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WO2025151374A1 - Polythérapie oncologique et méthodes d'utilisation - Google Patents

Polythérapie oncologique et méthodes d'utilisation

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Publication number
WO2025151374A1
WO2025151374A1 PCT/US2025/010480 US2025010480W WO2025151374A1 WO 2025151374 A1 WO2025151374 A1 WO 2025151374A1 US 2025010480 W US2025010480 W US 2025010480W WO 2025151374 A1 WO2025151374 A1 WO 2025151374A1
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WIPO (PCT)
Prior art keywords
administered
cancer
plinabulin
day
antibody
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.)
Pending
Application number
PCT/US2025/010480
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English (en)
Inventor
Lan Huang
Yingjuan June Lu
Key LLOYD
James Tonra
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BeyondSpring Pharmaceuticals Inc
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BeyondSpring Pharmaceuticals Inc
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Publication date
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Publication of WO2025151374A1 publication Critical patent/WO2025151374A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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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
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
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    • 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
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68037—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a camptothecin [CPT] or derivatives
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A—HUMAN NECESSITIES
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6855—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell
    • 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
    • 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
    • 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
    • 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
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • 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
    • A61K2039/507—Comprising a combination of two or more separate antibodies
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation

Definitions

  • the dose of the antibody-drug conjugate is from about 0.1 mg/kg to about 15 mg/kg. In some embodiments, the antibody-drug conjugate is from about 0.5 mg/kg to about 5 mg/kg. In some embodiments, the dose of the antibody-drug conjugate is 1.0 mg/kg. In some embodiments, the antibody-drug conjugate is administered intravenously.
  • the antibody-drug conjugate is administered on day 1 of the treatment cycle. In some embodiments, the antibody-drug conjugate is administered on day 8 of the treatment cycle.
  • the method disclosed herein further includes, administration of: radiation therapy, an immune checkpoint inhibitor, a chemotherapeutic agent, or a combination thereof, to the subject.
  • the methods disclosed herein comprises administration of an immune checkpoint inhibitor.
  • the one or more immune checkpoint inhibitor is administered intravenously.
  • the immune checkpoint inhibitor is administered to the subject in an amount of from 50 mg to 2000 mg.
  • the one or more immune checkpoint inhibitor is pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, pidilizumab, ipilimumab, BMS 936559, RMP1-14, durvalumab, or a combination thereof.
  • the method disclosed herein further includes administration of radiation therapy to the subject.
  • radiation therapy is administered in one to ten fractions.
  • radiation therapy is administered three to five fractions.
  • radiation therapy is administered in three fractions, four fractions or five fractions.
  • the total dose of radiation administered is from about 1 Gy to about 20 Gy.
  • the total dose of radiation administered is from about 2 Gy to about 15 Gy.
  • the total dose of radiation administered is from about 4 Gy to about 15 Gy.
  • the total dose of radiation administered is about 4 Gy, or about 8 Gy, or about 12.5 Gy.
  • radiation therapy is administered on days 1, 2, and 3 of the treatment cycle, or on days 1, 2, 3, and 4 of the treatment cycle, or on days 1, 2, 3, 4, and 5 of the treatment cycle.
  • the plinabulin is administered from about 3 hours to about 12 hours after completion of administration of the radiation therapy.
  • FIG. 1 depicts the single compound ICso tests against the NCI -Hl 975 nonsmall cell lung cancer cell line.
  • FIG. 2 depicts the single compound ICso tests against the KPL-4 metastatic breast cancer cell line.
  • FIG. 5 shows the Bliss synergy plot for combination testing of plinabulin with sacituzumab govetican on NCI-H1975 non-small cell lung cancer cells.
  • the present disclosure provides methods and therapeutic compositions for treating, ameliorating, or preventing a cancer or a tumor in a subject using plinabulin.
  • methods and compositions provided herein are useful in treating, delaying the progression of, preventing relapse of, or alleviating a symptom of a cancer or other neoplastic condition using plinabulin.
  • Plinabulin, (3Z,6Z)-3-Benzylidene-6- ⁇ [5-(2-methyl-2-propanyl)- l/7-imidazol-4-yl]methylene ⁇ -2,5-piperazinedione is a synthetic analog of the natural compound phenylahistin.
  • Plinabulin can be readily prepared according to methods and procedures detailed in U.S.
  • Trop-2 is a 40-kDa glycoprotein that was the first described transducer of intracellular calcium signaling Lipinski et al. Proc Natl Acad Set USA 1981, 78(8):5147-50; Ripani et al. Int J Cancer. 1998;76(5):671-676. It contains a 274-amino-acid extracellular epidermal growth factor-like repeat portion with three domains, a cysteine- rich domain, a thyroglobulin type-1 domain, and a cysteine-poor domain. Goldenberg et al. Oncotarget. 2018, 9(48):28989-29006.
  • the ADC is an anti-Human epidermal growth factor receptor-2 (HER2) ADC. In some embodiments, the ADC is an anti-Human epidermal growth factor receptor-3 (HER3) ADC. In some embodiments, the ADC is an anti-B7-H3 ADC. In some embodiments, the ADC is an anti- CDH6 ADC. In some embodiments, the ADC may be an anti-EGFR, anti- Nectin-4, anti-cMet, anti-Integrin-beta-6, anti-Tissue factor, anti-SEZ6 (seizure-related homolog protein 6), or anti-DLL3 (delta-like ligand 3) ADC. In some embodiments, the plinabulin and ADC may be administered in combination with one or more immune checkpoint inhibitor, additional chemotherapeutic agents, and/or radiation therapy.
  • Methods recited herein may be carried out in any order of the recited events which is logically possible, as well as the recited order of events.
  • antagonist refers to a compound that can combine with a receptor (e.g., an immune checkpoint receptor) to block a cellular activity.
  • a receptor e.g., an immune checkpoint receptor
  • An antagonist may be a ligand that directly binds to the receptor.
  • an antagonist may combine with a receptor indirectly by, for example, (a) forming a complex with another molecule that directly binds to the receptor, or (b) otherwise results in the modification of another compound so that the other compound directly binds to the receptor.
  • antibody or “antibody moiety” is intended to include any polypeptide chain-containing molecular structure with a specific shape that fits to and recognizes an epitope, where one or more non-covalent binding interactions stabilize the complex between the molecular structure and the epitope.
  • Antibodies utilized in the present disclosure may be polyclonal antibodies or monoclonal antibodies. Antibodies also include free antibodies and antigen binding fragments derived therefrom, and conjugates, e.g. pegylated antibodies, drug, radioisotope, or toxin conjugates, and the like. Monoclonal antibodies directed against a specific epitope, or combination of epitopes, will allow for the targeting and/or depletion of cellular populations expressing the marker.
  • antibody may refer to an immunoglobulin (Ig) defined as a protein belonging to the class IgG, IgM, IgE, IgA, or IgD (or any subclass thereof), or a functional binding fragment or binding domain of an immunoglobulin.
  • Ig immunoglobulin
  • An antibody or antibody fragment as disclosed herein may be conjugated or otherwise derivatized.
  • the antibody is an anti-Trop-2 antibody.
  • the antibody is an anti-Trop-2 monoclonal antibody.
  • cancer neoplasm
  • cancerma a cell which exhibit relatively autonomous growth, so that they exhibit an aberrant growth phenotype characterized by a significant loss of control of cell proliferation.
  • cells of interest for detection or treatment in the present application include precancerous (e.g., benign), malignant, pre-metastatic, metastatic, and non-metastatic cells. Detection of cancerous cells is of particular interest.
  • ADC or “antibody drug conjugate” as used herein refers to a compound that comprises an antibody (or fragment thereof) that is used to target and/or bind to the cell, a drug (or payload), and a linker which covalently binds the drug to the antibody.
  • anti-Trop-2 ADC or “anti-Trop 2-antibody drug conjugate” as used herein refers to an ADC wherein the antibody is an anti-Trop-2 antibody.
  • anti-HER2 ADC or “anti-HER2-antibody drug conjugate” as used herein refers to an ADC wherein the antibody is an anti-HER2 antibody.
  • anti-HER3 ADC or “anti-HER3 -antibody drug conjugate” as used herein refers to an ADC wherein the antibody is an anti-HER3 antibody.
  • polypeptide is used herein as a generic term to refer to native protein, fragments, or analogs of a polypeptide sequence. Hence, native protein fragments, and analogs are species of the polypeptide genus.
  • anti-Trop-2 ADCs for use as described herein may be prepared from a number of anti-Trop-2 antibodies.
  • anti-Trop-2 antibodies are commercially available from a number of sources and include, but are not limited to LS-C126418, LS- C178765, LS-C126416, LS-C126417 (LifeSpan BioSciences, Inc., Seattle, Wash.); 10428- MM01, 10428-MM02, 10428-R001, 10428-R030 (Sino Biological Inc., Beijing, China); MR54 (eBioscience, San Diego, Calif); sc-376181, sc-376746, Santa Cruz Biotechnology (Santa Cruz, Calif.); MM0588-49D6, (Novus Biologicals, Littleton, Colo.); ab79976, and ab89928 (ABCAM®, Cambridge, Mass.).
  • anti-Trop-2 antibodies 162-25.3 and 162-46.2 discloses anti-Trop-2 antibodies 162-25.3 and 162-46.2, which is incorporated herein by reference in its entirety.
  • the anti-Trop-2 antibodies may be sacituzumab or datopotamab. All of the antibodies disclosed above can be used in an ADC for use as described herein.
  • the anti-Trop-2 ADC comprises a drug (payload) that may be cytotoxic to cells.
  • the drug may belong to a variety of classes of drugs, including but not limited to auristatins, maytansinoids, pyrrolobenzodiazepines, tubulysins, erubulin, taxol derivatives, duocarmycins, camptothecins, topoisomerase inhibitors, calicheamicins, thalianstatins, or DNA damaging agents.
  • the drug may be ozogamicin, vedotin, emtansine, camptothecins, exatecan, topotecan, irinotecan, belotecan, deruxtecan, govitecan, mafodotin, pasudotox tesirine, calicheamicin yl, or doxorubicin.
  • the drug may be govitecan. In other specific embodiments, the drug may be deruxtecan.
  • the anti-Trop-2 ADC may be sacituzumab govitecan (IMMU-132, hRS7-SN-38, Trodelvy®), datopotamab deruxtecan, (Dato-Dxd, DS-1062a), SKB264, LCB84, STI-3258, BAT8008, FDA018-ADC, BIO-106, JS108, PF-06664178, or a combination thereof.
  • the anti-Trop-2 ADC may be sacituzumab govitecan.
  • the anti-Trop-2 ADC may be datopotamab deruxtecan.
  • HER2 is a protein (Human epidermal growth factor receptor-2) that normally resides in the membranes of cells. Overexpression of HER2 is believed to play a crucial role in the malignant transformation of normal cells and in the continued growth of normal cells. HER2 is a validated cancer target, and both monoclonal antibodies and small molecule inhibitors of HER2 have been approved for the treatment of various cancers.
  • Therapeutic conjugates comprising an anti-HER2 can be used to treat carcinomas such as breast cancer, lung cancer, ovarian cancer, gastric cancer, bladder cancer, pancreatic cancer, endometrial cancer, colon cancer, kidney cancer, esophageal cancer, or prostate cancer.
  • Anti HER2 ADCs may include, but are not limited to, trastuzumab emtansine, trastuzumab deruxtecan, and RC-48.
  • the anti-HER2 ADC comprises a drug (payload) that may be cytotoxic to cells.
  • the drug may belong to a variety of classes of drugs, including but not limited to auristatins, maytansinoids, pyrrolobenzodiazepines, tubulysins, erubulin, taxol derivatives, duocarmycins, camptothecins, topoisomerase inhibitors, calicheamicins, thalianstatins, or DNA damaging agents.
  • anti-HER2 ADCs for use as described herein may be prepared from a number of anti-HER2 antibodies.
  • anti-HER2 antibodies may include, but are not limited to, trastuzumab, margetuximab, pertuzumab, GB235, huMAb4D5-l, huMAb4D5- 2, huMAb4D5-3, huMAb4D5-4, huMAb4D5-5, huMAb4D5-6, huMAb4D5-7 and huMAb4D5-8.
  • HER3 Human epidermal growth factor receptor-3 is a membrane-bound protein. HER3, as a heterodimerization partner with HER2, is implicated in growth, proliferation, chemotherapeutic resistance, and the promotion of invasion and metastasis. Holbro et al., Proc. Natl. Acad. Set. U.S.A. 100 (15): 8933-8; Wang et al. Oncogene. 29 (29): 4225-36. HER3 is widely expressed in solid tumors and associated with tumor growth and drug resistance.
  • anti-HER3 ADCs could potentially be used to treat cancers.
  • anti HER3 ADCs maybe used to treat carcinomas such as breast cancer, lung cancer, ovarian cancer, gastric cancer, bladder cancer, pancreatic cancer, endometrial cancer, colon cancer, kidney cancer, esophageal cancer, or prostate cancer.
  • Anti HER3 ADCs may include, but are not limited to, Patritumab deruxtecan and SHR-A2009.
  • the anti-HER3 ADC comprises a drug (payload) that may be cytotoxic to cells.
  • the drug may belong to a variety of classes of drugs, including but not limited to auristatins, maytansinoids, pyrrolobenzodiazepines, tubulysins, erubulin, taxol derivatives, duocarmycins, camptothecins, topoisomerase inhibitors, calicheamicins, thalianstatins, or DNA damaging agents.
  • anti-HER3 antibodies may include, but are not limited to, Patritumab, Seribantumab, Lumretuzumab, GSK2849330, CDX-3379, Barecetamab, AV-203, Elgemtumab, HMBD-001, U3P1287/01, and SIBP-03.
  • ADCS Adsorption Control Codon
  • the anti-B7-H3 ADC may be ifinatamab deruxtecan.
  • the anti-CDH6 ADC may be DS-6000.
  • the ADC may be an anti-EGFR, anti-Nectin-4, anti-cMet, anti-Integrin-beta-6, anti-Tissue factor, anti-SEZ6 (seizure-related homolog protein 6), or anti-DLL3 (delta-like ligand 3) ADC.
  • one or more immune checkpoint inhibitor may be co-administered with plinabulin and the ADCs described herein.
  • a review describing immune checkpoint pathways and the blockade of such pathways with immune checkpoint inhibitor compounds is provided by Pardoll in Nature Reviews Cancer (April, 2012), pages 252-264, which is incorporated herein by reference in its entirety.
  • Immune check point inhibitor compounds display anti-tumor activity by blocking one or more of the endogenous immune checkpoint pathways that downregulate an antitumor immune response.
  • the inhibition or blockade of an immune checkpoint pathway typically involves inhibiting a checkpoint receptor and ligand interaction with an immune checkpoint inhibitor compound to reduce or eliminate the down regulation signal and resulting diminishment of the anti-tumor response.
  • the immune checkpoint inhibitor compound inhibits the signaling interaction between an immune checkpoint receptor and the corresponding ligand of the immune checkpoint receptor.
  • the immune checkpoint inhibitor compound can act by blocking activation of the immune checkpoint pathway by inhibition (antagonism) of an immune checkpoint receptor (some examples of receptors include CTLA-4, PD-1, LAG-3, TIM-3, BTLA, and KIR) or by inhibition of a ligand of an immune checkpoint receptor (some examples of ligands include PD-L1 and PD-L2).
  • the effect of the immune checkpoint inhibitor compound is to reduce or eliminate down regulation of certain aspects of the immune system anti-tumor response in the tumor microenvironment.
  • the Programmed Death 1 (PD-1) protein is an inhibitory member of the extended CD28/CTLA-4 family of T cell regulators (Okazaki et al. (2002) Curr Opin Immunol 14: 391779-82; Bennett et al. (2003) J. Immunol. 170:711-8; which are incorporated herein by reference in their entirety).
  • Other members of the CD28 family include CD28, CTLA-4, ICOS and BTLA.
  • PD-1 is suggested to exist as a monomer, lacking the unpaired cysteine residue characteristic of other CD28 family members. PD-1 is expressed on activated B cells, T cells, and monocytes.
  • the PD-1 gene encodes a 55 kDa type I transmembrane protein (Agata et al. (1996) Int Immunol. 8:765-72, which is incorporated herein by reference in its entirety). Although structurally similar to CTLA-4, PD-1 lacks the MYPPY motif that is important for B7-1 and B7-2 binding. Two ligands for PD-1 have been identified, PD-L1 (B7-H1) and PD- L2 (B7-DC), that have been shown to downregulate T cell activation upon binding to PD-1 (Freeman et al. (2000) J. Exp. Med. 192:1027-34; Carter et al. (2002) Eur. J. Immunol.
  • Both PD-L1 and PD-L2 are B7 homologs that bind to PD-1, but do not bind to other CD28 family members.
  • PD-L1 is abundant in a variety of human cancers (Dong et al. (2002) Nat. Med. 8:787-9, which is incorporated herein by reference in its entirety).
  • PD-1 is known as an immunoinhibitory protein that negatively regulates TCR signals (Ishida, Y. et al. (1992) EMBO J. 11 :3887-3895; Blank, C. et al. (Epub 2006 Dec. 29) Immunol. Immunother. 56(5): 739-745; which are incorporated herein by reference in their entirety).
  • the interaction between PD-1 and PD-L1 can act as an immune checkpoint, which can lead to, e.g., a decrease in tumor infiltrating lymphocytes, a decrease in T-cell receptor mediated proliferation, and/or immune evasion by cancerous cells (Dong et al. (2003) J. Mol. Med.
  • Immune suppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1 or PD-L2; the effect is additive when the interaction of PD-1 with PD-L2 is blocked as well (Iwai et al. (2002) Proc. Nat'l. Acad. Sci. USA 99: 12293-7; Brown et al. (2003) J. Immunol. 170: 1257-66; which are incorporated herein by reference in their entirety).
  • CTLA-4 cytotoxic T-lymphocyte associated antigen 4
  • the immune checkpoint receptor cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) is expressed on T-cells and is involved in signaling pathways that reduce the level of T-cell activation. It is believed that CTLA-4 can downregulate T-cell activation through competitive binding and sequestration of CD80 and CD86. In addition, CTLA-4 has been shown to be involved in enhancing the immunosuppressive activity of TR eg cells.
  • the immune checkpoint receptor B- and T-lymphocyte attenuator (BTLA) receptor is expressed on both resting and activated B-cells and T-cells.
  • BTLA T-lymphocyte attenuator
  • HVEM herpes virus entry mediator
  • T-cell activation and proliferation results in downregulation of both T-cell activation and proliferation.
  • HVEM is expressed by certain tumors (e.g., melanoma) and tumor-associated endothelial cells.
  • the immune checkpoint inhibitor compound is a small organic molecule (molecular weight less than 1000 daltons), a peptide, a polypeptide, a protein, an antibody, an antibody fragment, or an antibody derivative.
  • the immune checkpoint inhibitor compound is an antibody.
  • the antibody is a monoclonal antibody, specifically a human or a humanized monoclonal antibody.
  • anti-PD-Ll antibodies are described in U.S. Pat. No. 7,943,743 (Korman), which is incorporated herein by reference in its entirety.
  • the preparation and therapeutic uses of anti-TIM-3 antibodies are described in U.S. Pat. No. 8,101,176 (Kuchroo) and U.S. Pat. No. 8,552,156 (Tagayanagi), which are incorporated herein by reference in their entirety.
  • the preparation and therapeutic uses of anti-LAG-3 antibodies are described in U.S. Patent Application No. 2011/0150892 (Thudium) and International Publication Number W02014/008218 (Lonberg), which are incorporated herein by reference in their entirety.
  • the preparation and therapeutic uses of anti-KIR antibodies are described in U.S.
  • the immune checkpoint inhibitor is Pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, pembrolizumab, pidilizumab, ipilimumab, BMS 936559, RMP1-14, durvalumab, or any combinations thereof.
  • the immune checkpoint inhibitor may be RMP1-14.
  • the one or more immune checkpoint inhibitor may include an anti -PD-1 HuMAbs can be selected from 17D8, 2D3, 4H1, 5C4 (also referred to herein as nivolumab), 4A1 1, 7D3 and 5F4, all of which are described in U.S. Pat. No. 8,008,449, which is incorporated herein by reference in its entirety.
  • the anti-PD-1 HuMAbs can be selected from 3 G10, 12A4 (also referred to herein as BMS-936559), 10A5, 5F8, 10H10, 1B12, 7H1, 1 1E6, 12B7, and 13G4, all of which are described in U.S. Pat. No.
  • the immune checkpoint inhibitor compound is incorporated in a pharmaceutically acceptable liposome formulation, wherein the formulation is a passive or targeted liposome formulation.
  • a pharmaceutically acceptable liposome formulation wherein the formulation is a passive or targeted liposome formulation.
  • suitable liposome formulations of antibodies are described U.S. Pat. No. 5,399,331 (Loughrey), U.S. Pat. No. 8,304,565 (Wu) and U.S. Pat. No. 7,780,882 (Chang), which are incorporated herein by reference in their entirety.
  • the one or more immune checkpoint inhibitor may be an antibody.
  • the antibody is a dry, lyophilized solid that is reconstituted with an aqueous reconstitution solvent prior to use.
  • the antibody is incorporated in a pharmaceutically acceptable formulation and the pharmaceutically acceptable formulation is injected directly into a tumor.
  • the immune checkpoint inhibitor antibody is incorporated in a pharmaceutically acceptable formulation and the pharmaceutically acceptable formulation is injected into the peritumoral region surrounding a tumor. The peritumoral region may contain antitumor immune cells.
  • the antibody is incorporated in a pharmaceutically acceptable formulation and the pharmaceutically acceptable formulation is administered by intravenous injection or infusion.
  • the immune checkpoint inhibitor antibody is incorporated in a pharmaceutically acceptable formulation and the pharmaceutically acceptable formulation is administered by subcutaneous injection or intradermal injection. In some embodiments, the antibody is incorporated in a pharmaceutically acceptable formulation and the pharmaceutically acceptable formulation is administered by intraperitoneal injection or lavage.
  • the ADC is administered on day 1 of the treatment cycle and plinabulin is administered on day 1 of the treatment cycle. In other embodiments, the ADC is administered on day 1 of the treatment cycle and plinabulin is administered on day 1 and day 4 of the treatment cycle. In some embodiments, the ADC is administered on day 1 of the treatment cycle, plinabulin is administered on day 1 and day 4 of the treatment cycle. In some embodiments, the ADC is administered on day 1 and day 8 of the treatment cycle, plinabulin is administered on day 1 of the treatment cycle.
  • plinabulin is administered in about lmin-5min, Imin-lOmin, Imin- 15min, lmin-20min, 1 min-25min, 1 min-30min, 0.25h-0.5h, 0.25-0.75h, 0.25-lh,0.5h-lh, 0.5h-2h, 0.5h-2.5h, lh-2h, lh-3h, lh-5h, lh-24h, lmin-24h, or 1 min-2h, 1 day- 2days, Iday - 3days, 1 day-4 days, 1 day-5 days, or 1 day-6 days after the administration of one or more immune checkpoint inhibitor.
  • one or more immune checkpoint inhibitor used on the first administration day is the same as or different from one or more immune checkpoint inhibitor used on the fifth administration day. In some embodiments, one or more immune checkpoint inhibitor used on the first administration day is the same as or different from one or more immune checkpoint inhibitor used on the sixth administration day. In some embodiments, one or more immune checkpoint inhibitor used on the first administration day is the same as or different from one or more immune checkpoint inhibitor used on the seventh administration day.
  • the treatment cycle includes administration of one or more immune checkpoint inhibitor on day 1, day 3, day 5 in weekly treatment. In some embodiments, the treatment cycle includes administration of one or more immune checkpoint inhibitor on day 1, day 2, day 3, and day 4 in weekly treatment. In some embodiments, the treatment cycle includes administration of one or more immune checkpoint inhibitor on day 1 , day 2, day 3, day 4, and day 5 in weekly treatment. In some embodiments, the treatment cycle includes administration of one or more immune checkpoint inhibitor on day 1, day 2, day 3, day 4, day 5, and day 6 in weekly treatment.
  • the radiation therapy may be administered on day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and/or 28 of the treatment cycle.
  • the radiation therapy may be administered on day 1, 2, and 3 of the treatment cycle.
  • radiation therapy may be administered on day 1, 2, 3, and 4 of the treatment cycle.
  • radiation therapy may be administered on day 1, 2, 3, 4, and 5 of the treatment cycle.
  • radiation therapy may be administered on day 2, 3, and 4 of the treatment cycle.
  • the total dose of radiation administered to the subject during the treatment cycle can be about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, or 20 Gy, or more, or within a range defined by any two of the aforementioned values.
  • the total dose of radiation administered to the subject can be from about 1 Gy to about 20 Gy, from about 2 Gy to about 15 Gy, from about 4 Gy to about 15 Gy. In some embodiments, the total dose of radiation administered to the subject is about 4 Gy. In other embodiments, the total dose of radiation administered to the subject is about 8 Gy.
  • the total dose of radiation administered to the subject is about 12.5 Gy.
  • radiation may be administered in 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 fractions, or more.
  • radiation may be administered in three to five fractions.
  • radiation may be administered in three fractions.
  • radiation may be administered in four fractions.
  • radiation may be administered in five fractions.
  • the plinabulin when radiation therapy and plinabulin are administered on the same day, is administered from about 3 hours to about 12 hours after completion of administration of the radiation therapy.
  • the plinabulin is administered from about 4 hours to about 10 hours, about 4 hours to about 8 hours, or about 5 hours to about 8 hours after completion of administration of the radiation therapy.
  • the present disclosure provides a method for treating a breast cancer, a bladder cancer, a glioma, a glioblastoma, a head and neck cancer, a nonsmall cell lung cancer, a small cell lung cancer, recurrent small cell lung cancer (SCLC), a colorectal cancer, a gastrointestinal stromal tumor, a gastroesophageal carcinoma, a renal cell cancer, a prostate cancer, a liver cancer, a colon cancer, a pancreatic cancer, an ovarian cancer, a lymphoma, or a cutaneous T-cell lymphoma, or a melanoma.
  • the cancer is a colorectal cancer, a breast cancer, gastrointestinal stromal tumor, or a gastroesophageal carcinoma.
  • the cancer is triple negative breast cancer (TNBC).
  • the present disclosure provides a method for treating Fibrolamellar hepatocellular carcinoma, MSI-H cancers of any histology including but not limited to: colorectal, endometrial, adrenocortical, anal, appendiceal cancer, biliary, bladder, brain, breast, cervical, gastric or gastroesophageal junction, head and neck squamous cell, liver, mesothelioma, nasopharyngeal, neuroendocrine, ovarian, pancreatic, prostate, renal cell, retroperitoneal, salivary, sarcoma, small cell lung, small intestinal, testicular, thyroid, vaginal and vulvar.
  • MSI-H cancers of any histology including but not limited to: colorectal, endometrial, adrenocortical, anal, appendiceal cancer, biliary, bladder, brain, breast, cervical, gastric or gastroesophageal junction, head and neck squamous
  • the subject can be an animal, e.g., a mammal, a human. In some embodiments, the subject is a human.
  • plinabulin or a pharmaceutically acceptable salt thereof is incorporated in a pharmaceutically acceptable solution. In some embodiments, plinabulin or a pharmaceutically acceptable salt thereof is incorporated in an injectable formulation. In some embodiments, plinabulin or a pharmaceutically acceptable salt thereof is incorporated in an injectable formulation that substantially maintains plinabulin or a pharmaceutically acceptable salt thereof at or near the injection site.
  • the precise amount of plinabulin or a pharmaceutically acceptable salt thereof incorporated in a particular method or therapeutic combination of the disclosure may vary according to factors known in art such as for example, the physical and clinical status of the subject, the method of administration, the content of the formulation, the intended dosing regimen or sequence. Accordingly, it is not practical to specifically set forth an amount that constitutes an amount of plinabulin or a pharmaceutically acceptable salt thereof therapeutically effective for all possible applications. Those of ordinary skill in the art, however, can readily determine an appropriate amount with due consideration of such factors.
  • the ADC is incorporated in a pharmaceutically acceptable solution. In some embodiments, the ADC is incorporated in an injectable formulation. In some embodiments, ADC is incorporated in an injectable formulation that substantially maintains ADC at or near the injection site.
  • ADC ADC incorporated in a particular method or therapeutic combination of the disclosure
  • factors known in art such as for example, the physical and clinical status of the subject, the method of administration, the content of the formulation, the intended dosing regimen or sequence. Accordingly, it is not practical to specifically set forth an amount that constitutes an amount of ADC therapeutically effective for all possible applications. Those of ordinary skill in the art, however, can readily determine an appropriate amount with due consideration of such factors.
  • Pharmaceutically-acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropies, surface-active agents, and encapsulating substances.
  • Optional pharmaceutically-active materials may be included, which do not substantially interfere with the inhibitory activity of the compound or composition.
  • the amount of carrier employed in conjunction with the compound or composition is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
  • the pharmaceutically-acceptable carriers suitable for the preparation of unit dosage forms for peroral administration is well-known in the art.
  • Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc.
  • Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture.
  • Coloring agents such as the FD&C dyes, can be added for appearance.
  • Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.
  • Antimicrobial agents may also be included to achieve a bacteriostatic or fungistatic solution, including but not limited to phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.
  • plinabulin is administered at a dose in the range of about 1-2, 1-3, 1- 4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-11, 1-12, 1-13, 1-13.75, 1-14, 1-15, 1-16, 1-17, 1-18, 1-19, 1-20, 1-22.5, 1-25, 1-27.5, 1-30, 1.5-2, 1.5-3, 1.5-4, 1.5-5, 1.5-6, 1.5-7, 1.5-8, 1.5-9, 1.5-10,
  • one or more immune checkpoint inhibitors administered is about 5 mg-7.5 mg, 5 mg-9 mg, 5 mg- 10 mg, 5 mg-12mg, 5mg-14mg, 5mg-15 mg, 5 mg- 16 mg, 5 mg- 18 mg, 5 mg-20 mg, 5 mg-22 mg, 5 mg-24 mg, 5 mg-26 mg, 5 mg-28mg, 5mg-30mg, 5mg-32mg, 5mg-34mg, 5mg-36mg, 5mg- 38mg, 5mg-40mg, 5mg-42mg, 5mg-44mg, 5mg-46mg, 5mg-48mg, 5mg-50mg, 5mg-52mg, 5mg-54mg, 5mg-56mg, 5mg-58mg, 5mg-60mg, 7 mg-7.7 mg, 7 mg-9 mg, 7 mg- 10 mg, 7 mg- 12mg, 7mg-14mg, 7mg-15 mg, 7
  • one or more immune checkpoint inhibitor dose is about less than about 5 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150mg, or about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 1000 mg, about 2000 mg, or about 3000 mg.
  • compositions described herein can be used in combination with other therapeutic agents.
  • compositions described herein can be administered or used in combination with treatments such as additional chemotherapeutic agents, radiation therapy, and/or biologic therapies.
  • sacituzumab govitecan To groups 2 and 4, sacituzumab govitecan is administered biweekly via intravenous injection at a dosage of 1 mg/kg.
  • mice are weighed on day 1 prior to administration of treatment. The mice are subsequently weighed three times weekly through the end of the 4- week study. Tumor wet weight of the mice are obtained at the end of the four- week study.
  • Example 2 Combination of plinabulin with sacituzumab govitecan and immune checkpoint inhibito
  • Plinabulin Administration To groups 2, 5, 7, and 8, Plinabulin is administered biweekly starting on day 1 of the study via intraperitoneal injection at a dosage of 7.5 mg/kg. In study groups 5 and 8, the plinabulin is administered one hour after administration of sacituzumab govitecan is complete.
  • sacituzumab govitecan To groups 3, 5, 6, and 8, sacituzumab govitecan is administered biweekly via intravenous injection at a dosage of 1 mg/kg.
  • RMP1 -14 Administration To groups 4, 6, 7, and 8, MPR-14 is administered biweekly via intraperitoneal injection at a dosage of 1 mg/kg.
  • mice are weighed on day 1 prior to administration of treatment. The mice are subsequently weighed three times weekly through the end of the 4- week study. Tumor wet weight of the mice are obtained at the end of the four- week study.
  • This study assessed the combination effect of test compounds on a metastatic breast cancer cell line that overexpress HER2. The combination was assessed in reference to a cisplatin control. All solutions containing plinabulin were protected from direct exposure to white light for the duration of the study.
  • Table 6 Combination testing of sacituzumab govitecan and plinabulin against NCI-H1975 cells [0163] The results for the testing of the combination of Trastuzumab deruxtecan and plinabulin against the KPL-4 cell line are shown in Table 7. The bolded cells in Table 7 shows an increased effect of the two compounds together as compared to each individual compound as a single agent.
  • the combination testing data of trastuzumab deruxtecan and plinabulin against KPL-4 cells was also analyzed using the Bliss model (Bliss C. I. Ann. Appl. Biol. 1939, 26, 585-615, which is incorporated herein by reference in its entirety) and using the Loewe model (Loewe, S. ArzneimiettelForschung 1953, 3286-290, which is incorporated herein by reference in its entirety).
  • the Bliss model is a reference model for evaluating the combination effect of two drugs.
  • the basic assumption of this model is the expected effect of two drugs acting independently; i.e. when each target a different signaling pathway.
  • the Loewe model is based on the assumption that both drugs have similar modes of action on the same targets or pathways.
  • CI Di/Ei+ D2/E2
  • £>i and £>2 are the actual drug doses used in the combinations during dosing experiments and Ei and 2 are theoretical individual drug levels that would be expected to be needed to achieve the experimentally measured response. While Di and £>2 are known from experimental design, £ and £2 can be calculated using the D m and in values previously computed.
  • a CI value less than 1 indicates synergism, greater than 1 indicates antagonism, and equal to 1 indicating additivity.
  • Inhibition of KPL-4 cells was determined using a fixed molar ratio of trastuzumab deruxtecan to plinabulin of 4:1. These values are provided in Table 16. The Combination Index was determined for this concentration ratio of trastuzumab deruxtecan to plinabulin. Values of the fraction of cells affected and the CI are provided in Table 17. The median CI was found to be 0.25, indicating synergism.

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Abstract

La présente divulgation concerne des polythérapies comprenant de la plinabuline et des conjugués anticorps-médicament pour le traitement du cancer. Spécifiquement, la présente divulgation concerne des polythérapies comprenant de la plinabuline et des conjugués anticorps anti-Trop-2-médicament pour le traitement de tumeurs solides.
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WO2020037285A1 (fr) * 2018-08-16 2020-02-20 Beyondspring Pharmaceuticals, Inc. Méthode et composition pour stimuler une réponse immunitaire
JP2020189806A (ja) * 2019-05-22 2020-11-26 学校法人東京薬科大学 複合体
WO2022216908A1 (fr) * 2021-04-09 2022-10-13 Beyondspring Pharmaceuticals, Inc. Compositions thérapeutiques et méthodes de traitement de tumeurs

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020037285A1 (fr) * 2018-08-16 2020-02-20 Beyondspring Pharmaceuticals, Inc. Méthode et composition pour stimuler une réponse immunitaire
JP2020189806A (ja) * 2019-05-22 2020-11-26 学校法人東京薬科大学 複合体
WO2022216908A1 (fr) * 2021-04-09 2022-10-13 Beyondspring Pharmaceuticals, Inc. Compositions thérapeutiques et méthodes de traitement de tumeurs

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MUGURUMA, K. ET AL.: "Novel Hybrid Compound of a Plinabulin Prodrug with an IgG Binding Peptide for Generating a Tumor Selective Noncovalent-Type Antibody-Drug Conjugate", BIOCONJUGATE CHEMISTRY, vol. 27, no. 7, 2016, pages 1606 - 1613, XP055820432, DOI: 10.1021/acs.bioconjchem.6b00149 *

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