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WO2025171280A1 - Compositions pour administration ciblée à un tissu adipeux - Google Patents

Compositions pour administration ciblée à un tissu adipeux

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Publication number
WO2025171280A1
WO2025171280A1 PCT/US2025/015038 US2025015038W WO2025171280A1 WO 2025171280 A1 WO2025171280 A1 WO 2025171280A1 US 2025015038 W US2025015038 W US 2025015038W WO 2025171280 A1 WO2025171280 A1 WO 2025171280A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino acid
cyclic peptide
agent
seq
peptide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/015038
Other languages
English (en)
Inventor
Jonathan Y. HSU
Uyanga TSEDEV
Lavi Erisson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gensaic Inc
Original Assignee
Gensaic Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gensaic Inc filed Critical Gensaic Inc
Publication of WO2025171280A1 publication Critical patent/WO2025171280A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • 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
    • A61K47/50—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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1137—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/11—Antisense
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/315—Phosphorothioates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/321—2'-O-R Modification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/35—Nature of the modification
    • C12N2310/351—Conjugate
    • C12N2310/3513—Protein; Peptide
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y102/00—Oxidoreductases acting on the aldehyde or oxo group of donors (1.2)
    • C12Y102/01—Oxidoreductases acting on the aldehyde or oxo group of donors (1.2) with NAD+ or NADP+ as acceptor (1.2.1)
    • C12Y102/01003—Aldehyde dehydrogenase (NAD+) (1.2.1.3)

Definitions

  • Adipose tissue is an important metabolic and endocrine organ that contributes to biological functions including energy storage and energy homeostasis. Impairment of adipose tissue functions has been associated with various diseases. Delivery of agents to adipose tissue can be useful in the treatment of such diseases.
  • compositions comprising cyclic peptides that target adipose tissue, as well as the use of such cyclic peptides in the treatment of disease.
  • the present disclosure includes the unexpected finding that cyclic peptides disclosed herein can selectively target receptors present in adipose tissue.
  • the present disclosure therefore provides, among other things compositions cyclic peptides that selectively target adipose tissue, conjugates that include a cyclic peptide of the present disclosure and a therapeutic or diagnostic agent, pharmaceutical compositions, and the treatment of disease (e.g., treatment of diseases associated with adipose tissue) using agents disclosed herein.
  • the present disclosure therefore specifically provides, among other things, conjugates comprising a cyclic peptide disclosed herein associated with a therapeutic or diagnostic agent, and use of such conjugates in the treatment of disease.
  • the present disclosure is based at least in part on the recognition that conjugates comprising cyclic peptides can selectively delivery associated therapeutic or diagnostic agents to adipose tissue.
  • cyclic peptides of the present disclosure can be associated with a therapeutic or diagnostic agent that can be, without limitation, a nucleic acid, peptide, or chemical agent.
  • a nucleic acid agent can be, e.g., an inhibitory nucleic acid or a nucleic acid (e.g., a transgene) that encodes an expression product.
  • Inhibitory nucleic acids can be selected from, without limitation, small interfering RNA (siRNA), microRNA (miRNA), and inhibitory antisense oligonucleotides (ASOs).
  • the cyclic peptide includes an amino acid sequence selected from SEQ ID NOs: 1-3. In certain embodiments, the cyclic peptide includes an amino acid sequence having no more than three amino acid differences from SEQ ID NO: 1. In certain embodiments, the cyclic peptide includes an amino acid sequence according to SEQ ID NO: 1. In certain embodiments, the cyclic peptide includes an amino acid sequence having no more than three amino acid differences from SEQ ID NO: 2. In certain embodiments, the cyclic peptide includes an amino acid sequence according to SEQ ID NO: 2. In certain embodiments, the cyclic peptide includes an amino acid sequence having no more than three amino acid differences from SEQ ID NO: 3. In certain embodiments, the cyclic peptide includes an amino acid sequence according to SEQ ID NO: 3. In certain embodiments, the adipose tissue is white adipose tissue (WAT).
  • WAT white adipose tissue
  • the present disclosure provides a peptide conjugate including a cyclic peptide including an amino acid sequence having no more than three amino acid differences from a sequence selected from SEQ ID NOs: 1-161, where each amino acid difference is independently selected from an insertion of an amino acid, a deletion of an amino acid, or a substitution of an amino acid, and an agent associated with the cyclic peptide.
  • the cyclic peptide includes an amino acid sequence selected from SEQ ID NOs: 1-161.
  • the cyclic peptide includes an amino acid sequence having no more than three amino acid differences from a sequence selected from SEQ ID NOs: 1-3.
  • the cyclic peptide includes an amino acid sequence selected from SEQ ID NOs: 1-3. In certain embodiments, the cyclic peptide includes an amino acid sequence having no more than three amino acid differences from SEQ ID NO: 1. In certain embodiments, the cyclic peptide includes an amino acid sequence according to SEQ ID NO: 1. In certain embodiments, the cyclic peptide includes an amino acid sequence having no more than three amino acid differences from SEQ ID NO: 2. In certain embodiments, the cyclic peptide includes an amino acid sequence according to SEQ ID NO: 2. In certain embodiments, the cyclic peptide includes an amino acid sequence having no more than three amino acid differences from SEQ ID NO: 3. In certain embodiments, the cyclic peptide includes an amino acid sequence according to SEQ ID NO: 3.
  • the agent is a diagnostic agent or a therapeutic agent.
  • the therapeutic agent targets a target according to Table 2.
  • the agent is an inhibitory nucleic acid.
  • the agent is an antisense oligonucleotide.
  • the agent is an siRNA or a miRNA.
  • the antisense oligonucleotide is a phosphorodiamidate morpholino oligonucleotide (PMO) or a peptide nucleic acid (PNA).
  • the agent is an adeno-associated virus (AAV).
  • the agent is a lipid nanoparticle (LNP).
  • the agent is non-covalently associated with the cyclic peptide. In certain embodiments, the agent is covalently associated with the cyclic peptide. In certain embodiments, the agent is directly covalently associated with the cyclic peptide. In certain embodiments, the agent is indirectly covalently associated with the cyclic peptide. In certain embodiments, the agent is indirectly covalently associated with the cyclic peptide via a linker. In certain embodiments, the linker includes a thioether bond, a disulfide bond, an oxime, a thiazolidine, a hydrazone, an amide bond, an azide bond, or a maleimide bond.
  • alkenoxy or alkenoxyl
  • alkenoxyl means an alkenyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • the aromatic ring may be substituted at one or more ring positions with one or more substituents, such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluromethyl), cyano, or the like.
  • substituents such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, im
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is an aromatic hydrocarbon, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • the term “aryl” refers to a phenyl group.
  • “aryl” has from 6 to 10 carbon atoms.
  • a conservative substitution is one in which an amino acid has been replaced by a non-identical residue having appropriately similar structural and/or functional characteristics. For example, as is well known by those of ordinary skill in the art, certain amino acids are typically classified as “hydrophobic” or “hydrophilic” amino acids, and/or as having “polar” or “non-polar” side chains. Substitution of one amino acid for another of the same type may often be considered a conservative substitution. Certain non-limiting amino acid categorizations are summarized below. Those of skill in the art will be aware of the categorizations and relationships among amino acids that can be used to identify a conservative substitution. [0048] Cycloalkyl.
  • cycloalkyl means mono- or bicyclic or bridged saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Certain cycloalkyls have from 5-12 carbon atoms in their ring structure, and may have 6-10 carbons in the ring structure. Preferably, cycloalkyl is (C3-C7)cycloalkyl, which represents a monocyclic saturated carbocyclic ring, having from 3 to 7 carbon atoms.
  • Bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (z.e., a bridging group of the form -(CH2)>r-, where w is 1, 2, or 3).
  • Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane.
  • the fused bicyclic cycloalkyl is a 5 or 6 membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted.
  • Gene refers to a DNA sequence that is or includes a coding sequence (i.e., a DNA sequence that encodes an expression product, such as an RNA product and/or a polypeptide product), optionally together with some or all of the regulatory sequences that control expression of the coding sequence.
  • a coding sequence i.e., a DNA sequence that encodes an expression product, such as an RNA product and/or a polypeptide product
  • Heteroaryloxy means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Heteroatom The term “heteroatom” is art-recognized and refers to an atom of any element other than carbon or hydrogen. Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium, and alternatively oxygen, nitrogen or sulfur.
  • a nucleic acid can include one or more peptide nucleic acids, which are known in the art and have peptide bonds instead of phosphodiester bonds in the backbone.
  • a nucleic acid has one or more phosphorothioate and/or 5'-N-phosphoramidite linkages rather than phosphodiester bonds.
  • a nucleic acid includes one or more modified sugars (e.g., 2'- fluororibose, ribose, 2'-deoxyribose, arabinose, and hexose) as compared with those in natural nucleic acids.
  • a nucleic acid is or includes at least 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 1 10, 120, 130, 140, 150, 160, 170, 180, 190, 20, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000 or more residues.
  • a nucleic acid is partly or wholly single stranded, or partly or wholly double stranded.
  • materials which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer
  • composition or formulation As used herein, the term
  • a polypeptide may include only L-amino acids.
  • a polypeptide may include one or more pendant groups or other modifications, e.g., one or more amino acid side chains, e.g., at the polypeptide’s N-terminus, at the polypeptide’s C-terminus, at non-terminal amino acids, or at any combination thereof.
  • such pendant groups or modifications may be selected from acetylation, amidation, lipidation, methylation, phosphorylation, glycosylation, glycation, sulfation, mannosylation, nitrosylation, acylation, palmitoylation, prenylation, pegylation, etc., including combinations thereof.
  • a polypeptide may be cyclic, and/or may include a cyclic portion.
  • polypeptide may be appended to a name of a reference polypeptide, activity, or structure to indicate a class of polypeptides that share a relevant activity or structure.
  • a member of a polypeptide class or family shows significant sequence homology or identity with, shares a common sequence motif (e.g., a characteristic sequence element) with, and/or shares a common activity (in some embodiments at a comparable level or within a designated range) with a reference polypeptide of the class.
  • a member polypeptide shows an overall degree of sequence homology or identity with a reference polypeptide that is at least about 30-40%, and is often greater than about 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more and/or includes at least one region (e.g., a conserved region that can in some embodiments be or include a characteristic sequence element) that shows very high sequence identity, often greater than 90% or even 95%, 96%, 97%, 98%, or 99%.
  • a conserved region that can in some embodiments be or include a characteristic sequence element
  • a conserved region usually encompasses at least 3-4 and in some instances up to 20 or more amino acids; in some embodiments, a conserved region encompasses at least one stretch of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more contiguous amino acids.
  • a relevant polypeptide can be or include a fragment of a parent polypeptide.
  • a useful polypeptide may be or include a plurality of fragments, each of which is found in the same parent polypeptide in a different spatial arrangement relative to one another than is found in the polypeptide of interest (e.g., fragments that are directly linked in the parent may be spatially separated in the polypeptide of interest or vice versa, and/or fragments may be present in a different order in the polypeptide of interest than in the parent), so that the polypeptide of interest is a derivative of its parent polypeptide.
  • reference refers to a standard or control relative to which a comparison is performed.
  • an agent, sample, sequence, subject, animal, or individual, or population thereof, or a measure or characteristic representative thereof is compared with a reference, an agent, sample, sequence, subject, animal, or individual, or population thereof, or a measure or characteristic representative thereof.
  • a reference is a measured value.
  • a reference is an established standard or expected value.
  • a reference is a historical reference.
  • a reference can be quantitative of qualitative. Typically, as would be understood by those of skill in the art, a reference and the value to which it is compared represents measure under comparable conditions.
  • an appropriate reference may be an agent, sample, sequence, subject, animal, or individual, or population thereof, under conditions those of skill in the art will recognize as comparable, e.g., for the purpose of assessing one or more particular variables (e.g., presence or absence of an agent or condition), or a measure or characteristic representative thereof.
  • Sample typically refers to an aliquot of material obtained or derived from a source of interest.
  • a source of interest is a biological or environmental source.
  • a sample is a “primary sample” obtained directly from a source of interest.
  • sample refers to a preparation that is obtained by processing of a primary sample (e.g., by removing one or more components of and/or by adding one or more agents to a primary sample).
  • a “processed sample” can include, for example cells, nucleic acids, or proteins extracted from a sample or obtained by subjecting a primary sample to techniques such as isolation and/or purification of certain components.
  • Silyl includes hydrocarbyl derivatives of the silyl (HsSi-) group (i.e., (hydrocarbyl )3 Si-), wherein a hydrocarbyl groups are univalent groups formed by removing a hydrogen atom from a hydrocarbon, e.g., ethyl, phenyl.
  • the hydrocarbyl groups can be combinations of differing groups which can be varied in order to provide a number of silyl groups, such as trimethyl silyl (TMS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethyl silyl (TBS/TBDMS), triisopropyl silyl (TIPS), and [2- (trimethylsilyl)ethoxy]methyl (SEM).
  • TMS trimethyl silyl
  • TDPS tert-butyldiphenylsilyl
  • TIPS triisopropyl silyl
  • SEM [2- (trimethylsilyl)ethoxy]methyl
  • Silyloxy means a silyl group, as defined herein, is appended to the parent molecule through an oxygen atom.
  • Specific binding refers to an ability to discriminate between possible binding partners in the environment in which binding is to occur.
  • a binding agent that interacts with one particular target when other potential targets are present is said to "bind specifically" to the target with which it interacts.
  • specific binding is assessed by detecting or determining degree of association between the binding agent and its partner; in some embodiments, specific binding is assessed by detecting or determining degree of dissociation of a binding agent-partner complex; in some embodiments, specific binding is assessed by detecting or determining ability of the binding agent to compete an alternative interaction between its partner and another entity. In some embodiments, specific binding is assessed by performing such detections or determinations across a range of concentrations.
  • Subject refers to an organism, typically a mammal (e.g., a human, rat, or mouse).
  • a subject is suffering from a disease, disorder or condition.
  • a subject is susceptible to a disease, disorder, or condition.
  • a subject displays one or more symptoms or characteristics of a disease, disorder or condition.
  • a subject is not suffering from a disease, disorder or condition.
  • a subject does not display any symptom or characteristic of a disease, disorder, or condition.
  • a subject has one or more features characteristic of susceptibility to or risk of a disease, disorder, or condition.
  • a subject is a subject that has been tested for a disease, disorder, or condition, and/or to whom therapy has been administered.
  • a human subject can be interchangeably referred to as a “patient” or “individual.”
  • a subject administered an agent associated with treatment of a disease, disorder, or condition with which the subject is associated can be referred to as a subject in need of the agent, i.e., as a subject in need thereof.
  • substitution or substituted with. It will be understood that “substitution” or “substituted with,” as used herein with respect to molecular structures, includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, fragmentation, decomposition, cyclization, elimination, or other reaction, except in such instances as cyclization is desired in accordance with the present disclosure.
  • substituted is also contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described herein above.
  • the permissible substituents may be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • therapeutic agent refers to any agent that elicits a desired pharmacological effect when administered to a subject.
  • an agent is considered to be a therapeutic agent if it demonstrates a statistically significant effect across an appropriate population.
  • the appropriate population can be a population of model organisms or a human population.
  • an appropriate population can be defined by various criteria, such as a certain age group, gender, genetic background, preexisting clinical conditions, etc.
  • a therapeutic agent is a substance that can be used for treatment of a disease, disorder, or condition.
  • a therapeutic agent is an agent that has been or is required to be approved by a government agency before it can be marketed for administration to humans.
  • a therapeutic agent is an agent for which a medical prescription is required for administration to humans.
  • Therapeutic regimen refers to a dosing regimen whose administration across a relevant population may be correlated with a desired or beneficial therapeutic outcome.
  • therapeutically effective amount refers to an amount that produces the desired effect for which it is administered. In some embodiments, the term refers to an amount that is sufficient, when administered to a population suffering from or susceptible to a disease, disorder, and/or condition in accordance with a therapeutic dosing regimen, to treat the disease, disorder, and/or condition. In some embodiments, a therapeutically effective amount is one that reduces the incidence and/or severity of, and/or delays onset of, one or more symptoms of the disease, disorder, and/or condition. Those of ordinary skill in the art will appreciate that a therapeutically effective amount does not necessarily achieve successful treatment in every particular treated individual.
  • a therapeutically effective amount may be that amount that provides a particular desired pharmacological response in a significant number of subjects when administered to patients in need of such treatment.
  • reference to a therapeutically effective amount may be a reference to an amount as measured in one or more specific tissues (e.g., a tissue affected by the disease, disorder or condition) or fluids (e.g., blood, saliva, serum, sweat, tears, urine, etc.).
  • tissue e.g., a tissue affected by the disease, disorder or condition
  • fluids e.g., blood, saliva, serum, sweat, tears, urine, etc.
  • a therapeutically effective amount of a particular agent or therapy may be formulated and/or administered in a single dose.
  • a therapeutically effective agent may be formulated and/or administered in a plurality of doses, for example, as part of a dosing regimen.
  • Treatment refers to administration of a therapy that partially or completely alleviates, ameliorates, relieves, inhibits, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms, features, and/or causes of a particular disease, disorder, or condition, or is administered for the purpose of achieving any such result.
  • treatment can be of a subject who does not exhibit signs of the relevant disease, disorder, or condition and/or of a subject who exhibits only early signs of the disease, disorder, or condition.
  • such treatment can be of a subject who exhibits one or more established signs of the relevant disease, disorder and/or condition.
  • treatment can be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and/or condition.
  • treatment can be of a subject known to have one or more susceptibility factors that are statistically correlated with increased risk of development of the relevant disease, disorder, or condition.
  • the terms “disease,” “disorder,” and “condition,” and any equivalents thereto can be used interchangeably, such that use of any one likewise constitutes the use of its alternatives unless otherwise indicated.
  • the present disclosure includes the discovery of compositions comprising cyclic peptides that selectively target the adipose tissue, as set forth herein.
  • the present disclosure includes the recognition that, in various embodiments, cyclic peptides provided herein are useful for delivering an associated agent to adipose tissue, e.g., for treatment and/or diagnosis of a disease (e.g., a disease associated with adipose tissue).
  • a cyclic peptide of the present disclosure is or includes a sequence selected from SEQ ID NOs: 1-161 as set forth herein (e.g., in Table 1), or a variant thereof.
  • the present disclosure provides a cyclic peptide that is or comprises a polypeptide that differs from a sequence selected from SEQ ID NOs: 1- 161 by one or more amino acid sequence differences.
  • an amino acid difference refers to a deletion (the deletion of one amino acid), an insertion (an insertion of one amino acid), or a substitution (a substitution of one amino acid for another different amino acid).
  • each amino acid difference can be independently selected from, e.g., a deletion, an insertion, or a substitution.
  • Sequences that have one or more amino acid differences from a sequence disclosed herein can be referred to, e.g., as “variants” or “mutants.”
  • the present disclosure provides a cyclic peptide that is or comprises a polypeptide that differs from a sequence selected from SEQ ID NOs: 1-161 by at least 1, at least 2, at least 3, at least 4, or at least 5 amino acid sequence differences. In various embodiments, the present disclosure provides a cyclic peptide that is or comprises a polypeptide that differs from a sequence selected from SEQ ID NOs: 1-161 by exactly 1, exactly 2, exactly 3, exactly 4, or exactly 5 amino acid sequence differences.
  • the present disclosure provides a cyclic peptide that is or comprises a polypeptide that differs from a sequence selected from SEQ ID NOs: 1-161 by 1 to 5 amino acid differences, 1 to 4 amino acid differences, 1 to 3 amino acid differences, or 1 to 2 amino acid differences.
  • the present disclosure provides a cyclic peptide that is or includes a polypeptide having a sequence selected from SEQ ID NOs: 1-161, and/or a cyclic peptide that is or includes a variant of a polypeptide having a sequence selected from SEQ ID NOs: 1-161 (e.g., that includes at least one amino acid sequence difference as compared to a sequence selected from SEQ ID NOs: 1-161), where the N-terminal amino acid of the cyclic peptide is a cysteine residue, the C-terminal amino acid of the cyclic peptide is a cysteine residue, and/or both the N-terminal amino acid and the C-terminal amino acid of the cyclic peptide are cysteine residues.
  • a cyclic peptide of the present disclosure is or includes a sequence according to SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3 as set forth herein (e.g., in Table 1), or a variant thereof.
  • the present disclosure provides a cyclic peptide that is or comprises a polypeptide that differs from SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3 by one or more amino acid sequence differences.
  • the present disclosure provides a cyclic peptide that is or comprises a polypeptide that differs from SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3 by at least 1, at least 2, at least 3, at least 4, or at least 5 amino acid sequence differences.
  • the present disclosure provides a cyclic peptide that is or comprises a polypeptide that differs from SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3 by exactly 1, exactly 2, exactly 3, exactly 4, or exactly 5 amino acid sequence differences.
  • the present disclosure provides a cyclic peptide that is or comprises a polypeptide that differs from SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3 by 1 to 5 amino acid differences, 1 to 4 amino acid differences, 1 to 3 amino acid differences, or 1 to 2 amino acid differences.
  • a cyclic peptide of the present disclosure includes an amino acid sequence according to SEQ ID NO: 1. In various embodiments, a cyclic peptide of the present disclosure includes an amino acid sequence having no more than 1, 2, 3, 4, or 5 amino acid differences with SEQ ID NO: 1. In various embodiments, a cyclic peptide of the present disclosure includes an amino acid sequence having no more than 1, 2, 3, 4, or 5 amino acid substitutions, deletions, and/or insertions as compared to a cyclic peptide of SEQ ID NO: 1.
  • a cyclic peptide of the present disclosure includes an amino acid sequence according to SEQ ID NO: 2. In various embodiments, a cyclic peptide of the present disclosure includes an amino acid sequence having no more than 1, 2, 3, 4, or 5 amino acid differences with SEQ ID NO: 2. In various embodiments, a cyclic peptide of the present disclosure includes an amino acid sequence having no more than 1, 2, 3, 4, or 5 amino acid substitutions, deletions, and/or insertions as compared to a cyclic peptide of SEQ ID NO: 2.
  • a cyclic peptide of the present disclosure includes an amino acid sequence according to SEQ ID NO: 3. In various embodiments, a cyclic peptide of the present disclosure includes an amino acid sequence having no more than 1, 2, 3, 4, or 5 amino acid differences with SEQ ID NO: 3. In various embodiments, a cyclic peptide of the present disclosure includes an amino acid sequence having no more than 1, 2, 3, 4, or 5 amino acid substitutions, deletions, and/or insertions as compared to a cyclic peptide of SEQ ID NO: 3.
  • the present disclosure includes peptide sequences that are larger than one or more of the cyclic peptides disclosed in SEQ ID NOs: 1-161 and/or that are larger than one or more variants thereof.
  • the sequence of a cyclic peptide of the present disclosure, or a variant thereof can be present in a larger polypeptide that is partially or entirely cyclic (e.g., for which a contiguous backbone is partially or entirely cyclic).
  • a cyclic peptide of the present disclosure can have a length of, e.g., 3 to 40, or more, amino acids.
  • a cyclic peptide of the present disclosure can have a length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or more amino acids.
  • a cyclic peptide of the present disclosure can have a length that is between 8 and 40 amino acids, 8 and 35 amino acids, 8 and 30 amino acids, 8 and 25 amino acids, 8 and 20 amino acids, 8 and 19 amino acids, 8 and 18 amino acids, 8 and 17 amino acids, 8 and 16 amino acids, 8 and 15 amino acids, 8 and 14 amino acids, 8 and 13 amino acids, 8 and 12 amino acids, 8 and 11 amino acids, 8 and 10 amino acids, 8 and 9 amino acids, 8 and 8 amino acids.
  • a peptide comprising two amino acids that have a thiol group can be cyclized under conditions wherein a disulfide bridge between the thiol groups of the two amino acids containing a thiol group is formed.
  • Examples of amino acids having a thiol group and thus being capable of forming a bridge, i.e. a disulfide bridge include, but are not limited to, cysteine.
  • cyclic peptides disclosed herein include two or more cysteine residues.
  • cyclic peptides disclosed herein can include
  • AAV capsids include 12 hypervariable regions exposed on the capsid surface.
  • the AAV is indirectly covalently associated with a cyclic peptide via a linker.
  • the AAV is covalently associated with a cyclic peptide via a functional group (e.g., a chemical handle) of the AAV capsid.
  • the AAV is covalently associated with a cyclic peptide via a lysine or arginine residue on the AAV capsid.
  • the AAV capsid comprises an unnatural amino acid.
  • a covalent association between the AAV and a cyclic peptide is formed via a click chemistry reaction between an alkyne and an azide. In certain embodiments, a covalent association between the AAV and a cyclic peptide is formed via a click chemistry reaction between an alkyne of the cyclic peptide and an azide of the AAV capsid.
  • the AAV can be used as a vehicle, e.g., vehicle for the delivery of a nucleic acid (e.g., a nucleic acid provided in Table 2, or a nucleic acid encoding a protein or RNA provided in Table 2).
  • the agent is a lipid nanoparticle (LNP).
  • LNPs can include one or more lipid components.
  • LNPs may be used as carriers for therapeutic agents and can include synthetic ionizable or cationic lipids, phospholipids, cholesterol, and a polyethylene glycol (PEG) lipid.
  • PEG polyethylene glycol
  • the LNP is not covalently associated with a cyclic peptide.
  • the LNP is covalently associated with a cyclic peptide (e.g., via association of the cyclic peptide with an LNP component such as a synthetic ionizable or cationic lipid, phospholipid, cholesterol, or PEG lipid).
  • a covalent association between the LNP and a cyclic peptide is formed via an amidation reaction. In some embodiments, a covalent association between the LNP and a cyclic peptide is formed from an amine of the cyclic peptide and a carboxylic acid of the LNP.
  • the nucleic acid agent is a transgene (e.g., a transgene according to Table 2, or a transgene encoding a protein or RNA according to Table 2).
  • a transgene includes a nucleic acid (e.g., DNA or RNA) sequence encoding a protein or RNA (e.g., a functional non-coding RNA).
  • the transgene includes an open reading frame encoding a protein or RNA (e.g., a functional noncoding RNA).
  • a transgene may be isolated from an organism and introduced into a different organism of the same or different species to produce the transgene product (e.g., the protein or RNA).
  • a therapeutic agent includes a small molecule agent.
  • a small molecule agent includes DNA damaging agents, agents that inhibit DNA synthesis, microtubule and tubulin binding agents, anti-metabolites, inducers of oxidative damage, anti angiogenics, endocrine therapies, anti-estrogens, immuno-modulators such as Toll-like receptor agonists or antagonists, histone deacetylase inhibitors, inhibitors of signal transduction such as inhibitors of kinases, inhibitors of heat shock proteins, retinoids, inhibitors of growth factor receptors, anti-mitotic compounds, anti-inflammatories, cell cycle regulators, transcription factor inhibitors, and apoptosis inducers, and any combination thereof.
  • a therapeutic agent includes a chemotherapeutic agent.
  • chemotherapeutic agents include, but are not limited to methotrexate, daunomycin, mitomycin, cisplatin (cisplatinum or cis-dianminedichloroplatinum(II) (CCDP)), vincristine, epirubicin, fluorouracil, verapamil, cyclophosphamide, cytosine arabinoside, aminopterin, bleomycin, mitomycin C, democolcine, etoposide, mithramycin, chlorambucil, melphalan, daunorubicin, doxorubicin, tamoxifen, paclitaxel, vincristine, vinblastine, camptothecin, actinomycin D, and cytarabine, combrestatin and its derivatives.
  • Diagnostic agents of the present disclosure can include, e.g., agents that label tissue (e.g., adipose tissue) and/or are useful in the diagnosis of one or more medical conditions.
  • an agent includes an imaging agent.
  • Diagnostic agents of the present disclosure can include, e.g., without limitation, a fluorescent label, luminescent label, enzyme, or detectable tag.
  • imaging agents include, but are not limited to, the following: radioisotopes (e.g., 3 H, 14 C, 35 S, 125 I, 131 I) fluorescent labels (e.g., FITC, rhodamine, lanthanide phosphors), MRI contrast agents (e.g., Gadolinum chelates (Gd)) luminescent labels such as luminol; enzymatic labels (e.g., horseradish peroxidase, betagalactosidase, luciferase, alkaline phosphatase, acetylcholinesterase), biotinyl groups (which can be detected by marked avidin e.g., streptavidin containing a fluorescent marker or enzymatic activity that can be detected by optical or calorimetric methods), predetermined polypeptide epitopes recognized by a secondary reporter (e.g., leucine zipper pair sequences, binding sites for secondary antibodies, metal binding domains, epitope tags).
  • an image agent includes any suitable radionuclide, including but not limited to 227 Ac, 211 At, 131 Ba, 77 Br, 109 Cd, 51 Cr, 67 Cu, 165 Dy, 155 Eu, 153 Gd, 198 Au, 166 Ho, 113m In, 115m In, 123 I, 125 I, 131 I, 189 Ir, 191 Ir, 192 Ir, 194 Ir, 52 Fe, 55 Fe, 59 Fe, 177 Lu, 109 Pd, 32 P, 226 Ra, 186 Re, 188 Re, 153 Sm, 46 Sc, 47 Sc, 72 Se, 75 Se, 105 Ag, 89 Sr, 35 S, 177 Ta, 117 mSn, 121 Sn, 166 Yb, 169 Yb, 90 Y, 212 Bi, 119 Sb, 197 Hg, 100 Pd, 101m Rh, and 212 Pb.
  • a radionuclide may also be useful in delivering
  • Cyclic peptides and peptide conjugates of the present disclosure are useful for various applications (e.g., therapeutic or diagnostic applications), including without limitation the treatment of diseases (e.g., diseases associated with the adipose tissue).
  • the present disclosure includes the broad recognition that cyclic peptides and peptide conjugates of the present disclosure can be useful to deliver an agent to the adipose tissue and to treat a disease (e.g., diseases associated with the adipose tissue).
  • cyclic peptides and peptide conjugates of the present disclosure are not limited in use to the treatment of diseases associated with the adipose tissue, and can instead be used in the treatment of any condition in any tissue for which a cyclic peptide has selectivity.
  • compositions for delivery of one or more agents to a subject include pharmaceutical compositions for delivery of one or more agents to a subject.
  • a pharmaceutical composition may be in any form known in the art, including formulations for administration according to any route known in the art.
  • a suitable means of administration can be selected based on the age and condition of a subject.
  • composition forms of the present disclosure can include, e.g., liquid, semi-solid and solid dosage forms.
  • Pharmaceutical composition forms of the present disclosure can include, e.g., liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. Selection or use of any particular form may depend, in part, on the intended mode of administration and therapeutic application. Accordingly, the compositions can be formulated for administration by a parenteral mode (e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection).
  • a parenteral mode e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection.
  • parenteral administration refers to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intranasal, intraocular, pulmonary, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intrapulmonary, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intracerebral, intracranial, intracarotid, and intrasternal injection and infusion.
  • compositions provided herein are present in unit dosage form, which unit dosage form can be suitable for self-administration.
  • a unit dosage form may be provided within a container, e.g., a pill, vial, cartridge, prefilled syringe, or disposable pen.
  • a pharmaceutical composition of the present disclosure can be in an injectable or infusible form.
  • the present disclosure includes sterile formulations for injection, which can be formulated in accordance with conventional pharmaceutical practices.
  • Sterile injectable solutions can be prepared by incorporating a composition described herein in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filter sterilization.
  • Injectable solutions can be formulated, e.g., using distilled water, physiological saline, or an isotonic solution containing glucose and other supplements such as D-sorbitol, D-mannose, D-mannitol, or sodium chloride as an aqueous solution for injection, optionally in combination with a suitable solubilizing agent, for example, an alcohol such as ethanol and/or a polyalcohol such as propylene glycol or polyethylene glycol, and/or a nonionic surfactant such as polysorbate 80TM or HCO-50, and the like.
  • a suitable solubilizing agent for example, an alcohol such as ethanol and/or a polyalcohol such as propylene glycol or polyethylene glycol, and/or a nonionic surfactant such as polysorbate 80TM or HCO-50, and the like.
  • sterile powders for the preparation of sterile injectable solutions methods for preparation include vacuum drying and freeze-drying that yield a powder of a composition described herein plus any additional desired ingredient (see below) from a previously sterile-filtered solution thereof.
  • the proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prolonged absorption of injectable compositions can be brought about by including in the composition a reagent that delays absorption, for example, monostearate salts, and gelatin.
  • a pharmaceutical composition can be formulated, for example, as a buffered solution at a suitable concentration and suitable for storage, e.g., at 2-8°C (e.g., 4°C).
  • a pharmaceutical composition of the present disclosure can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable for stable storage at high concentration.
  • dispersions are prepared by incorporating a composition described herein into a sterile vehicle that contains a basic dispersion medium.
  • a pharmaceutical composition can be formulated to include a pharmaceutically acceptable carrier or excipient.
  • pharmaceutically acceptable carriers include, without limitation, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • Pharmaceutical composition of therapeutic agents of the present disclosure can include pharmaceutically acceptable salts, e.g., an acid addition salt or a base addition salt.
  • compositions can be formulated with a carrier that will protect the compound against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a carrier that will protect the compound against rapid release
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are known in the art. See, e.g., J. R. Robinson (1978) “Sustained and Controlled Release Drug Delivery Systems,” Marcel Dekker, Inc., New York.
  • Route of administration can be parenteral, for example, administration by injection, transnasal administration, transpulmonary administration, or transcutaneous administration.
  • Administration can be by intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection.
  • Administration can be systemic or local.
  • a composition described herein can be therapeutically delivered to a subject by way of local administration.
  • local administration or “local delivery,” can refer to delivery that does not rely upon transport of the composition or agent to its intended target tissue (e.g., adipose tissue) or site via the vascular system.
  • the composition may be delivered by injection or implantation of the composition or agent or by injection or implantation of a device containing the composition or agent.
  • following local administration in the vicinity of a target tissue or site e.g., adipose tissue
  • the composition or agent, or one or more components thereof may diffuse to an intended target tissue or site that is not the site of administration.
  • a pharmaceutical composition can be administered parenterally in the form of an injectable formulation comprising a sterile solution or suspension in water or another pharmaceutically acceptable liquid.
  • a pharmaceutical composition can be formulated by suitably combining the therapeutic molecule with pharmaceutically acceptable vehicles or media, such as sterile water and physiological saline, vegetable oil, emulsifier, suspension agent, surfactant, stabilizer, flavoring excipient, diluent, vehicle, preservative, binder, followed by mixing in a unit dose form required for generally accepted pharmaceutical practices.
  • pharmaceutically acceptable vehicles or media such as sterile water and physiological saline, vegetable oil, emulsifier, suspension agent, surfactant, stabilizer, flavoring excipient, diluent, vehicle, preservative, binder, followed by mixing in a unit dose form required for generally accepted pharmaceutical practices.
  • examples of oily liquid include sesame oil and soybean oil, and it may be combined with benzyl benzoate or benzyl alcohol as a solubilizing agent.
  • subcutaneous administration can be accomplished by means of a device, such as a syringe, a prefilled syringe, an auto-injector (e.g., disposable or reusable), a pen injector, a patch injector, a wearable injector, an ambulatory syringe infusion pump with subcutaneous infusion sets, or other device for combining with a therapeutic agent for subcutaneous injection.
  • a device such as a syringe, a prefilled syringe, an auto-injector (e.g., disposable or reusable), a pen injector, a patch injector, a wearable injector, an ambulatory syringe infusion pump with subcutaneous infusion sets, or other device for combining with a therapeutic agent for subcutaneous injection.
  • An injection system of the present disclosure may employ a delivery pen as described in U.S. Pat. No. 5,308,341.
  • Pen devices most commonly used for self-delivery of insulin to patients with diabetes, are well known in the art. Such devices can include at least one injection needle (e.g., a 31 gauge needle of about 5 to 8 mm in length), are typically prefilled with one or more therapeutic unit doses of a therapeutic solution, and are useful for rapidly delivering solution to a subject with as little pain as possible.
  • One medication delivery pen includes a vial holder into which a vial of a therapeutic or other medication may be received.
  • the pen may be an entirely mechanical device or it may be combined with electronic circuitry to accurately set and/or indicate the dosage of medication that is injected into the user.
  • the needle of the pen device is disposable and the kits include one or more disposable replacement needles.
  • Pen devices suitable for delivery of any one of the presently featured compositions are also described in, e.g., U.S. Pat. Nos. 6,277,099; 6,200,296; and 6,146,361, the disclosures of each of which are incorporated herein by reference in their entirety.
  • a microneedle-based pen device is described in, e.g., U.S. Pat. No. 7,556,615, the disclosure of which is incorporated herein by reference in its entirety. See also the Precision Pen Injector (PPI) device, MOLLYTM, manufactured by Scandinavian Health Ltd.
  • PPI Precision Pen Injector
  • compositions can be formulated in a composition suitable for intrapulmonary administration (e.g., for administration via an inhaler or nebulizer) to a mammal such as a human.
  • Methods for formulating such compositions are well known in the art.
  • Dry powder inhaler formulations and suitable systems for administration of the formulations are also known in the art.
  • Pulmonary administration may be oral and/or nasal.
  • Examples of pharmaceutical devices for pulmonary delivery include metered dose inhalers, dry powder inhalers (DPIs), and nebulizers.
  • a composition described herein can be administered to the lungs of a subject by way of a dry powder inhaler.
  • inhalers are propellant-free devices that deliver dispersible and stable dry powder formulations to the lungs.
  • DPI devices have been used for pulmonary administration of polypeptides such as insulin and growth hormone.
  • a composition described herein can be intrapulmonarily administered by way of a metered dose inhaler.
  • These inhalers rely on a propellant to deliver a discrete dose of a compound to the lungs.
  • compositions can be formulated for delivery to the eye, e.g., in the form of a pharmaceutically acceptable solution, suspension or ointment.
  • a preparation for use in treating an eye can be in the form of a sterile aqueous solution containing, e.g., additional ingredients such as, but not limited to, preservatives, buffers, tonicity agents, antioxidants and stabilizers, nonionic wetting or clarifying agents, and viscosity -increasing agents.
  • a preparation as described herein can be administered topically to the eye of the subject in need of treatment (e.g., a subject afflicted with AMD) by conventional methods, e.g., in the form of drops, or by bathing the eye in a therapeutic solution, containing one or more compositions.
  • a variety of devices for introducing drugs into the vitreal cavity of the eye may be appropriate, in certain embodiments, for administration of a composition as described herein.
  • U.S. Publication No. 2002/0026176 describes a pharmaceuticalcontaining plug that can be inserted through the sclera such that it projects into the vitreous cavity to deliver the pharmaceutical agent into the vitreous cavity.
  • U.S. Patent No. 5,443,505 describes an implantable device for introduction into a suprachoroidal space or an avascular region for sustained release of drug into the interior of the eye.
  • a composition described herein can be locally administered to a joint (e.g., an articulated joint).
  • a therapeutically appropriate composition can be administered directly to a joint (e.g., into a joint space) or in the vicinity of a joint.
  • intraarticular joints to which a composition described herein can be locally administered include, e.g., the hip, knee, elbow, wrist, sternoclavicular, temporomandibular, carpal, tarsal, ankle, and any other joint subject to arthritic conditions.
  • a composition described herein can also be administered to bursa such as, e.g., acromial, bicipitoradial, cubitoradial, deltoid, infrapatellar, ischial, and any other bursa known in the art of medicine.
  • bursa such as, e.g., acromial, bicipitoradial, cubitoradial, deltoid, infrapatellar, ischial, and any other bursa known in the art of medicine.
  • a composition can be formulated for storage at a temperature below 0°C (e.g., -20°C or -80°C).
  • the composition can be formulated for storage for up to 2 years (e.g., one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, 10 months, 11 months, 1 year, 11/2 years, or 2 years) at 2-8°C (e.g., 4°C).
  • the compositions described herein are stable in storage for at least 1 year at 2-8°C (e.g., 4°C).
  • a pharmaceutical composition can include a therapeutically effective amount of a therapeutic agent described herein.
  • a therapeutically effective amount can be an amount at which any toxic or detrimental effects of the composition are outweighed by therapeutically beneficial effects.
  • a dose can also be chosen to reduce or avoid production of antibodies or other host immune responses against a therapeutic agent.
  • data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the amount of active ingredient included in a pharmaceutical preparations is such that a suitable dose within the designated range can be administered to subjects.
  • the dose and method of administration can vary depending on weight, age, condition, and other characteristics of a patient, and can be suitably selected as needed by those skilled in the art.
  • compositions including certain therapeutic agents can be administered as a fixed dose, or in a milligram per kilogram (mg/kg) dose.
  • an exemplary single dose of certain pharmaceutical compositions described herein can include certain therapeutic agents as described herein in an amount equal to, e.g., 0.001 to 1000 mg/kg, 1-1000 mg/kg, 1-100 mg/kg, 0.5-50 mg/kg, 0.1-100 mg/kg, 0.5-25 mg/kg, 1-20 mg/kg, and 1-10 mg/kg body weight.
  • Exemplary dosages of a composition described herein include, without limitation, 0.1 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 4 mg/kg, 8 mg/kg, or 20 mg/kg. The present disclosure is not limited to such ranges or dosages.
  • adipose tissue refers to tissues characterized by the presence of adipocytes, and cells thereof. Adipose tissue contributes to biological functions including energy storage, energy homeostasis, and endocrine functions, and can also contribute to certain diseases.
  • adipose tissue examples include white adipose tissue, brown adipose tissue, visceral adipose tissue, and subcutaneous adipose tissue.
  • white adipose tissue is characterized by the presence of white adipocytes.
  • white adipocytes can be characterized by the presence of single lipid droplets of triglycerides in the adipocyte.
  • white adipose tissue is distributed throughout the body of a subject and includes visceral white adipose tissue and subcutaneous white adipose tissue.
  • visceral white adipose tissue is distributed around organs and provides protective padding.
  • subcutaneous white adipose tissue is located under the skin and provides insulation from heat or cold.
  • brown adipose tissue is characterized by the presence of brown adipocytes.
  • brown adipocytes can be characterized by the presence of triglycerides in smaller and multiple vacuoles in the adipocyte.
  • brown adipose tissue is distributed around interscapular (e.g., in the upper back region), axillary (e.g., under the shoulder joint), paravertebral, and perirenal areas.
  • adipose tissue can include adipocytes, pre-adipocytes, macrophages, neutrophils, lymphocytes, blood cells, and endothelial cells.
  • adipocytes specifically include white adipocytes and brown adipocytes.
  • adipose tissue specifically includes white adipose tissue.
  • Impairment of adipose tissue functions has been associated with various diseases. Delivery of agents to adipose tissue can be useful in the treatment of such diseases.
  • the present disclosure includes, among other things, use of a cyclic peptide of the present disclosure to delivery an agent to adipose tissue (e.g., where the cyclic peptide is covalently or non-covalently conjugated with the agent). Delivery of a therapeutic or diagnostic agent to a tissue can be useful, e.g., for treatment or diagnosis of diseases associated with adipose tissue.
  • Examples of disease for which delivery of a therapeutic or diagnostic agent to a tissue can be useful include, without limitation obesity, cachexia, hyperglycemia, insulin resistance, type 2 diabetes, high blood pressure, cancer, heart diseases, immune diseases, arthritis, diseases of the central nervous system, metabolic disorders, and aging related diseases.
  • a disease or disorder can be treated by administration of a composition of the present disclosure, peptide conjugate of the present disclosure, or agent (e.g., an agent covalently or non-covalently associated with a cyclic peptide of the present disclosure and/or a therapeutic agent) that targets a nucleic acid or protein, e.g., a nucleic acid (e.g., a gene encoding a protein or RNA) associated with the disease, a protein associated with disease, or a nucleic acid encoding such a protein.
  • the target of the composition, the peptide conjugate, or the agent can be a target according to Table 2.
  • a target nucleic acid (e.g., a gene encoding a protein or RNA) can be a nucleic acid according to Table 2.
  • a target protein can be, or the protein encoded by a target nucleic acid, can be a protein according to Table 2.
  • a target nucleic acid e.g., a gene encoding a protein or RNA
  • a target protein, or protein encoded by a target nucleic acid can be a nucleic acid or protein according to Table 2 and the composition of the present disclosure, peptide conjugate of the present disclosure, or agent can be used to treat a corresponding disease indicated in Table 2.
  • a disease can be obesity, a metabolic disorder, and/or cachexia.
  • a disease of the present disclosure e.g., a disease associated with adipose tissue or impairment of adipose tissue functions
  • a disease of the present disclosure is associated with the expression, production, and/or activity of, and/or can be treated by reducing the expression production and/or activity of, one or more targets (e.g., target nucleic acids, genes, peptides, proteins, or compounds) according to Table 2.
  • targets e.g., target nucleic acids, genes, peptides, proteins, or compounds
  • the expression, production, and/or activity of the one or more targets in Table 2 is diagnosed, monitored, or modulated (e.g., upregulated or downregulated) with the delivery of a therapeutic or diagnostic agent disclosed herein.
  • the present Examples demonstrate that cyclic peptides as set forth in the present disclosure are useful in delivering therapeutic agents to adipose tissue, of which presently exemplified antisense oligonucleotide (ASO) and small interfering RNA (siRNA) payloads are representative.
  • ASO antisense oligonucleotide
  • siRNA small interfering RNA
  • the present Examples provide data showing that a cyclic peptide of the present disclosure can effectively deliver a therapeutic agent to adipose tissue, as exemplified by delivery of representative payloads, such as an ASO or a siRNA that regulates gene expression in adipose tissue cells.
  • representative payloads such as an ASO or a siRNA that regulates gene expression in adipose tissue cells.
  • those of skill in the art can select payloads that will provide therapeutic benefit in the treatment of disease.
  • Example 1 Use of Cyclic Peptides of the Present Disclosure to Deliver a Representative
  • the present disclosure utilized cyclic peptides of the present disclosure conjugated with an ASO targeting Malatl (SEQ ID NO: 162).
  • Malatl is a long non-coding RNA transcript, the upregulation of which is correlated with the progression and development of a wide range of indications including cancers, diabetes, and inflammatory conditions (Biswas, S. el al. (2016) Sci Rep, 8: 6526.).
  • the Malatl ASO contains phosphorothioate substitutions and 2' sugar modifications, as indicated in Table 3, to inhibit nuclease degradation and to facilitate vehicle-free delivery to cells, and may contain one or more additional modifications.
  • Conjugated cyclic peptides of the present Example, and non-targeting controls, pre-formulated in isotonic saline, as well as a PBS injection control, were delivered in vivo through tail vein injections in male BL6 mice of 8-10 weeks of age. Mice received a total of 8 injections across 24 days at 1.5 mg/kg. On day 27, 3 days after the last dose, mice were perfused to collect tissues, including adipose tissue, muscle tissues, brain tissue, heart tissues, and kidney tissues for RNA processing or histology processing. For each of the collected tissues, a tissue sample was flash frozen, homogenized with SPEX SamplePrep with steel beads for 3 minutes at max speed in the presence of BME.
  • WAT White adipose tissue
  • brain and kidney tissues were processed through a Qiagen RNeasy kit
  • muscle and heart tissues were processed through a Qiagen RNeasy fibrous tissue kit.
  • RNA aliquots were prepped using High- Affinity cDNA Reverse Transcription mix by Applied Biosystems. cDNA samples were then processed for qPCR using Applied Biosystems Taqman reagents. Measurements were made for the target ASO gene (MALAT1) and housekeeping gene (GAPDH) based on dosing in each mouse group. Applied Biosystems Taqman primer probe IDs Mm01227912_sl (MALAT1) and Mm99999915_gl (GAPDH) were used. AACq analysis for all processed tissues was performed. Target gene mRNA expression profiles were visualized with respect to PBS control groups and non-targeting ASO control groups when relevant.
  • MALAT1 target ASO gene
  • GAPDH housekeeping gene

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Abstract

La présente divulgation comprend, entre autres, des compositions comprenant des peptides cycliques présentant une sélectivité pour des tissus adipeux. La présente divulgation comprend, entre autres, la reconnaissance que les peptides cycliques ayant une sélectivité pour des tissus adipeux peuvent être utilisés dans l'administration ciblée d'une charge utile (par exemple, un oligonucléotide antisens, ou un petit ARN interférent) à des tissus adipeux par conjugaison de tels peptides à la charge utile. La présente divulgation concerne en outre, entre autres, des compositions comprenant des conjugués peptidiques cycliques et leur utilisation dans le traitement d'états de tissus adipeux.
PCT/US2025/015038 2024-02-07 2025-02-07 Compositions pour administration ciblée à un tissu adipeux Pending WO2025171280A1 (fr)

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