WO2015182798A1 - Composition pour inhiber des cellules suppressives dérivées de myéloïde (mdsc) - Google Patents

Composition pour inhiber des cellules suppressives dérivées de myéloïde (mdsc) Download PDF

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WO2015182798A1
WO2015182798A1 PCT/KR2014/004760 KR2014004760W WO2015182798A1 WO 2015182798 A1 WO2015182798 A1 WO 2015182798A1 KR 2014004760 W KR2014004760 W KR 2014004760W WO 2015182798 A1 WO2015182798 A1 WO 2015182798A1
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mdsc
peptide
composition
cancer
adjuvant
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PCT/KR2014/004760
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English (en)
Korean (ko)
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김상재
미들톤개리
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주식회사 카엘젬백스
김상재
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Priority to PCT/KR2014/004760 priority Critical patent/WO2015182798A1/fr
Priority to PCT/KR2014/011571 priority patent/WO2015182837A1/fr
Priority to KR1020157003185A priority patent/KR101826753B1/ko
Publication of WO2015182798A1 publication Critical patent/WO2015182798A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • a composition for inhibiting myeloid-derived suppressor cells (MDSCs), a kit for inhibiting MDSC, a method for inhibiting MDSC, a composition for anticancer, a kit for anticancer, an anticancer method, or a novel use of telomerase peptide It is about.
  • MDSCs Myeloid-derived suppressor cells
  • cytotoxic T lymphocytes are a heterogeneous family of immature bone marrow cells that have had differentiation programs stagnated by various tumor-secreting factors. MDSCs inhibit the activity of cytotoxic T lymphocytes in a variety of ways.
  • the function of MDSC in vivo is, in part, to protect the body from the harmful effects of excessive immune stimulation in acute and chronic infections and to limit the development of autoimmune responses to tissue antigens released by trauma.
  • the proliferation of MDSCs is also associated with a pathological point of view. Activation is mediated through several transcription factors, resulting in upregulation and expression of immunosuppressive factors such as ARG1 and NOS2 and increased production of NO, ROS, RNS and cytokines.
  • the accumulation of MDSC allows the immunosuppressive environment to be sustained, which in turn exposes the living body to allergen and / or viral infections, which can lead to chronic inflammation. Chronic inflammation can lead to tissue damage if the body is unable to respond effectively.
  • chemotherapeutic agents known to directly reduce MDSC in preclinical models are gemcitabine and 5-fluorouracil (5-FU).
  • Gemcitabine has been reported to significantly reduce the number of MDSCs of the spleen in tumor-induced mice [Suzuki E, Kapoor V, Jassar AS, Kaiser LR, Albelda SM (2005) Gemcitabine eliminate eliminates splenic Gr-1 + / CD11b + myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res 11: 6713-6721].
  • 5-FU is also known to significantly reduce the percentage of MDSC, which is reported to be greater than gemcitabine.
  • miR-142 and / or miR-223 ribonucleotides can be added to MDSC (WO 2013/082591).
  • miR-142 and / or miR-223 ribonucleotides can be reduced in number by allowing MDSCs to differentiate into macrophages, dendritic cells, and the like.
  • Bisphosphonates include clodronate, zoleronate, palmidronate, ethidronate or other bisphosphonate drugs.
  • CCR2 inhibitors include RS 1028595 or PF-04178903.
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • the object of the present invention is to inhibit MDSC.
  • the object of the present invention is to activate immunity.
  • the object of the present invention is to activate immunity inhibited by MDSC.
  • an object of the present invention is to solve the problem that the immune response of the vaccine is inhibited by MDSC.
  • an object of the present invention is to solve the problem that the immune response of a cancer vaccine is inhibited by MDSC.
  • an object of the present invention is to alleviate, treat or prevent a disease or condition associated with MDSC.
  • an object of the present invention is to provide a cancer vaccine without the side effects of lowering the immune response according to MDSC.
  • the present invention is a composition for inhibiting myeloid-derived suppressor cells (MDSCs), the composition is a peptide comprising SEQ ID NO: 1 as an active ingredient for MDSC inhibition, the peptide sequence and 80% Peptide having a sequence homology, or a fragment thereof, the peptide is a composition for inhibiting myeloid-derived suppressor cells (MDSCs), contained in an amount effective for MDSC inhibition.
  • MDSCs myeloid-derived suppressor cells
  • the invention provides a peptide comprising SEQ ID NO: 1, a peptide having at least 80% sequence homology with the peptide sequence, or a fragment thereof; Anticancer agents; And it may be a composition for inhibiting MDSC containing an adjuvant.
  • the invention provides a peptide comprising SEQ ID NO: 1, a peptide having at least 80% sequence homology with the peptide sequence, or a fragment thereof; Anticancer agents; And it may be an anticancer composition comprising an adjuvant.
  • the invention provides a peptide comprising SEQ ID NO: 1, a peptide having at least 80% sequence homology with the peptide sequence, or a fragment thereof; Anticancer agents; And cancer vaccine compositions comprising an adjuvant.
  • the invention may be a kit for inhibiting MDSC.
  • the kit includes a peptide comprising SEQ ID NO: 1 as an active ingredient for MDSC inhibition, a peptide having 80% or more sequence homology with the peptide sequence, or a peptide thereof, wherein the peptide is effective for inhibiting MDSC.
  • MDSC inhibition composition contained in an amount; Anticancer agents; And instructions.
  • the kit may further comprise an adjuvant.
  • the kit for inhibiting MDSC may be to improve, prevent or treat a disease or symptom caused by MDSC through MDSC inhibition.
  • the kit for inhibiting MDSC may be to improve, prevent or treat cancer through MDSC inhibition.
  • the invention provides a composition comprising a peptide comprising SEQ ID NO: 1, a peptide having at least 80% sequence homology with the peptide sequence, or a fragment thereof; Anticancer agents; And an anticancer kit comprising instructions.
  • the kit may further comprise an adjuvant composition.
  • the present invention provides a method for inhibiting myeloid-derived suppressor cells (MDSCs), an effective amount of a peptide comprising SEQ ID NO: 1, the peptide sequence and at least 80% sequence Or a peptide that is homologous, or a fragment thereof, to a subject in need of MDSC inhibition.
  • the method may further comprise administering an anticancer agent in combination with the peptide.
  • the method may further comprise administering an adjuvant in combination with the peptide.
  • the present invention provides a method for improving, treating or preventing cancer, wherein the peptide comprises an effective amount of a peptide comprising SEQ ID NO: 1, a peptide having at least 80% sequence homology with the peptide sequence, or a fragment thereof.
  • the peptide comprises an effective amount of a peptide comprising SEQ ID NO: 1, a peptide having at least 80% sequence homology with the peptide sequence, or a fragment thereof.
  • an anticancer agent and / or adjuvant may be a method for cancer improvement, treatment or prevention comprising administering to a subject in need of improvement, treatment or prevention of cancer.
  • a peptide comprising SEQ ID NO: 1, having a sequence homology of 80% or more of the peptide sequence Peptides, or fragments thereof, may be used.
  • the present invention may inhibit MDSC.
  • the present invention may activate immune.
  • the present invention can activate immunity inhibited by MDSC.
  • the present invention can solve the problem that the immune response of the vaccine is inhibited by MDSC.
  • the present invention can solve the problem that the immune response of a cancer vaccine is inhibited by MDSC.
  • the present invention can alleviate, treat or prevent a disease or condition associated with MDSC.
  • the present invention may provide an anticancer composition, an anticancer kit, or an anticancer method that does not have the side effects of lowering the immune response according to MDSC.
  • the present invention can provide a cancer vaccine that is free of the side effects of lowering the immune response following MDSC.
  • 1 is a graph showing the relationship between MDSC and the levels of proinflammatory cytokine. Comparison of the proinflammatory cytokines of patients with high and low levels of MDSC showed no correlation between the levels of MDSC and proinflammatory cytokine.
  • Figure 2 is a log after analyzing and comparing the MDSC changes in the patient group (comparative example 2, arm2) that was administered only in combination with gemcitabine and capecitabine, and the patient group (Example 2, arm3) that was simultaneously administered GemCap and pep1 It is a graph in scale.
  • MDSC inhibition is a concept that includes not only reducing the number of MDSCs but also inhibiting the activity of MDSCs. Reducing the number includes not only inhibiting the production of cells, but also killing or differentiating cells that have already been formed. In addition, all mechanisms that are referred to as “inhibition” from a biological standpoint are included.
  • combined administration or “combined administration” refers not only to simultaneous administration in terms of physical time, but also to two or more drugs in combination, according to the unique schedule of each drug being combined as in conventional combination therapy. Administering.
  • MDSCs can inhibit the effectiveness of cancer vaccines administered for the treatment of cancer patients, and as a result can render cancer treatment impossible.
  • cancer treatment with cancer vaccines it is necessary to reduce the increased MDSC in cancer patients.
  • the present inventors used a combination of two chemotherapeutic agents, gemcitabine, and 5-fluorouracil (5-FU) or capecitabine, which are known to directly reduce MDSC. It has been found that, unlike single use, it does not reduce MDSC. Rather, a significant number of patients showed elevated MDSCs. This may act as a big limitation of the combination of gemcitabine and 5-fluorouracil (or capecitabine).
  • Using the peptides disclosed herein can significantly reduce MDSC. Reducing MDSCs can solve a series of pathological problems associated with MDSCs.
  • telomere is a genetic material repeatedly present at the end of a chromosome and is known to prevent damage to the chromosome or binding to another chromosome. Each time a cell divides, the telomeres become slightly shorter. After a certain number of cell divisions, the telomeres become very short, and the cells stop dividing and die. On the other hand, elongation of telomeres is known to prolong cell life. For example, cancer cells secrete an enzyme called telomerase, which prevents telomeres from shortening, so that cancer cells can continue to proliferate without dying.
  • the peptides disclosed herein are peptides having a sequence of SEQ ID NO: 1 or a peptide that is a fragment of sequence SEQ ID NO: 1, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, Peptides having at least 98%, at least 99% sequence homology.
  • the peptide comprises telomerase, specifically a peptide derived from human ( Homo sapiens ) telomerase.
  • the peptides disclosed herein may include peptides having sequence homology with a peptide comprising SEQ ID NO: 1 or a fragment thereof.
  • the peptide may consist of up to 30 amino acids.
  • the peptide described in SEQ ID NO: 1 is shown in Table 1 below.
  • the "name” in Table 1 below is to distinguish peptides.
  • the peptide set forth in SEQ ID NO: 1 represents the entire peptide of human telomerase.
  • a peptide having a sequence of SEQ ID NO: 1, a peptide that is a fragment of SEQ ID NO: 1, or a peptide having at least 80% sequence homology with the peptide sequence corresponds to a peptide included in telomerase.
  • synthetic peptides selected and synthesized at the positional peptides.
  • SEQ ID 2 shows the amino acid sequence of the entire telomerase.
  • amino acid changes belong to a property that allows the physicochemical properties of the peptide to be altered.
  • amino acid changes can be made, such as improving the thermal stability of the peptide, altering substrate specificity, changing the optimal pH, and the like.
  • amino acid includes not only the 22 standard amino acids that are naturally incorporated into the peptide, but also D-isomers and modified amino acids. Accordingly, in one aspect of the invention the peptide may be a peptide comprising D-amino acids. Meanwhile, in another aspect of the present invention, the peptide may include a non-standard amino acid or the like which has been post-translational modified.
  • post-translational modifications include phosphorylation, glycosylation, acylation (including, for example, acetylation, myristoylation and palmitoylation), alkylation ), Carboxylation, hydroxylation, glycation, biotinylation, ubiquitinylation, changes in chemical properties (e.g., beta-elimination deimidization) , Deamidation) and structural changes (eg, formation of disulfide bridges). It also includes changes in amino acids, such as changes in amino groups, carboxy groups or side chains, caused by chemical reactions that occur during the linkage with crosslinkers to form peptide conjugates.
  • Peptides disclosed herein can be wild-type peptides identified and isolated from a natural source.
  • a peptide disclosed herein may be an artificial variant, comprising an amino acid sequence in which one or more amino acids are substituted, deleted, and / or inserted as compared to a peptide that is SEQ ID NO: 1 or a fragment thereof.
  • Amino acid changes in the wild type polypeptide as well as in artificial variants include conservative amino acid substitutions that do not significantly affect the folding and / or activity of the protein.
  • conservative substitutions include basic amino acids (arginine, lysine and histidine), acidic amino acids (glutamic acid and aspartic acid), polar amino acids (glutamine and asparagine), hydrophobic amino acids (leucine, isoleucine, valine and methionine), aromatic amino acids (phenylalanine, Tryptophan and tyrosine), and small amino acids (glycine, alanine, serine and threonine). Amino acid substitutions that generally do not alter specific activity are known in the art.
  • the most common exchanges are Ala / Ser, Val / Ile, Asp / Glu, Thr / Ser, Ala / Gly, Ala / Thr, Ser / Asn, Ala / Val, Ser / Gly, Tyr / Phe, Ala / Pro, Lys / Arg, Asp / Asn, Leu / Ile, Leu / Val, Ala / Glu, and Asp / Gly, and vice versa.
  • Other examples of conservative substitutions are shown in the following table.
  • residue substitution Ala (A) val; leu; ile Val Arg (R) lys; gln; asn Lys Asn (N) gln; his; asp, lys; arg Gln Asp (D) glu; asn Glu Cys (C) ser; ala Ser Gln (Q) asn; glu Asn Glu (E) asp; gln Asp Gly (G) Ala Ala His (H) asn; gln; lys; arg Arg Ile (I) leu; val; met; ala; phe; norleucine Leu Leu (L) norleucine; ile; val; met; ala; phe Ile Lys (K) arg; gln; asn Arg Met (M) leu; phe; ile Leu Phe (F) leu; val; ile; ala; tyr Tyr
  • the present invention is a composition for inhibiting myeloid-derived suppressor cells (MDSCs), the composition is a peptide comprising SEQ ID NO: 1 as an active ingredient for MDSC inhibition, the peptide sequence and 80% Peptide having a sequence homology, or a fragment thereof, the peptide is a composition for inhibiting myeloid-derived suppressor cells (MDSCs), contained in an amount effective for MDSC inhibition.
  • MDSCs myeloid-derived suppressor cells
  • the invention provides a peptide comprising SEQ ID NO: 1, a peptide having at least 80% sequence homology with the peptide sequence, or a fragment thereof; Anticancer agents; And it may be a composition for inhibiting MDSC containing an adjuvant.
  • the invention provides a peptide comprising SEQ ID NO: 1, a peptide having at least 80% sequence homology with the peptide sequence, or a fragment thereof; Anticancer agents; And it may be an anticancer composition comprising an adjuvant.
  • the invention provides a peptide comprising SEQ ID NO: 1, a peptide having at least 80% sequence homology with the peptide sequence, or a fragment thereof; Anticancer agents; And cancer vaccine compositions comprising an adjuvant.
  • the invention may be a kit for inhibiting MDSC.
  • the kit includes the above-mentioned composition for inhibiting MDSC; Anticancer agents; And instructions.
  • the kit may further comprise an adjuvant.
  • the kit for inhibiting MDSC may be to improve, prevent or treat a disease or symptom caused by MDSC through MDSC inhibition.
  • the kit for inhibiting MDSC may be to improve, prevent or treat cancer through MDSC inhibition.
  • the invention provides a composition comprising a peptide comprising SEQ ID NO: 1, a peptide having at least 80% sequence homology with the peptide sequence, or a fragment thereof; Anticancer agents; And an anticancer kit comprising instructions.
  • the kit may further comprise an adjuvant composition.
  • the instructions may include a description of how the composition for inhibiting MDSC containing the peptide is used in combination with an anticancer agent. Specifically, it may include a description of the dosage, administration time, administration method and the like of each agent.
  • the instructions may include uses for inhibiting MDSC, anticancer use or cancer vaccine use. Specifically, all diseases or symptoms that need to inhibit MDSC can be included.
  • the instructions may include side effects and precautions associated with the administration.
  • the present invention provides a method for inhibiting myeloid-derived suppressor cells (MDSCs), an effective amount of a peptide comprising SEQ ID NO: 1, the peptide sequence and at least 80% sequence Or a peptide that is homologous, or a fragment thereof, to a subject in need of MDSC inhibition.
  • the method may further comprise administering an anticancer agent in combination with the peptide.
  • the method may further comprise administering an adjuvant in combination with the peptide.
  • the present invention provides a method for improving, treating or preventing cancer, wherein the peptide comprises an effective amount of a peptide comprising SEQ ID NO: 1, a peptide having at least 80% sequence homology with the peptide sequence, or a fragment thereof.
  • the peptide comprises an effective amount of a peptide comprising SEQ ID NO: 1, a peptide having at least 80% sequence homology with the peptide sequence, or a fragment thereof.
  • an anticancer agent and / or adjuvant may be a method for cancer improvement, treatment or prevention comprising administering to a subject in need of improvement, treatment or prevention of cancer.
  • the cancer is not particularly limited, but may be renal cell carcinoma (RCC), colorectal cancer (CRC), gastric cancer (GC), melanoma, lung cancer, blood cancer, prostate cancer, adenocarcinoma, prostate cancer or pancreatic cancer.
  • RCC renal cell carcinoma
  • CRC colorectal cancer
  • GC gastric cancer
  • melanoma lung cancer, blood cancer, prostate cancer, adenocarcinoma, prostate cancer or pancreatic cancer.
  • a peptide comprising SEQ ID NO: 1, having a sequence homology of 80% or more of the peptide sequence Peptides, or fragments thereof, may be used.
  • bone marrow-derived suppressor cells may be bone marrow-derived suppressor cells of an individual having a tumor.
  • the composition may be for administration to a subject in need of inhibition of MDSC.
  • MDSC functions to suppress immunity by inhibiting the activity of cytotoxic T lymphocytes.
  • cytotoxic T lymphocytes There is a net function of suppressing unnecessary and excessive immune responses, such as autoimmunity, but there is also a reverse function of inhibiting immunity in situations where an immune response is needed, causing or worsening disease, or impeding proper treatment.
  • MDSC is much increased in tumor or cancer patients, which negates the efficacy of cancer vaccines by significantly reducing the effects of cancer vaccine administration. In this situation, effectively reducing the number of MDSCs will enable smooth and effective cancer treatment.
  • Diseases or symptoms caused by MDSC are apparent in the art.
  • Diseases or symptoms caused by MDSC referred to herein include all diseases or symptoms caused by MDSC known in the art.
  • Bone diseases such as, for example, osteolytic bone disease; Multiple myeloma; Glioblastoma; Infections: bacterial & parasitic infections such as bacterial or parasitic infections; Acute or chronic inflammation; Traumatic stress; Sepsis and transplantation; Autoimmune diseases such as intraocular autoimmune diseases; Inflammatory bowel disease, Cancer cachexia; Or tuberculosis (TB), but is not limited thereto.
  • MDSC in this specification may include all MDSCs regardless of their phenotype.
  • Various phenotypes of MDSC are known in the art.
  • the phenotype is one selected from CD15, IL4Ra, CD14, CD11b, HLA-DR, CD33, Lin, FSC, DR and SSC, and optionally CD45, CD18, CD80, CD83, CD86, HLA-I and survival / killing identifiers.
  • CD15, IL4Ra, CD14, CD11b, HLA-DR, CD33, Lin, FSC, DR and SSC and optionally CD45, CD18, CD80, CD83, CD86, HLA-I and survival / killing identifiers.
  • CD14 CD11b
  • HLA-DR CD33
  • Lin Lin
  • FSC DR and SSC
  • CD45 CD18
  • CD80 CD83
  • CD86 HLA-I and survival / killing identifiers.
  • phenotypes include MDSC1 based on the labels IL4Ra + and CD14 +; MDSC2 based on the labels IL4Ra + and CD15 +; MDSC1 and MDSC2 based on the label IL4Ra +; MDSC3 based on the labels Lin-, HLA-DR- and CD33 +, and optionally CD18 + and HLA-I +; MDSC4 based on the label CD14 +, HLA-DR ( ⁇ / lo), FSChi and SSCim; MDSC5 based on the labels CD11b +, CD14- and CD15 +, and optionally FSChi, SSCim, CD80-, CD83-, CD86- and HLA-DR-; MDSC6 based on CD15 +, SClo and SSChi; And MDSC based on Lin, DR, and CD11b +, and the like.
  • the phenotype can be Lin-DR-CD11b +.
  • the concentration of peptides in the compositions disclosed herein can be routinely determined as known in the art.
  • the composition according to one aspect of the present invention comprises 10 mg / L to 1000 peptides comprising a peptide comprising the amino acid sequence of SEQ ID NO: 1, a peptide having a sequence homology of 80% or more with the amino acid sequence, or a fragment thereof. It may be included in the content of mg / L, specifically 10 mg / L to 500 mg / L, more specifically 30 mg / L to 200 mg / L, but when the difference in effect depending on the dose can be adjusted appropriately. When included in the above range or less, it is not only appropriate to exhibit the intended effect of the present invention, but also satisfies both the stability and safety of the composition, it may be appropriate to include in the above range in terms of cost-effectiveness. .
  • the dosage, administration method, administration cycle, and the like of the peptide herein are well known in the art, it may be administered according to the standards known in the art according to the condition of each patient. Specific dosage determinations are within the level of those skilled in the art, and their daily dosage may be, for example, specifically 1 ⁇ g / kg / day to 10 g / kg / day, more specifically 10 ⁇ g / kg / day to 100 mg / kg / day, and more specifically, 50 ⁇ g / kg / day to 10 mg / kg / day, but is not limited to this, depending on a variety of factors, such as age, health conditions, complications of the subject to be administered Can be.
  • the peptide can be administered via intradermal administration.
  • Dosage intervals may be administered once daily at two-day intervals and may be further extended over time. For example, after administration in weeks 1, 2, 3, and 4, the intervals may be spaced into weeks 6 and 10.
  • the dosage may be 0.1 to 3 mg once administered on an adult basis.
  • the dosage can be at least 0.1 mg, at least 0.2 mg, at least 0.3 mg, at least 0.4 mg at least 0.45 mg or at least 0.5 mg.
  • the dosage may be 3 mg or less, 2.5 mg or less, 2.0 mg or less, 1.5 mg or less, 1.0 mg or less, 0.9 mg or less, 0.8 mg or less, 0.7 mg or less, 0.6 mg or less.
  • the peptides described herein can be administered in combination with an anticancer agent.
  • Anticancer agents include, but are not limited to, chemotherapeutic and biotherapeutic agents. In particular, it may be a chemotherapeutic agent.
  • Chemotherapeutic agents include, but are not limited to, DNA alkylating agents, anti-metabolites, natural products, hormones, and the like.
  • the chemotherapeutic agent may be a metabolic antagonist.
  • Metabolism inhibitors refer to groups of molecules that interfere with DNA and RNA synthesis. Most metabolism inhibitors have a structure similar to the building blocks of DNA and RNA.
  • Subtypes of metabolic antagonists include, but are not limited to, folate antagonists (anti-folates), fluoropyrimidines, deoxynucleoside analogues and thiopurines.
  • Fluoropyrimidines include, but are not limited to, fluorouracil and capecitabine.
  • Capecitabine is a prodrug of 5-fluorouracil.
  • Deoxynucleoside analogues include cytarabine, gemcitabine, decitabine, vidaza, fludarabine, nelarabine, cladribine Cladribine, clofarabine and pentostatin, but are not limited thereto.
  • the chemotherapeutic agent may be one in which two or more agents are administered in combination.
  • fluoropyrimidine and deoxynucleoside analogs can be administered in combination.
  • gemcitabine and 5-fluorouracil or capecitabine, a prodrug thereof
  • gemcitabine and capecitabine may be administered in combination.
  • Appropriate dosages of the anticancer agents mentioned herein are already well known in the art and can be administered by criteria known in the art, depending on the condition of each patient. Specific dosage determinations are within the level of those skilled in the art, and their daily dosage may be, for example, specifically 1 ⁇ g / kg / day to 10 g / kg / day, more specifically 10 ⁇ g / kg / day to 100 mg / kg / day, and more specifically, 50 ⁇ g / kg / day to 10 mg / kg / day, but is not limited to this, depending on a variety of factors, such as age, health conditions, complications of the subject to be administered Can be.
  • gemcitabine may be administered intravenously, and the dosage and administration interval may be 1 to 6 times weekly at 2 to 8 week intervals at a dose of 100 to 10,000 mg / m 2 .
  • Dosage is at least 100 mg / m 2 , at least 200 mg / m 2, at least 300 mg / m 2, at least 400 mg / m 2, at least 500 mg / m 2, at least 600 mg / m 2 , at 700 mg / m 2 Or more, 800 mg / m 2 or more, or 900 mg / m 2 or more.
  • the dosage is 10,000 mg / m 2 or less, 9000 mg / m 2 or less, 8000 mg / m 2 or less, 7000 mg / m 2 or less, 6000 mg / m 2 or less, 5000 mg / m 2 or less, 4000 mg / m 2 or less, 3000 mg / m 2 or less, 2000 mg / m 2 or less, 1500 mg / m 2 or less, 1400 mg / m 2 or less, 1300 mg / m 2 or less, 1200 mg / m 2 or less, 1100 mg / m 2 Or less, 1050 mg / m 2 or less, 1030 mg / m 2 or less, 1020 mg / m 2 or less, or 1010 mg / m 2 or less.
  • capecitabine it may be administered orally.
  • the dosing interval may be twice daily.
  • Doses are at least 500 mg / m 2, at least 600 mg / m 2, at least 700 mg / m 2, at least 800 mg / m 2 , 900 mg / m 2 , 1,000 mg / m 2 , 1,100 mg / m 2 , 1,200 mg / m 2 , 1,300 mg / m 2 , 1,400 mg / m 2 , 1,500 mg / m 2 , 1,600 mg / m 2 or more.
  • the dosage is 15,000 mg / m 2 or less, 12,000 mg / m 2 or less, 10,000 mg / m 2 or less, 9000 mg / m 2 or less, 8000 mg / m 2 or less, 7000 mg / m 2 or less, 6000 mg / m 2 or less, 5000 mg / m 2 or less, 4000 mg / m 2 or less, 3000 mg / m 2 or less, 2000 mg / m 2 or less, 1,900 mg / m 2 or less, 1,800 mg / m 2 or less, 1,700 mg / m 2 It may be: The daily dose may be administered two or more times divided.
  • the peptides and / or anticancer agents described herein can be administered in combination with an adjuvant.
  • the adjuvant may be an adjuvant that increases MDSC. From an immunological point of view, the adjuvant is what is added to the vaccine to stimulate an immune response to the target antigen, but does not itself provide immunogenicity. All vaccines cause inflammation, resulting in the accumulation of bone marrow cells (monocytes and Neutrophils). Some of these cells are MDSCs. In addition to the purpose of stimulating the immune response, there are also adjuvants added to stabilize the formulation of the vaccine. Immunological adjuvant is well known in the art [J Biomed Biotechnol. 2012; 2012: 831486. Published online Mar 13, 2012].
  • Immunological adjuvant includes inorganic adjuvant such as aluminum salt and organic adjuvant such as oil based, virosome, squalane.
  • Organic adjuvants include, but are not limited to, emulsions, microbe-derived, synthetic adjuvants, cytokines, and the like. 9 kinds of cytokine adjuvant are known.
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • the adjuvant herein may be an adjuvant that increases MDSC.
  • the use of an adjuvant that increases MDSC inhibits the immune response and thus cannot achieve the effect of the vaccine. In this situation, a means is needed to prevent the increased action of MDSC of the adjuvant used.
  • Appropriate dosages of the adjuvant referred to herein are already well known in the art and can be administered according to criteria known in the art, depending on the condition of each patient. Specific dosage determinations are within the level of those skilled in the art, and their daily dosage may be, for example, specifically 1 ⁇ g / kg / day to 10 g / kg / day, more specifically 10 ⁇ g / kg / day to 100 mg / kg / day, and more specifically, 50 ⁇ g / kg / day to 10 mg / kg / day, but is not limited to this, depending on a variety of factors, such as age, health conditions, complications of the subject to be administered Can be.
  • intradermal doses of 7 to 700 mg prior to administration of the peptides disclosed herein such as from 1 minute to 150 minutes before, 5 to 80 minutes before, or 10 to 15 minutes before May be administered.
  • the administration time may be administered at least 1 minute before, at least 3 minutes, at least 5 minutes, at least 7 minutes, at least 8 minutes, at least 9 minutes or at least 10 minutes before the peptide administration.
  • the dosage can be at least 7 mg, at least 10 mg, at least 20 mg, at least 30 mg, at least 40 mg, at least 50 mg, at least 60 mg or at least 70 mg.
  • the dosage may be 700 mg or less, 600 mg or less, 500 mg or less, 400 mg or less, 300 mg or less, 200 mg or less, 100 mg or less, 90 mg or less, or 80 mg or less.
  • GM-CSF which is added as an adjuvant for vaccines in preclinical trials, is known to increase MDSC in tumor micro-environments [Curran MA, Allison JP (2009) Tumor vaccines expressing flt3 ligand synergize with ctla-4 blockade to reject preimplanted tumors. Cancer Res 69: 7747-7755.
  • low doses of GM-CSF as a vaccine adjuvant are known to increase the number of MDSCs in the blood [Filipazzi P, Valenti R, Huber V, Pilla L, Canese P, Iero MC, Mariani L, Parmiani].
  • GM-CSF has a big limitation that it is difficult to use as an adjuvant for cancer vaccine.
  • the present inventors have found a breakthrough method that can solve the problem of the loss of MDSC reduction ability by the combination of gemcitabine and 5-fluorouracil (or capecitabine) and the action of increasing MDSC in the tumor micro-environment of GM-CSF. Came out.
  • administration of low dose GM-CSF as an adjuvant of PEP1 did not increase Lin-DR-CD11b + MDSC in a group of patients receiving GemCap and PEP1 at the same time.
  • the composition may be a pharmaceutical, cosmetic or food composition.
  • each active ingredient may be administered according to criteria known in the art according to the condition of each patient.
  • Specific dosage determinations are within the level of those skilled in the art, and their daily dosage may be, for example, specifically 1 ⁇ g / kg / day to 10 g / kg / day, more specifically 10 ⁇ g / kg / day to 100 mg / kg / day, and more specifically, 50 ⁇ g / kg / day to 10 mg / kg / day, but is not limited to this, depending on a variety of factors, such as age, health conditions, complications of the subject to be administered Can be.
  • composition according to one aspect of the present invention can be applied to all animals including humans, dogs, chickens, pigs, cattle, sheep, guinea pigs or monkeys.
  • composition according to one aspect of the present invention may be administered orally, rectal, transdermal, intravenous, intramuscular, intraperitoneal, intramedullary, intradural or subcutaneous.
  • Formulations for oral administration may be, but are not limited to, tablets, pills, soft or hard capsules, granules, powders, solutions or emulsions.
  • Formulations for parenteral administration may be, but are not limited to, injections, drops, lotions, ointments, gels, creams, suspensions, emulsions, suppositories, patches or sprays.
  • compositions according to one aspect of the invention may include additives such as diluents, excipients, lubricants, binders, disintegrants, buffers, dispersants, surfactants, colorants, flavoring or sweetening agents as needed.
  • additives such as diluents, excipients, lubricants, binders, disintegrants, buffers, dispersants, surfactants, colorants, flavoring or sweetening agents as needed.
  • Pharmaceutical compositions according to one aspect of the invention may be prepared by conventional methods in the art.
  • Preferred embodiments of the invention include the most optimal mode known to the inventors for carrying out the invention. Variations of the preferred embodiments may become apparent to those skilled in the art upon reading the foregoing description. The inventors expect those skilled in the art to make appropriate use of such variations, and the inventors expect the invention to be practiced in a manner different from that described herein. Accordingly, the invention includes all modifications and equivalents of the subject matter referred to in the appended claims, as permitted by patent law. Moreover, any combination of the abovementioned elements within all possible variations is included in the invention unless expressly stated to the contrary or apparently contradictory in context. While the invention has been particularly shown and described with reference to exemplary embodiments, those skilled in the art will understand that various changes in form and detail may be made without departing from the spirit and scope of the invention as defined by the following claims .
  • a peptide comprising SEQ ID NO: 1, a peptide having at least 80% sequence homology with the peptide sequence, or a fragment thereof, was prepared according to a conventional solid phase peptide synthesis method. Specifically, peptides were synthesized by coupling amino acids one by one from the C-terminus through Fmoc solid phase synthesis (SPPS) using ASP48S (Peptron, Inc., Daejeon, Korea). As follows, the first amino acid at the C-terminus of the peptides was attached to the resin. For example:
  • Coupling reagent is HBTU [2- (1H-Benzotriazole-1-yl) -1,1,3,3-tetamethylaminium hexafluorophosphate] / HOBt [N-Hydroxxybenzotriazole] / NMM [4-Methylmorpholine] It was. Fmoc removal was performed using piperidine in DMF in 20% of DMF.
  • Each peptide was synthesized by repeating a process of reacting the amino acids with each other, washing with a solvent, and then deprotecting the amino acid using the state in which the amino acid protecting group was bound to the solid support.
  • the synthesized peptide was separated from the resin and then purified by HPLC, and confirmed by MS and lyophilized.
  • Pep 1 (EARPALLTSRLRFIPK) consisting of SEQ ID NO: 1, the specific process is as follows.
  • Example 2 (arm3): 21 pancreatic cancer patients, gemcitabine-capecitabine (GemCap) + pep1-GM-CSF administration
  • Gemcitabine (1,000 mg / m 2 ) was administered intravenously three times weekly at four week intervals, while capecitabine was administered orally twice a day for three weeks and not for one week.
  • the dosage 1,660mg / m 2 / day was (830mg / m 2 1 twice daily).
  • the MDSCs trajectories of 19 patients with arm2 during and after GemCap treatment and two cycles of GemCap treatment were analyzed.
  • the first pep1 was administered intra-dermally 0.56 mg of PEP1 on the 1st, 3rd, and 5th days of week 1, and the 2nd, 3rd, 4th, 6th, and 10th weeks, and 75mg GM 10-15 minutes before pep1 administration.
  • -CSF was administered intradermally at the same site as pep1 with the adjuvant of pep1.
  • Peripheral blood samples were taken before and after GemCap administration. Arm2 patients receiving only gemcitabine and capecitabine were taken with blood samples after 7 weeks of treatment, before the sixth gemcitabine, and when capecitabine was administered. After 10 weeks of treatment, the 7th gemcitabine immediately and before the 8th gemcitabine, and before the capecitabine, will be consistent with the immunomonitoring timing of the arm3 patient group receiving gemcitabine, capecitabine, and pep1. When a blood sample was taken.
  • PBMCs were separated using a Ficoll-Hypaque gradient, the cells were counted, frozen at minus 80 ° C for later analysis and stored in liquid nitrogen.
  • Peripheral blood mononuclear blood cells were recovered using 0.15 M phosphate-buffed saline solution (Dulbecco's A) (Oxoid, UK). Subsamples of recovered cells were used for MDSC analysis and the LIVE / DEAD Cell Stain kit (Invitrogen, UK) was used to distinguish between living and dead cells.
  • Anti-human monoclonal antibodies were used for analysis using flow cytometry. Cells were immunostained, washed with binding buffer solution, and analyzed using a MACSQuant flow cytometer using MACSQuantify software (Miltenyi Biotec).
  • DTH Delayed-type hypersensitivity
  • DTH reaction was accompanied by erythema and sclerosis, and the average diameter was 5mm.
  • PBMCs PBMCs were aliquoted into 48-well plates (ThermoFisher Scientific, USA) to be 2x10 6 cells per well and then X-VIVO (Lonza) containing 10% pooled human serum (Innovative Research, USA), 20 ug / ml pep1 peptide. , UK) cultured for 3 days. After incubation, 10 units / ml IL-2 (Peprotech, UK) was added to the medium. On day 11 of cultivation, after harvesting PEP1 cells, 1 ⁇ 10 5 cells per well were dispensed into round-bottom 96 well plates.
  • Cytokine levels of patient serum collected during PBMC collection were analyzed using BioRad BioPlex 27 Assay of BioRad BioPlex Instrument.
  • Tumor burden was measured using the sum of the long axis measurement of the tumor lesion and the short axis measurement of the pathological lymph.
  • Welch's correction and unpaired t-test were used to compare median values of Lin-DR-CD11b + cells in advanced pancreatic cancer patients and controls. Spearman's rank test was used to analyze the association between the MDSC baseline and cytokine baseline values, and the nonparametric Mann-Withney test was used to analyze the differences in cytokine dichotomized from the median MDSC values. Paired Wilcoxon tests were used to compare cytokine levels post-chemotherapy post-treatment.
  • the pre-treated MDSCs were subtracted from the post-treatment MDSC values.
  • the calculated data are asymmetrically distributed and graphically logged at log scale, but all analyzes represent the original dimensions using a nonparametric approach.
  • Wilcoxon signed rantks test was used to analyze differences in each treatment group.
  • the Wilcoxon two-sample tests were used to compare pre-treatment MDSC values, post-treatment MDSC values, MDSC difference absolute values, and MDSC difference% absolute values in arm 2 and arm 3 treatment groups.
  • Wilcoxon two-sample tests were used to compare the% absolute value of the (PD) MDSC difference between patients with disease control (PR, SD) and patients with progressive disease.
  • sensitivity analyzes include reanalyzed data on patients who are suppressing the disease to eliminate the effects of tumor size changes, and on reconstructed data on arm3 after 10 weeks of follow-up.
  • PBMCS peripheral blood mononuclear cells
  • the pretreatment baseline of 21 patients was used to calculate the association between pretreatment median and inflammatory cytokine MDSC levels.
  • Tumor volume Eight out of 19 patients (comparative example 2, arm 2) who received a combination of gemcitabine and capecitabine had decreased Lin-DR-CD11b + cell numbers. Of seven patients with advanced cancer (progressive disease, PD), five Lin-DR-CD11b + cell levels were elevated and two levels were reduced (range -60 to +662%). Of 10 patients with no advanced cancer (Stable disease, SD), 6 Lin-DR-CD11b + cell levels were elevated and 4 levels were decreased (range -68- + 604%). Patients who responded partially to the Pep1 vaccine had decreased Lin-DR-CD11b +%. The tumor size was accurately measured and no significant increase or decrease was found in the sum of the longest diameters of the significant tumors in 8 patients out of 10.
  • Lin-DR-CD11b +% increased in 5 patients and Lin-DR-CD11b +% decreased in 3 patients.
  • Lin-DR-CD11b + was not decreased by gemcitabine and capecitabine itself.
  • Changes in Lin-DR-CD11b +% tended to track tumor response. This has been demonstrated in patients with Lin-DR-CD11b + reference values greater than the median, and the reduction of MDSCs will be of great help immunologically in this patient group (Table 3).
  • the positive proliferation assay (the development of a positive DTH to PEP1) was analyzed in 21 arm3 patients who received GemCap and PEP1 at the same time. Nine of the 21 patients had an immune response, and eight of the nine had decreased MDSC% during treatment. The baseline value of Lin-DR-CD11b +% in 6 of 9 patients was higher than the median of patients and MDSC levels decreased.
  • Both granular and mononuclear MDSCs were extracted from fresh mesothelioma tissue and subjected to inhibition assay in the microenvironment of mesothelioma.
  • the experiment also uses Pemetrexed, which, when treated with mesothelioma, induces an senescence-associated secretory phenotype that results in STAT3 activation in tumor cells.
  • pep1 on cytokine release from tumor cells, pep1 on myeloid cell differentiation and pep1 on the inhibitory activity of MDSC.
  • DC maturation experiments were performed using adherent monocytes obtained from PBMCs from healthy donors. 5-day culture was performed. The conditions were as follows.
  • MoDCs Monocyte-derived Dendritic Cells
  • Mesothelioma cells were plated in 25 flasks and treated with the following samples at 40-50% confluence.
  • Example 5 Mesothelioma cell line + GV1001 (MCLG)
  • Example 6 Mesothelioma cell line + GV1001 / pemetrexed (MCLGP)
  • the treatment was performed for 24 hours, after which the medium was removed and replaced with fresh medium. After 36 hours the supernatant was collected and stored. Thereafter, the culture was incubated for 5 days using a comparative example without pep1 and an example with pep1 as a medium.
  • the purified MDSC from the patient was treated with pep1 (also + pemetrexed) overnight, and the cells were washed and used for the mixed lymphocyte reaction (MLR) for inhibition assay.
  • MDSCs were plated in 96 wells and treated at each concentration for MLR the next day (CD3 / CD28 stimulation). Apart from that, the treatment was performed during MLR and the treatment was also added to T cell treatment as a control.

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Abstract

L'invention concerne une nouvelle utilisation d'un peptide comprenant SEQ ID NO : 1, un peptide ayant une identité de séquence d'au moins 80 % de la séquence peptidique, ou un peptide sous la forme d'un fragment de ce dernier. Spécifiquement, l'invention concerne une utilisation du peptide pour inhiber des cellules suppressives dérivées de myéloïde (MDSC). Le problème de suppression de la réponse immunitaire par MDSC peut être résolu par inhibition de MDSC. Le peptide est utilisé en combinaison avec d'autres adjuvants et agents anticancéreux, en inhibant ainsi efficacement MDSC, et peut ainsi soulager, traiter ou prévenir des maladies ou symptômes liés à MDSC. En outre, l'invention concerne un vaccin n'ayant aucun effet secondaire associé à MDSC, en particulier, un vaccin contre le cancer, un kit contre le cancer ou un procédé contre le cancer.
PCT/KR2014/004760 2014-05-28 2014-05-28 Composition pour inhiber des cellules suppressives dérivées de myéloïde (mdsc) WO2015182798A1 (fr)

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WO2011116299A2 (fr) * 2010-03-18 2011-09-22 Colorado State University Research Foundation Agents d'inhibition des cellules myéloïdes suppressives
WO2013135266A1 (fr) * 2012-03-12 2013-09-19 Gemvax As Traitement du cancer du poumon non à petites cellules par immunothérapie active

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WO2011116299A2 (fr) * 2010-03-18 2011-09-22 Colorado State University Research Foundation Agents d'inhibition des cellules myéloïdes suppressives
WO2013135266A1 (fr) * 2012-03-12 2013-09-19 Gemvax As Traitement du cancer du poumon non à petites cellules par immunothérapie active

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"Findings from Royal Marsden hospital has provided new data on pancreatic cancer", WEBSITE: PHARMACY CHOICE - PHARMACY NEWS ARTICLE, 31 March 2014 (2014-03-31), Retrieved from the Internet <URL:http://www.pharmacychoice.com/news/article.cfm?Article_ID=1182638> *
ANNELS ET AL.: "The effects of gemcitabine and capecitabine combination chemotherapy and of low-dose adjuvant GM-CSF on the levels of myeloid-derived suppressor cells in patients with advanced pancreatic cancer", CANCER IMMUNOLOGY, IMMUNOTHERAPY, vol. 63, no. 2, pages 175 - 183, XP055240759, ISSN: 0340-7004 *
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