266 or NCI-H929 MM cells significantly increased MM cell expansion in 7-day culture.
  • mice transplanted with the progeny of cultures treated with si-EphB 1 displayed five-fold lower MM cell growth in mice (p ⁇ 0.001) (FIG. 3). These results confirm that EphBl can be targeted to inhibit MM repopulating cells that drive tumor growth in vivo.

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Abstract

L'invention concerne des procédés de traitement de certains cancers (par exemple, le myélome) avec des inhibiteurs de la signalisation éphrine-Eph. L'invention concerne également des compositions comprenant des inhibiteurs de la signalisation éphrine-Eph.
PCT/US2020/034137 2019-05-24 2020-05-22 Compositions et méthodes de traitement du cancer WO2020242910A1 (fr)

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WO2012038573A1 (fr) * 2010-09-21 2012-03-29 Fundación Centro Nacional De Investigaciones Oncológicas (Cnio) Anticorps dirigé contre l'éphrine b2 et utilisation correspondante

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