WO2024004869A1 - ペプチド及び該ペプチドを含む会合体又は組成物 - Google Patents

ペプチド及び該ペプチドを含む会合体又は組成物 Download PDF

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WO2024004869A1
WO2024004869A1 PCT/JP2023/023371 JP2023023371W WO2024004869A1 WO 2024004869 A1 WO2024004869 A1 WO 2024004869A1 JP 2023023371 W JP2023023371 W JP 2023023371W WO 2024004869 A1 WO2024004869 A1 WO 2024004869A1
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Prior art keywords
peptide
target
amino acid
region
hydrophobic
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English (en)
French (fr)
Japanese (ja)
Inventor
充訓 原田
昼也 吉田
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Mescue Janusys Inc
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Mescue Janusys Inc
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Priority to US18/876,803 priority Critical patent/US20260092084A1/en
Priority to EP23831311.8A priority patent/EP4549470A1/en
Priority to JP2023577916A priority patent/JP7610308B2/ja
Publication of WO2024004869A1 publication Critical patent/WO2024004869A1/ja
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein

Definitions

  • the present invention relates to a peptide and an association or composition containing the peptide.
  • Peptides which are composed of several to several dozen amino acid residues, are easier to manufacture and control quality at lower costs than proteins such as antibodies, and are difficult to exhibit antigenicity and penetrate deep into tissues. It has advantages such as easy to use. On the other hand, it is difficult to directly apply peptides to pharmaceuticals due to their biological instability and aggregation properties.
  • Patent Document 1 describes a spherical shape formed by self-association of amphiphilic peptide molecules containing a hydrophilic part containing a positively charged amino acid residue and a hydrophobic part covalently bonded to the hydrophilic part.
  • the use of nanoparticles as carrier formulations for hydrophobic drugs has been disclosed.
  • the main purpose of the present invention is to provide a peptide that can be used for active targeting DDS.
  • the following peptides [1] to [8], peptide complexes [9] to [11], and peptide compositions [12] to [13] are provided.
  • [1] It has a hydrophobic region and a hydrophilic region located on at least one end side of the hydrophobic region and has a lower degree of hydrophobicity than the hydrophobic region, and has a first hydrophobic region at one end.
  • [2] The peptide or a derivative thereof, or a salt thereof according to [1], wherein the first target and the second target are different from each other.
  • [3] The peptide or its derivative or salt thereof according to [1] or [2], which has 10 to 40 constituent amino acid residues.
  • [4] The peptide or a derivative thereof, or a salt thereof according to any one of [1] to [3], which has the hydrophilic region on both end sides of the hydrophobic region.
  • [5] The peptide or peptide according to [4], wherein the number of amino acid residues constituting the hydrophobic region is 2 to 15, and 60% or more of them are selected from nonpolar amino acid residues and tyrosine residues. Derivatives thereof or salts thereof.
  • [6] The peptide or a derivative thereof, or a salt thereof according to [4] or [5], wherein the number of amino acid residues constituting the two hydrophilic regions is independently 3 to 24.
  • a peptide complex comprising the peptide according to any one of [1] to [8], a derivative thereof, or a salt thereof.
  • the peptide according to the embodiment of the present invention has a hydrophobic region with relatively high hydrophobicity and a hydrophilic region with low hydrophobicity, and target binding sites having affinity for the target are arranged at both ends. It has a configuration. Peptides having such a structure can form an aggregate in which the ends facing the hydrophilic regions are placed on the outside by associating in an aqueous medium through hydrophobic interaction between the hydrophobic regions. .
  • the aggregate can be used for active targeting DDS by further containing a drug, using a physiologically active target binding site, etc.
  • FIG. 2 is a schematic diagram illustrating the relationship between a target binding site and a hydrophobic region or a hydrophilic region in the peptide according to the first embodiment of the present invention.
  • FIG. 2 is a schematic diagram illustrating the relationship between a target binding site and a hydrophobic region or a hydrophilic region in the peptide according to the first embodiment of the present invention.
  • (a) and (b) are schematic diagrams each illustrating the structure of a peptide according to a second embodiment of the present invention and a peptide complex formed by the peptide. It is a graph showing the relationship between peptide concentration and fluorescence intensity derived from pyrene. It is a graph showing the relationship between peptide concentration and ANS-derived fluorescence intensity. It is a graph showing the results of blood retention evaluation of peptides.
  • natural amino acids include alanine (A), leucine (L), arginine (R), lysine (K), asparagine (N), methionine (M), aspartic acid (D), phenylalanine (F), Cysteine (C), Proline (P), Glutamine (Q), Serine (S), Glutamic acid (E), Threonine (T), Glycine (G), Tryptophan (W), Histidine (H), Tyrosine (Y), Contains isoleucine (I) and valine (V).
  • unnatural amino acids include 2,3-diaminopropionic acid (DAP), 2,4-diaminobutanoic acid (DAB), ornithine (Orn), isoserine (Ise), and the like.
  • DAP 2,3-diaminopropionic acid
  • DAB 2,4-diaminobutanoic acid
  • Orn ornithine
  • Ise isoserine
  • A, L, M, F, I, V, P, W, and G are classified as nonpolar (hydrophobic) amino acids
  • acidic amino acids such as D, E, R, K, H, and DAP.
  • DAB, Orn and polar uncharged amino acids such as N, Q, S, T, C, Y, Ise, etc. are classified as polar (hydrophilic) amino acids.
  • Peptide A peptide according to an embodiment of the present invention has a hydrophobic region and a hydrophilic region located on at least one end side of the hydrophobic region and having a lower degree of hydrophobicity than the hydrophobic region; has a first target binding site capable of binding to a first target at one end thereof, and a second target binding site capable of binding to a second target at the other end thereof.
  • Peptides having such a structure (hereinafter sometimes referred to as "self-associating peptides”) can associate in an aqueous medium through hydrophobic interactions between hydrophobic regions to form aggregates. .
  • a drug may be bound to the peptide. Drugs can be grafted onto the side chains of peptides, for example.
  • the number of amino acid residues constituting the self-associating peptide is, for example, 10 to 40, preferably 12 to 38, more preferably 15 to 31, and still more preferably 18 to 24.
  • the number of amino acid residues constituting a self-associating peptide means the number of amino acid residues constituting the main chain of the self-associating peptide, and the number of amino acid residues constituting each region or site described below also has the same meaning. It is.
  • a self-associating peptide may be composed only of natural amino acid residues, may be composed only of non-natural amino acid residues, or may contain both natural amino acid residues and non-natural amino acid residues.
  • the self-associating peptide may be in the form of a derivative or salt as long as the effects of the present invention can be obtained.
  • a peptide may be a derivative of the peptide or a salt of the peptide or its derivative.
  • peptide derivatives include those in which functional groups such as the N-terminal amino group, C-terminal carboxyl group, side chain carboxyl group, amino group, guanidino group, hydroxyl group, and thiol group are substituted with various substituents. It will be done.
  • Substituents are not particularly limited, and include, for example, alkyl groups, acyl groups, hydroxyl groups, amino groups, alkylamino groups, nitro groups, amide groups, sulfonyl groups, phosphoric acid groups, halogens, and various protective groups. These substituents may be further substituted with halogen such as fluorine. Further, the substitution may be the introduction of a label such as a fluorescent label or a biotin label.
  • the peptide salt is preferably a pharmacologically acceptable salt.
  • Pharmaceutically acceptable salts include acid addition salts and base addition salts.
  • acid addition salts include inorganic acid salts and organic acid salts.
  • inorganic acid salts include hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, phosphate, and the like.
  • organic acid salts include citrate, oxalate, acetate, formate, propionate, benzoate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, Examples include paratoluenesulfonate.
  • Examples of base addition salts include inorganic base salts and organic base salts.
  • Examples of inorganic base salts include sodium salts, potassium salts, calcium salts, magnesium salts, and ammonium salts.
  • Examples of the organic base salt include organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt, and diisopropylammonium salt.
  • FIG. 1(a) is a schematic diagram illustrating the structure of a self-associating peptide according to a first embodiment of the present invention.
  • the self-associating peptide 10a includes a hydrophobic region 12, a first hydrophilic region 14 located at one end of the hydrophobic region 12, and a second hydrophilic region 16 located at the other end. and has.
  • the self-associating peptides 10a can associate in an aqueous medium through hydrophobic interaction between the hydrophobic regions 12 to form a peptide complex 100a.
  • either the end on the first hydrophilic region 14 side or the end on the second hydrophilic region 16 side may be the N-terminus.
  • Hydrophobic region 12 typically has non-polar amino acid residues or tyrosine residues at both ends thereof, for example 2 to 15, preferably 3 to 13, more preferably 4 to 12, even more preferably 6 to It is composed of 10 amino acid residues.
  • amino acid residues constituting the hydrophobic region are selected from nonpolar amino acid residues and tyrosine residues. Ru. Although tyrosine is classified as a polar amino acid, its solubility is very low, and its inclusion in the hydrophobic region may contribute to the self-association of peptides.
  • the total number of nonpolar amino acid residues and tyrosine residues contained in the hydrophobic region is, for example, 2 or more, preferably 3 to 13, more preferably 4 to 10.
  • the non-polar amino acid residues contained in the hydrophobic region are selected, for example, from L, A, W, F, V, I, and G, preferably from L, A, W, F, and G, and more preferably from L, A, W, F, and G. is selected from L, A, W, and F.
  • These non-polar amino acid residues may be advantageous in terms of peptide self-association.
  • the number of nonpolar amino acid residues contained in the hydrophobic region may be one, or two or more.
  • the hydrophobic region may include polar amino acid residues. From the viewpoint of peptide synthesis, when the hydrophobic region contains only one type of nonpolar amino acid residue, it is preferable to intersperse polar amino acid residues.
  • the number of polar amino acid residues that can be included in the hydrophobic region can be, for example, from 1 to 6, and also, for example, from 2 to 4.
  • the ratio of the number of polar amino acid residues to the total number of amino acid residues constituting the hydrophobic region may be, for example, 7% to 40%, or, for example, 13% to 30%.
  • the number of polar amino acid residues contained in the hydrophobic region may be only one, or two or more.
  • the degree of hydrophobicity of the hydrophobic region can be flexibly adjusted over a wide range.
  • the hydrophobic region comprises charged amino acid residues, preferably acidic amino acid residues.
  • the number of charged amino acid residues in the hydrophobic region is, for example, 1-6, and also, for example, 2-4.
  • Two or more charged amino acid residues may be arranged consecutively or discontinuously.
  • charged amino acid residues may be equally spaced within the hydrophobic region.
  • the charged amino acid residues are arranged adjacent to each other in the Helical Wheel Projection, preferably as illustrated in FIG. can be arranged through non-polar amino acid residues so that By arranging the charged amino acid residues in this way, peptide aggregation can be controlled.
  • a peptide in which polar amino acid residues such as charged amino acid residues are arranged on one side of an ⁇ -helix structure can have a so-called amphipathic helix structure, and the electrostatic By using repulsion, the degree of aggregation can be controlled.
  • Helical Wheel Projection can be obtained using amino acid sequence analysis software such as Gene Inspector (R) .
  • the Hydropathy Index of the hydrophobic region may be, for example, ⁇ 1.6 or more, preferably ⁇ 0.9 to 4.5, and more preferably 0.4 to 2.8.
  • "Hydropathy Index of a hydrophobic region” means the average value of the Hydropathy Index of all amino acids constituting the hydrophobic region. The values shown below are adopted as the Hydropathy Index of natural amino acids.
  • Each of the first hydrophilic region 14 and the second hydrophilic region 16 typically has a polar amino acid residue (excluding a tyrosine residue) at the end on the hydrophobic region 12 side, and It has a degree of hydrophobicity lower than 12.
  • the difference in hydrophobicity between the hydrophobic region and the first hydrophilic region or the second hydrophilic region is caused by the self-associating peptides associating in an aqueous medium through hydrophobic interaction between the hydrophobic regions.
  • the hydrophobic region of the self-associating peptide is arranged inside, and the first hydrophilic region and the second hydrophilic region are arranged outside.
  • Hydropathy Index of the hydrophobic region is independently, for example, 0 or more. , preferably from 0.4 to 6.4, more preferably from 1 to 6.
  • Hydropathy Index of a hydrophilic region means the average value of the Hydropathy Index of all amino acids constituting the hydrophilic region.
  • the number of amino acid residues constituting the first hydrophilic region or the second hydrophilic region is independently, for example, 3 to 24, preferably 3 to 18, more preferably 3 to 15, even more preferably 5 to It is 15.
  • the ratio of the number of amino acid residues constituting the first hydrophilic region to the number of amino acid residues constituting the hydrophobic region is not limited as long as the effects of the present invention can be obtained, and is, for example, 20% to 400%, preferably It is 30% to 300%. Further, the ratio of the number of amino acid residues constituting the second hydrophilic region to the number of amino acid residues constituting the hydrophobic region is not limited as long as the effects of the present invention can be obtained, and is, for example, 20% to 400%. , preferably 30% to 300%.
  • the amino acid residues constituting the first hydrophilic region or the second hydrophilic region are tyrosine residues.
  • Polar amino acid residues excluding groups.
  • the ratio of the number of polar amino acid residues excluding tyrosine residues to the number of amino acid residues constituting the hydrophilic region and the ratio of the number of polar amino acid residues excluding tyrosine residues to the number of amino acid residues constituting the hydrophobic region is, for example, 10% or more, preferably 20% or more, and may be, for example, 30% or more, 40% or more, or 50% or more.
  • Self-associating peptides containing charged amino acid residues i.e., acidic amino acid residues and/or basic amino acid residues in the hydrophilic region, form aggregates whose particle size can be changed by adjusting the pH of the aqueous medium. can be formed.
  • self-associating peptides containing one or more histidine residues in the hydrophilic region such as two or more or three or more, can form aggregates whose particle size can vary from neutral to weakly acidic.
  • the self-associating peptide has a first target binding site capable of binding to a first target at one end and a second target binding site capable of binding to a second target at the other end.
  • a first target binding site capable of binding to a first target at one end
  • a second target binding site capable of binding to a second target at the other end.
  • the first target binding site and the second target binding site are each comprised of an amino acid sequence capable of selectively binding to the first target and the second target to form a biological binding pair with the targets.
  • Ru an amino acid sequence
  • a known amino acid sequence may be used, and an amino acid sequence capable of selectively binding to the target is screened using mRNA display method, cDNA display method, Phage display, etc. It may be obtained by
  • the first target and the second target can be appropriately selected depending on the purpose.
  • the first target and the second target are typically substances derived from living organisms, viruses, etc., and for example, substances that specifically exist in living cells such as cancer cells, bacteria, fungi, and viruses. Or substances produced from these can be exemplified.
  • the first target and the second target may be different from each other or may be the same.
  • a peptide having directivity to the two targets can be obtained, and as a result, a DDS having directivity to the two targets can be realized.
  • the affinity (Avidity) for the target per peptide is determined.
  • the binding of the first target or the second target can be improved over a single peptide.
  • the first target binding site and the second target binding site may bind to the same site or different sites of the substance.
  • the amino acid sequences of the first target binding site and the second target binding site may be the same or different.
  • the first target binding site and the second target binding site has biological activity.
  • the peptide itself has physiological activity due to the end region having physiological activity and can exhibit medicinal efficacy, so it is not necessarily necessary for the peptide or peptide complex to carry a drug. isn't it.
  • the physiological activity of the target binding site can be appropriately selected depending on the use of the peptide, etc.
  • the physiological activity can be, for example, a hormonal effect, a neurotransmission effect, an antitumor effect, an antibacterial effect, an enzyme activity regulation effect, and the like.
  • the first target binding site and the second target binding site are respectively located at both ends of the self-associating peptide, and the number of constituent amino acid residues thereof is as long as it can bind to the first target and the second target. is not particularly limited, and may be, for example, 3 to 24, or, for example, 5 to 15. Furthermore, in the self-associating peptide illustrated in FIG. 1(a), the first hydrophilic region 14 corresponds to the first target binding site, and the second hydrophilic region 16 corresponds to the second target binding site. However, there is no requirement that the hydrophilic region and target binding site coincide.
  • the self-associating peptide illustrated in FIG. 3 has a first hydrophilic region composed of p amino acid residues and a first hydrophilic region composed of q amino acid residues from the N-terminal side to the C-terminal side. and a second hydrophilic region composed of r amino acid residues in this order, and from the N-terminal amino acid residue (A 1 ) to the N-terminal side of the hydrophobic region.
  • the region from the second amino acid residue (B 2 ) to the second amino acid residue (B 2 ) is the first target binding site, and the region from the second amino acid residue (C 2 ) from the N-terminal side of the second hydrophilic region to the C-terminus
  • the region up to the amino acid residue (C r ) is the second target binding site.
  • the second target binding site may include a portion of the hydrophobic region beyond the second hydrophilic region, or the first target binding site may include a portion of the hydrophobic region beyond the second hydrophilic region. It may be part of.
  • FIG. 4(a) is a schematic diagram illustrating the structure of a self-associating peptide according to a second embodiment of the present invention.
  • the self-associating peptide 10b has a hydrophobic region 12 and a first hydrophilic region 14 located on one end side of the hydrophobic region 12.
  • the self-associating peptides 10b can associate in an aqueous medium through hydrophobic interaction between the hydrophobic regions 12 to form a peptide complex 100b.
  • either the end on the hydrophobic region 12 side or the end on the first hydrophilic region 14 side may be the N-terminus.
  • the hydrophobic region 12 typically has a nonpolar amino acid residue or a polar amino acid residue selected from tyrosine residues, serine residues, and threonine residues at the end on the first hydrophilic region 14 side.
  • the hydrophobic region preferably contains at least one selected from proline residues, tryptophan residues, glycine residues, tyrosine residues, serine residues, and threonine residues, more preferably tryptophan residues and glycine residues. group, or at least one selected from tyrosine residues.
  • the hydrophobic region 12 is composed of, for example, 3 to 37, preferably 4 to 15, more preferably 5 to 13, and even more preferably 6 to 12 amino acid residues.
  • 50% or more of the amino acid residues constituting the hydrophobic region are nonpolar amino acid residues or polar amino acid residues selected from tyrosine residues, serine residues, and threonine residues
  • 50% or more is selected from proline residues, tryptophan residues, glycine residues, tyrosine residues, serine residues, and threonine residues, more preferably tryptophan residues, selected from glycine residues and tyrosine residues.
  • the total number of non-polar amino acid residues and polar amino acid residues selected from tyrosine residues, serine residues, and threonine residues contained in the hydrophobic region is, for example, 3 or more, preferably 4 to 4. 12, more preferably 6-10.
  • the non-polar amino acid residues included in the hydrophobic region may vary depending on the amino acid sequence of the target binding site, but in addition to the above, it may also include non-polar amino acid residues similar to those described in the first embodiment. preferable.
  • the hydrophobic region may further include polar amino acid residues other than tyrosine residues, serine residues, and threonine residues.
  • the number of polar amino acid residues (excluding tyrosine residues, serine residues, and threonine residues) that may be included in the hydrophobic region may be, for example, 1 to 6, or, for example, 2 to 4.
  • the ratio of the number of polar amino acid residues (excluding tyrosine residues, serine residues, and threonine residues) to the total number of amino acid residues constituting the hydrophobic region is, for example, 7% to 50%, or, for example, 13%. % to 30%.
  • the number of polar amino acid residues (excluding tyrosine residues, serine residues, and threonine residues) contained in the hydrophobic region may be one, or two or more.
  • the number of charged amino acid residues in the hydrophobic region is, for example, 0-6, and also, for example, 2-4.
  • the first hydrophilic region 14 typically has polar amino acid residues (excluding tyrosine residues, serine residues, and threonine residues) at the end on the hydrophobic region 12 side, and It has a degree of hydrophobicity lower than 12.
  • the difference in hydrophobicity between the hydrophobic region and the first hydrophilic region is as long as the self-associating peptide can associate in an aqueous medium through hydrophobic interaction between the hydrophobic regions to form an aggregate. There are no restrictions on this.
  • the hydrophobic region of the self-associating peptide is located inside and the first hydrophilic region is located outside.
  • an aqueous peptide solution When intermolecular hydrogen bonds (crosslinks) can be formed in an aqueous solution, an aqueous peptide solution can exhibit gel-like properties.
  • the Hydropathy Index of the hydrophobic region is as described in the first embodiment.
  • the difference between the Hydropathy Index of the hydrophobic region and the Hydropathy Index of the first hydrophilic region is, for example, -0.3 or more, preferably 0 to 6. , more preferably 0.4 to 5.
  • the number of amino acid residues constituting the first hydrophilic region is, for example, 3 to 24, preferably 5 to 15.
  • the ratio of the number of amino acid residues constituting the first hydrophilic region to the number of amino acid residues constituting the hydrophobic region is not limited as long as the effects of the present invention can be obtained, and is, for example, 25% to 400%, preferably It is 50% to 200%.
  • 20% or more, 30% or more, or 40% or more of the amino acid residues constituting the first hydrophilic region are polar amino acid residues, preferably 50% to 100%.
  • 20% or more, 30% or more, 40% or more, or 50% or more of the amino acid residues constituting the first hydrophilic region are polar amino acid residues excluding tyrosine residues, serine residues, and threonine residues. It may be a base.
  • the difference from the ratio of the number of polar amino acid residues excluding residues, serine residues, and threonine residues is, for example, 10% or more, preferably 20% or more, for example, 30% or more, 40% or more, or 50%. It can be more than that.
  • the self-associating peptide 10b in the illustrated example has a first target binding site capable of binding to a first target at the end on the first hydrophilic region 14 side, and a second target binding site at the end on the hydrophobic region 12 side. It has a second target binding site capable of binding to a target.
  • a self-associating peptide having such a configuration can form an aggregate in which the first target binding site is exposed to the outside, and can bind to the first target in the aggregate state, and the aggregate structure By collapsing, a second target binding site appears from inside the aggregate to the outside and can bind to the second target.
  • the first target binding site and the second target binding site are each as described with respect to the first embodiment.
  • Methods for producing self-associating peptides include chemical synthesis methods such as solid phase synthesis, stepwise elongation, and liquid phase synthesis, fermentation methods, and enzymatic methods. Among these, solid phase synthesis is preferred. Examples of the solid phase synthesis method include Fmoc synthesis method and Boc synthesis method.
  • a peptide complex comprising the peptide described in Section A, a derivative thereof, or a salt thereof.
  • a peptide complex can be formed by association of two or more molecules of self-associating peptides through intermolecular interactions. Intermolecular interactions to form aggregates typically include hydrophobic interactions between hydrophobic regions of the peptide, hydrogen bonds between peptide molecules, electrostatic interactions, and van der Waals interactions. It may further include other intermolecular interactions such as interactions.
  • the peptide complex is preferably a core-shell type complex as shown in FIG. 1(b) and FIG. 4(b).
  • a core-shell type peptide complex self-associating peptides are associated such that a hydrophobic region is located inside (core) and a hydrophilic region is located outside (shell).
  • self-associated peptides may associate with each other to form larger aggregates (eg, secondary aggregates).
  • the average particle diameter of the peptide complex can be any appropriate value depending on the purpose.
  • the average particle size of the peptide complex when administered intravenously is, for example, less than 300 nm, preferably 100 nm or less, more preferably 5 nm to 50 nm.
  • the average particle size of the peptide complex when used by other administration routes may be, for example, 3000 nm or less, preferably 1000 nm or less.
  • the particle size of the peptide complex can be adjusted by, for example, the degree of hydrophobicity of the hydrophobic region and/or the hydrophilic region, the pH of the aqueous medium, and the like.
  • the particle size of the peptide complex tends to become small.
  • the hydrophobicity of the hydrophobic region and/or hydrophilic region increases, resulting in a smaller particle size of the peptide complex.
  • the histidine content is high, the particle size of the peptide complex can be adjusted under neutral to weakly acidic conditions, which are physiological conditions.
  • the self-associating peptides forming the peptide complex have the same or no self-associating peptide with respect to the first target as the peptide complex as a whole, including the first target binding site. or higher binding affinity, preferably higher binding affinity.
  • the dissociation constant (K D ) for the first target per peptide of the peptide complex is the dissociation constant (K D ) for the first target of the non-self-associating peptide containing the first target binding site. and preferably less than that.
  • the dissociation constant (K D ) for the first target of the non-self-associating peptide comprising the first target binding site may be, for example, 10 ⁇ 6 M or less, preferably 10 ⁇ 7 M or less.
  • the self-associating peptide forming the peptide conjugate has the same or different binding site for the second target as the peptide conjugate as a whole as the non-self-associating peptide comprising the second target binding site. or higher binding affinity, preferably higher binding affinity.
  • the dissociation constant (K D ) for the second target per peptide of the peptide complex is the dissociation constant (K D ) for the second target of the non-self-associating peptide containing the second target binding site. and preferably less than that.
  • the dissociation constant (K D ) of the non-self-associating peptide containing the second target binding site for the second target may be, for example, 10 ⁇ 6 M or less, preferably 10 ⁇ 7 M or less.
  • the dissociation constant (K D ) for the first target or second target per peptide of the peptide complex means the binding affinity of the peptide complex for the first target or second target in terms of peptide.
  • the dissociation constant can be obtained by calculating the dissociation constant using the molar concentration of the peptide used to form the complex instead of the molar concentration of the peptide complex.
  • the peptide complex may further contain a drug.
  • Peptide complexes can exhibit targeting properties due to target binding sites, and therefore, peptide complexes containing drugs can deliver the drug to the target of interest.
  • the drug may be included in the peptide complex by being supported (e.g., encapsulated), or may be included in the peptide complex by being bonded to the self-associating peptide (e.g., bonded to the peptide side chain via a linker if necessary). May be included in the combination.
  • any appropriate drug can be used depending on the purpose.
  • examples include antitumor agents, signal transduction inhibitors, antimetabolites, analgesics, anti-inflammatory agents, antibacterial agents, contrast agents, and the like.
  • hydrophobic drugs are preferred. Hydrophobic drugs can be suitably supported inside the peptide complex. Examples of hydrophobic antitumor agents include paclitaxel, topotecan, camptothecin, cisplatin, daunorubicin hydrochloride, methotrexate, mitomycin C, docetaxel, vinculestine sulfate, and derivatives thereof.
  • the peptide complex can be produced, for example, by dissolving a self-associating peptide in an organic solvent, and if necessary, drying the resulting solution in the air to form a film under a nitrogen atmosphere, and further drying it under reduced pressure if necessary. It can be obtained by removing the organic solvent by drying to dryness, and then adding and mixing an aqueous medium to cause self-association of the self-associating peptide.
  • organic solvents for dissolving self-associating peptides include water-immiscible organic solvents such as dichloromethane, chloroform, diethyl ether, dibutyl ether, ethyl acetate, butyl acetate, methanol, ethanol, propyl alcohol, isopropyl alcohol, dimethyl sulfoxide, and dimethyl.
  • water-miscible organic solvents such as formamide, dimethylacetamide, acetonitrile, acetone, and tetrahydrofuran, and mixed solvents thereof.
  • aqueous medium examples include water and buffer solutions.
  • buffer examples include phosphate buffer, phosphate buffered saline, citrate buffer, Tris buffer, TAPS buffer, MES buffer, HEPES buffer, and the like.
  • the pH of the aqueous medium is, for example, 3 to 8, preferably 5 to 7.4.
  • the peptide complex may be produced by stirring a liquid mixture containing a self-associating peptide and, if necessary, a drug.
  • the mixed liquid is preferably stirred by applying energy such as ultrasonic waves.
  • a peptide composition includes an aqueous medium and a peptide complex according to Section B.
  • the peptide complex is formed by association via intermolecular interactions (typically, hydrophobic interactions between hydrophobic regions of self-associating peptides).
  • the peptide composition can further include a drug.
  • the drug may be supported (for example, encapsulated) in a peptide complex, or may be bound to a self-associating peptide (for example, bound to a peptide side chain via a linker if necessary).
  • the peptide complex, drug, and aqueous medium are as described in Section B.
  • the peptide composition is a pharmaceutical composition containing a bioactive self-associating peptide and/or a drug as an active ingredient, and in the pharmaceutical composition, the peptide complex targets the active ingredient. It can function as a DDS for efficient delivery.
  • the peptide composition is prepared in any suitable dosage form depending on the mode of administration.
  • the peptide composition can be used in injections such as subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, and drops, eye drops, nasal drops, and external preparations (e.g., eye ointments, oral ointments, etc.). etc.) and other parenteral agents.
  • it may be an oral preparation with a form that prevents decomposition by gastric acid, such as enteric coating.
  • the peptide composition can further contain any appropriate additives depending on the intended use.
  • additives include tonicity agents, buffers, preservatives, thickeners, stabilizers, pH adjusters, and the like.
  • the peptides of the examples are divided into three regions by two hyphens.
  • the N-terminal region and C-terminal region of the peptides of Examples 1-1 to 1-5 are an HA-binding site capable of binding to hydroxyapatite (HA) and an Rgp-binding site capable of binding to Arg-gingipain (Rgp), respectively. It is.
  • the N-terminal region and C-terminal region of the peptides of Examples 2-1 and 2-2 each have an amino acid sequence derived from a CD73-binding peptide capable of binding to CD73 and an amino acid sequence capable of binding to fetal Fc receptor (FcRn). Amino acid sequence derived from FcRn binding peptide.
  • the underlined portion indicates a hydrophobic region.
  • the peptide of the reference example is an amphipathic peptide, and the N-terminal region separated by one hyphen is a hydrophilic region (also an Rgp binding site), and the C-terminal region is a hydrophobic region.
  • the amino acid sequences constituting each target binding site can be found in previously published papers (for example, P. Steinbauer, et al. Single-Molecule Force Spectroscopy Reveals Adhesion-by-Demand in Statherin at the P. rotein-Hydroxyyapatite Interface Langmuir 2020,36, 13292-13300.) or determined by the cDNA display method.
  • Example 2 Formation of peptide complex
  • 5 mg of the peptides of Examples 1-1 to 1-5 and Reference Examples 1-1 to 1-8 were dissolved in dimethyl sulfoxide (DMSO) to prepare a stock solution (40 mM).
  • 4 ⁇ L of the stock solution was diluted 100 times by dropping it into a 10 mM HEPES, 150 mM NaCl buffer (pH 7) being stirred with a micromixer (Titec, E-36). After vortexing the diluted solution, it was allowed to stand overnight at room temperature.
  • the particle size distribution was measured at 25° C. by a dynamic light scattering method using Litesizer 500 (Anton Paar).
  • Table 3 shows the results of determining the main peak of the scattering intensity as the average particle diameter of the aggregates. However, when the polydispersity index exceeds 20%, the main peak was determined while also referring to the volume-based particle size distribution.
  • the average particle diameter of the peptide aggregate of Example 2-1 or 2-2 was smaller in the pH 7 buffer than in the pH 6 buffer, and from this, It can be seen that the average particle diameter of these peptide complexes is pH dependent.
  • the pH dependence of the average particle size is due to the fact that the ionization state of charged amino acid residues, especially the side chains of histidine, changes depending on the pH of the aqueous medium, and as a result, the hydrophobicity of the hydrophilic region changes. It is assumed that this is caused by.
  • Example 4 Evaluation of binding affinity for second target (Rgp)] Regarding the peptide of Example 1-2 and the Rgp-binding peptide A (RRKRR: SEQ ID NO: 16) constituting the Rgp-binding site of the peptide, the binding affinity for Rgp was determined using "Biacore-T100" (GE Healthcare). Measured by SPR method. Measurements were performed according to conventional methods. Specifically, for the measurement of the peptide in Example 1-2, streptavidin (Extravidin SIGMA E2511) was coupled to a chip (CM5 sensor chip) by amine coupling, followed by NHS-biotinylation at a 20-fold molar ratio.
  • Rgp biotinylated with a reagent (Thermo Fisher Scientific, EZ-Link (R) Sulfo-NHS-SS-Biotin) was immobilized.
  • Rgp was directly immobilized on the CM5 sensor chip by amine coupling.
  • the peptide stock solution (DMSO) was diluted with running buffer (10mM HEPES (pH 7.4), 150mM NaCl, 0.05% Tween, 0.2% DMSO) to give a final peptide concentration of 25, 100, 400, The concentration was adjusted to 1600 nM.
  • the self-associating peptide of Example 1-2 was more effective against Rgp (second target) than Rgp-binding peptide A (non-self-associating peptide containing a second target binding site). also showed high binding affinity. This is considered to be because the peptide of Example 1-2 formed an aggregate in the peptide solution, which allowed it to bind to the target at multiple points, resulting in an avidity effect.
  • the beads were fixed on a magnetic stand (Takara Bio Inc., Magnetic Stand (6 tubes), product code 5328), and after removing the supernatant, 100 ⁇ L of the peptide solution was added.
  • the peptide solution was prepared by diluting the 100 mM stock solution (DMSO) to 40 ⁇ M with 10 mM HEPES (pH 7.4)/1% DMSO, and then sequentially diluting the solution 4 to 5 times. After stirring at 4°C for 4 hours, the tube was placed on a magnetic stand to fix the beads, and the supernatant was collected.
  • the peptide concentration in the supernatant was measured using 50 ⁇ L of the supernatant using a plate reader (Thermo Fisher Scientific, VARIO-SCAN) based on the fluorescence intensity derived from tryptophan contained in the sequence (excitation wavelength: 280 nm, Emission wavelength: 355 nm).
  • the amount of peptide bound to the beads is determined by subtracting the peptide concentration in the supernatant from the total peptide concentration, and the obtained adsorption isotherm is curve-fitted to a theoretical formula (Microsoft Excel) to determine the hydroxyapatite content of the peptide.
  • the dissociation constant K D for the beads was determined. The results are shown in Table 6.
  • the self-associating peptide of Example 1-2 was able to bind HA (the first target) to HA-binding peptide A (a non-self-associating peptide containing the first target binding site). They showed almost equivalent binding affinities. From the results of Experimental Examples 4 and 5, the self-associating peptide of Example 1-2 binds to both the first target and the second target with almost the same or higher affinity than the target-binding peptide alone. It turns out it's possible. On the other hand, the self-associating peptides of Examples 1-5 showed higher binding affinity for HA than HA-binding peptide A.
  • the fluorescent probe method has conventionally been widely used as a method for measuring the critical micelle concentration (CMC) of a surfactant solution.
  • CMC critical micelle concentration
  • a hydrophobic fluorescent molecule is added to an aqueous surfactant solution and excited, weak fluorescence is emitted from the fluorescent molecules dispersed in the solution when the concentration of the surfactant is low.
  • the surfactant concentration exceeds the CMC, hydrophobic fluorescent molecules are taken into the micelle (hydrophobic environment) surrounded by the hydrophobic groups of the surfactant and emit strong fluorescence.
  • pyrene was used as a fluorescent probe, a peptide was used instead of a surfactant, and changes in fluorescence characteristics due to changes in peptide concentration were investigated.
  • Pyrene Fluji Film Wako Pure Chemical Industries, Ltd.
  • 80% ethanol was added, and dissolved using a vortex mixer to prepare a 5 mM stock solution.
  • the stock solution was diluted 500 times with 80% ethanol and adjusted to 10 ⁇ M.
  • the fluorescence intensity clearly increased as the peptide concentration increased.
  • the increase in fluorescence intensity means that a peptide complex was formed that provides a hydrophobic environment in which pyrene can be encapsulated.
  • the concentration at the intersection (point of inflection) of the two obtained straight lines was taken as the critical aggregation concentration (CAC)
  • CAC value of the peptide of Example 1-1 was 50 ⁇ M.
  • the peptides of Examples 1-2 and 1-5 had approximately the same fluorescence intensity up to 0.1 mM. Although a tendency for the fluorescence intensity to increase was observed for all peptides at 0.2 mM, it was judged that determining the CAC value was difficult.
  • the fluorescence intensity increased with increasing peptide concentration for all peptides.
  • ANS is widely used as a probe molecule because its fluorescence intensity increases significantly when placed in a hydrophobic environment compared to pure water.
  • the increase in fluorescence intensity means that a peptide complex that provides a hydrophobic environment capable of encapsulating ANS has been formed.
  • the peptide complexes of Examples 1-2 and 1-5 have a hydrophobicity that can be presented at 0.1 mM, for example.
  • the environment can contain ANS, it can be considered that the environment is not highly hydrophobic enough to contain pyrene.
  • the CAC value was 50 ⁇ M for all peptides.
  • the peptide of Example 3-1 has a hydrophobic region (LLLLLLGG) underlined in Table 7, and is located at its N-terminal side and C-terminal side, both of which have lower hydrophobicity than the hydrophobic region. It has a first hydrophilic region (GYSEWRKWE) and a second hydrophilic region (HWRGWV). It has been confirmed that the peptides of Example 3-1 and Comparative Example 2 form aggregates in water.
  • LLLLGG hydrophobic region underlined in Table 7, and is located at its N-terminal side and C-terminal side, both of which have lower hydrophobicity than the hydrophobic region. It has a first hydrophilic region (GYSEWRKWE) and a second hydrophilic region (HWRGWV). It has been confirmed that the peptides of Example 3-1 and Comparative Example 2 form aggregates in water.
  • mice Male mice (Jackson Laboratory Japan Co., Ltd.) were divided into 6 groups of 3 mice each as shown in Table 8 for experiments. Served.
  • the administration solution was administered into the tail vein of non-fasting mice using a syringe equipped with an injection needle (1 mg/4 mL/kg).
  • the dose administered to each individual was calculated from the body weight measured on the day of administration.
  • approximately 0.1 mL of blood was collected from the jugular vein under anesthesia using a heparin-treated syringe equipped with an injection needle at the predetermined collection time shown in Table 8.
  • the entire amount of blood was collected from the posterior vena cava under isoflurane anesthesia.
  • the collected blood was immediately transferred to a polypropylene tube and cooled on ice.
  • the entire amount of blood collected was centrifuged (approximately 10,000 ⁇ g, 3 minutes, 4° C.), and a plasma sample was immediately collected into a sample storage container and protected from light. Plasma samples were stored frozen until measurement (controlled temperature: approximately -80°C).
  • the plasma sample (10 ⁇ L) after freezing and thawing was diluted 10 times with PBS (90 ⁇ L), and its fluorescence intensity was measured using a plate reader (TECAN, SPARK (R) multi-detection mode microplate reader). Wavelength: 495 nm, emission wavelength: 520 nm).
  • the plasma concentration of the peptide was calculated from the calibration curves prepared in each of Comparative Example 1, Comparative Example 2, and Example 3-1. The obtained plasma concentration was plotted logarithmically against the time after administration, and the four time points including the final blood collection time were approximated by an exponential function (Microsoft Excel), and the elimination half-life was calculated from the slope of the straight line.
  • Example 3-1 has a significantly longer half-life after intravenous administration than the peptides of Comparative Examples 1 and 2. Furthermore, when Comparative Example 1 and Comparative Example 2 were compared, Comparative Example 2 showed a longer half-life. Such an effect of improving blood retention is thought to be due to an increase in the apparent molecular weight of the peptide due to the formation of aggregates. Furthermore, Example 3-1 is thought to exhibit a significantly longer half-life than Comparative Example 2 due to the interaction of the peptide sequence of HWRGWV with the Fc region of immunoglobulin present in the blood.
  • Peptides, peptide complexes, or peptide compositions according to embodiments of the present invention can be suitably used, for example, in DDS systems, pharmaceutical compositions, and the like.

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BYEONGJUN YU; DOBEEN HWANG; HYUNGSU JEON; HYUNGJUN KIM; YONGHYUN LEE; HYEONGSEOP KEUM; JINJOO KIM; DONG YUN LEE; YUJIN KIM; JUNHO : "A Hybrid Platform Based on a Bispecific Peptide–Antibody Complex for Targeted Cancer Therapy", ANGEWANDTE CHEMIE INTERNATIONAL EDITION, VERLAG CHEMIE, HOBOKEN, USA, vol. 58, no. 7, 25 January 2019 (2019-01-25), Hoboken, USA, pages 2005 - 2010, XP072098272, ISSN: 1433-7851, DOI: 10.1002/anie.201811509 *
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