WO2020240445A1 - Liposomes de phosphatidylcholine destinés à être utilisés dans des maladies auto-immunes - Google Patents

Liposomes de phosphatidylcholine destinés à être utilisés dans des maladies auto-immunes Download PDF

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WO2020240445A1
WO2020240445A1 PCT/IB2020/055040 IB2020055040W WO2020240445A1 WO 2020240445 A1 WO2020240445 A1 WO 2020240445A1 IB 2020055040 W IB2020055040 W IB 2020055040W WO 2020240445 A1 WO2020240445 A1 WO 2020240445A1
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previous
liposome
liposomes
antibody
liposome according
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PCT/IB2020/055040
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English (en)
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Ana Cláudia FERNANDES LIMA
Rui Luís GONÇALVES DOS REIS
Helena Susana DA COSTA MACHADO FERREIRA
Nuno João MELEIRO ALVES DAS NEVES
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Association For The Advancement Of Tissue Engineering And Cell Based Technologies & Therapies A4Tec - Associação
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds

Definitions

  • the present disclosure relates to new liposomes for use in medicine, namely in the field of autoimmune diseases (ADs) and therapeutic treatments of these diseases based on Nanotechnology.
  • ADs autoimmune diseases
  • the present invention presents a therapy for ADs based on a nanotherapeutic approach relying on the: enhanced vascular permeability of inflamed synovial tissues for liposome accumulation; antioxidant and antiangiogenic effects as well as disease monitoring and/or liposomes biodistribution conferred by gold nanoparticles; IL-23 neutralization by antibodies immobilized at the surface of the liposomes to inhibit Thl7 cells differentiation and, consequently, to reduce the production of IL-17.
  • the combination of these approaches is innovative and presents a great potential to increase anti-IL-23 antibodies bioavailability, while decreasing adverse off-target effects.
  • ADs Autoimmune diseases
  • RA rheumatoid arthritis
  • AS ankylosing spondylitis
  • PsA psoriatic arthritis
  • Cytokines the proteins that enable the communication in the immune system, regulate a broad range of the inflammatory processes that are implicated in the pathogenesis of autoimmune arthritis. 5 7 Therefore, pro-inflammatory cytokines, such as interleukins (IL; IL-Ib, IL-6, IL-17, IL-23), tumour necrosis factor-a (TNF-a) and interferon-g (IFN-y), are attractive therapeutic targets in these conditions.
  • IL interleukins
  • TNF-a tumour necrosis factor-a
  • IFN-y interferon-g
  • Thl7 cells are crucial to incite local tissue inflammation, since they stimulate the production of inflammatory cytokines, including IL-17, IL-22, TNF-a and granulocyte-macrophage colony-stimulating factor (GMCSF).
  • IL-17 also stimulates the upregulation of pro-inflammatory cytokines (IL-6, IL-8, TNF-a) as well as of chemokines and metalloproteinases.
  • IL-17 and TNF-a act synergistically to promote increased expression of endothelial cell adhesion molecules, thereby further increasing granulocyte recruitment to sites of inflammation. Therefore, IL-23 is an early factor of the immune cascade.
  • Ustekinumab a human monoclonal antibody that inhibits both IL-12 and IL-23 is approved by the US Food and Drug Administration (FDA) to use in PsA.
  • FDA US Food and Drug Administration
  • Guselkumab is a human monoclonal antibody that binds to the pl9 subunit of IL-23 to inhibit its downstream signalling.
  • Liposomes have been used to improve drug efficacy and safety in several pharmaceutical and medical applications. 12 Indeed, after the first liposomal formulation was introduced in the market, Doxif in 1995, many others are following the same trend. They are spherical vesicles of phospholipids bilayers enclosing an aqueous cavity. These carriers can be designed with specific characteristics adjusted to the requirements of the therapeutic agent chemical properties and mode of action as well as to the specificity of the disease. Furthermore, the lipidic carriers can incorporate drugs and/or imaging agents.
  • AuNPs Gold nanoparticles
  • VEGF vascular endothelial growth factor
  • AuNPs can be use in the treatment of autoimmune arthritis (especially RA), as VEGF, osteoclasts and ROS are the main contributors to their pathogenesis. 16 Furthermore, AuNPs have optical properties that allow their use as a contrast agent to monitorthe biodistribution of the liposomes by e.g. Computer Assisted Tomography scanning or X-Ray.
  • the present invention discloses a therapy for autoimmune diseases (ADs) based on a nanotherapeutic approach relying on the: enhanced vascular permeability of inflamed synovial tissues for unilamellar liposomes (LUVs) accumulation; antioxidant and antiangiogenic effects as well as disease monitoring and liposomes biodistribution conferred by gold nanoparticles (AuNPs); IL-23 neutralization by antibodies immobilized at the surface of the liposomes to inhibit Thl7 cells differentiation and, consequently, to reduce the production of IL-17.
  • AuNPs gold nanoparticles
  • the combination of these strategies is innovative and presents a great potential to increase anti-IL-23 antibodies bioavailability, while decreasing adverse off-target effects.
  • An aspect of the present disclosure comprises a liposome for targeted delivery comprising cholesterol, phosphatidylcholine, a PEG-lipid molecule and a vitamin; wherein the liposome wall comprises cholesterol, phosphatidylcholine, 1,2-distearoyl- sn-glycero-3-phosphoethanolamine (DSPE) and the vitamin; wherein the PEG molecule is bounded to the liposome wall surface through DSPE (namely at the liposome external wall); and at least one antibody bounded to the liposome wall surface or at least one antibody bounded to the PEG-lipid molecule, wherein the antibody is able to bind and/or neutralize an antigen.
  • DSPE 1,2-distearoyl- sn-glycero-3-phosphoethanolamine
  • the vitamin is a-tocopherol.
  • the liposome encapsulates a nanoparticle, an active substance, or mixtures thereof.
  • the liposome further comprises at least a nanoparticle encapsulated by the liposomes.
  • the nanoparticle is a gold nanoparticle.
  • the PEG-lipid molecule and the antibody are bounded by a covalent bond.
  • the PEG-lipid molecule is 1,2-distearoyl-sn-glycero-B- phosphoethanolamineN-[maleimide(polyethyleneglycol)-2000.
  • the antibody is an antibody against a pro-inflammatory cytokine.
  • the antibody is an anti-interleukin, preferably anti-interleukin 23.
  • said phosphatidylcholine is phosphatidylcholine from egg- yolk.
  • the liposome is for use in medicine or veterinary.
  • the liposome is for use in the treatment or therapy of autoimmune diseases and its symptoms, namely joint inflammation, joint swelling, cartilage and bone degradation, skin rashes, eye inflammation, hair loss, dry mouth or fever.
  • the liposome is for use in the treatment or therapy of autoimmune arthritis, namely rheumatic diseases.
  • the liposome is for use in the treatment or therapy of rheumatoid arthritis, ankylosing spondylitis, colitis or psoriatic arthritis.
  • the liposome is for use as an antioxidant or as an antiangiogenic agent.
  • the liposome is a large unilamellar liposome.
  • the large unilamellar liposomes has a size between around 100 nm and 200 nm, particularly between 120 nm and 150 nm.
  • the size of the large unilamellar functionalized liposomes ranges between 120-140 nm; preferably 124 nm -130 nm.
  • the large unilamellar liposomes have a size around 124 nm when empty and around 130 nm when functionalized/encapsulate with/a substance/nanoparticle.
  • the liposome shape is spherical.
  • the method for the production of the liposomes comprises the steps of:
  • MUVs multilamellar liposomes
  • Antibodies immobilization at LUVs surface comprising:
  • the method for the production of unilamellar liposomes comprises the steps of:
  • a buffer preferably a buffered gold nanoparticles suspension (i.e. a suspension prepared from a buffer solution and gold nanoparticles),
  • the method for the production of unilamellar liposomes further comprises a step for antibody immobilization at unilamellar liposomes surface by covalent link between the terminal maleimide group of the LUVs surface and the thiol group of the antibody.
  • the method for the production of unilamellar liposomes further comprises an antibody activation by previously inserting a thiol group into the antibody, preferably through the reaction with the Traut's reagent (2-iminothiolane) and EDTA.
  • Figure 1 Size distribution of the LUVs+AuNPs (A). Stability evaluation of LUVs+AuNPs kept in Heppes buffer at 4 °C for 6 months (B). TEM micrographs of the AuNPs (C) and LUVs+AuNPs (D).
  • Figure 2 Biological performance of the endothelial cell line (EA.hy926)(A) and human articular chondrocytes (hACs) (B) cultured with different concentrations of LUVs: cell viability (I), cell proliferation (II) and total protein synthesis (III) after 1, 3, and 7 days of culture.
  • Asterisk (*) denotes significant differences (p ⁇ 0.01) compared to the control (0 mM).
  • FIG. 3 SEM micrographs of LUVs cultured with EA cell line (A) and hACs (B) in the absence (control, I) and in the presence of liposomes at different concentrations: 1000 (II) and 2000 pM (III). Scale bar 10 pm.
  • FIG. 4 Percentage of THP-1 cell line viability after cultured with different concentrations of LUVs (A). IL-23 quantification on the conditioned cultured medium of activated (LPS+INF) THP-1 cell line without treatment and with treatment with biofunctionalized liposomes (LUVs+Abs) (B). Asterisk (*) denotes significant differences (p ⁇ 0.05).
  • Figure 5 Biological effects of the PBMCs of healthy donors (A) and RA patients (B) with neutral activation (Ctr) and Thl7 activation without treatment (No treat), treatment with LUVs (LUVs) and treatment with the biofunctionalized LUVs with anti-IL- 23 antibodies (LUVs+Abs) and analysed regarding metabolic activity (I) and IL-17A production (II) a denotes significant difference compared to the Ctr, and b compared to No treat group, being * p ⁇ 0.05, ** p ⁇ 0.01, *** p ⁇ 0.001 and **** p ⁇ 0.0001.
  • Figure 6 Shows a schematic representation of an embodiment of a liposomes production and functionalization.
  • the present disclosure relates to new liposomes for use in medicine, in particular a therapy for autoimmune diseases relying on the (i) enhanced vascular permeability of inflamed synovial tissues for liposomes accumulation; (ii) antioxidant and antiangiogenic effects as well as disease monitoring and/or liposomes biodistribution conferred by gold nanoparticles; (iii) IL-23 neutralization, by antibodies immobilized at the surface of the liposomes, to inhibit Thl7 cells differentiation and, consequently, to reduce the production of IL-17.
  • This strategy presents a great potential to increase anti-IL-23 bioavailability, while decreasing adverse off-target effects.
  • the liposomes of the present invention comprise cholesterol, egg-yolk phosphatidylcholine (EPC), l,2-distearoyl-sn-glycero-3- phosphoethanolamineN-[maleimide(polyethyleneglycol)-2000] (DSPE-PEG-Mal) and a- tocopherol.
  • EPC egg-yolk phosphatidylcholine
  • DSPE-PEG-Mal l,2-distearoyl-sn-glycero-3- phosphoethanolamineN-[maleimide(polyethyleneglycol)-2000]
  • DSPE-PEG-Mal l,2-distearoyl-sn-glycero-3- phosphoethanolamineN-[maleimide(polyethyleneglycol)-2000]
  • DSPE-PEG-Mal l,2-distearoyl-sn-glycero-3- phosphoethanolamineN-[maleimide(
  • the liposomes are prepared from phospholipids, the main components of cells membranes. They act as non-irritating moisturizing agents and they are biocompatible, biodegradable and nontoxic. 17
  • the PEG present in the DSPE-PEG-Mal increases the circulation time by reducing the opsonisation process.
  • a- tocopherol is a vitamin with antioxidant properties.
  • Gold nanoparticles (AuNPs) were also incorporated into the liposomes to potentiate the antioxidant and antiangiogenic effects, as well as, for disease monitoring and/or liposomes biodistribution.
  • the present invention is intended to provide the following technical effects: a) to increase the therapeutic index of biological agents through their binding to the liposomes; b) dual synergistic effect of the biological agents and the AuNPs, c) to monitor the biodistribution of the liposomes by the AuNPs; d) validate the therapeutic potential of the proposed therapy after its systemic injection; e) exceed the performance of the currently used therapies;// increase future treatment modalities, by including other therapeutic agents into the liposomes.
  • the LUVs cytocompatibility was assessed in the presence of (1) an endothelial cell line (EA.hy926), (2) a human monocyte-like cell line (THP-1); and (3) human articular chondrocytes (hACs). Then, the capture ability of the immobilized antibodies was assessed using stimulated macrophages.
  • EA.hy926 an endothelial cell line
  • THP-1 human monocyte-like cell line
  • hACs human articular chondrocytes
  • peripheral blood mononuclear cell from healthy and RA patients were activated through Thl7 differentiation, which was achieved by stimulation with anti-CD3/anti-CD28 beads, 10 ng/ml of IL-Ib and 10 ng of IL-23. Then, the inhibition of Thl7 differentiation and, consequently, IL-17A production was assessed.
  • RA The safety and efficacy of the new therapy is evaluated in established RA animal models, and show to have activity and effect. Indeed, RA are selected and utilized as a 'proof of concept' of the innovative therapy due to its high prevalence. Indeed, RA affects up to 1% of the worldwide population. 18
  • LUVs comprising cholesterol/EPC/DSPE-PEG-Mal at 1:0.85:0.15 (n/n) and a-tocopherol at 1:200 (M/M) were successfully produced and characterized in terms of size, PDI and zeta potential (Table 1).
  • the size was 3 ⁇ 4124 nm for empty liposomes and 3 ⁇ 4130 nm for liposomes encapsulating AuNPs.
  • Both formulations revealed low PDI values ( ⁇ 0.2), which indicates the homogeneity of the populations.
  • zeta potential measurements revealed that the surface charge is around -20 mV. Storage stability was also assessed, and as shown in Figure IB, the liposomes were stable for 6 months (at this time the size increased 10%).
  • an indirect method was used, namely the measurement of the fluorescence of the unbound secondary antibody.
  • the difference of the fluorescence obtained in the presence of the total amount and unbound of the secondary antibody demonstrated that 82.1 ⁇ 8.4% of anti-IL-23 antibodies were efficiently immobilized at the liposomes surface.
  • Table 1 Size distribution and zeta potential of the developed liposomes incorporating or not AuNPs.
  • Endothelial cells and hACs are suitable models to assess any toxic interaction between the developed formulation with the blood vessels and the cells from the targeted tissue. Indeed, hACs isolated from diseased knee arthroplasties have a phenotype associated with arthritic diseases. Additionally, since the immune system has an important role in these diseases, the cytocompatibility with macrophages was assessed. [0056] Different biological assays were conducted to assess cell viability (Alamar Blue assay), proliferation (DNA quantification), total protein synthesis and morphology (SEM) after 1, 3, and 7 days of culture.
  • the biologic effects from IL-23 neutralization by functionalized liposomes were studied.
  • PBMCs from healthy and RA donors were activated for the Thl7 phenotype (stimulation with anti- CD3/anti-CD28 beads, 10 ng/mL of IL-Ib and 10 ng of IL-23) for 24 h.
  • three different conditions were tested: (1) no treatment (no treat), (2) treatment with LUVs (LUVs) and (3) treatment with biofunctionalized LUVs (LUVs+Abs).
  • Non activated PBMCs were used as controls (Ctr).
  • the Thl7 differentiation reduced the metabolic activity in healthy donors ( Figure 5A), since there was a significant decrease in the stimulation without treatment (p ⁇ 0.05) in comparison with the control. This reduction was prevented by the LUVs.
  • the capture and inactivation of the IL-23 conferred by the LUVs significantly increased the metabolic activity.
  • the method of production of the liposomes is also an object of the present invention.
  • liposomes production and functionalization may be performed as described in the diagram of Figure 6.

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Abstract

La présente invention concerne de nouveaux liposomes destinés à être utilisés en médecine, et en particulier un traitement contre des maladies auto-immunes reposant sur (i) une augmentation de la perméabilité vasculaire des tissus synoviaux enflammés permettant l'accumulation des liposomes ; (ii) des effets antioxydants et antiangiogéniques ainsi que la possibilité du suivi de la maladie et/ou de la biodistribution de liposomes conférée par des nanoparticules d'or ; (iii la neutralisation de l'IL-23 par des anticorps immobilisés à la surface des liposomes, permettant d'inhiber la différenciation des cellules Th17 et, par conséquent, permettant de réduire la production d'IL-17. Cette stratégie présente un grand potentiel pour augmenter la biodisponibilité de l'anti-IL-23, tout en diminuant les effets hors cible indésirables.
PCT/IB2020/055040 2019-05-27 2020-05-27 Liposomes de phosphatidylcholine destinés à être utilisés dans des maladies auto-immunes WO2020240445A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130115269A1 (en) * 2011-11-04 2013-05-09 Henry John Smith Anti-tumor necrosis factor alpha (TNF-a) antibody used as a targeting agent to treat arthritis and other diseases
US20140335164A1 (en) * 2011-12-07 2014-11-13 Universidade Do Minho Liposomes and its production method

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130115269A1 (en) * 2011-11-04 2013-05-09 Henry John Smith Anti-tumor necrosis factor alpha (TNF-a) antibody used as a targeting agent to treat arthritis and other diseases
US20140335164A1 (en) * 2011-12-07 2014-11-13 Universidade Do Minho Liposomes and its production method

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