WO2001047549A2 - Composant pour vaccin - Google Patents

Composant pour vaccin Download PDF

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Publication number
WO2001047549A2
WO2001047549A2 PCT/GB2000/004951 GB0004951W WO0147549A2 WO 2001047549 A2 WO2001047549 A2 WO 2001047549A2 GB 0004951 W GB0004951 W GB 0004951W WO 0147549 A2 WO0147549 A2 WO 0147549A2
Authority
WO
WIPO (PCT)
Prior art keywords
peptide
compound according
group
vaccine
monomer unit
Prior art date
Application number
PCT/GB2000/004951
Other languages
English (en)
Other versions
WO2001047549A3 (fr
Inventor
Jane Nicola Zuckerman
Bala Subramaniyam Ramesh
Original Assignee
University College London
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 University College London filed Critical University College London
Publication of WO2001047549A2 publication Critical patent/WO2001047549A2/fr
Publication of WO2001047549A3 publication Critical patent/WO2001047549A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A61K39/29—Hepatitis virus
    • A61K39/292—Serum hepatitis virus, hepatitis B virus, e.g. Australia antigen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/385—Haptens or antigens, bound to carriers
    • 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
    • A61K47/56—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55555—Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6018—Lipids, e.g. in lipopeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6093—Synthetic polymers, e.g. polyethyleneglycol [PEG], Polymers or copolymers of (D) glutamate and (D) lysine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/62—Medicinal preparations containing antigens or antibodies characterised by the link between antigen and carrier
    • A61K2039/627—Medicinal preparations containing antigens or antibodies characterised by the link between antigen and carrier characterised by the linker
    • 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
    • C12N2730/00—Reverse transcribing DNA viruses
    • C12N2730/00011—Details
    • C12N2730/10011—Hepadnaviridae
    • C12N2730/10111—Orthohepadnavirus, e.g. hepatitis B virus
    • C12N2730/10122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • 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
    • C12N2730/00—Reverse transcribing DNA viruses
    • C12N2730/00011—Details
    • C12N2730/10011—Hepadnaviridae
    • C12N2730/10111—Orthohepadnavirus, e.g. hepatitis B virus
    • C12N2730/10134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • the present invention relates to a component comprising a polymerisable compound for use as a medicament, especially for use as an immunogenic component for a vaccine.
  • a vaccine is a pharmaceutical which, when given to a subject, is intended to elicit an immune response which protects the subject from subsequent infection by a pathogen such as a virus or bacterium.
  • a vaccine comprises an attenuated version of the pathogen or some part of it. It is often possible to identify one or more proteins in a pathogen which are antigenic. Identification of the antigenic regions of these proteins can form part of a strategy for vaccine production where the antigenic regions are in some way replicated in a vaccine composition.
  • the present invention aims to overcome the drawbacks of the prior art and provides a polymerisable compound for use as a medicament, comprising a peptide; a spacer covalently linked to the peptide; and a monomer unit covalently linked to the spacer and capable of forming a polymer with at least one further monomer unit in a further polymerisable compound. It has been surprisingly found that a relatively simple peptide-containing monomer can be used as an immunogenic component for a vaccine in spite of its relatively small size.
  • the peptide-containing compound is endocytosed or phagocytosed in an antigen presenting cell such as a macrophage, the peptide is induced to polymerise by free radicals produced by the macrophage or by the redox potential in the cell.
  • the monomeric units can polymerise together, or even copolymerise with other units, to form a larger complex which may be presented to the immune system.
  • two forms of processing take place within the cell; an exogenous and an endogenous antigen processing which may occur simultaneously. Endogenous processing of the polymerised peptide-containing compound could stimulate cellular immunity, especially cytotoxic T- lymphocyte response. A good humoral response is also achieved.
  • the peptide part of the compound is substantially non-immunogenic when in unconjugated form.
  • Such forms include those where the peptide is not conjugated or linked to a further protein or to a spacer and monomer unit, as required by the present invention.
  • the peptide typically has from 10 to 20 amino acids, preferably around 12 amino acids.
  • the peptide preferably comprises an amino acid sequence from a part of a target protein such as a protein from a pathogen, especially a surface protein such as a coat protein of a pathogen.
  • the target protein is therefore generally a naturally-occurring protein and although the peptide sequence may be produced synthetically, it generally represents a sequence from a natural protein, optionally with modifications or deletions which do not substantially affect the antigenicity of the peptide in the compound. Whilst it is preferred that the amino acids making up the peptide are L amino acids, a sequence comprising D amino acids would also be effective provided that the sequence was reversed.
  • the pathogen is typically a microorganism such as a virus, bacterium or fungus and the compound is found to be particularly effective towards viruses such as a hepatitis virus.
  • the target protein may comprise VP1 or VP3 from hepatitis A.
  • the target protein may comprise hepatitis B surface antigen.
  • Other virus targets include retroviruses, herpes, influenza, meazles, polio and others.
  • the spacer and peptide are covalently linked together either by a direct covalent bond or indirectly by covalent bonds interrupted by further atoms or groups.
  • the amino terminus of the peptide is linked to the spacer.
  • the exact size and nature of the spacer may be determined by routine experimentation.
  • a function of the spacer is to be linked to the peptide and monomer unit so that they are spaced apart to prevent polymerisation at the monomer unit from interfering with the immunogenic properties of the peptide. This is preferably achieved where the spacer is linked to the peptide and monomer unit such that at least 4 atoms separate the peptide from the monomer unit, typically 6 to 8 atoms .
  • the spacer has an SH containing side group.
  • Such a side group may be capable of forming disulphide bridges and/or may contribute to the immunogencity of the peptide.
  • Such a side group may be provided as part of a cysteine residue.
  • the spacer group comprises a hexanoyl group, preferably linked to cysteine .
  • the monomer unit must be capable of forming a polymer with further monomer units either directly as a homopoly er or indirectly by polymerisation with one or more comonomers .
  • the monomer unit is capable of such polymer formation by redox-mediated or free radical-mediated polymerisation .
  • the monomer unit comprises an olefinic group, such as one found in an acryloyl group or similar.
  • the monomer unit is thought to be sufficiently reactive in vivo in the presence of an antigen presenting cell that a polymer is formed.
  • the present invention provides use of a compound as described above, for the preparation of a composition for use as a vaccine.
  • a vaccine composition which comprises a compound as described above and an adjuvant.
  • the adjuvant may comprise any conventional adjuvant such as Freund' s adjuvant for use in certain animals or an aluminium-based adjuvant such as is typically used in humans.
  • the adjuvant comprises an adjuvant of the type described in copending
  • the adjuvant comprises a plurality of components, each of which is the same or different, is capable of micelle formation and comprises a peptide head group for binding to an antigen-presenting cell, and a lipophilic tail group.
  • the peptide head group capable of binding to an antigen-presenting cell such as a macrophage confers upon the adjuvant an advantage over conventional receptor-mediated endocytosis because there is no restriction on the size of particles that can be internalised by the antigen-presenting cell.
  • the peptide head group comprises a binding motif, especially for a cell surface receptor.
  • the motif may comprise a plurality of amino acids in the peptide head group. It is particularly preferred that the motif comprises an integrin-binding motif.
  • an integrin is a known cell surface transmembrane receptor which participates in cell-cell adhesion and as a "sensor" between cells and components of the extra cellular matrix.
  • a number of ligands are known to interact with integrins, including extracellular matrix glycoproteins such as fibronectin and vitronectin.
  • the integrin-binding motif generally comprises the amino acids R, G and D.
  • the integrin binding motif comprises L amino acids, preferably having the sequence RGD where the lipophilic tail group is N terminal of the R amino acid.
  • the peptide head group may comprise D amino acids.
  • the integrin binding motif comprises the D amino acid sequence DDDGGGGGRRR and the lipophilic tail group is N terminal of the D amino acid.
  • the lipophilic tail group comprises a single tail group.
  • the component is preferably an unbranched molecule which is simpler to synthesis and will be capable of micelle formation, unlike more complex branched molecules such as Pam 3 Cys-Ser-POE.
  • the lipophilic tail group may be any suitable lipophilic group such as one having a sufficiently long hydrocarbyl chain as to promote micelle forming ability.
  • the lipophilic tail group may comprise a C 4 to Cie alkyl group and preferably comprises a Cs to C ⁇ 2 fatty acid.
  • a particularly useful fatty acid is lauric acid.
  • the present invention provides a process for the production of a vaccine as described above, which process comprises formulating the vaccine from a compound as described above and an adjuvant as described above .
  • Synthetic peptide corresponding to virtually any accessible region of a native protein may elicit antibodies reactive with that protein.
  • a synthetic peptide antigen incorporated in an immunogen may generate antibodies that cross-react with proteins containing the amino acid sequence homologous with that of the peptide.
  • Such antibodies are thus directed against a specific region of the protein, selected in advance, and therefore possess site-specific or predetermined specificity.
  • Such peptide antigens used to generate site-specific antibodies to proteins are of interest in the development of novel vaccines. The requirement to conjugate them to a carrier protein for optimal immunogenicity and deliver them with a suitable adjuvant can result in a number of problems.
  • ACP Acrylated- Cysteinyl Peptide
  • Lauroyl-RGD integrin-targetted lipopeptide
  • the peptides were synthesized directly by the solid-phase technique. The amino terminal of the completed peptide were coupled to hexanoic acid and terminated with cysteine sequentially. The amino terminus of the cysteine was then capped with acrylic acid.
  • the synthesis of the adjuvant comprises a lauryl acid coupled to amino acids of which are D-amino acids.
  • the 11- residue peptide incorporating the lauric acid was synthesized sequentially directly onto a polystyrene solid- phase .
  • the acrylate-cysteinyl-peptide (ACP) when complexed with the Lauryl peptide (Lauryl-RGD) as micelles was highly immunogenic in non-responder mice and randomly bred mice.
  • the antibodies reacted with the peptides and there were no antibodies detected to the Lauryl-RGD peptides.
  • the antibody titre were comparable to peptides conjugated to a carrier protein (Keyhole Limpet Haemocynin, KLH) and emulsified with Freund' s complete adjuvant. The potential exists using this construct to design immunogens for third generation vaccines.
  • Lauric acid (Dodecanoic acid) was purchased from Fluka (UK) Ltd., Dimethylformamide (DMF) , Dichioromethane
  • the peptide was synthesized using the stepwise solid-phase procedure using the Fmoc protection strategy.
  • the Rink- amide resin (0. 5g) derivatized with Fmoc-amide was put through normal deprotection cycle with 20% pipridine in DMF in a reaction vessel for 12 minutes. After deprotection the resin was washed with DMF (lo lig; 5x1 mm) . A 5-fold molar excess (based on the loading) of acylating species in 0.2M NMP in DMF (5ml) were added automatically in all subsequent couplings.
  • the synthesis was carried using the batch synthesis mode on an automated peptide synthesizer (Rainin PS3, Protein Technologies, USA) with standard protocols and scale (0.1 mmol theoretical yield of crude peptide).
  • the cycle for the addition of protected amino acid consisted of 2x6 min wash of the solid support with 20% piperidine in DMF to cleave the N ⁇ -Fmoc group, 10x1 min DMF wash, 25 mm coupling reaction with 5 equivalents of Fmoc-amino acid activated by TBTU in 0.2M NMP in DMF as an active ester, and an 10x1 min DMF wash for a total cycle time of about 60 min.
  • Fmoc-6-amino hexanoic acid was coupled as the active ester using TBTU as described to the deprotected N-terminus of the assembled protected peptide.
  • activated Fmoc-cysteine was added as decribed above for preparing active esters for coupling and allowed to react for 25 minutes under nitrogen.
  • acrylation of the N- terminus of the resin bound cysteinyl-hexanoyl-peptide was carried out manually with nitrogen agitation at 0°C in a fume cupboard.
  • mice were eight-week old males with the following haplotypes, Balb/c (H-2d) Balb/c(h-2k) and B. 10.S(H-2s) .
  • the mice were immunized with lOO ⁇ g of acrylated cystemyl peptide complexed m lOO ⁇ g of lauroyl-RGD m PBS.
  • non-acrylated peptides were also injected with lauroyl-RGD peptide.
  • a combined mtrape ⁇ toneal and subcutaneous route was used for the primary injection. Groups of 3 of each strain were given acrylated and non- acrylated peptide complex. 3 weeks later they were boosted with the same doses and by the same routes . Blood was then collected 3 weeks later from the retro-orbital sinus and the serum collected after clotting.
  • Polystyrene flat bottom wells (Immulon 2 Dividast ⁇ p, Dynatech Laboratories Inc) were used to test antisera for the ability to react with the peptide ('a' determinant of HBV surface antigen ,119-137) .
  • Peptides (l ⁇ g/ml) in carbonate/bicarbonate buffer pH9 was incubated at 4°C overnight in microtitre strips before being washed. Additional binding sites were blocked with 5% skimmed milk (Marvel) for 2 hours at room temperature. The plates were washed 3 times with wash buffer (PBS containing 0.05% Tween 20, and milk) . Antibodies were then added (dilutions of murine sera) to the plates and incubated for 1 hour at room temperature.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Virology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biophysics (AREA)
  • Communicable Diseases (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne un composé pouvant être polymérisé prévu pour être utilisé comme médicament. Ce composé comprend un peptide, un bras écarteur lié par covalence au peptide, et un monomère lié par covalence au bras écarteur et pouvant former un polymère avec au moins un monomère dans un autre composé pouvant être polymérisé.
PCT/GB2000/004951 1999-12-23 2000-12-21 Composant pour vaccin WO2001047549A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9930585A GB9930585D0 (en) 1999-12-23 1999-12-23 Component for vaccine
GB9930585.6 1999-12-23

Publications (2)

Publication Number Publication Date
WO2001047549A2 true WO2001047549A2 (fr) 2001-07-05
WO2001047549A3 WO2001047549A3 (fr) 2001-12-27

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103275178A (zh) * 2013-05-21 2013-09-04 首都医科大学 正十二酸-rgd-正十四醇介导利尼法尼靶向脂质体的制备及抗肿瘤活性评价
WO2019195766A1 (fr) * 2018-04-06 2019-10-10 AMMA Therapeutics, Inc. Composition pour la libération contrôlée d'agents thérapeutiques

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998034968A1 (fr) * 1997-02-11 1998-08-13 The Council Of The Queensland Institute Of Medical Research Polymeres dans lesquels sont incorpores des peptides

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998034968A1 (fr) * 1997-02-11 1998-08-13 The Council Of The Queensland Institute Of Medical Research Polymeres dans lesquels sont incorpores des peptides

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 101, no. 21, 19 November 1984 (1984-11-19) Columbus, Ohio, US; abstract no. 189405, PETROV, R. V. ET AL: "Vaccinating effect of conjugates of influenza virus surface antigens with synthetic polymer carrier" XP002167382 & DOKL. AKAD. NAUK SSSR (1984), 277(3), 752-5 ÄIMMUNOL.Ü , 1984, *
D C JACKSON ET AL.: "Free radical induced polymerization of synthetic peptides into polymeric immunogens" VACCINE., vol. 15, no. 15, 1997, pages 1697-1705, XP002167381 BUTTERWORTH SCIENTIFIC. GUILDFORD., GB ISSN: 0264-410X cited in the application *
N M O'BRIEN-SIMPSON ET AL.: "Polymerization of unprotected synthetic peptides: a view toward synthetic peptide vaccines " JOURNAL OF THE AMERICAN CHEMICAL SOCIETY., vol. 119, no. 6, 1997, pages 1183-1188, XP002167380 AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC., US ISSN: 0002-7863 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103275178A (zh) * 2013-05-21 2013-09-04 首都医科大学 正十二酸-rgd-正十四醇介导利尼法尼靶向脂质体的制备及抗肿瘤活性评价
CN103275178B (zh) * 2013-05-21 2015-04-29 首都医科大学 正十二酸-rgd-正十四醇介导利尼法尼靶向脂质体的制备及抗肿瘤活性评价
WO2019195766A1 (fr) * 2018-04-06 2019-10-10 AMMA Therapeutics, Inc. Composition pour la libération contrôlée d'agents thérapeutiques
CN112074287A (zh) * 2018-04-06 2020-12-11 阿玛治疗公司 用于控释治疗剂的组合物
US11191802B2 (en) 2018-04-06 2021-12-07 AMMA Therapeutics, Inc. Composition for controlled release of therapeutic agents
EP3773483A4 (fr) * 2018-04-06 2022-01-26 Amma Therapeutics, Inc. Composition pour la libération contrôlée d'agents thérapeutiques

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GB9930585D0 (en) 2000-02-16

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