WO2020008404A1 - Entités chimiques appropriées pour une thérapie présentant un temps de séjour prolongé dans la circulation - Google Patents

Entités chimiques appropriées pour une thérapie présentant un temps de séjour prolongé dans la circulation Download PDF

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Publication number
WO2020008404A1
WO2020008404A1 PCT/IB2019/055708 IB2019055708W WO2020008404A1 WO 2020008404 A1 WO2020008404 A1 WO 2020008404A1 IB 2019055708 W IB2019055708 W IB 2019055708W WO 2020008404 A1 WO2020008404 A1 WO 2020008404A1
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chemical entity
agent
biomarker
active
bonding portion
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PCT/IB2019/055708
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English (en)
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Ofer Nussbaum
Boaz Musafia
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Ofer Nussbaum
Boaz Musafia
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Publication of WO2020008404A1 publication Critical patent/WO2020008404A1/fr

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    • 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
    • C12N15/115—Aptamers, i.e. nucleic acids binding a target molecule specifically and with high affinity without hybridising therewith ; Nucleic acids binding to non-nucleic acids, e.g. aptamers
    • 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
    • A61K47/54—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 an organic compound
    • A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
    • 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
    • C12N2310/16—Aptamers
    • 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
    • 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
    • C12N2310/50—Physical structure
    • C12N2310/51—Physical structure in polymeric form, e.g. multimers, concatemers
    • 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
    • C12N2320/00—Applications; Uses
    • C12N2320/30—Special therapeutic applications
    • C12N2320/32—Special delivery means, e.g. tissue-specific

Definitions

  • an artificial chemical entity comprising:
  • a biomarker-bonding portion that selectively binds to a specified biomarker, selected from the group consisting of a DNA strand, an RNA strand, a strand including both RNA and DNA, and a strand including a modified nucleic acid; and b. an active-agent portion that under in vivo conditions leads to a biological effect.
  • such teachings allow an active- agent portion which in isolation from the biomarker-bonding portion has a relative short residence time after administration to have a longer residence time as a result of the binding of the biomarker-bonding portion with the specified biomarker in the body of a subject.
  • the specified biomarker is a circulation protein.
  • the circulation protein is selected from the group consisting of: serum albumin, fibrinogen, and a globulin. (IgG, IgA, IgE, IgD and IgM).
  • the biomarker-bonding portion comprises a chemical group selected from the group consisting of: an oligonucleotide that constitutes an oligonucleotide aptamer strand; an oligopeptide that constitutes a peptide aptamer strand; and a ligand to the specified biomarker.
  • the biomarker-bonding portion is not less than 15 nucleic acid residues long. In some embodiments, the biomarker-bonding portion is not more than 90 nucleic acid residues long.
  • the active-agent portion is selected from the group consisting of: an oligonucleotide, an oligonucleotide aptamer strand, a peptide, a gly copeptide, a ganglioside, a lipid, a phospholipid, an oligopeptide, a carbohydrate and a small molecule.
  • the active-agent portion is configured to associate with autologous biomarkers.
  • the active-agent portion is configured to associate with in vivo invasive biomarkers, e.g., biomarkers that are not of the subject such as biomarkers of pathogens like bacteria and viruses, toxins and drugs.
  • biomarkers e.g., biomarkers that are not of the subject
  • biomarkers of pathogens like bacteria and viruses, toxins and drugs.
  • Some such embodiments allow treatment of infections from pathogens, neutralize toxins, venoms or drugs.
  • the active-agent portion is a small-molecule active agent residue selected from the group consisting of:
  • a pharmaceutical drug so that the chemical entity is functional as a therapeutic agent (the biological effect, e.g., being treatment of a pathological condition),
  • an anti-toxin agent the biological effect, e.g., being reducing the effect of a toxin
  • an anti-venom agent the biological effect , e.g., being reducing the effect of a venom
  • an anti-allergy agent the biological effect , e.g., being reducing an allergic reaction
  • an anti-hormone agent the biological effect , e.g., being reducing the effects of an in vivo hormone
  • the chemical entity further comprises a linker bonded to the biomarker-bonding portion with a non-covalent associative bond.
  • the covalent bond is through a residue of a reactive group selected from the group consisting of NH 2 , SH, COOH, P0 4 , tosyl, thiol, a Vogel Chemistry reagent, a photo-reactive group and a member of an affinity couple.
  • a reactive group selected from the group consisting of NH 2 , SH, COOH, P0 4 , tosyl, thiol, a Vogel Chemistry reagent, a photo-reactive group and a member of an affinity couple.
  • the active-agent portion is bonded to the linker with a non- covalent associative bond.
  • the active-agent portion is covalently bonded to the linker.
  • the linker is a chain comprising at least one monomer residue selected from the group consisting of monosaccharide residues, polysaccharide residue, nucleotide residues, polynucleotide residue, ethylene glycol residue, polyethylene glycol residue, dextran residue or polydextran residue and combinations thereof.
  • the chain is linear.
  • the chain is not less than 3 monomer residues long.
  • the chain is not more than 50 monomer residues long.
  • the biomarker-bonding portion comprises an oligonucleotide aptamer strand that selectively binds to a circulating blood or lymph protein under in-vivo conditions.
  • the biomarker-bonding portion comprises an oligonucleotide aptamer strand that selectively binds to a circulating blood or lymph protein under in-vitro conditions, and then introduce into the patient.
  • a pharmaceutical composition comprising: a chemical entity according to the teachings herein; and a pharmaceutically-acceptable carrier.
  • the pharmaceutical composition is for the treatment of a pathological condition.
  • the pharmaceutical composition is suitable for administration by a method selected from the group consisting of intravenous injection, intraperitoneal injection, subcutaneous injection, intradermal injection and intramuscular injection, inter alia, by use of a suitable carrier.
  • the pharmaceutical composition is prepared (inter alia, by selecting a suitable carrier) so that the pharmaceutical composition is suitable for administration by a method selected from the group consisting of intravenous injection, intraperitoneal injection, subcutaneous injection, intradermal injection and intramuscular injection.
  • a method of treatment of a pathological condition comprising administering a pharmaceutically-effective amount of a chemical entity according to the teachings herein to a subject in need thereof.
  • the subject is a human.
  • the subject is a non-human animal.
  • the need is that the subject suffers from a pathological condition.
  • the need is a need to vaccinate the subject to prevent the subject from developing a pathological condition.
  • the chemical entity is administered using a method selected from the group consisting of intravenous injection, intraperitoneal injection, subcutaneous injection, intradermal injection and intramuscular injection.
  • the method includes direct administration of the chemical entity (in vivo administration). In some alternative embodiments, the method includes a step of combining the chemical entity with a circulating blood or lymph protein under in vitro conditions so that the biomarker-bonding portion selectively binds to a specified biomarker in vitro, and subsequently the bound artificial chemical entity is introduced into the subject (ex vivo administration).
  • Systemic administration may be achieved by a composition configured for injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as for transdermal, transmucosal, inhalation, oral or pulmonary administration.
  • a composition configured for injection e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as for transdermal, transmucosal, inhalation, oral or pulmonary administration.
  • a receptor ligand for injection, may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • aspects of the invention herein relate to artificial chemical entities, pharmaceutical compositions comprising such chemical entities, uses of such chemical entities and methods using the chemical entities.
  • aspects of the invention may be used for cell therapy, involve in therapy of pathologies such as, but not limited to, cancer cells (solid and circulating tumors and tumor cells), Autoimmune diseases, allergies and infectious diseases (bacteria and viruses as well as infected cells), nerve system related diseases, muscles related diseases, skin related diseases glands related diseases, liver related diseases, kidney related diseases, lung related diseases, heart related diseases, blood related diseases.
  • aspects of the invention may be used for vaccination employing antigens such as small molecules and oligopeptides.
  • the artificial chemical entity is one joined unit which composed of two elements, an active-agent portion that acts as (or connected to) therapeutic bioactive molecule and the biomarker-bonding portion as a binding element to a specified biomarker, preferably for a particular circulating protein, such as serum albumin and IgG (see Fig 1 A).
  • the artificial chemical entities such as an aptamer, binds and connects a circulating protein to a molecule used as therapeutic bioactive molecule, such as nucleic acid aptamer, small interference RNA, oligopeptide or small molecule.
  • the binding of the artificial chemical entities to a specified biomarker such as a circulating protein can occurs in-vivo, in the circulation as well as employing ex-vivo procedure.
  • Some embodiments of the invention describe a novel approach for inducing slow pharmacokinetics of the administered artificial chemical entity, allowing the artificial chemical entity to stay for long time in the circulation and improve the drug accessibility to its target cells and organs.
  • the biomarker-bonding portion of the artificial chemical entity comprises a nucleic acid aptamer directed against a serum circulating proteins, such as IgG or serum albumin, which is covalently conjugated to an active-agent portion, directed against a specific biological target or used as antigen for vaccination.
  • a serum circulating proteins such as IgG or serum albumin
  • the idea of increasing the half-life of small and medium size molecules that being use as injected pharmaceutics drugs (MW of between about 5x10e2 to 5x10e4 Daltons), by attaching them to serum circulating proteins, is based on the long half-life these proteins in the circulation.
  • the novelty of some embodiments of the invention is in the use of the natural serum protein as a carrier, without modifying it; by binding to it a nucleic acid aptamer in-vivo, in the blood circulation
  • nucleic acid aptamers for binding an active-agent portion to a selected serum proteins, will reduce and may be even avoided the induction of immunologic respond to the injected chemical entities, as nucleic acid has low immunogenicity. Also, injection of nucleic acid aptamers dose not induce toxicity or side effects. Moreover, as nucleic acid aptamers do not undergo cell penetration, the use of artificial chemical entities described herein can prevent the toxicity of a conjugated small molecule drug, especially when conducting a vaccination process. It is also noted that in some embodiments, manufacture and regulation of such artificial chemical entities is easy and cheap.
  • a novel therapeutic concept for the use of AptuDrugs for reducing the rate of clearance of small molecules, oligopeptides and oligo-nucleotide base therapeutic drugs from the circulation in cell therapy, for the treatment of, but not limited to, cancer cells (solid and circulating tumors and tumor cells), Autoimmune diseases, allergies and infectious diseases (bacteria and viruses as well as infected cells), nerve system related diseases, muscles related diseases, skin related diseases glands related diseases, liver related diseases, kidney related diseases, lung related diseases, heart related diseases, blood related diseases.
  • the injected drug are an antigen, such as small molecule or oligopeptide, used for vaccination.
  • the nucleic acid aptamer can be composed of RNA or DNA or a mix of nucleic acid or modified nucleic acid.
  • the aptamer is selected against its target employing SELEX method, or/and any other nucleic acid aptamers selection method.
  • the circulation protein binding aptamer comprises a reactive group at the 3' and/or 5' termini.
  • the "binder"/Drug coupling could be either by chemical binding employing linkers and cross linkers, an enzyme, or as associative coupling.
  • the drug itself is a nucleic acid fragment, such as an aptamer or siRNA, and therefore the "AptuDrug" is composed of two oligo-nucleotides fragments covalently bound with a "DNA skeleton sugar" bridge, formed as one component during AptuDrugs synthesis.
  • the "binder aptamer” can be directed against the serum albumin protein which composes 50%-60% of blood plasma proteins (about 50mg/ml). In some embodiments, this guarantees that the injected "AptuDrug” base drug will bind almost simultaneously to the serum albumin molecule, therefore will not rapidly clear from the circulation, allow it to attack its target cells.
  • the AptuDrugs are adjusted for the treatment a human, a primate, a household animal and any other animal, by selecting a proper circulating protein binding unit, such as, but not limited to, spices specific serum albumin directed aptamer.
  • the linker is a chain that includes complementary DNA strands to link the two portions; the strength of the linkage can be adjusted by the length and the complementarity rate of the linking strand.
  • a method of treatment comprising administering a pharmaceutically-effective amount of a chemical entity according to the teachings herein to a subject in need thereof.
  • method of treatment of a pathological condition comprising administering a pharmaceutically-effective amount of a chemical entity according to the teachings herein to a subject in need thereof.
  • the subject is a human.
  • the subject is a non-human animal.
  • the need is that the subject suffers from a pathological condition.
  • a pharmaceutical composition comprising: a chemical entity according to the teachings herein; and a pharmaceutically-acceptable carrier, for the treatment of a pathological condition.
  • the pathological condition is selected from the group consisting of cancer cells (solid and circulating tumors and tumor cells), Autoimmune diseases, allergies and infectious diseases (bacteria and viruses as well as infected cells), nerve system related diseases, muscles related diseases, skin related diseases glands related diseases, liver related diseases, kidney related diseases, lung related diseases, heart related diseases, blood related diseases.
  • the pathological condition is selected from the group consisting of vaccination process.
  • biomarker-bonding portion is an oligonucleotide aptamer 1
  • biomarker-bonding portion is an oligonucleotide aptamer 1
  • the biomarker-binding portion is an oligonucleotide aptamer 1
  • Fig. 2B depicts how the circulating protein ⁇ drug complex, compound II, can bind in- vivo to a cell surface target, compound III, to form a drug/cell complex IV.
  • Fig. 2C depicts how the circulating protein ⁇ drug complex, compound II, can bind in- vivo to a circulating biomarker (drug, toxin, hormone, venom, protein, ect.), compound V, to form a drug/dimarker complex, compound VI.
  • a circulating biomarker drug, toxin, hormone, venom, protein, ect.
  • Fig. 2D depicts how the circulating protein ⁇ drug complex, compound II, can prolong the target element half-life in the circulation, allows time for the immune system, compound VII activation and anti-target element antibodies formation, compound VIII.
  • the circulating protein ⁇ drug complex, compound II can be used as a method to prolong the administrated drug half-life in the circulation, also in a case that the small molecule or oligopeptide drug is used for vaccination.
  • the principal object of some embodiments of the teachings herein is the construction of novel chemical entities called AptuDrugs, for the prolongation of the time period the bioactive molecules will remain in circulation as well as improve the pharmacokinetics and the available concentrations of the active molecule.
  • Some embodiments of the teachings herein relate to a novel approach for the improving the small molecules base drugs pharmacokinetics in the circulation, by attaching the base drug molecule, in-vivo, to a serum protein that is found in a high amount and concentration in the circulation and has a long half-life (Tl/2) in the circulation.
  • Some artificial chemical entities according to the teachings herein comprise or consist of ative-agent / aptamer complexes (AptuDrugs) that can bind a circulating protein, such as serum albumin, via a specific nucleic acid aptamer strand, directed against the circulating protein.
  • a circulating protein such as serum albumin
  • the advantage in using an aptamer for circulating protein binding in-vivo is achieved as single strand nucleic acid aptamers have poor immunity, and therefore a low immune response to it is expected.
  • the active agent portion can be a small molecule, an oligopeptide, an oligo-nucleotide or other, directed for the therapy of pathological situations such as cancer (solid and circulating tumors and tumor cells), autoimmune diseases, allergies and infectious diseases (bacteria and viruses as well as infected cells), nerve system related diseases, muscles related diseases, skin related diseases glands related diseases, liver related diseases, kidney related diseases, lung related diseases, heart related diseases, blood related diseases and vaccinations.
  • pathological situations such as cancer (solid and circulating tumors and tumor cells), autoimmune diseases, allergies and infectious diseases (bacteria and viruses as well as infected cells), nerve system related diseases, muscles related diseases, skin related diseases glands related diseases, liver related diseases, kidney related diseases, lung related diseases, heart related diseases, blood related diseases and vaccinations.
  • Chemical binding of an aptamer strand that serves as a biomarker-bonding portion, directed against a circulating protein (serum albumin or other) to a drug can be induced in several ways, depending on the nature of the drug.
  • oligonucleotide aptamer can be covalently binds to maleimide modified drug. Any other chemistry that will not affect the drug activity or the aptamer activity is valid.
  • linkers such as PEG or others
  • association binding is the use of "fused" two aptamers, which one is acts as drug and the other directed against the circulating protein, such as serum albumin, see Figure 1.
  • the "fused" aptamers can also be achieved by synthesis of what is called a Dual Aptamers Complex (DAC) particle (see Figure 1B).
  • DAC Dual Aptamers Complex
  • the use of such DAC particles has the advantage of, inter alia: a) eliminating the needs for reagents and cross-linking procedure between the drug and the targeting element (i.e., circulating protein); b) possess low immunity as complexes drug and d) DAC particles are prepared chemically (e.g., solid state oligonucleotide synthesis), and therefore can easily be manufacture as a reagent for drug use, at low cost.
  • the active-agent portions are any small molecule, oligo- peptide, oligo-nucleotide and others.
  • IV intravenous
  • IP intra-peritoneum
  • SC subcutaneous injection
  • an artificial chemical entity has a prolonged residence time in the circulation because the biomarker bonding portion binds to a specified biomarker, so that the residence time of the active-agent portion is substantial so there is an increased biological effect of the active-agent portion.
  • the assay is based on the relatively rapid in-vivo binding of the aptamer to its target circulating serum protein, such as Serum Albumin, which composes 50%-60% of blood plasma proteins (about 50mg/ml).
  • the binding may be performed ex-vivo, by drowning blood from the patient, add the AptuDrugs to the drown sample and let it bound to the chosen circulating protein (like serum albumin), and administrate back to the patient.
  • serum albumin like serum albumin
  • This experiment tests the ability of the anti-Serum albumin aptamer (aSA-Apt) / anti- Muc-l aptamer AptuDrug to bind Serum Albumin in-vivo and prolong Tl/2 values of the anti-MUC-l aptamer in the circulation.
  • aSA-Apt anti-Serum albumin aptamer
  • anti- Muc-l aptamer AptuDrug to bind Serum Albumin in-vivo and prolong Tl/2 values of the anti-MUC-l aptamer in the circulation.
  • 50ul sera samples will be test tor the amount of injected fluorescence AptuDrug, by reading the fluorescence intensity in the samples, in the related excitation and emission units.
  • the OD values will be plotted against time of blood withdrawn, for Tl/2 estimation.
  • ELISA plate preparation 3'-NH2 labeled oligo-nucleotide with complementary sequence for the MUC-l aptamer will be covalently conjugated to the Casein coated plate, employing the cross linkers SATA and SMCC as describe in ref. 21.
  • This experiment tests the ability of the anti-IgG aptamer / anti-MUC-l aptamer AptuDrug, to bind Serum Albumin in-vivo and prolong Tl/2 values of the anti-MUC- 1 aptamer in the circulation.
  • Such a construct can allow the efficient use of aptamers as a drug in in-vivo cell therapy and as drug for fighting infectious diseases (22).
  • This experiment tests the ability of the anti-serum albumin/oligopeptide AptuDrugs, to bind serum albumin in-vivo and prolong Tl/2 values of AptuDrug in the circulation.
  • Such a construct can allow the efficient use of oligopeptides as a drug in in-vivo cell therapy and infectious diseases therapy, as well as the efficient use of oligopeptides for vaccination.
  • ELISA plate preparation 3'-NH2 labeled oligo-nucleotide with complementary sequence for the anti-serum albumin aptamer or to the anti-Listeria aptamer will be covalently conjugated to the Casein coated plate, employing the cross linkers SATA and SMCC as describe in ref. 21.
  • This experiment tests the ability of the anti-serum albumin/small molecule AptuDrugs, to bind serum albumin in-vivo and prolong Tl/2 values of AptuDrug in the circulation.
  • Such a construct can allow the efficient use of small molecule as a drug in in-vivo cell therapy and infectious diseases therapy, as well as the efficient use of small molecule for vaccination.
  • a phrase in the form“A and/or B” means a selection from the group consisting of (A), (B) or (A and B).
  • a phrase in the form“at least one of A, B and C” means a selection from the group consisting of (A), (B), (C), (A and B), (A and C), (B and C) or (A and B and C).
  • aptamer is used as a synonym for "oligonucleotide aptamer strand”.

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Abstract

L'invention concerne des entités chimiques artificielles, des compositions pharmaceutiques comprenant de telles entités chimiques et des méthodes utilisant les entités chimiques. Dans certains modes de réalisation, une telle entité chimique artificielle comprend une partie agent actif et une partie de liaison à un biomarqueur qui se lie sélectivement à un biomarqueur in vivo spécifié tel qu'une protéine de circulation in vivo (chez un sujet vivant, en particulier un mammifère), ce qui permet de prolonger le temps de séjour de l'entité chimique dans la circulation. La partie agent actif de l'entité chimique artificielle a ainsi un temps et une concentration notables dans l'organisme pour fournir un effet biologique.
PCT/IB2019/055708 2018-07-05 2019-07-04 Entités chimiques appropriées pour une thérapie présentant un temps de séjour prolongé dans la circulation WO2020008404A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006081546A2 (fr) * 2005-01-27 2006-08-03 California Institute Of Technology Acides nucleiques inhibiteurs

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006081546A2 (fr) * 2005-01-27 2006-08-03 California Institute Of Technology Acides nucleiques inhibiteurs

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
KUHLMANN, MATTHIAS ET AL.: "An albumin-oligonucleotide assembly for potential combinatorial drug delivery and half-life extension applications", MOLECULAR THERAPY-NUCLEIC ACIDS, vol. 9, 10 July 2017 (2017-07-10), pages 284 - 293, XP55672430, Retrieved from the Internet <URL:https://core.ac.uk/download/pdf/145226903.pdf> [retrieved on 20191120] *
MYUNG GEUN SONG: "In vivo imaging of 64Cu-HSA-aptamer as a targeting agent for HER2 ( Human Epidermal Growth Factor Receptor 2) expressing cancer cells", INTERDISCIPLINARY PROGRAM IN TUMOR BIOLOGY SEOUL NATIONAL UNIVERSITY COLLEGE OF MEDICINE, 15 August 2014 (2014-08-15), XP055672432, Retrieved from the Internet <URL:http://s-space.snu.ac.kr/bitstream/10371/121767/1/000000021788.pdf> [retrieved on 20191120] *
SCHM?KEL, JULIE ET AL.: "Site-selective conjugation of an anticoagulant aptamer to recombinant albumins and maintenance of neonatal Fc receptor binding", NANOTECHNOLOGY, vol. 28.20, 31 March 2017 (2017-03-31), pages 204004, XP020316306, Retrieved from the Internet <URL:https://iopscience.iop.org/article/10.1088/1361-6528/aa6a9b> [retrieved on 20191120] *

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