WO2019084284A1 - Cellules nk destinées à être utilisées dans le traitement du cancer chez les chiens - Google Patents

Cellules nk destinées à être utilisées dans le traitement du cancer chez les chiens

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Publication number
WO2019084284A1
WO2019084284A1 PCT/US2018/057540 US2018057540W WO2019084284A1 WO 2019084284 A1 WO2019084284 A1 WO 2019084284A1 US 2018057540 W US2018057540 W US 2018057540W WO 2019084284 A1 WO2019084284 A1 WO 2019084284A1
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WO
WIPO (PCT)
Prior art keywords
cells
canine
administered
cancer
optionally
Prior art date
Application number
PCT/US2018/057540
Other languages
English (en)
Inventor
Hans G. KLINGEMANN
Original Assignee
Coneksis, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Coneksis, Inc. filed Critical Coneksis, Inc.
Publication of WO2019084284A1 publication Critical patent/WO2019084284A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A61K39/4613—Natural-killer cells [NK or NK-T]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/463—Cellular immunotherapy characterised by recombinant expression
    • A61K39/4631—Chimeric Antigen Receptors [CAR]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/4644—Cancer antigens
    • A61K39/464402—Receptors, cell surface antigens or cell surface determinants
    • A61K39/464403—Receptors for growth factors
    • A61K39/464406—Her-2/neu/ErbB2, Her-3/ErbB3 or Her 4/ ErbB4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/7051—T-cell receptor (TcR)-CD3 complex
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
    • A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the cancer treated
    • A61K2239/48—Blood cells, e.g. leukemia or lymphoma
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
    • A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the cancer treated
    • A61K2239/49—Breast
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/03—Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment

Definitions

  • Tumor vaccines are an appealing immunotherapy because the logistics of preparing the vaccines are usually manageable and administration is easy. However, identification of canine specific tumor antigens to be vaccine targets is lacking. A host of immune modulatory molecules are being considered for stimulation of innate canine immune effector cells. None has yet confirmed efficacy.
  • the methods selecting a canine having cancer and administering to the canine a therapeutically effective amount of NK-92, wherein administration treats the cancer in the canine.
  • Figure 1 is a graph showing cytotoxicity of NK-92 cells against three canine osteosarcoma cell lines.
  • Figure 2 is a graph showing cytotoxicity of NK-92 HER-2 CAR expressing cells against three osteosarcoma cell lines.
  • Figure 3 is a graph showing NK-92 cells kill DH82 canine cell line at least as efficiently as K562 cell line.
  • Figure 4 is a graph showing K-92 cells kill DH82 canine cell line at least as efficiently as K562 cell line.
  • Figure 5 is a graph showing NK-92 cells do not kill normal canine peripheral blood mononuclear cells (PBMC).
  • Figure 6 is a graph showing cytotoxicity of NK-92 cells against various canine cancer cell lines: DH82 (histiocytosis), CF41 (mammary tumor), BW KOS (osteosarcoma).
  • Figure 7 is a graph showing cytotoxicity of primary canine NK cells against various canine cancer cell lines: DH82 (histiocytosis), CF41 (mammary tumor), BW KOS
  • the human K562 and the canine CTAC thyroid adenocarcinoma
  • Canine NK cells were obtained from the peripheral blood of healthy dogs by Ficoll- Hypaque density gradient centrifugation, followed by depletion of CD5 positive cells to remove T-cell population.
  • the enriched canine NK cells were used fresh without cytokine stimulation and expansion. Different effector to target ratios are presented for the 4 hr flow cytometric-based cytotoxicity assay.
  • the methods include selecting a canine having cancer and administering to the canine a therapeutically effective amount of NK-92, wherein administration treats the cancer in the canine.
  • the cancer is an osteosarcoma.
  • a canine with an osteosarcoma, a lymphoma, or an adenovarcinoma is selected.
  • the cancer is an adenosarcoma.
  • the cancer is a solid tumor.
  • from 1 x 10 3 to 1 x 10 10 , per m 2 of the NK-92 cells are administered to the canine.
  • the NK-92 cells are administered to the canine.
  • the NK-92 cells are administered parenterally, intravenously, intratumorally or peritum orally.
  • the NK-92 cells are administered to the canine by infusion over a period of time.
  • the period of time is between 1 minute and 150 minutes.
  • the period of time is between 5 and 130 minutes.
  • the period of time is between 90 and 120 minutes.
  • the period of time is between 15 to 30 minutes.
  • the cancer in the canine is resistant to chemotherapy.
  • the NK-92 cells are administered to the canine once daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more days.
  • the NK- 92 cells are administered in a cycle of once daily for two days.
  • the NK-92 cells are administered in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more cycles.
  • the method further comprises administering to the canine a second therapeutic agent.
  • the second therapeutic agent is a chemotherapeutic agent.
  • the second therapeutic agent is an anti-inflammatory agent.
  • the method further comprises administering radiation to the canine.
  • the method further comprises surgery.
  • the NK-92 cell line is a human, IL-2-dependent NK cell line that was established from the peripheral blood mononuclear cells (PBMCs) of a 50-year-old male diagnosed with non-Hodgkin lymphoma (Gong, et al., Leukemia. 8:652-8 (1994)).
  • PBMCs peripheral blood mononuclear cells
  • NK-92 cells are characterized by the expression of CD56 bnght and CD2, in the absence of CD3, CD8, and CD16.
  • a CD56 bright /CD16 neg /low phenotype is typical for a minor subset of NK cells in peripheral blood, which have immunomodulatory functions as cytokine producers.
  • NK-92 lacks expression of most killer cell inhibitor receptors (KIRs) (Maki, et al., J Hematother Stem Cell Res. 10:369-83 (2001)).
  • KIRs killer cell inhibitor receptors
  • KIR2DL4 is considered to mediate inhibitory effects through binding to the HLA allele G (Suck, Cancer Immunol. Immunother. 65(4):485-92 (2015)).
  • NK-92 expresses high levels of perforin and granzyme B (Maki, et al., J Hematother Stem Cell Res. 10:369-83 (2001)).
  • NK-92 cells have a very broad cytotoxic range and are active against cell lines derived from hematologic malignancies and solid tumors (Klingemann, Blood, 87(11):4913-4 (1996); Swift, Haematologica. 97(7): 1020-8 (2012); Yan, et al., Clin Cancer Res. 4:2859-68
  • NK-92 cells administered to mice challenged with human leukemia cells or mouse models of human melanoma resulted in improved survival and suppression of tumor growth, including complete remissions in some mouse tumors (Tam, et al., J Hematother. 8:281-90
  • NK-92 cell line Characterization of the NK-92 cell line is disclosed in WO 1998/49268 and U.S. Patent Application Publication No. 2002-0068044, which are incorporated by reference herein in their entireties.
  • NK-92 cells are known and include, but are not limited to, those described in, e.g., U.S. Patent Nos. 7,618,817, 8,034,332, and 8,313,943, US Patent Application Publication No. 2013/0040386, all of which are incorporated herein by reference in their entireties, such as wild type NK-92, NK-92-CD16, NK-92-CD16-y, ⁇ -92- ⁇ 16- ⁇ , NK-92-CD16(F176V), NK-92MI and NK-92CI.
  • the modified NK-92 cells express the Fc receptor CD 16.
  • Fc receptor refers to a protein found on the surface of certain cells (e.g., natural killer cells) that contribute to the protective functions of the immune cells by binding to part of an antibody known as the Fc region. Binding of the Fc region of an antibody to the Fc receptor (FcR) of a cell stimulates phagocytic or cytotoxic activity of a cell via antibody- mediated phagocytosis or antibody-dependent cell-mediated cytotoxicity (ADCC). FcRs are classified by the type of antibody they recognize. For example, Fc-gamma receptors (FcyR) bind to the IgG class of antibodies.
  • FcyRIII-A (also called CD 16) is a low affinity Fc receptor that binds to IgG antibodies and activates ADCC. FCyRIII-A are typically found on NK cells.
  • a representative amino acid sequence encoding CD16 is shown in SEQ ID NO:2.
  • a representative polynucleotide sequence encoding CD16 is shown in SEQ ID NO: l . The complete sequences of CD16 can be found in the SwissProt database as entry P08637.
  • the modified NK-92 cells comprise a nucleic acid sequence with 70%, 80%, 90%, or 95% identity to SEQ ID NO: l .
  • the modified NK-92 cells comprise a nucleic acid sequence with 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 1.
  • the modified NK-92 cells comprise a polypeptide with 70%, 80%, 90%, or 95% identity to SEQ ID NO:2.
  • the modified NK-92 cells comprise a polypeptide with 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:2.
  • modified NK-92 cells are further modified to express at least one cytokine.
  • the at least one cytokine is IL-2, IL-12, IL-15, IL-18, IL-21 or a variant thereof.
  • the IL-2 is expressed with a signal sequence that directs the IL-2 to the endoplasmic reticulum. Directing the IL-2 to the endoplasmic reticulum permits expression of IL-2 at levels sufficient for autocrine activation and without releasing substantial amounts of IL-2 extracellularly.
  • the modified NK-92 cells comprise a nucleic acid sequence with 70%, 80%, 90%, or 95% identity to SEQ ID NO:3.
  • the modified NK-92 cells comprise a nucleic acid sequence with 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:3.
  • the modified NK-92 cells comprise a polypeptide with 70%, 80%, 90%, or 95% identity to SEQ ID NO:4.
  • the modified NK-92 cells comprise a polypeptide with 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:4.
  • the provided modified NK-92 cells advantageously are capable of being maintained in the absence of IL-2 without secreting IL-2 in an amount to cause a clinical adverse effect.
  • the modified NK-92 cells are further engineered to express a chimeric antigen receptor (CAR) on the cell surface.
  • CAR chimeric antigen receptor
  • the CAR is specific for a tumor- specific antigen.
  • Tumor-specific antigens include, without limitation, PD-L1, NKG2D, CS1, GD2, CD138, EpCAM, EBNA3C, GPA7, CD244, CA-125, ETA, MAGE, CAGE, BAGE, HAGE, LAGE, PAGE, NY-SEO-1, GAGE, CEA, CD52, CD30, MUC5AC, c-Met, EGFR, FAB, WT-1, PSMA, NY-ESOl, AFP, CEA, CTAG1B, CD19 and CD33.
  • CARs can be engineered as described, for example, in Patent Publication Nos. WO 2014039523; US 20140242701; US 20140274909; US 20130280285; and WO 2014099671, each of which is incorporated herein by reference in its entirety.
  • the CAR is a CD 19 CAR, a CD33 CAR or CSPG-4 CAR.
  • the CAR is HER-2.
  • NK-92 cells expressing HER- 2 CAR are described in, for example, U.S. Publication NO. 2017-0129967 and WO
  • the methods include selecting a canine having cancer and administering to the canine a therapeutically effective amount of NK-92, wherein administration treats the cancer in the canine.
  • administration treats the cancer in the canine.
  • from 1 x 10 3 to 1 x 10 10 , per m 2 of the NK-92 cells are administered o the canine.
  • 2* 10 9 per m 2 , of the NK-92 cells are administered to the canine.
  • the NK-92 cells are administered parenterally, intraveneously or peri turn orally.
  • the NK-92 cells are administered to the canine by infusion over a period of time.
  • the period of time is between 5 and 130 minutes, for example, between 90 and 120 minutes or 15 to 30 minutes.
  • the NK-92 cells may be administered to the canine by a variety of routes.
  • the NK-92 cells can be administered to the canine by infusion (e.g., intravenous infusion) over a period of time.
  • infusion e.g., intravenous infusion
  • the period of time is between 5 and 130 minutes.
  • the period of time is between 90 and 120 minutes.
  • the period of time is between 15 to 30 minutes.
  • NK-92 cells, and optionally other anti-cancer agents can be administered once to a patient with cancer can be administered multiple times, e.g., once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 hours, or once every 1, 2, 3, 4, 5, 6 or 7 days, or once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks during therapy, or any ranges between any two of the numbers, end points inclusive.
  • NK-92 cells can be administered to the canine once daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more days.
  • the NK-92 cells are administered in a cycle of once daily for two days.
  • cycle refers to a treatment that is repeated on a regular schedule with periods of rest (e.g., no treatment or treatment with other agents) in between. For example, treatment given for one week followed by two weeks of rest is one treatment cycle. Such cycles of treatment can be repeated one or more times.
  • the NK-92 cells can be administered in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more cycles.
  • NK-92 cells can be administered to a canine by absolute numbers of cells, e.g., said canine can be administered from about 1000 cells/injection to up to about 10 billion cells/injection, such as at about, at least about, or at most about, 1 ⁇ 10 10 , 1 10 9 , 1 10 8 , 1 10 7 , 5x l0 7 , l x lO 6 , 5x l0 6 , ⁇ ⁇ ⁇ 5 , 5 ⁇ 10 5 , ⁇ ⁇ ⁇ 4 , 5 ⁇ 10 4 , ⁇ ⁇ ⁇ 3 , 5 ⁇ 10 3 (and so forth) NK-92 cells per injection, or any ranges between any two of the numbers, end points inclusive.
  • the cells are administered to the canine.
  • the cells are administered one or more times weekly for one or more weeks.
  • the cells are administered once or twice weekly for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks.
  • canine are administered from about 1000 cells/injection/m 2 to up to about 10 billion cells/injection/m 2 , such as at about, at least about, or at most about, lxl0 10 /m 2 , lxl0 m 2 , lxl0 8 /m 2 , lxl0 7 /m 2 , 5x l0 7 /m 2 , 1x107m 2 , 5x l0 6 /m 2 , lxl0 5 /m 2 , 5x l0 5 /m 2 , 1 x lOVm 2 , 5x 10 4 /m 2 , 1 ⁇ 10 3 /m 2 , 5x 10 3 /m 2 (and so forth) NK-92 cells per injection, or any ranges between any two of the numbers, end points inclusive.
  • NK-92 cells per injection or any ranges between any two of the numbers, end points inclusive.
  • NK-92 cells can be administered to such individual by relative numbers of cells, e.g., said individual can be administered about 1000 cells to up to about 10 billion cells per kilogram of the individual, such as at about, at least about, or at most about, 1 ⁇ 10 , ⁇ ⁇ ⁇ 9 , l x lO 8 , l x lO 7 , 5x l0 7 , ⁇ ⁇ ⁇ 6 , 5 ⁇ 10 6 , ⁇ ⁇ ⁇ 5 , 5 ⁇ 10 5 , ⁇ ⁇ ⁇ 4 , 5 ⁇ 10 4 , ⁇ ⁇ ⁇ 3 , 5 ⁇ 10 3 (and so forth) NK-92 cells per kilogram of the individual, or any ranges between any two of the numbers, end points inclusive.
  • the total dose may calculated by m 2 of body surface area, including about
  • NK-92 cells are administered to a patient.
  • the amount of NK-92 cells injected per dose may calculated by m2 of body surface area, including l x lO 11 , l x lO 10 , l x lO 9 , l x lO 8 , l x lO 7 , l x lO 6 , l x lO 5 , l x lO 4 , l x lO 3 , per m 2 .
  • NK-92 cells are administered in a composition comprising NK-92 cells and a medium, such as canine serum or an equivalent thereof.
  • the medium comprises canine plasma.
  • the medium comprises about 1% to about 15% serum or serum equivalent.
  • the medium comprises about 1% to about 10% serum or serum equivalent.
  • the medium comprises about 1% to about 5% serum or serum equivalent.
  • the medium comprises about 2.5% serum or serum equivalent.
  • NK-92 cells are administered in a composition comprising NK-92 cells and an isotonic liquid solution that supports cell viability.
  • NK-92 cells are administered in a composition that has been reconstituted from a cryopreserved sample.
  • an antibody is administered to the patient in conjunction with the NK-92 cells.
  • the NK-92 cells and an antibody are administered to the canine together, e.g., in the same formulation; separately, e.g., in separate formulations, concurrently; or can be administered separately, e.g., on different dosing schedules or at different times of the day.
  • the antibody can be administered in any suitable route, such as intravenous or oral administration.
  • antibodies may be used to target cancerous cells or cells that express cancer-associated markers.
  • a number of antibodies have been approved for the treatment of cancer, alone.
  • the provided methods may be further combined with other tumor therapies such as radiotherapy, surgery, hormone therapy and/or immunotherapy.
  • the provided methods can further include administering one or more additional therapeutic agents to the canine.
  • additional therapeutic agents include, but are not limited to, analgesics, anesthetics, analeptics, corticosteroids, anticholinergic agents, anticholinesterases, anticonvulsants, antineoplastic agents, allosteric inhibitors, anabolic steroids, antirheumatic agents, psychotherapeutic agents, neural blocking agents, anti-inflammatory agents, antihelmintics, antibiotics, anticoagulants, antifungals, antihistamines, antimuscarinic agents,
  • antimycobacterial agents antiprotozoal agents, antiviral agents, dopaminergics,
  • the additional therapeutic agent is octreotide acetate, interferon, pembrolizumab, glucopyranosyl lipid A, carboplatin, etoposide, or any combination thereof.
  • the cells in accordance with the present invention are also suitably co-administered with known antiinflammatory agents.
  • agents include both steroidal (e.g.,
  • the additional therapeutic agent is a chemotherapeutic agent.
  • a chemotherapeutic treatment regimen can include administration to a canine of one chemotherapeutic agent or a combination of chemotherapeutic agents.
  • Chemotherapeutic agents include, but are not limited to, alkylating agents, anthracyclines, taxanes, epothilones, histone deacetylase inhibitors, inhibitors of Topoisomerase I, inhibitors of Topoisomerase II, kinase inhibitors, monoclonal antibodies, nucleotide analogs and precursor analogs, peptide antibiotics, platinum-based compounds, retinoids, and vinca alkaloids and derivatives.
  • the chemotherapeutic agent is carboplatin.
  • Combinations of agents or compositions can be administered either concomitantly (e.g., as a mixture), separately but simultaneously (e.g., via separate intravenous lines) or sequentially (e.g., one agent is administered first followed by administration of the second agent).
  • the term combination is used to refer to concomitant, simultaneous, or sequential administration of two or more agents or compositions.
  • the course of treatment is best determined on an individual basis depending on the particular characteristics of the canine and the type of treatment selected.
  • the treatment such as those disclosed herein, can be administered to the canine on a daily, twice daily, bi-weekly, monthly, or any applicable basis that is therapeutically effective.
  • the treatment can be administered alone or in combination with any other treatment disclosed herein or known in the art.
  • the additional treatment can be administered simultaneously with the first treatment, at a different time, or on an entirely different therapeutic schedule (e.g., the first treatment can be daily, while the additional treatment is weekly).
  • cancer refers to all types of cancer, neoplasm, or malignant tumors found in mammals, including leukemia, carcinomas and sarcomas.
  • exemplary cancers include cancer of the brain, breast, cervix, colon, head & neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus and
  • Medulloblastoma Additional examples include, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine and exocrine pancreas, and prostate cancer.
  • the cancer is a bone cancer.
  • the cancer is an osteosarcoma.
  • the cancer is an adenosarcoma.
  • the terms “metastasis,” “metastatic,” and “metastatic cancer” can be used interchangeably and refer to the spread of a proliferative disease or disorder, e.g., cancer, from one organ or another non-adjacent organ or body part. Cancer occurs at an originating site, e.g., breast, which site is referred to as a primary tumor, e.g., primary breast cancer. Some cancer cells in the primary tumor or originating site acquire the ability to penetrate and infiltrate surrounding normal tissue in the local area and/or the ability to penetrate the walls of the lymphatic system or vascular system circulating through the system to other sites and tissues in the body.
  • a second clinically detectable tumor formed from cancer cells of a primary tumor is referred to as a metastatic or secondary tumor.
  • the metastatic tumor and its cells are presumed to be similar to those of the original tumor.
  • the secondary tumor at the site of the breast consists of abnormal lung cells and not abnormal breast cells.
  • the secondary tumor in the breast is referred to a metastatic lung cancer.
  • metastatic cancer refers to a disease in which a canine has or had a primary tumor and has one or more secondary tumors.
  • non-metastatic cancer or canines with cancer that is not metastatic refers to diseases in which canines have a primary tumor but not one or more secondary tumors.
  • metastatic lung cancer refers to a disease in a canine with or with a history of a primary lung tumor and with one or more secondary tumors at a second location or multiple locations, e.g., in the breast.
  • treating or “treatment of a condition, disease or disorder or symptoms associated with a condition, disease or disorder refers to 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 condition, disorder or disease, stabilization of the state of condition, disorder or disease, prevention of development of condition, disorder or disease, prevention of spread of condition, disorder or disease, delay or slowing of condition, disorder or disease progression, delay or slowing of condition, disorder or disease onset, amelioration or palliation of the condition, disorder or disease state, and remission, whether partial or total. "Treating” can also mean prolonging survival of a canine beyond that expected in the absence of treatment.
  • Treating can also mean inhibiting the progression of the condition, disorder or disease, slowing the progression of the condition, disorder or disease temporarily, although in some instances, it involves halting the progression of the condition, disorder or disease permanently.
  • treatment, treat, or treating refers to a method of reducing the effects of one or more symptoms of a disease or condition characterized by expression of the protease or symptom of the disease or condition characterized by expression of the protease.
  • treatment can refer to a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of an established disease, condition, or symptom of the disease or condition.
  • a method for treating a disease is considered to be a treatment if there is a 10% reduction in one or more symptoms of the disease in a canine as compared to a control.
  • the reduction can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any percent reduction in between 10% and 100% as compared to native or control levels.
  • treatment does not necessarily refer to a cure or complete ablation of the disease, condition, or symptoms of the disease or condition.
  • references to decreasing, reducing, or inhibiting include a change of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater as compared to a control level and such terms can include but do not necessarily include complete elimination.
  • administering refers to providing, contacting, and/or delivering a compound or compounds by any appropriate route to achieve the desired effect.
  • Administration may include, but is not limited to, oral, sublingual, parenteral (e.g., intravenous, subcutaneous, intracutaneous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional or intracranial injection), ophthalmic, via inhalation, and implants.
  • parenteral e.g., intravenous, subcutaneous, intracutaneous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional or intracranial injection
  • ophthalmic via inhalation, and implants.
  • the K-92 cells are administered parenterally.
  • the K-92 cells are administered intravenously.
  • the NK-92 cells are administered peritum orally.
  • the canine is administered an effective amount of one or more of the agents provided herein.
  • effective amount and effective dosage are used interchangeably.
  • effective amount is defined as any amount necessary to produce a desired physiologic response (e.g., reduction of
  • Effective amounts and schedules for administering the agent may be determined empirically by one skilled in the art, e.g., a veterinarian.
  • the dosage ranges for administration are those large enough to produce the desired effect in which one or more symptoms of the disease or disorder are affected (e.g., reduced or delayed).
  • the dosage should not be so large as to cause substantial adverse side effects, such as unwanted cross- reactions, anaphylactic reactions, and the like.
  • the dosage will vary with the age, condition, sex, type of disease, the extent of the disease or disorder, route of administration, or whether other drugs are included in the regimen, and can be determined by one of skill in the art.
  • the dosage can be adjusted by the individual physician in the event of any contraindications. Dosages can vary and can be administered in one or more dose
  • an effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Efficacy can also be expressed as "-fold" increase or decrease. For example, a therapeutically effective amount can have at least a 1.2- fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control. The exact dose and formulation will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques.
  • compositions can include a variety of carriers and excipients.
  • a variety of aqueous carriers can be used, e.g., buffered saline and the like. These solutions are sterile and generally free of undesirable matter. Suitable carriers and their formulations are described in Remington: The Science and Practice of Pharmacy, 22nd Edition, Loyd V. Allen et al., editors, Pharmaceutical Press (2012).
  • pharmaceutically acceptable carrier is meant a material that is not biologically or otherwise undesirable, i.e., the material is administered to a canine without causing undesirable biological effects or interacting in a deleterious manner with the other components of the pharmaceutical composition in which it is contained.
  • the carrier is optionally selected to minimize degradation of the active ingredient and to minimize adverse side effects in the canine.
  • the term pharmaceutically acceptable is used synonymously with physiologically acceptable and pharmacologically acceptable.
  • a pharmaceutical composition will generally comprise agents for buffering and preservation in storage and can include buffers and carriers for appropriate delivery, depending on the route of administration.
  • compositions may contain acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents and the like, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like.
  • concentration of cells in these formulations and/or other agents can vary and will be selected primarily based on fluid volumes, viscosities, body weight and the like in accordance with the particular mode of administration selected and the canine's needs.
  • Example 1 NK-92 cells and CAR expressing NK-92 cells kill canine osteosarcoma cells.
  • NK-92 cells kill osteosarcoma cells and cell killing is augmented by HER-2 CAR expressing NK-92 cells.
  • NK-92 cells were tested against canine DH82 cells and normal PBMC cell lines.
  • Figures 3 and 4 show NK-92 cells kill DH82 cells at least as well as K562 cells.
  • Figure 5 shows NK-92 cells do not kill normal PBMC canine cells.
  • NK-92 A spectrum of canine cancer cell lines were tested as to whether they can be killed by the human natural killer cell line NK-92. Cytotoxicity of NK-92 and canine NK cells was tested against various canine cancer cell lines: DH82 (histiocytosis), CF41 (mammary tumor), BW KOS (osteosarcoma). The human K562 and the canine CTAC (thyroid adenocarcinoma), which are known to be sensitive to NK killing, were used as human and canine positive control cell lines. Canine NK cells were obtained from the peripheral blood of healthy dogs by Ficoll-Hypaque density gradient centrifugation, followed by depletion of CD5 positive cells to remove T-cell population.
  • the enriched canine NK cells were used fresh without cytokine stimulation and expansion. Different effector to target ratios are presented for the 4 hr flow cytometric-based cytotoxicity assay.
  • Figure 6 shows that NK-92 killed all tested canine cancer targets very effectively. Fresh, non-activated dog NK cells did not kill the same targets to a meaningful degree. See Figure 7.

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Abstract

L'invention concerne des méthodes de traitement du cancer chez un chien. Les méthodes consistent à sélectionner un chien ayant un cancer et à administer au chien une quantité thérapeutiquement efficace de cellules NK-92, l'administration traitant le cancer chez le chien.
PCT/US2018/057540 2017-10-27 2018-10-25 Cellules nk destinées à être utilisées dans le traitement du cancer chez les chiens WO2019084284A1 (fr)

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US11091526B2 (en) 2017-12-06 2021-08-17 Pandion Operations, Inc. IL-2 muteins and uses thereof
US11739146B2 (en) 2019-05-20 2023-08-29 Pandion Operations, Inc. MAdCAM targeted immunotolerance
US11981715B2 (en) 2020-02-21 2024-05-14 Pandion Operations, Inc. Tissue targeted immunotolerance with a CD39 effector

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US11466068B2 (en) 2017-05-24 2022-10-11 Pandion Operations, Inc. Targeted immunotolerance
US10946068B2 (en) 2017-12-06 2021-03-16 Pandion Operations, Inc. IL-2 muteins and uses thereof
US11091526B2 (en) 2017-12-06 2021-08-17 Pandion Operations, Inc. IL-2 muteins and uses thereof
US11091527B2 (en) 2017-12-06 2021-08-17 Pandion Operations, Inc. IL-2 muteins and uses thereof
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US11945852B2 (en) 2017-12-06 2024-04-02 Pandion Operations, Inc. IL-2 muteins and uses thereof
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