WO2018034356A1 - 悪性腫瘍標的ペプチド - Google Patents
悪性腫瘍標的ペプチド Download PDFInfo
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- WO2018034356A1 WO2018034356A1 PCT/JP2017/030003 JP2017030003W WO2018034356A1 WO 2018034356 A1 WO2018034356 A1 WO 2018034356A1 JP 2017030003 W JP2017030003 W JP 2017030003W WO 2018034356 A1 WO2018034356 A1 WO 2018034356A1
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- cancer
- amino acid
- peptide
- iii
- acid sequence
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
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- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0056—Peptides, proteins, polyamino acids
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- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
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- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/085—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier conjugated systems
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- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/14—Peptides, e.g. proteins
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- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4721—Lipocortins
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- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
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- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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- C07K5/08—Tripeptides
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- C07K5/08—Tripeptides
- C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
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- C07K5/10—Tetrapeptides
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- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
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- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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- C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
- C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
- C08G69/08—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from amino-carboxylic acids
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- C12N15/09—Recombinant DNA-technology
Definitions
- the present invention relates generally to the field of cancer biology, and more particularly to peptides that bind to annexin A1 and uses thereof.
- glioma a malignant brain tumors.
- glioblastoma grade 4 glioblastoma
- temozolomide a new drug effective against glioblastoma, was approved in Japan in 2006.
- the blood-brain barrier is not a passive method that relies on the diffusion of small molecules, but it accumulates in brain tumors at an overwhelmingly high concentration and actively Development of therapeutic agents that can cross the endothelial wall is essential.
- Fukuda one of the inventors, has hosted a laboratory at Sanford Burnham Prebys Medical Discovery Institute in the United States for over 30 years before being assigned to the National Institute of Advanced Industrial Science and Technology in 2014. Meanwhile, Fukuda succeeded for the first time in the world in inhibiting sugar chain-dependent cancer metastasis using a peptide that mimics the structure of a sugar chain (Non-patent Document 1). Furthermore, in the process of examining the vascular endothelial receptor with which these sugar chain mimetic peptide groups interact, it was found that a peptide named IF7 binds to Annexin A1 (Annexin A1; Anxa1) (Non-patent Document 2).
- Anxa1 has been revealed by the group of Jan Schnitzer et al. To have the highest specificity among the currently known tumor blood vessel specific marker molecules, and is expressed intracellularly in normal cells, but tumor neovascular endothelial cells Then, it is strongly expressed on the surface of the lumen in contact with blood flow (Non-patent Document 3). Fukuda et al. Revealed that a drug (IF7-SN38) obtained by binding an anticancer drug (SN38) to IF7 eliminates tumors of tumor-bearing mice at a low dose (Non-patent Document 2). IF7 binds to the N-terminal region of mouse Anxa1, but the amino acid sequence in that region is highly conserved between mouse and human. Therefore, IF7-SN38 may be effective in humans, so this discovery was featured in “In this issue in PNAS” of PNAS magazine, NIH introduced feature articles, and media from all over the world. It received a lot of attention, such as reporting.
- IF7 When IF7 is intravenously administered to tumor-bearing mice, IF7 reaches the blood vessels around the tumor, then is taken into the vesicles from the luminal side of the vascular endothelial cells, moves to the basal side, and is released to the stroma where cancer cells are present Is done. Also in mouse vascular endothelial F2 cells, IF7 bound to Anxa1 actively transected tumor vascular endothelial cells through transcytosis. Therefore, it was suggested that IF7 has an activity to cross the blood vessel-brain tumor barrier in the brain tumor.
- IF7 has excellent malignant tumor target activity, but there are problems in two points of poor solubility and low stability in aiming for clinical development. That is, first, the IF7 peptide is protease sensitive and easily degraded. In fact, in an experiment in which A488-IF7 was administered to the vein of a healthy mouse, the peripheral blood fluorescence signal almost disappeared in about 1 hour. However, in the tail vein administration of tumor-bearing mice, A488-IF7 had significantly less fluorescence recovered from peripheral blood than healthy mice. This result suggests that A488-IF7 undergoes degradation, but most accumulates rapidly in the tumor. In addition, IF7 is difficult to formulate, such as adding a surfactant after dissolving in DMSO to avoid precipitation when intravenously administering a compound that is highly hydrophobic and bound to an anticancer agent.
- an object of the present invention is to provide a novel peptide that binds to annexin A1 and its use, which can at least partially overcome the above-mentioned problems associated with IF7.
- the present inventors have intensively studied in order to solve the above-mentioned problems, and have come up with the idea of searching for a D-type peptide that can bind to annexin A1.
- the present inventors have mirror-image relationship with a 16-residue L-type peptide (L-MC16) in which a modifying Cys residue is added to the N-terminal 15 residue of Anxa1, which is known to bind to IF7.
- L-MC16 16-residue L-type peptide
- a D-type peptide (D-MC16) was synthesized, and a plurality of 7-amino acid L-type peptides that bind to D-MC16 were identified by screening using a T7 phage library.
- TIT7 peptide a peptide that is mirror image with the TIT7 peptide binds to Anxa1. Furthermore, the present inventors have conducted in vivo experiments that dTIT7 peptide accumulates at the tumor site when administered to the brain tumor model mouse via the tail vein, and dTIT7 peptide conjugated with an anticancer drug (geldanamycin).
- GA-dTIT7 significantly inhibited tumor growth when intravenously administered to tumor-bearing mice, and caused a large amount of necrosis at the tumor site.
- GA-dTIT7 was a brain tumor model in which C6 cells were transplanted into the brain. In both cases of mice and brain metastasis model mice transplanted with B16 cells in the brain, the tumor growth was suppressed when administered orally, and the tumor continued to decrease after the administration of the drug was stopped. It was demonstrated that complete healing was obtained in these animals.
- the anticancer agent is selected from the group consisting of an antimetabolite, an alkylating agent, an anticancer antibiotic, a microtubule inhibitor, a platinum preparation, a topoisomerase inhibitor, a molecular target drug, and an antiangiogenic agent.
- the anticancer agent is Enocitabine, capecitabine, carmofur, cladribine, gemcitabine, cytarabine, cytarabine ocphosphate, tegafur, tegafur uracil, tegafur gimeracil oteracil potassium, doxyfluridine, nelarabine, hydroxycarbamide, fluorouracil, fludarabine, pometredoline Methotrexate; Cyclophosphamide, ifosfamide, melphalan, busulfan, thiotepa, nimustine, ranimustine, dacarbacin, procarbacin, temozolomide, carmustine, streptozotocin, bendamustine; Actinomycin D, aclarubicin, amrubicin, idarubicin, epirubicin, dinostatin stimamarer, daunorubicin, doxorubicin,
- the detectable substance is X-ray imaging, computed tomography (CT), nuclear magnetic resonance imaging (MRI), ultrasonography, scintigraphy, positron tomography (PET), endoscope, and abdominal cavity
- CT computed tomography
- MRI nuclear magnetic resonance imaging
- PET positron tomography
- endoscope endoscope
- abdominal cavity The conjugate according to [9] which enables detection of the conjugate in vivo by means selected from the group consisting of mirrors.
- the detectable substance is a radioisotope, an MRI enhancement agent, a radiopaque substance, a contrast agent, or a fluorescent substance.
- the detectable substance is 18 F, 51 Mn, 52 m Mn, 52 Fe, 55 Co, 62 Cu, 64 Cu, 68 Ga, 72 As, 75 Br, 76 Br, 82 m Rb, 83 Sr, 86 Y, 89 Zr, 94 m Tc, 110 In , 120 I, 124 I, 51 Cr, 57 Co, 58 Co, 59 Fe, 67 Cu, 67 Ga, 75 Se, 97 Ru, 99m Tc, 111 In, 114 m In, 123 I, 125 I, 131 I, 169 A radionuclide selected from Yb, 197 Hg, and 201 Tl; Chromium (III), manganese (II), iron (III), iron (II), cobalt (II), nickel (II), copper (II), neodymium (III), samarium (III), ytterbium (III), Paramagnetic ions selected from gadolinium (III), vanadium (I), van
- a composition comprising the peptide according to any one of [1] to [4] or the conjugate according to any one of [5] to [12], and a pharmaceutically acceptable carrier.
- a composition for treating cancer comprising the conjugate according to any one of [6] to [8] and a pharmaceutically acceptable carrier.
- a composition for testing cancer comprising the conjugate according to any one of [9] to [12] and a pharmaceutically acceptable carrier.
- the composition according to [14] or [15], wherein the cancer is solid cancer or liquid cancer.
- Solid cancer is brain / nervous cancer, head and neck cancer, digestive organ cancer, urinary or genital cancer, respiratory cancer, breast cancer, skin cancer, bone cancer Or the composition of [16] or [17], which is a muscle cancer.
- Solid cancer is brain tumor, spinal cord tumor, laryngeal cancer, oral cancer, salivary gland cancer, sinus cancer, thyroid cancer, stomach cancer, esophageal cancer, small intestine cancer, colon cancer, rectum Cancer, anal cancer, liver cancer, biliary tract cancer, pancreatic cancer, renal cancer, renal cell cancer, bladder cancer, prostate cancer, renal pelvis and ureteral cancer, gallbladder cancer, bile duct cancer, Testicular cancer, penile cancer, uterine cancer, endometrial cancer, uterine sarcoma, cervical cancer, vaginal cancer, vulvar cancer, ovarian cancer, fallopian tube cancer, lung cancer, breast cancer, malignant melanoma
- the brain tumor is meningioma, pituitary adenoma, schwannoma, astrocytoma, oligodendrocyte glioma, anaplastic astrocytoma, anaplastic oligodendrocytes
- the composition according to [20] or [21] which is a glioma, an anaplastic oligodendrocyte astrocytoma, or a glioblastoma (glioblastoma).
- the composition of [16], wherein the liquid cancer is B cell lymphoma.
- a novel peptide that binds to annexin A1 is provided.
- Annexin A1 targeted by the peptide of the present invention is the most specific molecule among neovascular target markers for malignant tumors that can be known at present. It can show an excellent therapeutic effect compared with anticancer agents.
- the peptide-anticancer agent conjugate is not only capable of accumulating anticancer agents with high efficiency in malignant tumors, but also is resistant to proteases, it is expected to reduce the number of effective administrations and further lower dosages. It is.
- Annexin A1 A characteristic feature of Annexin A1 is that it is expressed on the blood side of neovascular endothelial cells formed in the tumor, and when the ligand such as the peptide of the present invention is bound on the blood side, the ligand is transported to the basal side by transcytosis. It is an active release to the stroma where cancer cells are present. This property is thought to work as a mechanism to actively overcome the vascular brain barrier.
- the peptide of the present invention targeting annexin A1 enables treatment of malignant brain tumors by an innovative mechanism.
- chemotherapeutic agents that pass through the blood-brain barrier, those that accumulate in tumor tissue, and those that can be stably administered orally in the body have been developed. It is not present except for the peptides of the invention (FIG. 10). Since the peptide of the present invention can be combined with various anticancer agents, the physiological activity can be widened.
- the present invention opens a breakthrough in the treatment of brain tumors.
- ANXA1 is known to be expressed on the blood vessel surface of various malignant tumors, and dTIT7-binding anticancer agents are expected to be clinically applied not only as brain tumors but also as a wide range of cancer therapeutic agents.
- the peptide of the present invention is easy to chemically synthesize and modify, it has a very high potential as a medium-molecular biopharmaceutical that replaces an antibody drug.
- the peptide of the present invention can be a short chain peptide (for example, 7 amino acid residues), it can be produced inexpensively by chemical synthesis.
- the peptide of the present invention and the conjugate containing the peptide and another functional moiety are excellent in stability and can also be used as a pharmaceutical for oral administration. Therefore, clinical trials are easy. After being actually approved as a medical drug, it can be spread as a medical drug even in developing countries where medical facilities are scarce.
- the conjugate containing the peptide of the present invention and a detectable substance is useful, for example, in cancer diagnosis.
- the present inventors tried a PET examination of a mouse using IF7, but a tumor-specific image was not obtained. The reason for the failure is thought to be that although IF7 was bound to a radioactive reagent, IF7 was buried inside the compound due to high hydrophobicity. It is believed that this point can be overcome because the peptides of the present invention can be water soluble.
- the peptide of the present invention can be relatively easily modified at the N-terminus, can be labeled with 3D imaging reagents such as PET, and diagnostic agents can be developed.
- FIG. 2 is an enlarged view of the brain tumor tissue section shown in FIG. 1.
- Vascular endothelial cells were stained with a CD31 specific antibody (red).
- IF7-A488 green passes through blood vessels and reaches stromal cancer cells.
- RQ7 is a reverse sequence control of IF7.
- BBTB blood vessel-brain tumor barrier
- Luc luciferase
- C6-Luc cells (cells in which luciferase was forcibly expressed in rat glioma) were transplanted subcutaneously into the brain of immunodeficient SCID mice to form tumors, which were used as dual tumor models.
- the survival rate of C6-Luc cells was measured by administering IF7-SN38 daily from the tail vein and measuring the luminescence due to luciferase activity in the tumor.
- IF7-SN38 not only suppressed the growth of brain tumors, but also suppressed brain tumors more strongly than subcutaneous tumors. It is a figure which shows the quantitative analysis of the fluorescence which remain
- A488-IF7 was administered to the melanoma B16 subcutaneous tumor-bearing mouse from the tail vein, and peripheral blood was collected from the ocular vein over time to measure fluorescence. The recovered fluorescence decreased depending on the size of the tumor. It is a figure explaining the screening of the D-type peptide couple
- Rat glioma cells (C6-Luc) in which luciferase was forcibly expressed were transplanted into the brains of nude mice to prepare brain tumor model mice.
- DTIT7 (IRDye-dTIT7, unpurified product) labeled with a near-infrared fluorescent reagent (IRDye800CW) was injected into the tail vein, and the fluorescence was observed with an IVIS Imager every time. It was observed that fluorescent signals were accumulated in the brain tumor site and the kidney after 24 hours.
- A Overall image over time
- B Enlarged photo
- C Signal quantification with IVIS imager software. It is a figure which shows the structure of GA-dTIT7 condensate.
- GA-dWIP7 in which geldanamycin was bound to WIPTTMT (a peptide in which only the order of the D-type amino acid sequence constituting dTIT7 was changed) was administered to mice as a control.
- the graph (upper right) and the survival curve (lower right) which quantified the live cell signal (left figure) of the malignant tumor are shown. It is a figure which illustrates conceptually the target treatment of the malignant brain tumor by IF7, dTIT7 binding anticancer agent.
- the brain blood barrier is raised from the neck to the top.
- Common anticancer agents do not have tumor targeting ability. Temozolomide penetrates brain tumors to some extent by diffusion but is not concentrated. Avastin works on new blood vessels but does not directly affect tumor cells.
- Anxa1-binding peptides cross the blood brain tumor barrier and accumulate at high concentrations only in tumors. It is a figure which shows the result of the intermolecular interaction of dLRF7, dSPT7, dMPT7 and dLLS7 peptide, and Anxa1. All peptides tested showed positive binding to Anxa1. It is a figure which shows the result of the administration experiment to the brain tumor model nude mouse of IRDye-dLRF7, IRDye-dSPT7, IRDye-dMPT7, and IRDye-dLLS7.
- mice except for those injected with dLLS7 showed strong signals at the brain tumor site, indicating that the three peptides dLRF7, dMPT7 and dSPT7 other than dLLS7 have the ability to target brain tumors via the vasculature pathway.
- Peptide The present invention provides a peptide comprising any one of the following amino acid sequences (I) to (III).
- the present invention also provides a peptide comprising any one of the following amino acid sequences (i) to (vii).
- (I) T [D] I [D] T [D] W [D] P [D] T [D] M [D] amino acid sequence (Ii) the amino acid sequence of L [D] R [D] F [D] P [D] T [D] V [D] L [D], (Iii) L [D] L [D] S [D] W [D] P [D] S [D] A [D] amino acid sequence, (Iv) the amino acid sequence of S [D] P [D] T [D] S [D] L [D] L [D] F [D], (V) the amino acid sequence of M [D] P [D] T [D] L [D] T [D] F [D] R [D], (Vi) an amino acid sequence having an insertion, substitution or deletion of one or several amino acids, or a combination thereof in any one of the amino acid sequences of (i) to (
- amino acid sequence of a chain peptide is described with the N-terminal side on the left side and the C-terminal side on the right side according to the convention of peptide designation.
- each amino acid symbol with the symbol [D] immediately after the amino acid sequence indicates the D form of the amino acid, and each amino acid symbol without the symbol [D] immediately after the amino acid sequence is contrary to the context.
- the L form of the amino acid is shown.
- a peptide including any one of the amino acid sequences (I) to (II) and a peptide including any one of the amino acids (i) to (vii) are collectively referred to as a peptide of the present invention. .
- amino acid sequence of (I) is W [D] P [D] S [D], W [D] P [D] T [D], F [D] P [D] S [D], or F Any of [D] P [D] T [D] may be used.
- n is 0-4, preferably 2-3.
- X may be any amino acid selected independently of each other.
- the peptide of the present invention may be composed of the amino acid sequence of any of the above (I)-(III) and (i)-(vii), and the N-terminal side and / or the C-terminal side of these sequences One or more amino acids may be added to the side.
- a peptide means a peptide in which two or more amino acids are bonded to each other.
- the length of the peptide of the present invention is not particularly limited.
- the peptide of the present invention has at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, It may comprise at least 14 or at least 15 amino acids.
- the peptides of the present invention can be up to 50, up to 45, up to 40, up to 35, up to 30, up to 25, up to 20, up to 19, up to 18, up to 17, up to 16, It may consist of up to 15, up to 14, up to 13, up to 12, up to 11, up to 10, up to 9, up to 8, or up to 7 amino acids.
- the peptides of the present invention are 3-10, 3-15, 3-20, 3-25, 3-30, 3-40, 3-50, 4-10, 4-15 4-20, 4-25, 4-30, 4-40, 4-50, 5-10, 5-15, 5-20, 5-25, 5-30 5-40, 5-50, 6-10, 6-15, 6-20, 6-25, 6-30, 6-40, 6-50, 7-10 7-15, 7-20, 7-25, 7-30, 7-40, 7-50, 8-10, 8-15, 8-20, 8-25 , 8-30, 8-40, or 8-50 amino acids in length.
- the peptides of the present invention have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids. It may be a length.
- the peptide of the present invention may be composed of a combination of D-type amino acid and L-type amino acid. More specifically, all of the amino acids constituting the peptide comprising the amino acid sequence of any of (I)-(II) and (i)-(vi) may be D-type amino acids, In addition to the amino acid, it may contain an L-type amino acid, and all of the amino acids constituting the peptide containing the amino acid sequence of (III) or (vii) may be an L-type amino acid, In addition, it may contain a D-type amino acid.
- the L-type amino acid may be a naturally occurring L-type amino acid, for example, glycine, alanine, leucine, proline, phenylalanine, tyrosine, methionine, serine, threonine, cysteine, aspartic acid, glutamic acid, all of which are L-forms. , Asparagine, glutamine, lysine, arginine, hydroxylysine, histidine, tryptophan, valine and the like.
- D-type amino acids include optical isomers of L-type amino acids as described above.
- glycine which is an amino acid that does not exhibit optical activity, can be read as being an L-type or D-type amino acid unless it is contrary to the context.
- the peptide of the present invention is 37C. F. R. It may contain modified or unusual amino acids such as those mentioned in 1.821-1.822. Alternatively, in one embodiment, the peptides of the invention do not contain modified or unusual amino acids.
- modified or abnormal amino acids include 3-aminoadipic acid, ⁇ -alanine, 2-aminobutyric acid, 4-aminobutyric acid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid, 2-aminopimelic acid, 2,4-diaminobutyric acid, desmosine, 2,2′-diaminopimelic acid, 2,3-diaminopropionic acid, N-ethylglycine, N-ethylasparagine, hydroxylysine, allo-hydroxylysine, 3- Examples include hydroxyproline, 4-hydroxyproline, isodesmosine, allo-isoleucine,
- the amino terminus and / or carboxy terminus of the peptide of the present invention may be modified.
- the amino terminal modification may be methylation (eg, —NHCH 3 , or —N (CH 3 ) 2 ), acetylation (eg, with acetic acid or a halogenated derivative thereof), or benzyloxycarbonyl group, carboxylate functions (RCOO-) or a sulfonyl functional group (R-SO 2 -) ( . wherein R is an alkyl, aryl, such as heteroaryl, and alkyl aryl) any protective groups, such as May be introduced.
- R is an alkyl, aryl, such as heteroaryl, and alkyl aryl
- any protective groups such as May be introduced.
- Examples of the modification at the carboxy terminus include amidation (—CONH 2 ) and esterification (—COOR).
- R in the ester for example, a C 1-6 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl; for example, a C 3-8 cycloalkyl group such as cyclopentyl, cyclohexyl; C 6-12 aryl groups such as ⁇ -naphthyl; for example, phenyl-C 1-2 alkyl groups such as benzyl and phenethyl; C 7-14 aralkyl groups such as ⁇ -naphthyl-C 1-2 alkyl groups; pivalo An yloxymethyl group or the like is used.
- a C 1-6 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl
- a C 3-8 cycloalkyl group such as cyclopentyl, cyclohexyl
- the peptide of the present invention may have various modifications other than at the N-terminus or C-terminus.
- the chemical modification may be, for example, methylation, acetylation, phosphorylation and the like.
- the carboxyl group may be amidated or esterified.
- the ester in this case, for example, the above-mentioned C-terminal ester or the like is used.
- a substituent on the side chain of an amino acid in the molecule is a suitable protecting group (eg, formyl group, acetyl group, C And a C 1-6 acyl group such as a 1-6 alkanoyl group).
- the peptide of the present invention containing the amino acid sequence of (vi) above is a partial sequence consisting of four consecutive amino acids or a partial sequence consisting of five consecutive amino acids in the amino acid sequences of (i) to (v) above. Or a partial sequence consisting of 6 consecutive amino acids.
- the peptide has the amino acid sequence of T [D] I [D] T [D] W [D], I [D] Amino acid sequence of T [D] W [D] P [D], Amino acid sequence of T [D] W [D] P [D] T [D], W [D] P [D] T [D] M [ D] amino acid sequence, T [D] I [D] T [D] W [D] P [D] amino acid sequence, I [D] T [D] W [D] P [D] T [D] Amino acid sequence of T [D] W [D] P [D] T [D] M [D], T [D] I [D] T [D] W [D] W [D] P [D] T [ D] or an amino acid sequence of I [D] T [D] W [D] P [D] T [D] M [D].
- the position of the mutation (that is, insertion, substitution, deletion, and combinations thereof) in the amino acid sequence of (vi) above is not particularly limited.
- the mutation is (a) only insertion, (b) only substitution, (c) only deletion, (d) only insertion and substitution, (e) only insertion and deletion, (f) only substitution and deletion, or (G) It may be composed of a combination of insertion, substitution and deletion.
- the number of mutations (a) to (g) is, for example, 1-5, preferably 1-4, more preferably 1-3, still more preferably 1 or 2, and even more preferably 1. is there.
- the amino acid inserted in the amino acid sequence of (vi) may be any amino acid as described above.
- the amino acid may be an L-type or D-type amino acid, for example, a naturally occurring L-type amino acid as described above, or a D-type amino acid that is an optical isomer thereof.
- the amino acid may be subjected to various chemical modifications as described above.
- conservative amino acid substitution is well known in the art.
- conservative amino acid substitutions can be defined as substitutions between amino acids that have similar side chain properties.
- conservative amino acid substitutions include, for example, (1) substitution between aromatic amino acids (Phe, Trp, Tyr), (2) nonpolar aliphatic amino acids (Gly, Ala, Val, Leu, Met, Ile, Pro ), (3) substitution between uncharged polar amino acids (Ser, Thr, Cys, Asn, Gln), (4) substitution between basic amino acids (Lys, Arg, His), or (5 ) Substitution between acidic amino acids (Asp, Glu).
- a conservative amino acid substitution can also include substituting a D-type amino acid with its optical isomer, an L-form amino acid. Therefore, a conservative amino acid substitution is a substitution between two L-type amino acids, a substitution between two D-type amino acids, or an L-type amino acid and a D-type amino acid within the groups (1) to (5) above. May be a substitution between.
- the sequence (vi) may be included in the sequence (I) or (II).
- the sequence (vii) is included in the sequence (III).
- the fourth amino acid in the sequence (i) is W [D] or F [D]
- the fifth amino acid is P [D]
- the sixth amino acid is T [D].
- S [D] the third amino acid in the sequence (ii) is W [D] or F [D] and the fourth amino acid is P [D] and the fifth
- the amino acid may be T [D] or S [D]
- the fourth amino acid is W [D] or F [D] and the fifth amino acid is P [D] in the sequence (iii) above.
- the sixth amino acid may be T [D] or S [D], the second amino acid is P [D] and the third amino acid is T [D] in the sequence (iv) above.
- the sixth amino acid may be F [D], Serial (v) 2 amino acid in the sequence is P [D] and the third amino acid of a T [D] and 5 amino acids may be F [D].
- Retro-inverso isomers of peptides are those in which the chirality of each amino acid residue is opposite to the original peptide ("inverso") and the direction of the amino acid sequence is reversed (“Retro”).
- Retro-inverso isomers are known to exhibit similar structure and function as the original peptide (eg, Acc. Chem. Res., 1993, 26 (5), pp 266-273, and PLoS One. 2013 Dec 2: 8 (12): e80390).
- examples of the amino acid sequence (vii) include, for example, MTPWTIT (SEQ ID NO: 1) which is Retro-inverso of the sequence (i), and LVTPFRL (Retro-inverso of the sequence (ii)).
- SEQ ID NO: 2 SEQ ID NO: 2
- ASPWSLL which is Retro-inverso of the sequence (iii) above
- FLLSTPS which is Retro-inverso of the sequence (iv) above
- SEQ ID NO: 4 FLLSTPS which is Retro-inverso of the sequence (iv) above
- SEQ ID NO: 5 An example is RFLTTPM (SEQ ID NO: 5) which is Retro-inverso.
- the peptide of the present invention may contain two or more sequences selected from the above (I)-(III) and (i)-(vii).
- the peptide of the present invention has a tandem repeat of any of the sequences (I)-(III) and (i)-(vii) (that is, the same sequence portion is directly linked to each other). Structure).
- the peptide of the present invention comprises a structure in which two or more different sequences of (I)-(III) and (i)-(vii) are directly linked.
- the peptide of the present invention may constitute a multivalent peptide by a dendrimer.
- the peptide of the present invention may be a free form or a salt form.
- the salt of the peptide of the present invention include pharmaceutically acceptable acid addition salts and base addition salts.
- the acid addition salt include salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, and salts with organic acids such as acetic acid, malic acid, succinic acid, tartaric acid and citric acid.
- Base addition salts include salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, and salts with amines such as ammonium and triethylamine.
- the peptides of the present invention can bind to annexin A1.
- Annexin A1 (Annexin A1; Anxa1) is a known protein belonging to the annexin family, also known as lipocortin 1 (lipocortin 1).
- the gene sequence and amino acid sequence of Anxa1 are known for various biological species. For example, RefSeq No. of mRNA for human Anxa1. NM — 00700.2 (SEQ ID NO: 6), protein RefSeq No. NP_000691.1 (SEQ ID NO: 7); RefSeq No. of mRNA for mouse Anxa1. NM — 010730.2 (SEQ ID NO: 8), protein RefSeq No.
- NP — 034860.2 (SEQ ID NO: 9) may be mentioned.
- the peptide of the present invention may bind to the N-terminal region of Anxa1. More specifically, the peptide of the present invention is a region consisting of amino acids 1 to 15 in SEQ ID NO: 7 in human Anxa1, or a region consisting of amino acids 1 to 15 in SEQ ID NO: 9 in mouse Anxa1. Can be combined.
- the peptide of the present invention is preferably less than 10 ⁇ 6 M, more preferably less than 10 ⁇ 7 M, for example, when the intermolecular interaction with mouse or human Anxa1 is measured using the QCM (Quartz Crystal Microbalance) method.
- Kd value a dissociation constant (Kd value) of less than 5 ⁇ 10 ⁇ 8 M.
- a human recombinant Anxal protein composed of 346 amino acid residues commercially available from ATGen (Seongnam-si, South Korea) can be used.
- the peptide of the present invention can be produced according to a known peptide synthesis method.
- the peptide synthesis method may be, for example, either a solid phase synthesis method or a liquid phase synthesis method.
- the target peptide can be produced by removing the protecting group.
- the condensation and the removal of the protecting group can be carried out according to a method known per se, for example, the method described in the following (1) to (8). (1) M.M. Bodanszky & M. A.
- the peptide thus obtained can be purified and isolated by a known purification method.
- the purification method include solvent extraction, distillation, column chromatography, liquid chromatography, recrystallization, and combinations thereof.
- the peptide obtained by the above method is a free form
- the free form can be converted into an appropriate salt by a known method or a method analogous thereto, and conversely, when the peptide is obtained as a salt
- the salt can be converted into a free form or other salt by a known method or a method analogous thereto.
- annexin A1 is known to have the highest specificity among currently known tumor blood vessel specific marker molecules, and is expressed in cells in normal cells, but in tumor neovascular endothelial cells. It is strongly expressed on the surface of the lumen in contact with the bloodstream (Oh et al., Nature 429: 629-35, 2004).
- the peptides of the invention can selectively bind to angiogenic tumors in vivo.
- Anxa1 is expressed on the blood side of neovascular endothelial cells formed in the tumor, and when bound to the blood side with a ligand such as the peptide of the present invention, the ligand is transported to the basal side by transcytosis, and cancer cells are Active release to existing interstitium.
- the peptides of the present invention can target malignant tumors in vivo.
- the peptides of the present invention are useful, for example, for malignant tumor targeting applications.
- conjugates of the present invention also provides conjugates in which one or more components are bound to the above-described peptides of the present invention (hereinafter also referred to as conjugates of the present invention).
- the component is not particularly limited as long as it can be linked to the peptide of the present invention, can be suitable for administration to animals (for example, humans), and can perform some function in the body of the animals.
- Ingredients can be natural or non-natural.
- components include biological materials (eg, cells, phages, viruses, etc.), oligonucleotides and nucleic acids (eg, DNA, RNA, or DNA / RNA chimeras, etc.), peptides, polypeptides, and proteins, antibodies, Examples include, but are not limited to, lipids, polysaccharides, low-molecular compounds (for example, organic or inorganic compounds having a Da of 1000 Da or less), particles (for example, gold particles, various nanoparticles), and combinations thereof.
- the component may perform a given functionality at a target site in an animal (eg, human) body.
- the type of functionality is not particularly limited. Since the conjugate of the present invention can be targeted to malignant tumors by the action of the moiety corresponding to the peptide of the present invention, preferable examples of the functionality include imparting anticancer activity and detectability.
- the component may be, for example, an anticancer agent or a detectable substance.
- the anticancer agent refers to a drug intended to suppress the growth of malignant tumor (cancer).
- the action mechanism of the anticancer agent is not particularly limited.
- the anticancer agent may be an antimetabolite, an alkylating agent, an anticancer antibiotic, a microtubule inhibitor, a platinum preparation, a topoisomerase inhibitor, a molecular target drug, or the like.
- the conjugate of the present invention may comprise two or more identical or different anticancer agents.
- Antimetabolites include, for example, folate antimetabolite, dihydropteroate synthase inhibitor, dihydrofolate reductase inhibitor (DHFR inhibitor), pyrimidine metabolism inhibitor, thymidylate synthase inhibitor, purine metabolism inhibitor, IMPDH inhibitor , A ribonucleotide reductase inhibitor, a ribonucleotide reductase inhibitor, a nucleotide analog, L-asparaginase, and the like.
- DHFR inhibitor dihydrofolate reductase inhibitor
- pyrimidine metabolism inhibitor thymidylate synthase inhibitor
- purine metabolism inhibitor IMPDH inhibitor
- a ribonucleotide reductase inhibitor a ribonucleotide reductase inhibitor
- nucleotide analog L-asparaginase, and the like.
- antimetabolite examples include enositabine (sanrabin), capecitabine (Xeloda), carmofur (miflor), cladribine (leustatin), gemcitabine (gemzar), cytarabine (kiloside), cytarabine okphosphat (staraside), tegafur ( Atilon, Aftfur, Tefsir, Futraful, Lunacin, etc., Tegafur Uracil (YFT), Tegafur Gimeracil Oteracil Potassium (TS-1: TS-1), Doxyfluridine (Flutulon), Neralabine (Alanonji), Hydroxycarbamide (Hydrea) ), Fluorouracil (5-FU, carzonal, bennan, lunacol, lunabon), fludarabine (fludara), pemetrexed (Alimta), pentostatin Kohorin), mercaptopurine (Roikerin), and the like methotre
- alkylating agents include nitrogen mustard alkylating agents such as cyclophosphamide (endoxan), ifosfamide (ifhomide), melphalan (alkeran), busulfan, thiotepa (tespamine), nimustine (nidran), ranimustine Nitrosourea alkylating agents such as (cymerin), dacarbacin (dacarbacin), procarbacin (procarbacin hydrochloride), temozolomide (temodal), carmustine (gigliadel), streptozotocin (Zanocer), and bendamustine (treaxin).
- nitrogen mustard alkylating agents such as cyclophosphamide (endoxan), ifosfamide (ifhomide), melphalan (alkeran), busulfan, thiotepa (tespamine), nimustine (nidran), ranimustine
- Nitrosourea alkylating agents such as (c
- anti-cancer antibiotics include actinomycin D (cosmegen), aclarubicin (acracinone), amrubicin (calced), idarubicin (idamycin), epirubicin (epirubicin hydrochloride, famorphicin), dinostatin stimamer (Smanx) ), Daunorubicin (daunomycin), doxorubicin (adriacin), pirarubicin (pinorbin, terarubicin), bleomycin (bleo), pepromycin (pepleo), mitomycin C (mitomycin), mitoxantrone (novantrone), liposomal doxorubicin (doxyl), etc. Is mentioned.
- Microtubule inhibitors include, for example, vinca alkaloid microtubule polymerization inhibitors such as vinblastine (exal), vincristine (oncobin), vindesine (fordessin), and taxane microtubule depolymerization such as paclitaxel (taxol) and docetaxel (taxotere). Examples include inhibitors.
- platinum preparation examples include oxaliplatin (Elplat), carboplatin (carboplatin, carbomerk, paraplatin), cisplatin (IACO, Konaburi, cisplatin, etc.), nedaplatin (Akpra), and the like.
- topoisomerase inhibitors examples include type I topoisomerase inhibitors such as camptothecin and its derivatives (for example, irinotecan (campto), nogitecan (Hycamtin), SN-38, etc.); anthracycline drugs such as doxorubicin (adriacin), etoposide Type II topoisomerase inhibitors such as epipodophyllotoxin drugs such as (lasted, bepsid) and quinolone drugs such as levofloxacin (cravit) and ciprofloxacin (ciproxan).
- type I topoisomerase inhibitors such as camptothecin and its derivatives (for example, irinotecan (campto), nogitecan (Hycamtin), SN-38, etc.); anthracycline drugs such as doxorubicin (adriacin), etoposide Type II topoisomerase inhibitors such as epipodophyllotoxin
- molecular target drugs examples include regorafenib (Stivaga), cetuximab (Arbitux), panitumumab (Bectibix), ramcilmab (Siramza), gefitinib (Iressa), erlotinib (Tarceva), afatinib (Diotrif), crizotinib, Alectinib (Alecensa), Ceritinib, Lenvatinib (Lembima), Trastuzumab (Herceptin), Lapatinib (Tykerb), Pertuzumab (Perjeta), Sunitinib (Sutent), Sorafenib (Nexavar), Axitinib (Inlite), Pazoente Opdivo), pembrolizumab, ipilimumab (Yervoy), vemurafenib (Zelboraf), everolimus (Affinitol), temshiro Mus
- the anticancer agent may also be an antiangiogenic agent.
- Anti-angiogenic agents can be those that inhibit vascular endothelial growth factor (VEGF) or other angiogenic factors, or their receptors.
- VEGF vascular endothelial growth factor
- Specific examples of the anti-angiogenic agent include angiostatin, endostatin, metastatin, anti-VEGF antibody (eg Avastin), VEGFR-2 inhibitor (eg SU5416, SU6668) and the like.
- a detectable substance refers to any substance that makes the conjugate of the invention containing it detectable.
- the detectable substance allows detection of the conjugates of the invention in vivo, either directly or indirectly using suitable visualization or imaging means.
- Visualization or imaging means include, for example, X-ray imaging, computed tomography (CT), nuclear magnetic resonance imaging (MRI), ultrasonography, scintigraphy, positron tomography (PET), endoscope, laparoscope
- CT computed tomography
- MRI nuclear magnetic resonance imaging
- PET positron tomography
- endoscope laparoscope
- the detectable substance may be, for example, a radioisotope, an MRI enhancement agent (for example, paramagnetic ions), a radiopaque substance, a contrast agent, a fluorescent substance, and the like.
- radionuclides for PET examples include 18 F, 51 Mn, 52 m Mn, 52 Fe, 55 Co, 62 Cu, 64 Cu, 68 Ga, 72 As, 75 Br, 76 Br, 82 m Rb, 83 Sr, 86 Y, 89 Zr, 94m Tc, 110 In, 120 I, 124 I and the like.
- Radionuclides useful for the detection of gamma rays include, for example, 51 Cr, 57 Co, 58 Co, 59 Fe, 67 Cu, 67 Ga, 75 Se, 97 Ru, 99m Tc, 111 In, 114 m In, 123 I, 125 I, 131 I, 169 Yb, 197 Hg, 201 Tl, and the like.
- Suitable paramagnetic ions include, for example, chromium (III), manganese (II), iron (III), iron (II), cobalt (II), nickel (II), copper (II), neodymium (III), Examples include samarium (III), ytterbium (III), gadolinium (III), vanadium (II), terbium (III), dysprosium (III), holmium (III), erbium (III), and gadolinium is particularly preferable. Metals such as lanthanum (III), gold (III), lead (II), bismuth (III) are also useful in applications such as X-ray imaging.
- radiopaque substances and contrast agents examples include iodine compounds (eg, organic iodic acids such as iodocarboxylic acid, iodoform, triiodophenol, tetraiodoethylene, etc.), barium compounds (eg, barium sulfate, etc.), gallium, and the like. Examples thereof include compounds (for example, gallium citrate) and thallium compounds (for example, thallium chloride).
- iodine compounds eg, organic iodic acids such as iodocarboxylic acid, iodoform, triiodophenol, tetraiodoethylene, etc.
- barium compounds eg, barium sulfate, etc.
- gallium examples include compounds (for example, gallium citrate) and thallium compounds (for example, thallium chloride).
- fluorescent substance examples include rhodamine, fluorescein, Cy dye, Alexa (registered trademark) Fluor, phycoerythrin (PE), allophycocyanin (APC), and derivatives thereof.
- fluorescent substance examples include rhodamine, fluorescein, Cy dye, Alexa (registered trademark) Fluor, phycoerythrin (PE), allophycocyanin (APC), and derivatives thereof.
- near infrared fluorescent reagents such as indocyanine are also exemplified as preferred fluorescent substances.
- the mode of binding between the peptide of the present invention and one or more components in the conjugate of the present invention is not particularly limited.
- the bond may be direct or indirect via a linker or the like.
- the bond may be covalent, non-covalent, or a combination thereof.
- One or more components may be linked directly or indirectly at the N-terminus, C-terminus, or other position of the peptides of the invention. Linking a peptide with another component (or a second peptide) is well known in the art, and in the conjugates of the invention, the linkage may be by any known means.
- crosslinker crosslinking agent
- crosslinking agent such as NHS ester, imide ester, maleimide, carbodiimide, allyl azide, diazirine, isocyanine, psoralen
- the peptide of the present invention may be appropriately modified depending on the crosslinker used.
- cysteine can be added in advance to the C-terminus of the peptide of the present invention for conjugation with a maleimide linker.
- chelating agents for example, ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), 4, 7, 10.
- EDTA ethylenediaminetetraacetic acid
- DTPA diethylenetriaminepentaacetic acid
- 4 Suitable chelating agents for linking the radioactive metal or paramagnetic ion as described above with the peptides of the present invention.
- DOTA N' '-tetraacetic acid
- metallothionein etc. can be used.
- compositions comprising the peptide or conjugate of the present invention and a pharmaceutically acceptable carrier (hereinafter also referred to as the composition of the present invention).
- the composition may be provided as a dosage form suitable for oral or parenteral administration.
- composition for parenteral administration for example, an injection, a suppository and the like are used, and the injection is a dosage form such as an intravenous injection, a subcutaneous injection, an intradermal injection, an intramuscular injection, or an infusion. Can be included.
- an injection can be prepared according to a known method.
- the peptide or conjugate of the present invention can be prepared by dissolving, suspending or emulsifying in a sterile aqueous liquid or oily liquid usually used for injection.
- aqueous solution for injection for example, isotonic solutions containing physiological saline, glucose and other adjuvants are used, and suitable solubilizers such as alcohol (eg, ethanol), polyalcohol (eg, Propylene glycol, polyethylene glycol), nonionic surfactants (eg, polysorbate 80, HCO-50 (polyoxyethylene (50 mol) additive of hydrogenated castor oil)) and the like may be used in combination.
- alcohol eg, ethanol
- polyalcohol eg, Propylene glycol, polyethylene glycol
- nonionic surfactants eg, polysorbate 80, HCO-50 (polyoxyethylene (50 mol) additive of hydrogenated castor oil)
- oily liquid for example, sesame oil, soybean oil and the like are used, and benzyl benzoate, benzyl alcohol and the like may be used in combination as a solubilizing agent.
- the prepared injection solution is preferably filled in a suitable ampoule.
- compositions for oral administration include solid or liquid dosage forms, specifically tablets (including dragees and film-coated tablets), pills, granules, powders, capsules (including soft capsules), syrups Agents, emulsions, suspensions and the like.
- Such a composition is produced by a known method and may contain a carrier, a diluent or an excipient usually used in the pharmaceutical field.
- a carrier and excipient for tablets for example, lactose, starch, sucrose, and magnesium stearate are used.
- composition described above may contain other active ingredients as long as an undesirable interaction is not caused by blending with the above peptide or conjugate.
- the above parenteral or oral pharmaceutical composition is conveniently prepared in a dosage unit form suitable for the dose of the active ingredient.
- dosage form of such a dosage unit include tablets, pills, capsules, injections (ampoules), and suppositories.
- the content of the peptide or conjugate is preferably 1 to 500 mg per dosage unit dosage form, preferably 1 to 100 mg for injections, and 10 to 250 mg for other dosage forms. .
- composition of the present invention can target a tumor, particularly a malignant tumor that is vascularized, and preferably can accumulate the peptide or conjugate in the tumor. Accordingly, the compositions of the present invention comprising an anticancer agent in the conjugate are useful for the treatment or prevention of targeted malignancies.
- composition of the present invention containing a detectable substance in the conjugate is also useful for examination or diagnosis of malignant tumors.
- the malignant tumor may be any kind of cancer, and may be a solid cancer or a liquid cancer.
- the solid cancer preferably includes a solid cancer that expresses Anxa1 on the cell surface, and thus a solid cancer that is vascularized.
- Examples of solid cancer include brain and nervous system cancer (eg, brain tumor, spinal cord tumor), head and neck cancer (eg, laryngeal cancer, oral cancer, salivary gland cancer, sinus cancer, thyroid gland).
- gastrointestinal cancer eg, stomach cancer, esophageal cancer, small intestine cancer, colon cancer, rectal cancer, anal cancer, liver cancer, biliary tract cancer, pancreatic cancer, etc.
- urinary organs or Genital cancer eg, renal cancer, renal cell cancer, bladder cancer, prostate cancer, renal pelvis and ureteral cancer, gallbladder cancer, bile duct cancer, testicular cancer, penile cancer, uterine cancer , Endometrial cancer, uterine sarcoma, cervical cancer, vaginal cancer, vulva cancer, ovarian cancer, fallopian tube cancer, etc.
- respiratory cancer eg lung cancer (small cell lung cancer, non-cell lung cancer, non-cancerous) Small cell lung cancer, including metastatic lung cancer), bronchial cancer, etc.
- breast cancer eg, skin cancer (eg, malignant melanoma), bone cancer (eg, bone meat) Etc.), muscle cancer (e.g., rhabdomyos
- liquid cancer examples include leukemia, malignant lymphoma, multiple myeloma, and myelodysplastic syndrome.
- leukemia examples include acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, and chronic lymphocytic leukemia.
- Malignant lymphoma is classified into Hodgkin lymphoma and non-Hodgkin lymphoma, and as non-Hodgkin lymphoma, B-cell lymphoma, adult T-cell lymphoma, lymphoblastic lymphoma, diffuse large cell lymphoma, Burkitt lymphoma, follicular lymphoma , MALT lymphoma, peripheral T cell lymphoma, mantle cell lymphoma and the like.
- a brain tumor can be mentioned as a particularly preferred target.
- the brain tumor may be a primary brain tumor or a metastatic brain tumor.
- the brain tumor may be a benign (eg meningioma, pituitary adenoma, schwannoma) or a malignant brain tumor, and preferably a malignant brain tumor.
- grade 2 brain tumors such as astrocytoma and oligodendrogliomas, anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic Examples include Grade 3 brain tumors such as oligodendrocyte astrocytoma and Grade 4 brain tumors such as glioblastoma (glioblastoma).
- composition of the present invention can be administered to an animal expressing annexin A1, particularly a mammal.
- mammals include laboratory animals such as rodents and rabbits such as mice, rats, hamsters, and guinea pigs, domestic animals such as pigs, cows, goats, horses, sheep and minks, pets such as dogs and cats, humans, Examples include, but are not limited to, primates such as monkeys, rhesus monkeys, marmosets, orangutans and chimpanzees.
- the dose of the composition of the present invention varies depending on the purpose of administration, the subject of administration, the target disease, symptoms, administration route, and the like.
- the conjugate of the present invention containing an anticancer agent is used as a single dose, usually about 0.1 to 10 mg / kg body weight, Conveniently administered weekly intravenously or orally.
- the conjugate of the present invention containing a detectable substance is usually intravenously injected in an amount of about 0.1 to 10 mg / kg body weight prior to the examination. Or it is convenient to administer orally.
- Rat glioma C6 cells were cultured in Dulbecco's Modified Eagles Medium supplemented with 10% fetal calf serum, high glucose and antibiotics.
- the lentiviral vector PGK-Luc was constructed at the Virus Core Facility at Sanford-Burnham-Prebys Medical Discovery Institute.
- C6 cells and B16 cells were infected with PGK-Luc lentivirus to prepare luciferase positive cells.
- C6-Luc cells (4.8 ⁇ 10 4 cells suspended in 4 ⁇ l PBS) were injected into the striatum of C57BL / 6 mice using a stereotaxic frame. Two days later, mice were imaged for tumors expressing luciferase.
- mice After injecting 100 ⁇ l of luciferin (30 mg / ml PBS) into the peritoneal cavity, the mice were anesthetized with oxygen (1 ml / min) and isoflurane gas (20 ml / min), and a camera equipped with a Xenogen IVIS 200imager. Placed below. The number of photons was measured for 1-10 seconds.
- C6-Luc cells were similarly injected into the brains of NOD-SCID mice and tumor growth was monitored by Xenogen imager. When brain tumors became detectable, C6-Luc cells (2 ⁇ 10 5 cells suspended in 100 ⁇ l PBS) were injected subcutaneously into the dorsal flank of the mice.
- Photon numbers in brain tumors and subcutaneous tumors were measured using a Xenogen imager.
- a dual tumor model using B16-Luc cells in syngeneic C57BL / 6 mice was also produced.
- B16-Luc cells (5 ⁇ 10 4 cells) were injected into the brains of 8-10 week old C57BL / 6 female mice as described above for C6-Luc cells.
- B16-Luc cells (2 ⁇ 10 5 cells) were injected subcutaneously.
- IF7 that is, L-type peptide having the amino acid sequence of IFLLWQR (SEQ ID NO: 10)
- IF7 reached blood vessels around the tumor. Later, it was taken into the vesicle from the luminal side of the vascular endothelial cells, moved to the basal side, and released to the stroma where cancer cells were present. Also in mouse vascular endothelial F2 cells, IF7 bound to Anxa1 actively transected tumor vascular endothelial cells through transcytosis. Therefore, it was suggested that IF7 has an activity to cross the blood vessel-brain tumor barrier in the brain tumor.
- IF7-SN38 Administration experiment of IF7-SN38 to dual tumor model
- the therapeutic effect of IF7-SN38 was verified using a mouse having a subcutaneous tumor and a brain tumor (dual tumor model) in the same mouse.
- the experiment was performed as follows. When the number of photons in the brain tumor was> 1.0 ⁇ 10 6 (this usually occurred after 2 weeks), IF7C (RR) -SN38 was injected into the tumor bearing mice via the tail vein.
- IF7C (RR) -SN38 (14.2 mg or 6.63 mmol) was dissolved in 100 ⁇ l of dimethyl sulfoxide (DMSO), and then 1 ⁇ L of solution (142 mg or 66.3 nmoles) was added to 50% Cremophor EL in ethanol (10 ⁇ l).
- DMSO dimethyl sulfoxide
- IF7 has an excellent target activity for malignant tumors, but it has poor solubility and stability in aiming for clinical development. There are problems with two points of low. That is, first, the IF7 peptide is protease sensitive and easily degraded. In fact, in an experiment in which A488-IF7 was administered to the veins of healthy mice, the peripheral blood fluorescence signal almost disappeared in about 1 hour (FIG. 5). However, when tail vein was administered to cancer-bearing mice, A488-IF7 had significantly less fluorescence recovered from peripheral blood than healthy mice. This result suggests that A488-IF7 undergoes degradation, but most accumulates rapidly in the tumor. In addition, IF7 is difficult to formulate, such as adding a surfactant after dissolving in DMSO to avoid precipitation when intravenously administering a compound that is highly hydrophobic and bound to an anticancer agent.
- Example 1 Identification of dTIT7 Peptide
- the present inventors considered that a better therapeutic agent could be created if the above-mentioned weaknesses associated with IF7 could be overcome, and started the development of next-generation peptides consisting of novel sequences.
- Technology underlying the present study is the method of screening a phage library surface display random peptide 1 billion kinds of 7 residues amino acid (20 seven). All of the amino acids that constitute an organism are L-type amino acids with some exceptions. Therefore, it is impossible to obtain a sequence of a D-type peptide that binds to a target by ordinary phage library screening. Therefore, mirror image screening (Funke et al., Mol. Biosystem.
- IF7 interacts with the N-terminal 15 residues of Anxa1 (MAMVSEFLKQAWFIE; SEQ ID NO: 11), and IF7 is a 16-residue L-peptide obtained by adding a modifying Cys residue to the N-terminal 15 residues of Axna1 It has been shown to bind to (L-MC16) (Sasai et al., Unpublished).
- D-MC16 (16 bases are all D-type) mirror-imaged with L-MC16, and 7 amino acids (L-type TIT7 binding to D-MC16) by screening using a T7 phage library. Peptide).
- a TIT7 peptide (dTIT7) composed of D-type amino acids was synthesized based on the obtained sequence. This dTIT7 peptide is expected to bind to Anxa1.
- dTIT7 TIT7 peptide
- an optimal peptide sequence can be evaluated and identified at once from a total of 10,000 or more candidate peptide sequences.
- TIT threonine-isoleucine-threonine
- TITWPTM TIT7 sequence “SEQ ID NO: 12”
- IF7 IFLLWQR
- the dissociation constant (Kd value) was 4.57 ⁇ 10 ⁇ 8 M.
- LRFPTVL SEQ ID NO: 13
- SPTSLLLF SEQ ID NO: 14
- MPTLTFR SEQ ID NO: 15
- LKGMLRI SEQ ID NO: 16
- LLSWPSA SEQ ID NO: 16
- Example 2 Brain tumor targeting ability of dTIT7 peptide
- IRDye-dTIT7 labeled with the near-infrared fluorescent reagent IRDye800CW.
- a brain tumor nude mouse model was prepared by transplanting rat glioma into the brain of a nude mouse, and IRDye-dTIT7 was injected from the tail vein of the mouse. As a result, it was observed by in vivo imaging that IRDye-dTIT7 accumulates at the tumor site of the brain tumor model mouse (FIG. 7).
- Example 3 Antitumor effect of dTIT7-binding anticancer agent on brain tumor model
- GA-dTIT7 (FIG. 8) in which the anticancer drug geldanamycin is bound to the dTIT7 peptide is considered to be resistant to proteases and esterases and more stable in vivo.
- Example 4 Intermolecular interaction between dLRF7, dSPT7, dMPT7, and dLLS7 peptide and Anxa1 LRFPTVL (SEQ ID NO: 13), SPTSLLLF (SEQ ID NO: 13) with high frequency of appearance other than TIT7 sequence (SEQ ID NO: 12) described in Example 1 14)
- SEQ ID NO: 13 the sequences of MPTLTFR (SEQ ID NO: 15) and LLSWPSA (SEQ ID NO: 17)
- peptides composed of D-type amino acids are also used in the same manner as the dTIT7 peptide.
- Synthesis and intermolecular interaction with Anxa1 were measured by the following methods.
- the sensor chip was washed twice with piranha solution for 5 minutes and then immersed in a solution of 0.9 mM hydroxy-EG3-undecanthiol (Dojindo) and 0.1 mM amino-EG6-undecanthiol (Dojindo) overnight. After washing with water, the chip was treated with 1 mM GMBS (Dojindo) and incubated for 1 hour at room temperature. After washing off the remaining GMBS, a 1 mM peptide solution was added onto the chip and incubated for 30 minutes.
- the peptide bond sensor chip was placed in a QCM device (Single-Q, ASONE), and 0.5 ml of PBS was added to the well.
- Various doses of Anxa1 were injected into the reaction chamber to determine the binding affinity (kd value) for each peptide. As a result, all the peptides tested showed positive binding to Anxa1 (Table 1 and FIG. 11).
- Example 5 Brain tumor targeting ability of dLRF7, dSPT7, dMPT7 and dLLS7 peptides
- the dLRF7, dSPT7, dMPT7 and dLLS7 peptides extended by adding terminal cysteine were chemically synthesized. Subsequently, each peptide and the near-infrared fluorescent dye IRDye 800CW maleimide (Li-Cor) were coupled via a cysteine residue. The resulting peptide conjugate was purified by HPLC and then lyophilized. Each peptide-IRDye conjugate was dissolved in DMSO and 6% glucose and injected intravenously into brain tumor model nude mice at 100 ⁇ l / mouse.
- the present invention is based on Japanese Patent Application No. 2006-159743 (filing date: August 16, 2016) filed in Japan, and all the contents thereof are included in the present specification.
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Abstract
Description
[1]下記式(I)−(III)のいずれかのアミノ酸配列を含むペプチド。
(I)(X1)[D]P[D](X2)[D]のアミノ酸配列(該配列中、X1はWまたはFを示し、X2はSまたはTを示し、直後に記号[D]を付した各アミノ酸記号は該アミノ酸のD体を示す。)、
(II)P[D]T[D](X)nF[D]のアミノ酸配列(該配列中、(X)nは互いに独立して選択されるn個の任意のアミノ酸を示し、nは0−4の整数を示し、記号[D]は前記と同義を示す。)、
(III)前記(I)または(II)のいずれかのアミノ酸配列のRetro−inversoであるアミノ酸配列。
[2]下記(i)−(vii)のいずれかのアミノ酸配列を含むペプチド(下記の配列中、記号[D]は前記と同義を示す。)。
(i)T[D]I[D]T[D]W[D]P[D]T[D]M[D]のアミノ酸配列、
(ii)L[D]R[D]F[D]P[D]T[D]V[D]L[D]のアミノ酸配列、
(iii)L[D]L[D]S[D]W[D]P[D]S[D]A[D]のアミノ酸配列、
(iv)S[D]P[D]T[D]S[D]L[D]L[D]F[D]のアミノ酸配列、
(v)M[D]P[D]T[D]L[D]T[D]F[D]R[D]のアミノ酸配列、
(vi)前記(i)−(v)のいずれかのアミノ酸配列において1もしくは数個のアミノ酸の挿入、置換もしくは欠失、またはこれらの組み合わせを有するアミノ酸配列、
(vii)前記(i)−(vi)のいずれかのアミノ酸配列のRetro−inversoであるアミノ酸配列。
[3]上記(i)のアミノ酸配列を含む、[2]に記載のペプチド。
[4]上記(i)のアミノ酸配列からなる、[2]に記載のペプチド。
[5][1]~[4]のいずれかに記載のペプチドおよび1つ以上の成分を含む、コンジュゲート。
[6]前記1つ以上の成分が抗がん剤を含む、[5]に記載のコンジュゲート。
[7]前記抗がん剤が、代謝拮抗剤、アルキル化剤、抗がん性抗生物質、微小管阻害剤、白金製剤、トポイソメラーゼ阻害剤、分子標的薬、および抗血管新生剤からなる群から選択される、[6]に記載のコンジュゲート。
[8]前記抗がん剤が、
エノシタビン、カペシタビン、カルモフール、クラドリビン、ゲムシタビン、シタラビン、シタラビンオクホスファート、テガフール、テガフール・ウラシル、テガフール・ギメラシル・オテラシルカリウム、ドキシフルリジン、ネララビン、ヒドロキシカルバミド、フルオロウラシル、フルダラビン、ペメトレキセド、ペントスタチン、メルカプトプリン、メトトレキサート;
シクロホスファミド、イホスファミド、メルファラン、ブスルファン、チオテパ、ニムスチン、ラニムスチン、ダカルバシン、プロカルバシン、テモゾロマイド、カルムスチン、ストレプトゾトシン、ベンダムスチン;
アクチノマイシンD、アクラルビシン、アムルビシン、イダルビシン、エピルビシン、ジノスタチンスチマラマー、ダウノルビシン、ドキソルビシン、ピラルビシン、ブレオマイシン、ペプロマイシン、マイトマイシンC、ミトキサントロン、リポソーマルドキソルビシン;
ビンブラスチン、ビンクリスチン、ビンデシン、パクリタキセル、タキソール、ドセタキセル;
オキサリプラチン、カルボプラチン、シスプラチン、ネダプラチン;
カンプトテシン、イリノテカン、ノギテカン、SN−38、ドキソルビシン、エトポシド、レボフロキサシン、シプロフロキサシン;
レゴラフェニブ、セツキシマブ、パニツムマブ、ラムシルマブ、ゲフィチニブ、エルロチニブ、アファチニブ、クリゾチニブ、アレクチニブ、セリチニブ、レンバチニブ、トラスツズマブ、ラパチニブ、ペルツズマブ、スニチニブ、ソラフェニブ、アキシチニブ、パゾパニブ、ニボルマブ、ペムブロリズマブ、イピリムマブ、ベムラフェニブ、エベロリムス、テムシロリムス、リツキシマブ、ベバシズマブ、ゲルダナマイシン;
アンギオスタチン、エンドスタチン、メタスタチン、抗VEGF抗体、およびVEGFR−2インヒビター
からなる群から選択される、[6]または[7]に記載のコンジュゲート。
[9]前記1つ以上の成分が検出可能な物質を含む、[5]に記載のコンジュゲート。
[10]前記検出可能な物質が、X線撮影、コンピュータ断層撮影(CT)、核磁気共鳴画像法(MRI)、超音波検査、シンチグラフィ、ポジトロン断層法(PET)、内視鏡、および腹腔鏡からなる群から選択される手段によりインビボにおける該コンジュゲートの検出を可能にするものである、[9]に記載のコンジュゲート。
[11]前記検出可能な物質が、放射性同位体、MRI用増強剤、放射線不透過性物質、造影剤、または蛍光性物質である、[9]または[10]に記載のコンジュゲート。
[12]前記検出可能な物質が、
18F、51Mn、52mMn、52Fe、55Co、62Cu、64Cu、68Ga、72As、75Br、76Br、82mRb、83Sr、86Y、89Zr、94mTc、110In、120I、124I、51Cr、57Co、58Co、59Fe、67Cu、67Ga、75Se、97Ru、99mTc、111In、114mIn、123I、125I、131I、169Yb、197Hg、および201Tlから選択される放射性核種;
クロム(III)、マンガン(II)、鉄(III)、鉄(II)、コバルト(II)、ニッケル(II)、銅(II)、ネオジム(III)、サマリウム(III)、イッテルビウム(III)、ガドリニウム(III)、バナジウム(II)、テルビウム(III)、ジスプロシウム(III)、ホルミウム(III)、およびエルビウム(III)から選択される常磁性イオン、ランタン(III)、金(III)、鉛(II)、ビスマス(III);
ヨウ素化合物、バリウム化合物、ガリウム化合物、タリウム化合物;
ローダミン、フルオレセイン、Cy dye、Alexa(登録商標)Fluor、フィコエリトリン(PE)、アロフィコシアニン(APC)、およびこれらの誘導体、ならびに近赤外線蛍光試薬
からなる群から選択される、[9]~[11]のいずれかに記載のコンジュゲート。
[13][1]~[4]のいずれかに記載のペプチドまたは[5]~[12]のいずれかに記載のコンジュゲート、および薬学的に許容される担体を含む、組成物。
[14][6]~[8]のいずれかに記載のコンジュゲート、および薬学的に許容される担体を含む、がんの治療用組成物。
[15][9]~[12]のいずれかに記載のコンジュゲート、および薬学的に許容される担体を含む、がんの検査用組成物。
[16]がんが固形がんまたは液性がんである、[14]または[15]に記載の組成物。
[17]固形がんが、血管新生する固形がんである、[16]に記載の組成物。
[18]固形がんが、脳・神経系のがん、頭頸部がん、消化器がん、泌尿器または生殖器のがん、呼吸器系のがん、乳がん、皮膚がん、骨のがん、または筋肉のがんである、[16]または[17]に記載の組成物。
[19]固形がんが、脳腫瘍、脊髄腫瘍、喉頭がん、口腔がん、唾液腺がん、副鼻腔がん、甲状腺がん、胃がん、食道がん、小腸がん、結腸がん、直腸がん、肛門がん、肝臓がん、胆道がん、膵臓がん、腎がん、腎細胞がん、膀胱がん、前立腺がん、腎盂および尿管がん、胆嚢がん、胆管がん、精巣がん、陰茎がん、子宮がん、子宮内膜がん、子宮肉腫、子宮頚がん、膣がん、外陰がん、卵巣がん、卵管がん、肺がん、乳がん、悪性黒色腫、骨肉腫、または横紋筋肉腫である、[16]~[18]のいずれかに記載の組成物。
[20]固形がんが良性または悪性の脳腫瘍である、[19]に記載の組成物。
[21]脳腫瘍が原発性脳腫瘍または転移性脳腫瘍である、[20]に記載の組成物。
[22]脳腫瘍が、髄膜腫、下垂体腺腫、神経鞘腫、星細胞腫(アストロサイトーマ)、乏突起神経膠腫(オリゴデンドログリオーマ)、退形成性星細胞腫、退形成性乏突起膠腫、退形成性乏突起星細胞腫、または膠芽腫(グリオブラストーマ)である、[20]または[21]に記載の組成物。
[23]液性がんがB細胞性リンパ腫である、[16]に記載の組成物。
エリスロポエチンや最近の抗PD−1抗体の例で明らかなように、臨床で成功している医薬品は薬剤が標的とする生体内分子の発現特異性が非常に高い。本発明のペプチドが標的とするアネキシンA1は、現在知り得る悪性腫瘍の新生血管標的マーカーの中で最も特異性の高い分子であるので、本発明のペプチドと結合させた抗がん剤は既存の抗がん剤と比べて優れた治療効果を示し得る。
特に、当該ペプチド−抗がん剤コンジュゲートは、悪性腫瘍に高効率で抗がん剤を集積し得るだけでなく、プロテアーゼ耐性であるので、有効投与回数の減少と更なる低投与量が見込まれる。更に免疫機構が温存されると考えられるため、抗がん剤と免疫治療の併用による悪性腫瘍の完全治癒が期待され得る。
アネキシンA1の特徴的な点は、腫瘍内にできた新生血管内皮細胞の血液側に発現し、本発明のペプチドのようなリガンドと血液側で結合すると、リガンドをトランスサイトーシスによって基底側に運び、癌細胞が存在する間質へ積極的に放出することである。この性質は血管脳障壁を積極的に乗り越える機序としても働いていると考えられる。アネキシンA1を標的とする本発明のペプチドは、従来の血管新生阻害剤(アバスチン)やテモゾロミド(上記)とは異なり、画期的なメカニズムによる悪性脳腫瘍の治療を可能にするものである。即ち、現在、化学療法剤として血液脳関門を通過するもの、腫瘍組織に集積するもの、体内で安定で経口投与可能なものがそれぞれ開発されているが、その全てを兼ね備え得る化学療法剤は本発明のペプチド以外には存在しない(図10)。
本発明のペプチドは様々な抗がん剤と結合させることができるので、生理活性にも幅を持たせることができる。
本発明は、脳腫瘍の治療にブレークスルーを開くものである。さらにANXA1は様々な悪性腫瘍の血管表面に発現することが公知であり、dTIT7結合抗癌剤は、脳腫瘍のみでなく広範な癌治療薬として臨床応用が期待される。
また、本発明のペプチドは化学合成や修飾が容易であることから、抗体医薬品に代わる中分子バイオ医薬品として将来性が極めて高い。特に、本発明のペプチドは短鎖ペプチド(例えば、アミノ酸7残基)であり得るので、化学合成で安価に製造し得る。
更に、本発明のペプチドや、該ペプチドと他の機能性部分を含むコンジュゲートは、安定性に優れ、また経口投与用医薬としても用い得る。従って、臨床試験も容易である。実際に医療薬として承認された後は、医療施設の乏しい後進国においても医薬品として普及させることが可能である。
本発明は、下記(I)−(III)のいずれかのアミノ酸配列を含むペプチドを提供する。
(I)(X1)[D]P[D](X2)[D]のアミノ酸配列(該配列中、X1はWまたはFを示し、X2はSまたはTを示す。)、
(II)P[D]T[D](X)nF[D]のアミノ酸配列(該配列中、(X)nは互いに独立して選択されるn個の任意のアミノ酸を示し、nは0−4の整数を示す。)、
(III)前記(I)または(II)のいずれかのアミノ酸配列のRetro−inversoであるアミノ酸配列。
(i)T[D]I[D]T[D]W[D]P[D]T[D]M[D]のアミノ酸配列、
(ii)L[D]R[D]F[D]P[D]T[D]V[D]L[D]のアミノ酸配列、
(iii)L[D]L[D]S[D]W[D]P[D]S[D]A[D]のアミノ酸配列、
(iv)S[D]P[D]T[D]S[D]L[D]L[D]F[D]のアミノ酸配列、
(v)M[D]P[D]T[D]L[D]T[D]F[D]R[D]のアミノ酸配列、
(vi)前記(i)−(v)のいずれかのアミノ酸配列において1もしくは数個のアミノ酸の挿入、置換もしくは欠失、またはこれらの組み合わせを有するアミノ酸配列、
(vii)前記(i)−(vi)のいずれかのアミノ酸配列のRetro−inversoであるアミノ酸配列。
ここで、縮合や保護基の脱離は、自体公知の方法、例えば、以下の(1)−(8)に記載された方法に従って行うことができる。
(1)M.Bodanszky & M.A.Ondetti,Peptide Synthesis,Interscience Publishers,New York(1966年)
(2)Schroeder & Luebke,The Peptide,Academic Press,New York(1965年)
(3)泉屋信夫他、ペプチド合成の基礎と実験、丸善(株)(1975年)
(4)矢島治明および榊原俊平、生化学実験講座1、蛋白質の化学IV 205(1977年)
(5)矢島治明監修、続医薬品の開発、第14巻、ペプチド合成、廣川書店
(6)Stewart,J.M.& Young,J.D.,“Solid phase peptide synthesis(2nd ed.)”,Pierce Chemical Company,Rockford(1984年)
(7)Atherton,E.& Sheppard,R.C.,“Solid Phase peptide synthesis:a practical approach”,IRL Press,Oxford(1989年)
(8)“Fmoc Solid Phase Peptide Synthesis:A Practical Approach(Practical Approach Series)”,Oxford University Press(2000年)
上記方法で得られるペプチドが遊離体である場合には、該遊離体を公知の方法あるいはそれに準じる方法によって適当な塩に変換することができるし、逆にペプチドが塩として得られた場合には、該塩を公知の方法あるいはそれに準じる方法によって遊離体または他の塩に変換することができる。
本発明はまた、上記の本発明のペプチドに1つ以上の成分が結合したコンジュゲート(以下、本発明のコンジュゲートともいう。)を提供する。
本明細書において、抗がん剤とは、悪性腫瘍(がん)の増殖を抑えることを目的とした薬剤をいう。抗がん剤の作用機序は特に限定されない。抗がん剤は、代謝拮抗剤、アルキル化剤、抗がん性抗生物質、微小管阻害剤、白金製剤、トポイソメラーゼ阻害剤、分子標的薬などであってよい。本発明のコンジュゲートは、2つ以上の同一または異なる抗がん剤を含んでいてもよい。
本明細書において、検出可能な物質とは、それを含む本発明のコンジュゲートを検出可能にする任意の物質をいう。好ましくは、検出可能な物質は、直接的にまたは適切な可視化もしくは画像化手段を用いて間接的に、インビボにおける本発明のコンジュゲートの検出を可能にする。可視化または画像化手段としては、例えば、X線撮影、コンピュータ断層撮影(CT)、核磁気共鳴画像法(MRI)、超音波検査、シンチグラフィ、ポジトロン断層法(PET)、内視鏡、腹腔鏡などが挙げられるが、これらに限定されない。検出可能な物質は、例えば、放射性同位体、MRI用増強剤(例えば、常磁性イオン)、放射線不透過性物質、造影剤、蛍光性物質などであってもよい。
本発明のコンジュゲートにおける本発明のペプチドと1つ以上の成分との間の結合の様式は特に限定されない。結合は、直接的なものであってもよいし、またはリンカーなどを介した間接的なものであってもよい。結合は、共有結合、非共有結合、またはこれらの組み合わせによるものであってもよい。1つ以上の成分は、直接的または間接的に、本発明のペプチドのN末端、C末端、またはそれ以外の位置において結合していてもよい。ペプチドと他の成分(または第2のペプチド)との連結は当該技術分野において周知であり、本発明のコンジュゲートにおいても、該結合は任意の公知の手段によるものであってよい。
本発明はまた、本発明のペプチドまたはコンジュゲート、および薬学的に許容される担体を含む組成物(以下、本発明の組成物ともいう。)を提供する。該組成物は、経口または非経口投与に適する剤形として提供され得る。
ラットグリオーマC6細胞を10%ウシ胎仔血清、高グルコースおよび抗生物質を添加したDulbecco’s Modified Eagles Medium中で培養した。レンチウイルスベクターPGK−LucをSanford−Burnham−Prebys Medical Discovery InstituteのVirus Core Facilityにおいて作製した。C6細胞およびB16細胞をPGK−Lucレンチウイルスに感染させ、ルシフェラーゼ陽性細胞を作製した。定位フレームを用いてC6−Luc細胞(4μl PBSに懸濁した4.8x104細胞)をC57BL/6マウスの脳線条体に注射した。2日後、ルシフェラーゼを発現する腫瘍についてマウスを画像化した。そのために、100μlのルシフェリン(30mg/ml PBS)を腹膜腔に注射した後、マウスを酸素(1ml/分)と共にイソフルラン気体(20ml/分)を用いて麻酔し、Xenogen IVIS 200imagerを備えたカメラの下に置いた。光子数を1−10秒間測定した。dual tumor modelについて、同様にC6−Luc細胞をNOD−SCIDマウスの脳に注射し、腫瘍増殖をXenogen imagerによりモニタリングした。
脳腫瘍が検出可能になった時に、C6−Luc細胞(100μlPBSに懸濁した2x105細胞)を同マウスの背側脇腹に皮下注射した。脳腫瘍および皮下腫瘍における光子数をXenogen imagerを用いて測定した。同系C57BL/6マウスにおいてB16−Luc細胞を用いたdual tumor modelも作製した。C6−Luc細胞について上述したように8−10週齢のC57BL/6雌性マウスの脳にB16−Luc細胞(5x104細胞)を注射した。脳のB16−Luc腫瘍が検出可能になった時に、B16−Luc細胞(2x105細胞)を皮下に注射した。
担癌マウスにIF7(即ち、IFLLWQR(配列番号10)のアミノ酸配列を有するL型ペプチド)を静脈投与すると、IF7は腫瘍周囲の血管に到達した後、血管内皮細胞の管腔側から小胞に取り込まれて基底側へ移動し、癌細胞が存在する間質へ遊離された。
マウス血管内皮F2細胞においても、Anxa1に結合したIF7はトランスサイトーシスで能動的に腫瘍血管内皮細胞を縦断した。従って、IF7は脳腫瘍内の血管−脳腫瘍関門を通過する活性を有することが示唆された。
驚くべきことに、グリオーマ細胞を移植した脳腫瘍モデルマウスに、蛍光ラベルしたIF7を静脈注射したところ、蛍光が脳腫瘍部位に高濃度で集積する様子が観察された(図1および2)。また、蛍光は血管を乗り越えて脳の間質にあるがん細胞へ到達した。
同一マウス内に皮下腫瘍と脳腫瘍を有するマウス(dual tumor model)を用いて、IF7−SN38の治療効果を検証した。実験は以下の通りに行った。
脳腫瘍の光子数が〉1.0x106となったら(これは通常、2週間後に起こった)、IF7C(RR)−SN38を担癌マウスに尾静脈注射した。IF7C(RR)−SN38(14.2mgまたは6.63mモル)を100μlのジメチルスルホキシド(DMSO)に溶解した後、1μLの溶液(142mgまたは66.3nmoles)を50%Cremophore ELのエタノール溶液(10μl)で希釈し、更に90μlのPBSを加えた。注射あたりのIF7C(RR)−SN38量は142mg/マウスまたは7.1mg/kgであった。IF7の逆配列または同様に作製したRQ7C(RR)−SN38をコントロールとした。PBS中に溶解したイリノテカン、およびPBS単独をネガティブコントロールとした。
その結果、脳腫瘍と皮下腫瘍の両方が抑制され、その効果は皮下腫瘍よりも脳腫瘍の方が高かった(図3および4)。B16メラノーマの転移脳腫瘍モデルにおいても同様の結果が得られ、ホストマウスをC57BL/6やSCIDの系統に変えても結果は変わらなかった。これらの事実は、Anxa1を標的とするDDSは効率よく血液−脳腫瘍関門を越えるだけでなく、腫瘍細胞の種類やマウスの系統に関係なく脳腫瘍で優れた治療効果をあげることを示している。
検討例1および2において実証されたように、IF7は優れた悪性腫瘍標的活性をもつが、臨床開発を目指す上で、難溶解性であることと安定性が低いことの2点に問題がある。即ち、まずIF7ペプチドはプロテアーゼ感受性であり分解されやすい。実際、A488−IF7を健常マウスの静脈に投与した実験では、末梢血の蛍光シグナルが1時間程度でほとんど消失した(図5)。しかし、担癌マウスへの尾静脈投与では、A488−IF7は末梢血から回収される蛍光が健常マウスよりも顕著に少なかった。この結果は、A488−IF7が分解を受けつつも大部分が腫瘍に急速に集積することを示唆する。また、IF7は疎水性が高く抗癌剤と結合させた化合物を静脈投与する際に沈殿を避けるためにDMSOに溶解した後に界面活性剤を加えるなど剤形に困難が伴う。
本発明者らは、IF7に伴う上述したような弱点を克服できればより優れた治療薬が創り出されると考え、新規配列からなる次世代ペプチドの開発に着手した。
本研究の基礎となる技術は、7残基アミノ酸からなる約10億種類(207種類)のランダムペプチドを表面提示したファージライブラリーをスクリーニングするという方法である。生物を構成するアミノ酸は一部の例外を除いてすべてがL型のアミノ酸である。従って、通常のファージライブラリースクリーニングでは、標的に結合するD型ペプチドの配列を得ることは不可能である。そこで、新たにT7ファージライブラリーを用いた鏡像スクリーニング(Funke et al.,Mol.Biosyst.2009,783−6)を実施した(図6)。
下記の知見・仮定に基づきスクリーニングを実施し、Anxa1と高い結合親和性を有するファージを取得した。IF7がAnxa1のN末端15残基(MAMVSEFLKQAWFIE;配列番号11)と相互作用すること、また、IF7はAxna1のN末端15残基に修飾用Cys残基を付加した16残基のL−体ペプチド(L−MC16)と結合することが明らかになっている(Sasai et al.,未発表)。まず、L−MC16と鏡像関係にあるD−MC16(16塩基が全てD−型)を合成し、T7ファージライブラリーを用いたスクリーニングにより、D−MC16と結合する7アミノ酸(L−型のTIT7ペプチド)を同定した。得られた配列を元にD−型のアミノ酸で構成されるTIT7ペプチド(dTIT7)を合成した。このdTIT7ペプチドはAnxa1と結合することが予想される。
また、ファージが提示するペプチド配列を解析する時に、以前はペプチド配列に様々な変異を導入して配列の最適化をするのが一般的であったが、現在我々は、得られたファージ群を次世代DNAシーケンサーにかけることで、のべ10,000種類以上の候補ペプチドの配列の中から最適なペプチド配列を一度に評価、同定できる。
解析の結果、Anxa1のN末部位に結合する配列として、TIT(トレオニン−イソロイシン−トレオニン)で始まる7アミノ酸の出現頻度が多く、中でもTIT7配列「TITWPTM」(配列番号12)が突出していることが明らかになった。TIT7の部分配列の頻度も上位に現れた一方、TIT7の配列置換体にあたるものは見出されなかった。また、TIT7のペプチドはIF7(IFLLWQR;配列番号10)の配列とは全く異なる新規の配列より構成されていた。
以上の結果は、7つのアミノ酸が全てD体アミノ酸で構成される直鎖型ペプチドdTIT7の取得に成功したことを示すものであった。
さらに、dTIT7とAnxa1の分子間相互作用をQCM法にて測定したところ、解離定数(Kd値)は4.57x10−8Mであった。
また、図6Dに示す通りTIT7配列(配列番号12)以外に、LRFPTVL(配列番号13)、SPTSLLF(配列番号14)、MPTLTFR(配列番号15)、LKGMLRI(配列番号16)、およびLLSWPSA(配列番号17)の配列のペプチドの出現頻度も高く、109種類という膨大な数のランダムペプチドのうち、これら6つのペプチドが全体の50%程度を占めていた。
我々は、近赤外線蛍光試薬IRDye800CWで標識したdTIT7(IRDye−dTIT7)を作製した。ラットグリオーマをヌードマウスの脳に移植した脳腫瘍ヌードマウスモデルを作製し、マウスの尾静脈からIRDye−dTIT7を注入した。その結果、IRDye−dTIT7が脳腫瘍モデルマウスの腫瘍部位に集積することがin vivoイメージングによって観察された(図7)。
次に、我々はdTIT7−抗癌剤のコンジュゲートが脳腫瘍モデルマウスに与える影響を調べた。
dTIT7ペプチドに抗癌剤ゲルダナマイシンを結合させたGA−dTIT7(図8)は、プロテアーゼにもエステラーゼにも耐性で生体内でより安定であると考えられる。推奨投与量の1/10量(モル数換算)のGA−dTIT7を担癌マウス(メラノーマB16細胞、皮下投与)に1−2日おきに静脈投与したところ、腫瘍の増殖は顕著に抑制され、病理組織学的観察ではGA−dTIT7投与マウスの腫瘍部位に大量の壊死が観察された。このような効果は、連日投与が必要であったIF7よりも(Hatakeyama et al.,Proc.Natl.Acad.Sci USA,108:19587−92,2011)、dTIT7が優れている可能性を強く示唆する。
さらに驚くべきことに、B16細胞を脳に移植した脳腫瘍モデルにGA−dTIT7を経口投与すると腫瘍退縮が観察され、薬剤の投与を中止した後にも腫瘍が減少し続け、ついには完全治癒が4匹中2匹で観察された(図9)。同様の治療効果がC6細胞を使った脳腫瘍モデルでも観察された。このことは、GA−dTIT7が経口投与可能な抗癌剤として脳腫瘍を完全治癒に導く可能性を示すものである。
実施例1に記載のTIT7配列(配列番号12)以外の出現頻度が高かったLRFPTVL(配列番号13)、SPTSLLF(配列番号14)、MPTLTFR(配列番号15)およびLLSWPSA(配列番号17)の配列のペプチドについても、dTIT7ペプチドと同様に、D−型のアミノ酸で構成されるペプチド(dLRF7、dSPT7、dMPT7およびdLLS7ペプチド)を合成し、下記方法により、Anxa1との分子間相互作用を、それぞれ測定した。
センサーチップをピラニア溶液で5分間2回洗浄し、その後、0.9mMヒドロキシ−EG3−ウンデカンチオール(Dojindo)および0.1mMアミノ−EG6−ウンデカンチオール(Dojindo)の溶液に一晩浸した。水で洗浄した後、チップを1mMGMBS(Dojindo)で処理し、室温で1時間インキュベートした。残りのGMBSを洗い流した後、1mMのペプチド溶液をチップ上に加え、30分間インキュベートした。ペプチド結合センサーチップをQCM装置(Single−Q、ASONE)に設置し、0.5mlのPBSをウェルに添加した。種々の投与量のAnxa1を反応チャンバに注入し、各ペプチドに対する結合親和性(kd値)を決定した。
結果、試験した全てのペプチドがAnxa1への陽性結合を示した(表1および図11)。
末端システインを付加して伸長させたdLRF7、dSPT7、dMPT7およびdLLS7ペプチドを化学合成した。次いで、各ペプチドと近赤外蛍光色素IRDye 800CWマレイミド(Li−Cor)とを、システイン残基を介して結合させた。生じたペプチドコンジュゲートをHPLCで精製し、次いで、凍結乾燥した。各ペプチド−IRDyeコンジュゲートをDMSOおよび6%グルコースに溶解し、そして脳腫瘍モデルヌードマウスに、100μl/マウスで静脈注射した。24時間後、IVISスペクトル(Perkin Elmer)により蛍光画像を測定した。
結果、dLLS7を注射したマウス以外の全てのマウスで、脳腫瘍部位にIRDyeの強いシグナルを示し、dLLS7以外のdLRF7、dMPT7およびdSPT7の3つのペプチドが、血管系経路を介した脳腫瘍標的能を有することを示した(図12)。
Claims (23)
- 下記式(I)−(III)のいずれかのアミノ酸配列を含むペプチド。
(I)(X1)[D]P[D](X2)[D]のアミノ酸配列(該配列中、X1はWまたはFを示し、X2はSまたはTを示し、直後に記号[D]を付した各アミノ酸記号は該アミノ酸のD体を示す。)、
(II)P[D]T[D](X)nF[D]のアミノ酸配列(該配列中、(X)nは互いに独立して選択されるn個の任意のアミノ酸を示し、nは0−4の整数を示し、記号[D]は前記と同義を示す。)、
(III)前記(I)または(II)のいずれかのアミノ酸配列のRetro−inversoであるアミノ酸配列。 - 下記(i)−(vii)のいずれかのアミノ酸配列を含むペプチド(下記の配列中、記号[D]は前記と同義を示す。)。
(i)T[D]I[D]T[D]W[D]P[D]T[D]M[D]のアミノ酸配列、
(ii)L[D]R[D]F[D]P[D]T[D]V[D]L[D]のアミノ酸配列、
(iii)L[D]L[D]S[D]W[D]P[D]S[D]A[D]のアミノ酸配列、
(iv)S[D]P[D]T[D]S[D]L[D]L[D]F[D]のアミノ酸配列、
(v)M[D]P[D]T[D]L[D]T[D]F[D]R[D]のアミノ酸配列、
(vi)前記(i)−(v)のいずれかのアミノ酸配列において1もしくは数個のアミノ酸の挿入、置換もしくは欠失、またはこれらの組み合わせを有するアミノ酸配列、
(vii)前記(i)−(vi)のいずれかのアミノ酸配列のRetro−inversoであるアミノ酸配列。 - 上記(i)のアミノ酸配列を含む、請求項2に記載のペプチド。
- 上記(i)のアミノ酸配列からなる、請求項2に記載のペプチド。
- 請求項1~4のいずれか1項に記載のペプチドおよび1つ以上の成分を含む、コンジュゲート。
- 前記1つ以上の成分が抗がん剤を含む、請求項5に記載のコンジュゲート。
- 前記抗がん剤が、代謝拮抗剤、アルキル化剤、抗がん性抗生物質、微小管阻害剤、白金製剤、トポイソメラーゼ阻害剤、分子標的薬、および抗血管新生剤からなる群から選択される、請求項6に記載のコンジュゲート。
- 前記抗がん剤が、
エノシタビン、カペシタビン、カルモフール、クラドリビン、ゲムシタビン、シタラビン、シタラビンオクホスファート、テガフール、テガフール・ウラシル、テガフール・ギメラシル・オテラシルカリウム、ドキシフルリジン、ネララビン、ヒドロキシカルバミド、フルオロウラシル、フルダラビン、ペメトレキセド、ペントスタチン、メルカプトプリン、メトトレキサート;
シクロホスファミド、イホスファミド、メルファラン、ブスルファン、チオテパ、ニムスチン、ラニムスチン、ダカルバシン、プロカルバシン、テモゾロマイド、カルムスチン、ストレプトゾトシン、ベンダムスチン;
アクチノマイシンD、アクラルビシン、アムルビシン、イダルビシン、エピルビシン、ジノスタチンスチマラマー、ダウノルビシン、ドキソルビシン、ピラルビシン、ブレオマイシン、ペプロマイシン、マイトマイシンC、ミトキサントロン、リポソーマルドキソルビシン;
ビンブラスチン、ビンクリスチン、ビンデシン、パクリタキセル、タキソール、ドセタキセル;
オキサリプラチン、カルボプラチン、シスプラチン、ネダプラチン;
カンプトテシン、イリノテカン、ノギテカン、SN−38、ドキソルビシン、エトポシド、レボフロキサシン、シプロフロキサシン;
レゴラフェニブ、セツキシマブ、パニツムマブ、ラムシルマブ、ゲフィチニブ、エルロチニブ、アファチニブ、クリゾチニブ、アレクチニブ、セリチニブ、レンバチニブ、トラスツズマブ、ラパチニブ、ペルツズマブ、スニチニブ、ソラフェニブ、アキシチニブ、パゾパニブ、ニボルマブ、ペムブロリズマブ、イピリムマブ、ベムラフェニブ、エベロリムス、テムシロリムス、リツキシマブ、ベバシズマブ、ゲルダナマイシン;
アンギオスタチン、エンドスタチン、メタスタチン、抗VEGF抗体、およびVEGFR−2インヒビター
からなる群から選択される、請求項6または7に記載のコンジュゲート。 - 前記1つ以上の成分が検出可能な物質を含む、請求項5に記載のコンジュゲート。
- 前記検出可能な物質が、X線撮影、コンピュータ断層撮影(CT)、核磁気共鳴画像法(MRI)、超音波検査、シンチグラフィ、ポジトロン断層法(PET)、内視鏡、および腹腔鏡からなる群から選択される手段によりインビボにおける該コンジュゲートの検出を可能にするものである、請求項9に記載のコンジュゲート。
- 前記検出可能な物質が、放射性同位体、MRI用増強剤、放射線不透過性物質、造影剤、または蛍光性物質である、請求項9または10に記載のコンジュゲート。
- 前記検出可能な物質が、
18F、51Mn、52mMn、52Fe、55Co、62Cu、64Cu、68Ga、72As、75Br、76Br、82mRb、83Sr、86Y、89Zr、94mTc、110In、120I、124I、51Cr、57Co、58Co、59Fe、67Cu、67Ga、75Se、97Ru、99mTc、111In、114mIn、123I、125I、131I、169Yb、197Hg、および201Tlから選択される放射性核種;
クロム(III)、マンガン(II)、鉄(III)、鉄(II)、コバルト(II)、ニッケル(II)、銅(II)、ネオジム(III)、サマリウム(III)、イッテルビウム(III)、ガドリニウム(III)、バナジウム(II)、テルビウム(III)、ジスプロシウム(III)、ホルミウム(III)、およびエルビウム(III)から選択される常磁性イオン、ランタン(III)、金(III)、鉛(II)、ビスマス(III);
ヨウ素化合物、バリウム化合物、ガリウム化合物、タリウム化合物;
ローダミン、フルオレセイン、Cy dye、Alexa(登録商標)Fluor、フィコエリトリン(PE)、アロフィコシアニン(APC)、およびこれらの誘導体、ならびに近赤外線蛍光試薬からなる群から選択される、請求項9~11のいずれか1項に記載のコンジュゲート。 - 請求項1~4のいずれか1項に記載のペプチドまたは請求項5~12のいずれか1項に記載のコンジュゲート、および薬学的に許容される担体を含む、組成物。
- 請求項6~8のいずれか1項に記載のコンジュゲート、および薬学的に許容される担体を含む、がんの治療用組成物。
- 請求項9~12のいずれか1項に記載のコンジュゲート、および薬学的に許容される担体を含む、がんの検査用組成物。
- がんが固形がんまたは液性がんである、請求項14または15に記載の組成物。
- 固形がんが、血管新生する固形がんである、請求項16に記載の組成物。
- 固形がんが、脳・神経系のがん、頭頸部がん、消化器がん、泌尿器または生殖器のがん、呼吸器系のがん、乳がん、皮膚がん、骨のがん、または筋肉のがんである、請求項16または17に記載の組成物。
- 固形がんが、脳腫瘍、脊髄腫瘍、喉頭がん、口腔がん、唾液腺がん、副鼻腔がん、甲状腺がん、胃がん、食道がん、小腸がん、結腸がん、直腸がん、肛門がん、肝臓がん、胆道がん、膵臓がん、腎がん、腎細胞がん、膀胱がん、前立腺がん、腎盂および尿管がん、胆嚢がん、胆管がん、精巣がん、陰茎がん、子宮がん、子宮内膜がん、子宮肉腫、子宮頚がん、膣がん、外陰がん、卵巣がん、卵管がん、肺がん、乳がん、悪性黒色腫、骨肉腫、または横紋筋肉腫である、請求項16~18のいずれか1項に記載の組成物。
- 固形がんが良性または悪性の脳腫瘍である、請求項19に記載の組成物。
- 脳腫瘍が原発性脳腫瘍または転移性脳腫瘍である、請求項20に記載の組成物。
- 脳腫瘍が、髄膜腫、下垂体腺腫、神経鞘腫、星細胞腫(アストロサイトーマ)、乏突起神経膠腫(オリゴデンドログリオーマ)、退形成性星細胞腫、退形成性乏突起膠腫、退形成性乏突起星細胞腫、または膠芽腫(グリオブラストーマ)である、請求項19または20に記載の組成物。
- 液性がんがB細胞性リンパ腫である、請求項16に記載の組成物。
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WO2020158959A1 (ja) * | 2019-02-01 | 2020-08-06 | 国立研究開発法人産業技術総合研究所 | 抗mc16抗体 |
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EP3997093A1 (en) | 2019-07-10 | 2022-05-18 | Cybrexa 2, Inc. | Peptide conjugates of cytotoxins as therapeutics |
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WO2019244954A1 (ja) * | 2018-06-20 | 2019-12-26 | 国立大学法人弘前大学 | ホウ素中性子捕捉療法用の腫瘍組織を短時間で選択的ないし局所的に標的化できる集積性ボロン10薬剤 |
JP7440914B2 (ja) | 2018-06-20 | 2024-02-29 | 国立大学法人弘前大学 | ホウ素中性子捕捉療法用の腫瘍組織を短時間で選択的ないし局所的に標的化できる集積性ボロン10薬剤 |
JPWO2019244954A1 (ja) * | 2018-06-20 | 2021-07-01 | 国立大学法人弘前大学 | ホウ素中性子捕捉療法用の腫瘍組織を短時間で選択的ないし局所的に標的化できる集積性ボロン10薬剤 |
JP2020125253A (ja) * | 2019-02-01 | 2020-08-20 | 国立研究開発法人産業技術総合研究所 | 抗mc16抗体 |
JP7224628B2 (ja) | 2019-02-01 | 2023-02-20 | 国立研究開発法人産業技術総合研究所 | 抗mc16抗体 |
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WO2020195504A1 (ja) * | 2019-03-26 | 2020-10-01 | 国立大学法人新潟大学 | ペプチド及びその使用 |
JPWO2020195504A1 (ja) * | 2019-03-26 | 2020-10-01 | ||
CN113795501A (zh) * | 2019-03-26 | 2021-12-14 | 国立大学法人新潟大学 | 肽及其应用 |
JP2022525791A (ja) * | 2019-03-26 | 2022-05-19 | 株式会社島津製作所 | 光免疫療法およびそれに用いる薬剤 |
JP7429454B2 (ja) | 2019-03-26 | 2024-02-08 | 国立大学法人 新潟大学 | ペプチド及びその使用 |
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CA3032775C (en) | 2024-01-23 |
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