Classifications

• • 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
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
  • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
  • A61K31/231—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having one or two double bonds
• • 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
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
• • 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
  • A61K31/66—Phosphorus compounds
  • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• • 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
  • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
  • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
  • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
• • 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
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
• • 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
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
  • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
  • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/24—Heavy metals; Compounds thereof
  • A61K33/243—Platinum; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• a neoplasia such as a tumor
• methods and compositions comprising a) one or more chemotherapeutic agents such as AC-regimen and b) a monoacetyl diacylglycerol compound such as 1-palmitoyl-2-linoleoyl-3-acetylglycerol (PLAG).
• chemotherapeutic agents such as AC-regimen
• a monoacetyl diacylglycerol compound such as 1-palmitoyl-2-linoleoyl-3-acetylglycerol (PLAG).
• BACKGROUND Cancers are characterized by abnormal and uncontrolled cell growth. Cancer can involve any tissue in the body, and can spread outside the tissue of origin. Uncontrolled proliferation and other cellular abnormalities can lead to the formation of cancerous tumors.
• Tumors can disrupt the function of and destroy the tissues in which they originate, and, when cancer cells metastasize, secondary tumors can develop near to or disparate from the site of primary growth.
• causes of cancer have been linked to various chemicals, viruses, bacteria, and environmental exposures. It thus would be desirable to have improved cancer therapies.
• SUMMARY in one aspect, we now provide new therapies for treatment and prevention of a patient suffering from cancer.
• methods and compositions are provided for reducing or suppressing tumor growth in a patient, that includes administration of one or more chemotherapeutic agents in conjunction with administration of a monoacetyl diacylglycerol compound of Formula (I), where the compound of Formula (I) is distinct from the one or more chemotherapeutic agents.
• the present methods comprise administering to a subject such as a human having a tumor or other neoplasia a therapeutically effective amount of: a) one or more chemotherapeutic agents; and b) a monoacetyl diacylglycerol compound of Formula (I): wherein R1 and R2 are independently a fatty acid group comprising 14 to 20 carbon atoms.
• the b) compound of Formula (I) is distinct from the a) one or more chemotherapeutic agents.
• the a) one or more chemotherapeutic agents and b) compound of Formula (I) are suitably administered to the patient in combination or other coordinated manner.
• the b) monoacetyl diacylglycerol is a compound of Formula II:
• the compound of Formula (II) is also referred to herein as PLAG (1- palmitoyl-2-linoleoyl-3-acetylglycerol), PLAG or EC- 18.
• the one or more chemotherapeutic agents in addition to PLAG comprise one ormore immune checkpoint inhibitor compounds or agents.
• the immune checkpoint inhibitor is an antibody or fragment thereof, including a monoclonal antibody or fragment thereof.
• Preferred checkpoint inhibitor agents for use in the present compositions and methods include PD-1 inhibitors such as Pembrolizumab (Keytruda), Nivolumab (Opdivo); and Cemiplimab (Libtayo).
• Additonal preferred checkpoint inhibitor agents for use in the present compositions and methods include PD-L1 inhibitors such as Atezolizumab (Tecentriq); Avelumab (Bavencio); and Durvalumab (Imfinzi).
• Additonal preferred checkpoint inhibitor agents for use in the present compositions and methods include CTLA-4 inhibitors such as Ipilmumab (Yervoy).
• the checkpoint inhibitor is a PD-L1 inhibitor.
• the one or more chemotherapeutic agents comprise doxorubicin.
• trhe one ormore chemotherpaueitc agents comprise cyclophosphamide.
• the one or more chemotherapeutic agents comprise both doxorubicin and cyclophosphamide, where those agents may be administered at least substantially simultaneously or sequentially.
• the one or more chemotherapeutic agents comprise 5-FU (5-fluorouracil) and/or cisplatin.
• the one or more chemotherapeutic agents comprise AC regimen which includes doxorubicin such as doxorubicin hydrochloride (Adriamycin) and cyclophosphamide.
• the one or more chemotherapeutic agents comprise AC-T or AC-Taxol regimen which includes doxorubicin such as doxorubicin hydrochloride (Adriamycin) and cyclophosphamide, followed by treatment with paclitaxel (Taxol).
• doxorubicin such as doxorubicin hydrochloride (Adriamycin) and cyclophosphamide
• Other chemotherapeutic agents that may be administered to a subject in accordance with the present methods include for instance cyclophosphamide etoposide, ifosfamide, mesna, gemcitabine and/or tamoxifen, or one or more other chemotherapeutic agents.
• the treatment approaches of the invention also may also be combined with any of the following therapies: radiation, chemotherapy, surgery, therapeutic antibodies, immunomodulatory agents, proteasome inhibitors, pan-DAC inhibitors, H-DAC inhibitors, checkpoint inhibitors, adoptive cell therapies include CAR T and NK cell therapy and vaccines.
• the a) one or more chemotherapeutic agents do not include granulocyte-colony stimulating factor (G-CSF).
• a subject is not administered granulocyte-colony stimulating factor (G-CSF) as part of or in conjuniction with the methods, compositions or kits disclosed herein.
• a subject has not been administered granulocyte-colony stimulating factor (G- CSF) for at least 0.5, 1, 2, 3, 4, 6, 8 weeks or more before being treated with the a) one or more chemotherapeutic agents and b) compound of Formula (I) as dislosed herein, and/or a subject has not been administered granulocyte-colony stimulating factor (G-CSF) for at least 0.5, 1, 2, 3, 4, 6, 8 weeks or more after being treated with the a) one or more chemotherapeutic agents and b) compound of Formula (I) as dislosed herein.
• G- CSF granulocyte-colony stimulating factor
• compositions comprising a) one or more chemotherapeutic agents such as doxorubicin and/or one or more checkpoint inhibitor compounds; and b) a monoacetyl diacylglycerol compound such as PLAG (1-palmitoyl-2-linoleoyl-3-acetylglycerol) that is distinct form the a) one or more chemotherapeutic agents.
• kits are provided for use to treat or prevent a neoplasia including a solid tumor.
• Kits of the invention suitably may comprise a) one or more chemotherapeutic agents; and b) a monoacetyl diacylglycerol compound such as PLAG (1-palmitoyl-2-linoleoyl-3-acetylglycerol) that is distinct from the a) one or more chemotherapeutic agents.
• a kit will comprise a therapeutically effective amount of each of the a) one or more chemotherapeutic agents and b) monoacetyl diacylglycerol compound such as PLAG.
• kits also may comprise instructions for use of the a) one or more chemotherapeutic agents and b) monoacetyl diacylglycerol compound such as PLAG to treat a neoplasia such as a solid tumor, including breast cancer.
• the instructions suitably may be in written form, including as a product label.
• Methods, compositions and kits of the invention may be used to treat subjects suffering from a variety of types of neoplasias and cancers. In certain aspects, the methods, compositions and kits may be used to treat a subject suffering from breast cancer.
• methods of the invention include identifying and selecting a subject suffering from a neoplasia, such as a solid tumor, or breast cancer, and then administering to the selected subject the a) one or more chemotherapeutic agents and b) monoacetyl diacylglycerol compound such as PLAG.
• a neoplasia such as a solid tumor, or breast cancer
• compositions and kits dislosed herein do not include granulocyte-colony stimulating factor (G-CSF).
• G-CSF granulocyte-colony stimulating factor
• FIG.1 shows an exemplary experimental design to investigate the synergistic effect on therapeutic efficacy of tumor using simultaneous treatment of PLAG and AC- regimen.
• FIG.2A shows the change of weekly recorded tumor mass in Xenograft mouse during AC-regimen treatment (2/20) and PLAG co-treatment.
• FIG.2B shows analysis of tumor weight of each group from FIG.2A measured at sacrifice day.
• FIG.2C shows tumor mass in xenograft mice during AC-regimen (2/20) and PLAG co-treatment shown in FIG.2A.
• FIG.2D shows staining and apoptosis-related protein expression of tumor tissue in the sacrificed mice after AC-regimen treatment (2/20) and PLAG co-treatment of FIG.2A.
• FIG.2E shows the changes in apoptosis-related protein expression level in tumor tissue at sacrifice after AC-regimen (2/20) and PLAG co-treatment shown in FIG.2A.
• FIG.2F shows the change of weekly recorded tumor mass in Xenograft mouse during AC-regimen treatment (5/50) and PLAG co-treatment.
• FIG.2G shows analysis of tumor weight of each group from FIG.2F measured at sacrifice day.
• FIG.2H shows tumor mass in xenograft mice during AC-regimen (5/50) and PLAG co-treatment shown in FIG.2F.
• FIG.2I shows staining and apoptosis-related protein expression of tumor tissue in the sacrificed mice after AC-regimen treatment (5/50) and PLAG co-treatment of FIG. 2F.
• FIG.2J shows the changes in apoptosis-related protein expression level in tumor tissue at sacrifice after AC-regimen (5/50) and PLAG co-treatment shown in FIG.2F.
• FIGS.3A-3D show suppression or inhibition of neutrophil chemotaxis during co- administrating PLAG and AC-regimen.
• FIG.3A shows verification of tumor infiltration neutrophil using immunohistochemistry with antibodies. Anti-Ly6C+/Ly6G+ antibodies and anti- Ly6G+ only antibodies were used.
• FIGS.4A-4G show growth inhibition of cancer by PLAG treatment.
• FIG.4A shows effects of PLAG on tumor mass in Xenograft mice.
• FIG.4C shows change of weekly counted tumor mass in PLAG treated Xenograft mice.
• FIG.4F shows verification of neutrophil chemotaxis related chemokine expression in tumor using immunohistochemistry.
• FIG.4G shows verification of tumor cell cycle inducing factor expression in tumor using immunohistochemistry.
• FIGS.5A-5D show inhibition of cancer growth and neutrophil infiltration by PLAG treatment.
• FIG.5A shows PLAG effects on tumor mass in Xenograft mice.
• FIG.5C shows change of weekly counted tumor mass in PLAG treated Xenograft mice.
• FIG.5D shows Verification of tumor infiltration neutrophil using immunohistochemistry.
• FIGS.6A-6B show inhibition of cancer proliferation by enhanced PAR2 degradation.
• FIG.6A shows inhibition of cell growth by PLAG treatment with dose-dependent manner in neutrophil-activated MDA-MB-231 breast cancer cells.
• FIG.6B shows inhibitory effect of PLAG on cell cycle activity in the neutrophil activated cancer cells.
• FIG.6C shows expression level of cell cycle related gene and protein was evaluated by PCR and Western blotting in the neutrophil and PLAG treated cells.
• FIG.6D shows verification of protein expression and phosphorylation related with PAR2 degradation in the PLAG and neutrophil co-treated activated cancer cells by western blot analysis.
• FIG.6E shows identification of PAR2 binding proteins using immunoprecipitation assay.
• FIG.6F shows degradation of PAR2 was verified with ubiquitin activity in the PLAG and neutrophil co-treated cancer cells by ubiquitination assay with anti-PAR2 antibody.
• FIG.7 shows an exemplary experimental design to investigate the synergistic effect of PLAG on PD-L1 immune-checkpoint drug therapy in the MB49 bladder cancer model in Example 3.
• FIG.8A shows analysis of tumor size change in each group estimate 3 days interval.
• FIG.8B shows changes in morphology and tumor size of mice on the day of sacrifice.
• FIG.8C shows tumor weight analysis in PLAG or aPD-L1 co-treat mice evaluated at the sacrificed day.
• FIG.9A shows PLAG modulating neutrophil count via complete blood count (CBC) analysis.
• FIG.9B shows analysis of blood Ly6G and CD11b positive cell sorting results according to PLAG and aPD-L1 treatment.
• FIG.9C shows analysis of tissue infiltrated Ly6G and CD11b positive cell sorting results according to PLAG and aPD-L1 treatment.
• FIGS.9D shows the graphs represented FIG.9B (Blood) and FIG.9C (Tumor).
• FIG.9E show analysis of neutrophil infiltration control effect by PLAG treatment in tumor tissue through IHC staining.
• Lo6G neutrophil population
• Neutrophil Elastase active neutrophil.
• N.S Not significant. Mean ⁇ SD.
• FIG.10A shows PLAG modulating lymphocyte count via complete blood count (CBC) analysis.
• FIGS.10B shows quantitative analysis of NLR levels in blood according to PLAG treatment.
• FIGS.10C-10D show analysis of blood CD4 and CD8 positive cell sorting results according to PLAG and aPD-L1 treatment.
• FIGS.10E and 10F show analysis of tumor tissue infiltrated CD4 and CD8 positive cell sorting results according to PLAG and aPD-L1 treatment.
• FIG.10G shows analysis of lymphocyte infiltration effect by PLAG treatment in tumor tissue through IHC staining.
• FIGS.11A-11B show that chemokine and growth factor secretion changes involved in neutrophil infiltration and activity.
• FIGS.11C-11D show that chemokine and cytokine secretion changes involved in T- cell polarity.
• FIG.11E shows that cytokine secretion changes involved in lymphocyte formation and activity.
• FIG.12 shows an exemplary experimental design to investigate the synergistic effect of PLAG on PD-L1 immune-checkpoint inhibitor treatment in the LLC-1 model in Example 4.
• FIG.13A shows analysis of tumor size change in each group estimate 3 days interval.
• FIG.13B shows changes in morphology and tumor size of mice on the day of sacrifice.
• FIG.13C shows tumor weight analysis in PLAG or aPD-1 co treat mice evaluated at the sacrificed day
• FIG.14A shows PLAG modulating immune-cell count via complete bloodcount (CBC) analysis.
• FIG.14B shows analysis of blood/tumor CD4 or CD8 positive cell sorting results according to PLAG and aPD-1 treatment.
• FIG.14C shows analysis of blood/tissue infiltrated Ly6G positive cell sorting results according to PLAG and aPD-1 treatment.
• FIG.14D shows analysis of neutrophil infiltration control effect by PLAG treatment in tumor tissue through IHC staining.
• N.S Notsignificant. Mean ⁇ SD.
• FIGS.15A-15B show analysis of blood/tumor Th17 cell population sorting results according to PLAG and aPD-1 treatment.
• N.S Notsignificant. Mean ⁇ SD.
• FIG.16A shows changes in morphology and tumor size of mice on the weekly sacrifice.
• FIG.16B shows compounds modulating immune-cell count via complete blood count (CBC) analysis.
• FIG.16C shows analysis of blood/tissue infiltrated Ly6G positive cell sorting results according to compounds treatment.
• FIG.16D shows analysis of blood/tumor Th 17 cell population sorting results according to PLAG and aPD-1 treatment.
• each experiment n 6.
• FIG.17A shows analysis of adenosine concentration in plasma on sacrifice day according to PLAG and aPD-1 treatment.
• FIG.17B shows analysis of adenosine concentration in plasma on weekly sacrificed according to compounds treatment.
• compositions of the present invention refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient.
• pharmaceutically acceptable excipients include water,
• NaCl normal saline solutions
• lactated Ringer normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like.
• Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
• auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
• auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
• auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents
• Treating” and “treatment” as used herein include prophylactic treatment.
• Treatment methods include administering to a subject a therapeutically effective amount of an active agent.
• the administering step may consist of a single administration or may include a series of administrations.
• the length of the treatment period depends on a variety of factors, such as the severity of the condition, the age of the patient, the concentration of active agent, the activity of the compositions used in the treatment, or a combination thereof.
• the effective dosage of an agent used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required.
• compositions are administered to the subject in an amount and for a duration sufficient to treat the patient.
• treating and conjugations thereof, may include prevention of an injury, pathology, condition, or disease.
• treating is preventing.
• treating does not include preventing.
• prevent refers to a decrease in the occurrence of disease symptoms in a patient. As indicated above, the prevention may be complete (e.g., no detectable symptoms) or partial, such that fewer symptoms are observed than would likely occur absent treatment.
• “Patient,” “subject,” “patient in need thereof,” and “subject in need thereof” are herein used interchangeably and refer to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein.
• Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non- mammalian animals.
• a patient or subject is human.
• An “effective amount” or a “therapeutically effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g.
• an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount.”
• a “reduction” of a symptom or symptoms means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s).
• a “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms.
• the full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
• a prophylactically effective amount may be administered in one or more administrations.
• An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist.
• a “function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). As used herein, the term “in combination” in the context of the administration of a therapy to a subject refers to the use of more than one therapy for therapeutic benefit.
• combination in the context of the administration can also refer to the prophylactic use of a therapy to a subject when used with at least one additional therapy.
• the use of the term “in combination” does not restrict the order in which the therapies (e.g., a first and second therapy) are administered to a subject.
• a first therapy e.g.
• administration of either i) one or more chemotherapeutic agents or ii) a monoacetyl diacylglycerol compound of Formula (I) such as PLAG can be administered prior to (e.g., 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours or up to about one 1 week before), concomitantly with, or subsequent to (e.g., 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours or up to about one 1 week after) the administration of a second therapy (e.g.
• a second therapy e.g.
• a monoacetyl diacylglycerol compound of Formula (I) such as PLAG or ii) ) one or more chemotherapeutic agents
• the therapies are administered to a subject in a sequence and within a time interval such that the therapies can act together.
• the therapies are administered to a subject in a sequence and within a time interval such that they provide an increased benefit than if they were administered otherwise. Any additional therapy can be administered in any order with the other additional therapy.
• proliferative disorder” and “proliferative disease” refer to disorders associated with abnormal cell proliferation such as cancer.
• Tumor and “neoplasm” or similar term as used herein refer to any mass of tissue that result from excessive cell growth or proliferation, either benign or malignant including pre-cancerous lesions.
• neoplasia is meant a disease or disorder characterized by excess proliferation or reduced apoptosis.
• Illustrative neoplasms for which the invention can be used include, but are not limited to cancers including solid tumors.
• neoplasms for which the invention can be used include, but are not limited to bladder cancer, leukemias (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (Hodgkin's disease, non-Hodgkin's disease), Waldenstrom's macroglobulinemia, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosar
• the neoplasia is multiple myeloma, beta-cell lymphoma, urothelial/bladder carcinoma or melanoma.
• a “chemotherapeutic agent” is a chemical compound useful in the treatment of cancer.
• chemotherapeutic agents include Erlotinib (TARCEVA TM , Genentech/OSI Pharm.), Bortezomib (VELCADE TM , Millennium Pharm.), Fulvestrant (FASLODEX TM , Astrazeneca), Sutent (SU11248, Pfizer), Letrozole (FEMARA TM , Novartis), Imatinib mesylate (GLEEVEC TM , Novartis), PTK787/ZK 222584 (Novartis), Oxaliplatin (Eloxatin TM , Sanofi), 5-FU (5-fluorouracil), Leucovorin, Rapamycin (Sirolimus, RAPAMUNE TM , Wyeth), Lapatinib (GSK572016, GlaxoSmithKline), Lonafarnib (SCH 66336), Sorafenib (BAY43-9006, Bayer Labs.), and Gefitinib (IRESSA TM , A
• dynemicin including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, anthramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN TM doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin
• chemotherapeutic agent include: (i) anti- hormonal agents that act to regulate or inhibit hormone action on tumors such as anti- estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX), raloxifene, droloxifene, 4- hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON TM (toremifene); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)- imidazoles, aminoglutethimide, MEGASE TM (megestrol acetate), AROMASIN TM (exemestane), formestanie, fadrozole, RIVISOR TM (vorozole), FEMARA TM (letrozole), and ARIMIDEX TM (anastrozo
• SERMs selective
• preferred chemotherapeutic agents include immune checkpoint inhibitor agents.
• suitable and preferred checkpoint inhibitors for use in the present methods and compositions include inhibitors of Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, 2B4, A2aR, B7H1, B7H3, B7H4, BTLA, CD2, CD27, CD28, CD30, CD40, CD70, CD80, CD86, CD137, CD160, CD226, CD276, DR3, GAL9, GITR, HAVCR2, HVEM, IDO1, IDO2, ICOS (inducible T cell costimulator), KIR, LAIR1, LIGHT, MARCO (macrophage receptor with collageneous structure), PS (phosphatidylserine), OX-40, SLAM, TIGHT, VISTA,
• PD-L1 Programmed Death-
• the immune checkpoint inhibitor is an inhibitor of IDO1, CTLA4, PD- 1, LAG3, PD-L1, TIM3, or combinations thereof. In certain preferred compositions and methods, the immune checkpoint inhibitor is an inhibitor of PD-L1. In certain preferred compositions and methods some embodiments, the immune checkpoint inhibitor is an inhibitor of PD-1. In certain preferred compositions and methods, the immune checkpoint inhibitor is an inhibitor of CTLA-4. In certain preferred compositions and methods, the immune checkpoint inhibitor is an inhibitor of LAG3. In certain preferred compositions and methods, the immune checkpoint inhibitor is an inhibitor of TIM3. In certain preferred compositions and methods, the immune checkpoint inhibitor is an inhibitor of IDO1.
• the present methods and compositions can effectively reduce or suppress tumor growth in a patient, for example a cancer patient that receives a therapy of a) one or more chemotherapeutic agents and b) a monoacetyl diacylglycerol compound of Formula (I) such as PLAG.
• Co-treatment with PLAG and one or more distinct chemotherapeutic agents may result in a 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 percent or more reduction in tumor volume.
• a wide variety of type of cancers may be treated in accordance with the present methods and compositions.
• a cancer to be treated may be a solid tumor.
• Illustrative cancers for which the invention can be used include, but are not limited to breast cancer, leukemias (e.g., kemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (Hodgkin's disease, non-Hodgkin's disease), Waldenstrom's macroglobulinemia, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endot
• a chemical synthetic method for the preparation of monoacetyldiacylglycerol compounds of Formula (I) is shown, for example, in Korean Registered Patents No. 10-0789323 and No.10-1278874, the contents of which are incorporated herein by reference.
• PLAG can be synthesized by acylating the hydroxy groups of glycerol with acetyl, palmitoyl and linoleoyl functional groups.
• Therapeutically effective amounts of a monoacetyl diacylglycerol compound of Formula (I) such as PLAG and one or more distinct chemotherapeutic agents can be initially determined from cell culture assays.
• Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art.
• Treatment amounts of a monoacetyl diacylglycerol compound of Formula (I) such as PLAG and one or more distinct chemotherapeutic agents also have been previously reported.
• therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above.
• Dosages may be varied depending upon the requirements of the patient and the compound being employed.
• the dose administered to a patient, in the context of the present invention should be sufficient to effect a beneficial therapeutic response in the patient over time.
• the size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached.
• Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.
• an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity and yet is effective to treat the clinical symptoms demonstrated by the particular patient. This planning should involve the careful choice of active compound by considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration and the toxicity profile of the selected agent.
• the dosage and frequency (single or multiple doses) administered to a mammal can vary depending upon a variety of factors, for example, whether the mammal suffers from another disease, and its route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated, kind of concurrent treatment, complications from the disease being treated or other health-related problems.
• Other therapeutic regimens or agents can be used in conjunction with the methods and compounds of Applicants' invention. Adjustment and manipulation of established dosages (e.g., frequency and duration) are well within the ability of those skilled in the art.
• the frequency of administration of the composition of the present invention is not particularly limited, but it may be administered once a day or several times a day with divided dosage.
• An exemplary daily dosages for a patient such as a human in need of treatment of a compound of Formula (I) or Formula (II) (i.e. EC-18) include between 0.0001 mg/kg and 4 mg/kg body weight, or between 0.01 mg/kg and 4 mg/kg body weight e.g., up to or about 0.001, 0.003, 0.005, 0.01.0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, or 4 mg/kg body weight of the subject such as a human patient in need thereof.
• an effective weekly dose of a compound of Formula (I) or Formula (II) may between 0.1 ⁇ g /kg body weight and 400 ⁇ g/kg body weight such as a human patient in need thereof.
• an oral formulation is utilized such as a tablet or capsule (e.g. soft gelatin capsule) that contains 250-1000 mg, e.g., 500 mg, of a compound of Formula (I) or Formula (II).
• Optimal dosage amounts also can be determined empirically for particular patients or identified group of patients.
• Exemplary effective daily doses of the distinct chemotherapeutic agent(s) also can vary and can be determined empirically for particular patients or identified group of patients.
• exemplary daily doses of the distinct chemotherapeutic agent(s) may be between, for example, 0.1 ⁇ g/kg and 100 ⁇ g/kg body weight, e.g., 0.1, 0.3, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 99 ⁇ g/kg body weight.
• a monoacetyl diacylglycerol compound of Formula (I) such as PLAG and one or more chemotherapeutic agents can be administered to a subject by any of a number of routes such as topical contact, oral, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject.
• Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial.
• compositions may include compositions wherein one or both of a monoacetyl diacylglycerol compound of Formula (I) such as PLAG and one or more chemotherapeutic agents is contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose.
• a therapeutically effective amount i.e., in an amount effective to achieve its intended purpose.
• the actual amount effective for a particular application will depend, inter alia, on the condition being treated.
• Such compositions When administered in methods to treat a disease, such compositions will contain an amount of active ingredient effective to achieve the desired result, e.g., modulating the activity of a target molecule, and/or reducing, eliminating, or slowing the progression of disease symptoms.
• Pharmaceutical composition may be manufactured with additional pharmaceutically acceptable carrier for each formulation.
• the term “pharmaceutically acceptable carrier” may refer to a carrier or diluent that does not stimulate organism and not inhibiting biological activity and characteristic of the injected compound.
• the type of the carrier that can be used in the present invention is not particularly limited, any carrier conventionally used in the area of industry and pharmaceutically acceptable may be used.
• Saline, sterilized water, IV fluids, buffer saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol are non-limiting examples of the usable carriers. These carriers may be used alone or in combination of two or more.
• the carrier may include a non-naturally occurring carrier.
• additives like an antioxidant, a buffer and / or a bacteriostatic agent may be added and used. It may be formulated with diluent, a dispersant, a surfactant, a bonding agent, a lubricant to make an injection solution like aqueous solution, suspension, emulsion, and pills, capsules, granules or tablets, and the like.
• particularly suitable admixtures for the compounds included in the pharmaceutical composition may be injectable, sterile solutions, oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories.
• carriers for parenteral administration include aqueous solutions of dextrose, saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene-block polymers, and the like. Ampoules are convenient unit dosages.
• Pharmaceutical admixtures suitable for use in the pharmaceutical compositions presented herein may include those described, for example, in Pharmaceutical Sciences (17th Ed., Mack Pub. Co., Easton, PA) and WO 96/05309, the teachings of both of which are hereby incorporated by reference. As discussed, kits are also provided.
• a monoacetyl diacylglycerol compound of Formula (I) such as PLAG and one or more chemotherapeutic agents each suitably can be packaged in suitable containers labeled for a specified treatment.
• the containers can include a PLAG compound or composition, one or more chemotherapeutic agents and one or more of a suitable stabilizer, carrier molecule and/or the like, as appropriate for the intended use.
• the kit further comprises one or more therapeutic reagents for an intended treatment, such as one or more additional chemotherapeutic agents.
• a product can include a container (e.g., a vial, jar, bottle, bag, or the like) containing a PLAG compound or composition and/or one or more chemotherapeutic agents.
• a container e.g., a vial, jar, bottle, bag, or the like
• an article of manufacture or kit further may include, for example, packaging materials, instructions for use, syringes, delivery devices, for treating or monitoring the condition for which prophylaxis or treatment is required.
• the product may also include a legend (e.g., a printed label or insert or other medium describing the product's use (e.g., an audio- or videotape)).
• the legend can be associated with the container (e.g., affixed to the container) and can describe the manner in which the compositions therein should be administered (e.g., the frequency and route of administration), indications therefor, and other uses.
• the compositions can be ready for administration (e.g., present in dose-appropriate units), and may include one or more additional pharmaceutically acceptable adjuvants, carriers or other diluents and/or an additional therapeutic agent.
• the compositions for example can be provided in a concentrated form with a diluent and instructions for dilution.
• a monoacetyl diacylglycerol compound such as PLAG and one or more distinct chemotherapeutic agents suitably are administered in a coordinated manner, for example either simultaneously or sequentially.
• a monoacetyl diacylglycerol compound such as PLAG and one or more distinct chemotherapeutic agents may be administered to a subject at substantially the same time, or the agents instead may be administered to the subject at different times, suitably within hours although longer periods between the separate administrations also may be suitable.
• Example 1 Anti-cancer effects of PLAG in combination with AC-regimen in a xenograft mouse model MDA-MB-231 breast cancer Xenograft model was used. Tumor growth was evaluated in the AC-regimen alone and PLAG co-treated animals. AC- regimen was delivered via IP injection twice a week with dose of 2/20 and 5/50 mph (Doxorubicin/Cyclophosphamide), and PLAG was daily administered with 100 and 250 mpk. Tumor growth was calculated with 3 day intervals.
• Neutrophil chemotaxis related chemokines, CXCL1/2/8 and circulating neutrophils were also evaluated with 2 week internal. Expression of apoptosis molecular markers, Bax/Bak and tumor-infiltrating neutrophil (TIN) in the tumor lesion was analyzed by immunohistochemistry (IHC).
• PLAG has synergistic effects decreasing the tumor burden in the PLAG and AC-regimen co-regimen co-treated Xenograft mice. In AC-regimen with 2/20 or 5/50 mpk treated groups, retardation of tumor growth was observed by calculating tumor size and processed apoptosis was proved by TUNEL and apoptosis-related proteins expression in the regressed tumor burden with AC-regimen.
• PLAG has a synergistic effect on regression of tumor burden in the subjects co-treated with AC-regimen. Analysis of tumor tissue with IHC revealed that TIN was dramatically reduced in the PLAG cotreated group. Results also are set forth in Figures 1, 2 (includes FIGS.2A-2J) and 3(includes FIGS. 3A-3D) .
• Example 3 The effect of PLAG on the PD-L1 immune-checkpoint drug therapy in the MB49 bladder cancer syngeneic model
• immune-checkpoint drugs a fourth-generation anticancer drug
• Cancer therapy using immune-checkpoint drugs are still enlarged.
• modulation of the tumor microenvironment is essentially required.
• PLAG After a week from tumor implantation, PLAG at different dosages (50/100 mpk) were daily administered orally for another 4 weeks with or without 5 mpk PD-L1 antibody (10F.9G2). PD-L1 antibody was delivered via IP injection once a week.
• FIG.7, Table 1 Results The PLAG treatment groups demonstrated that the tumor burden decreased in a concentration-dependent manner. In 50 and 100 mpk of PLAG treated mice, the tumor burden was decreased to a significant value compared to a positive control (p ⁇ 0.05). In the group treated with the PD-L1 antibody alone, the growth rate of the tumor decreased until about 2 weeks.
• FIG.8A-8C Control of neutrophil population and tumor infiltration by PLAG treatment is demonstrated in FIGS.9A-9E and control of lymphocyte population and tumor infiltration by PLAG treatment is demonstrated in FIGS.10A-10G.
• NLR neutrophil-to- lymphocyte ratio
• PLAG provides an enhanced PD-L1 antibody effect on the regression of tumor burden in the syngeneic mice model via reducing the number of TINs.
• PLAG may be utilized for improving the efficacy of the PD-L1 antibody on reducing the tumor burden at the devastating tumor microenvironment. PLAG not only increases the anti-tumor effect of aPD-L1 more effectively, but it can suppress tumor progression on its own.
• TINs tumor infiltrating neutrophils
• CTLs cytotoxic T-lymphocytes
• mice In PLAG treated 50 and 100 mpk mice group, the tumor burden was significantly reduced compared to a positive control p 005 In the group treated with aPD-1 alone, the tumor growth decreased by about 65 compared to the positive control. However, in mice co-treated with PLAG, the tumor was significantly reduced 18 compared to the aPD-1 alone. Synergistic anti tumor effect of PLAG with anti PD 1 antibody(aPD-1) is demonstrated in FIGS.13A-13D. The neutrophil to lymphocyte ratio levels in the group co treated with PLAG were decreased remarkably compared to the aPD-1 alone. In particular, the degree of neutrophil infiltration in the tumor was effectively reduced upon PLAG treatment.
• FIGS.14A-14D Effects on the immune cell population and tumor infiltration by PLAG and aPD 1 treatment are demonstrated in FIGS.14A-14D and effects on the modulation of Th17 population and tumor infiltration by PLAG and aPD-1 treatment are demonstrated in FIGS.15A-15B.
• PLAG may act as a modulator, not an inhibitor of neutrophil infiltration and migration.
• PLAG may prevent the increase of DAMP by tumor progression through the rapid removal of DAMP.
• CTLs cytotoxic T-Lymphocyte
• PLAG enhanced the anti cancer effect of aPD-1 synergistically on the regression of tumor burden via decreasing the tumor infiltrating neutrophils and Th 17 population while increasing the CTLs Therefore, combining aPD-1 with PLAG, which has excellent safety profiles, may contribute to enhancing the antitumor response of aPD-1 while lowering immune related toxicities by reducing the dose of ICI.
• PLAG has not only a synergistic anti tumor effects on the tumor progression with aPD-1 but it suppress tumor progression on its own.
• PLAG reduced tumor infiltrating neutrophils (TIN) via an rapid removal of DAMP (adenosine) originated from tumor.
• DAMP adenosine
• PLAG reduced the Th 17 population and tumor infiltrating Th 17 cells involved in excessive neutrophil infiltration into tumor site.
• combination of aPD-1 and PLAG may improve treatment outcomes of aPD-1 compared to aPD-1 alone contributing to enhancing anti tumor immune responses via treating the suppressive tumor microenvironment (TME).
• TME suppressive tumor microenvironment
• PLAG treatment may transform the immunosuppressive TME into an immune enhanced TME via inhibition of neutrophil recruitment into the TME and enhancement of anti tumor immunity of T cells.

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Epidemiology (AREA)
• Molecular Biology (AREA)
• Emergency Medicine (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Inorganic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Priority Applications (5)

Applications Claiming Priority (2)

Publications (2)

Family

ID=75714907

Family Applications (1)

Country Status (6)

Cited By (1)

Families Citing this family (1)

Family Cites Families (11)

• 2020
  • 2020-10-28 JP JP2022524928A patent/JP2022553421A/ja active Pending
  • 2020-10-28 KR KR1020227017330A patent/KR20220114532A/ko not_active Ceased
  • 2020-10-28 EP EP20882109.0A patent/EP4051260A4/en active Pending
  • 2020-10-28 US US17/770,990 patent/US20220370397A1/en active Pending
  • 2020-10-28 CN CN202080076324.7A patent/CN114650815A/zh active Pending
  • 2020-10-28 WO PCT/IB2020/060104 patent/WO2021084441A2/en not_active Ceased

Also Published As

Similar Documents

Legal Events