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WO2025073102A1 - Peptide oncolytique et son utilisation pour inhiber la viabilité des cellules cancéreuses - Google Patents

Peptide oncolytique et son utilisation pour inhiber la viabilité des cellules cancéreuses Download PDF

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Publication number
WO2025073102A1
WO2025073102A1 PCT/CN2023/123134 CN2023123134W WO2025073102A1 WO 2025073102 A1 WO2025073102 A1 WO 2025073102A1 CN 2023123134 W CN2023123134 W CN 2023123134W WO 2025073102 A1 WO2025073102 A1 WO 2025073102A1
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Prior art keywords
cancer
cancer cells
seq
peptide
cells
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Pending
Application number
PCT/CN2023/123134
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English (en)
Inventor
Jya-Wei Cheng
Chih-Lung Wu
Kuang-Li PENG
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Lt Biopharma Inc
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Lt Biopharma Inc
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Priority to PCT/CN2023/123134 priority Critical patent/WO2025073102A1/fr
Publication of WO2025073102A1 publication Critical patent/WO2025073102A1/fr
Pending legal-status Critical Current
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    • 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
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This disclosure relates to peptide-based therapeutic compositions and methods for resulting in an anti-tumor response and the effective regression of the cancer.
  • Cancer is a leading cause of death worldwide. Different types of cancer correspond to various cell types of the body. Cancer cells are characterized by uncontrolled proliferation and the ability to invade surrounding normal tissue or distant sites by homological and/or lymphatic spread.
  • the difficulty for the effective treatment of cancer relates to establishing the distinction between malignant and normal cells of the body. Both are derived from the same source and are very similar, and for this reason, there is no significant recognition by the immune system as to the threat.
  • the present invention provides the search for new ways to treat cancer is a process in constant progress, and within this dynamic, new active principles were developed to be useful in the treatment of cancer.
  • Another aspect of the present invention provides methods for inhibiting or reducing cancer cells by administering to a subject in need thereof a therapeutically effective amount of the peptides.
  • Fig. 1A-1B are schematic diagram of Hepa 1-6 hepatocellular carcinoma experiments.
  • the right flank of the mouse was administrated with SEQ ID NO: 4 in Fig. 1A.
  • Fig. 1B shows that Hepa 1-6 tumor cells were harvested, and washed in medium and injected subcutaneously (S.C. ) into the right flank of C57BL/6 mice. (3 ⁇ 10 6 Hepa 1-6 cells per mouse/50 ⁇ l RPMI-1640) .
  • Palpable tumors 80-100 mm 3 ) were injected (I.T. ) with single doses of SEQ ID NO: 4 dissolved in PBS (1.0 mg peptide/50 ⁇ l PBS) once a day for 3 consecutive days, and the vehicle control was saline only (0.9%NaCl) .
  • Fig. 3 are schematic diagram of EO771 breast cancer experiments.
  • Fig. 3 shows that EO771 tumor cells were harvested, and washed in medium and injected subcutaneously (S.C. ) into the right flank of C57BL/6 mice. (2 ⁇ 10 5 EO771 cells per mouse/50 ⁇ l RPMI-1640) .
  • Palpable tumors 75 mm 3 ) were injected (I.T. ) with single doses of SEQ ID NO: 4 dissolved in PBS (1.0 mg peptide/50 ⁇ l PBS) once a day for 5 consecutive days, and the vehicle control was saline only (0.9%NaCl) .
  • the right flank of the mouse was administrated with SEQ ID NO: 4 as shown in Fig. 1A.
  • Fig. 5A-5B show that treatment of SEQ ID NO: 4 in EO7711tumor-bearing mice model remained the body weight and feed intake compared to control group.
  • the body weight of control (wild-type) , and SEQ ID NO: 4 treated group (Fig. 5A) .
  • the percentage of intake of control (wild-type) , and SEQ ID NO: 4 treated group (Fig. 5B) .
  • Fig. 6A-6B are schematic diagram of B16-F10 melanoma experiments.
  • the right flank of the mouse was administrated with SEQ ID NO: 4, and the left flank of the mouse was an untreated flank (tumor only) in Fig. 6A.
  • Fig. 6B shows that B16-F10 tumor cells were harvested, and washed in medium and injected intradermally (i.d. ) into the both flanks of C57BL/6 mice. (3 ⁇ 10 6 B16-F10 cells per mouse/50 ⁇ l RPMI-1640) .
  • Palpable tumors (20–30 mm 3 ) were injected (I.T. ) with single doses of SEQ ID NO: 4 dissolved in PBS (1.0 mg peptide/50 ⁇ l PBS) once a day for 5 consecutive days, and the vehicle control was saline only (0.9%NaCl) .
  • Fig. 7A-7D show the antitumor effects of SEQ ID NO: 4 in B16-F10 tumor-bearing mice model.
  • Representative images of B16F10 tumors-bearing mice on day 8 (before treatment) and on day 12 after SEQ ID NO: 4 treatment or untreated groups (Fig. 7A) .
  • Survival curve of SEQ ID NO: 4 treated mice compared to untreated mice. Animal survival curves (Kaplan–Meier plot) were compared using the log-rank (Mantel–Cox) test (Fig. 7D) .
  • Fig. 8A-8B show the treatment of SEQ ID NO: 4 in B16-F10 tumor-bearing mice model remained the body weight and feed intake compared to control group.
  • the body weight of untreated (tumor only) , and SEQ ID NO: 4 treated group (Fig. 8A) .
  • the percentage of intake of control (wild-type) , and SEQ ID NO: 4 treated group (Fig. 8B) .
  • Fig. 9 are schematic diagram of MN-11 fibrosarcoma experiments.
  • MN-11 tumor cells were harvested, and washed in medium and injected subcutaneously (S. C. ) into the both flanks of C57BL/6 mice. (5 ⁇ 10 5 MN-11 cells per mouse/50 ⁇ l RPMI-1640) .
  • Palpable tumors 100 mm 3 ) were injected (I.T. ) with single doses of SEQ ID NO: 4 dissolved in PBS (1.0 mg peptide/50 ⁇ l PBS) once a day for 5 consecutive days, and the vehicle control was saline only (0.9%NaCl) .
  • the right flank of the mouse was administrated with SEQ ID NO: 4, and the left flank of the mouse was an untreated flank (tumor only) as shown in Fig. 6A.
  • Fig. 11A-11B show that treatment of SEQ ID NO: 4 in MN-11tumor-bearing mice model remained the body weight and feed intake compared to control group.
  • the body weight of control (wild-type) , and SEQ ID NO: 4 treated group (Fig. 11A) .
  • the percentage of intake of control (wild-type) , and SEQ ID NO: 4 treated group (Fig. 11B) .
  • amino acid sequence ” “protein, ” “polypeptide” and “peptide” are used interchangeably herein to refer to two or more amino acids, or “residues, ” covalently linked by an amide bond or equivalent. Amino acid sequences can be linked by non-natural and non-amide chemical bonds.
  • the basic acid is selected from the group consisting of lysine, arginine, and histidine.
  • the aromatic amino acid is selected from the group consisting of tryptophan, phenylalanine, and tyrosine.
  • the non-polar acid is selected from the group consisting of leucine, alanine, valine, isoleucine, proline, phenylalanine, methionine, and tryptophan.
  • the non-natural amino acid is selected from the group consisting of ⁇ -naphthylalanine (Nal) , (benzothien-3-yl) alanine (Bal) , diphenylalanine (Dip) , (4, 4′-biphen-yl) alanine (Bip) , (anthracen-9-yl) alanine (Ath) and (2, 5, 7-tri-tert-butyl-indol-3-yl) alanine (Tht) .
  • a C-terminus of the oncoytic peptide is formed in part by the group of modifications consisting of amidation, acetylation, formylation, hydroxylation, lipid modification, methylation and phosphorylation.
  • the present invention further provides a pharmaceutical composition for treating cancer or inhibiting tumor growth, comprising a therapeutically effective amount of an oncolytic peptide of the present invention and a pharmaceutically acceptable excipient.
  • the cancer comprises melanoma, fibrosarcoma, prostate cancer, breast cancer, uterine cancer, leukemia, ovarian cancer, endometrial cancer, cervical cancer, colorectal cancer, testicular cancer, lymphoma, rhabdomyosarcoma, neuroblastoma, pancreatic cancer, lung cancer, brain tumor, skin cancer, stomach cancer, oral cancer, liver cancer, laryngeal cancer, gallbladder cancer, thyroid cancer, liver cancer, kidney cancer, or nasopharyngeal carcinoma.
  • the oncolytic peptides consideration is also given that the amount of each of the therapeutic agent used for the treatment of a subject is low enough to avoid undesired or severe side effects, within the scope of sound medical judgment.
  • the therapeutically effective amount when used in combination will vary with the age and physical condition of the end user, the severity of cancer, the duration of the treatment, the nature of any other concurrent therapy, the specific type of therapeutic agent employed for the treatment, the particular pharmaceutically acceptable carrier utilized in the pharmaceutical compositions containing the therapeutic agents and other relevant factors.
  • Subjects as used herein are generally human subjects and includes, but is not limited to, cancer patients.
  • the subjects may be male or female and may be of any race or ethnicity.
  • the subjects may be of any age, including newborn, neonate, infant, child, adolescent, adult, and geriatric.
  • Subjects may also include animal subjects, particularly mammalian subjects such as canines, felines, bovines, caprines, equines, ovines, porcines, rodents (e.g. mouse, rat, guinea pig, and hamster) , lagomorphs, primates (including non-human primates) , etc.
  • the dose of the oncolytic peptide of the present invention is appropriately determined depending upon a purpose for therapy, and conditions such as sexuality, age, weight of a test subject, an administration route, and degree of a disease.
  • administration includes routes of introducing the oncolytic peptides of the invention to a subject to perform their intended function.
  • the oncolytic peptide of the present invention can be administered orally, buccally, parenterally, by inhalation spray, rectally, intradermally, transdermally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired.
  • Treating” or “treatment” as used herein refers to the treating or treatment of a disease or medical condition (such as cancer, tumor, neoplasm conditions) in a subject/patient, such as a mammal (particularly a human) which includes ameliorating the disease or medical condition, i.e., eliminating or causing regression of the disease or medical condition in a subject/patient; suppressing the disease or medical condition, i.e., slowing or arresting the development of the disease or medical condition in a subject/patient; or alleviating the symptoms of the disease or medical condition in a subject/patient.
  • a disease or medical condition such as cancer, tumor, neoplasm conditions
  • a subject/patient such as a mammal (particularly a human) which includes ameliorating the disease or medical condition, i.e., eliminating or causing regression of the disease or medical condition in a subject/patient; suppressing the disease or medical condition, i.e., slowing or arresting the development of the disease or medical condition in a subject/patient; or
  • MTT assay is a colorimetric method for measuring the activity of enzymes in living cells that reduce Thiazolyl blue tetrazolium bromide (MTT) to formazan dyes, giving a purple color.
  • MTT Thiazolyl blue tetrazolium bromide
  • a colorimetric 3- (4.5-dimethylthiazol-2-yl) -2.5-diphenyltetrazodium bromide (MTT) viability assay was used to assess the in vitro cytotoxicity of oncolytic peptides.
  • mice Female C57BL/6 mice (4-to 6-week old) as allogeneic model animals were purchased from the BioLASCO Taiwan Co., Ltd. and maintained in a specific pathogen-free and controlled environment. During the experiments, female mice, weighing 180–240 g each, were kept in groups of 4 to 6 animals per cage under climate-controlled conditions, with 12 h light/dark cycles and an ambient temperature. The mice were housed in an enriched individually ventilated cage (IVC) system with free access to standard rodent chow and water ad libitum. The animals were anesthetized during the experimental procedures with 2.5%Isoflurane gas. The animals were monitored daily. All the procedures were conducted according to the regulations of Laboratory Animal Care and Use Committee or Group Setup and Management and the law ofAnimal Protection.
  • IVC individually ventilated cage
  • Palpable tumors for example, 80-100 mm 3 for Hepa 1-6 tumor-bearing mice, 20–30 mm 3 for B16-F10 tumor-bearing mice, 100 mm 3 for MN-11 tumor-bearing mice, 75 mm 3 for EO771 tumor-bearing mice
  • PBS 1.0 mg oncolytic peptide/50 ⁇ l PBS
  • Pre-cultured B16-F10 was harvested in a DMEM medium and i. d. inoculated total of3 ⁇ 10 6 cells (mixed equal volume of matrigel) into the both flank of C57BL/6 mice (6/group) .
  • Established tumors 100 mm 3 mean tumor size) were i. t. injected with peptides (dissolved in sterile H 2 O with 0.9%NaCl) .
  • Treatment doses of peptides 1 mg/mouse, 50 ⁇ l, 1 time/day and give 5 times.
  • Use a 0.5mL syringe needle 29G x 12.7mm (Becton, Dickinson and Company; Franklin Lakes, New Jersey) .
  • the embodiment was used the EO771 allogeneic model in C57BL/6 mice (Fig. 3) .
  • EO771 tumor cells were harvested, and washed in medium and injected subcutaneously (S.C. ) into the right flank ofC57BL/6 mice (2 ⁇ 10 5 EO771 cells per mouse/50 ⁇ l RPMI-1640) .
  • SEQ ID NO: 4 significantly inhibited tumor growth in vivo compared to the saline control group (Fig. 4A-4C) .
  • SEQ ID NO: 4 may not have toxic effects in vivo (Fig. 5A-5B) .
  • SEQ ID NO: 4 significantly inhibited unilateral (right side) tumor growth in vivo compared to the saline control group (panel) (Fig. 10A-10D) .
  • SEQ ID NO: 4 may not have toxic effects in vivo.
  • the reason for the weight loss after treatment was presumed to be caused by the tumor excessive swelling (Fig. 11A-11B) .

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne un nouveau peptide oncolytique. De plus, le nouveau peptide oncolytique peut être utilisé pour traiter le cancer et inhiber la croissance tumorale plus efficacement.
PCT/CN2023/123134 2023-10-07 2023-10-07 Peptide oncolytique et son utilisation pour inhiber la viabilité des cellules cancéreuses Pending WO2025073102A1 (fr)

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PCT/CN2023/123134 WO2025073102A1 (fr) 2023-10-07 2023-10-07 Peptide oncolytique et son utilisation pour inhiber la viabilité des cellules cancéreuses

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016091490A1 (fr) * 2014-12-11 2016-06-16 Lytix Biopharma As Associations chimiothérapeutiques de peptides cationiques antimicrobiens et d'agents chimiothérapeutiques
US20230116760A1 (en) * 2019-12-16 2023-04-13 Dana-Farber Cancer Institute, Inc. Structurally-stabilized oncolytic peptides and uses thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016091490A1 (fr) * 2014-12-11 2016-06-16 Lytix Biopharma As Associations chimiothérapeutiques de peptides cationiques antimicrobiens et d'agents chimiothérapeutiques
US20230116760A1 (en) * 2019-12-16 2023-04-13 Dana-Farber Cancer Institute, Inc. Structurally-stabilized oncolytic peptides and uses thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEAH YU-HUAN, LIU CHUN-YU, YIP BAK-SAU, WU CHIH-LUNG, PENG KUANG-LI, CHENG JYA-WEI: "Strategy to Enhance Anticancer Activity and Induced Immunogenic Cell Death of Antimicrobial Peptides by Using Non-Nature Amino Acid Substitutions", BIOMEDICINES, MDPI, BASEL, vol. 10, no. 5, 1 May 2022 (2022-05-01), Basel , pages 1097, XP093299320, ISSN: 2227-9059, DOI: 10.3390/biomedicines10051097 *
CHIANGJONG, W. ET AL.: "Anticancer peptide: Physicochemical property, functional aspect and trend in clinical application", INTERNATIONAL JOURNAL OF ONCOLOGY, vol. 57, 31 December 2020 (2020-12-31), pages 678 - 696, XP055765558, DOI: 10.3892/ijo.2020.5099 *
HAUG BENGT ERIK, CAMILIO KETIL ANDRÉ, ELIASSEN LIV TONE, STENSEN WENCHE, SVENDSEN JOHN SIGURD, BERG KRISTEL, MORTENSEN BJARTE, SER: "Discovery of a 9-mer Cationic Peptide (LTX-315) as a Potential First in Class Oncolytic Peptide", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 59, no. 7, 14 April 2016 (2016-04-14), US , pages 2918 - 2927, XP093012004, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.5b02025 *
TORNESELLO ANNA LUCIA, BORRELLI ANTONELLA, BUONAGURO LUIGI, BUONAGURO FRANCO MARIA, TORNESELLO MARIA LINA: "Antimicrobial Peptides as Anticancer Agents: Functional Properties and Biological Activities", MOLECULES, MDPI AG, CH, vol. 25, no. 12, CH , pages 2850, XP093196647, ISSN: 1420-3049, DOI: 10.3390/molecules25122850 *

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