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WO2017216768A1 - Antigène artificiel dérivé d'un dendrimère, procédés associés et utilisations - Google Patents

Antigène artificiel dérivé d'un dendrimère, procédés associés et utilisations Download PDF

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Publication number
WO2017216768A1
WO2017216768A1 PCT/IB2017/053596 IB2017053596W WO2017216768A1 WO 2017216768 A1 WO2017216768 A1 WO 2017216768A1 IB 2017053596 W IB2017053596 W IB 2017053596W WO 2017216768 A1 WO2017216768 A1 WO 2017216768A1
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dendrimer
previous
composition according
mixtures
cancer
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Inventor
Daniel BARREIRA RODRIGUES
Tírcia CARLOS SANTOS
Joaquim Miguel Antunes De Oliveira
Rui Luís GONÇALVES DOS REIS
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Association for the Advancement of Tissue Engineering and Cell Based Technologies and Therapies A4TEC
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    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
    • 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
    • A61K47/59—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 otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/595—Polyamides, e.g. nylon
    • 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
    • A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • A61K47/6929—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
    • A61K47/6931—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer
    • A61K47/6935—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2809—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • 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
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/515—Animal cells
    • A61K2039/5154—Antigen presenting cells [APCs], e.g. dendritic cells or macrophages
    • 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
    • A61K2039/55522—Cytokines; Lymphokines; Interferons
    • A61K2039/55527—Interleukins
    • A61K2039/55538—IL-12
    • 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

Definitions

  • the present disclosure relates to the design and production of a novel artificial antigen-presenting cells (aAPCs) system based on natural origin dendronized polymers at the nanoscale that can be loaded with cytokines in their inner core and coated with recombinant molecules at their surface to prime and expand tumor-specific T-cell responses.
  • aAPCs artificial antigen-presenting cells
  • the methodology to modify and functionalize the dendronized polymers is included.
  • the dendrimers are multifunctional, biocompatible, biodegradable and highly permeable, which allows the surface engineering and functionalization of the aAPCs systems with different molecules that serve not only to expand ongoing T-cell responses but also to modulate their functions by means of preventing the development of their "terminal differentiation” or "exhaustion.
  • Cancer is a shocking disease that, despite several clinical and research efforts, still kills millions of people each year worldwide, 8.2 million in 2012. Immunotherapy is being presented as an alternative treatment approach to delay tumour growth and eventually tumour regression.
  • DCs Dendritic cells
  • APCs antigen-presenting cells
  • the goal of DCs-based cancer immunotherapy is to prime specific antitumor immunity through the generation of effector cells that attack and lyse tumours.
  • the current approaches are far from optimal as many patients treated with DCs failed to respond. This is likely a result of the modulation of DC function by the tumour microenvironment, hindering the antigen presenting capacity of the DCs and their cytokine production, critical elements to generate efficient anti-tumour T-cell responses.
  • dendrimers- derived artificial antigen presentation to overcome this drawback is to develop a biotherapy by means of using a novel approach based on artificial APCs synthesized from surface modified dendrimers (dendronized polymers), whose function is not modulated by the tumour microenvironment, to prime and expand ongoing tumour- specific T-cell responses and ultimately eliminate tumour cells.
  • dendrimers and the surface-modified dendrimers (dendronized polymers) as drug delivery systems is closely related to the possibility of tailoring drug delivery profile due to their monodispersity.
  • anticancer agents can damage both malignant and normal cells in a similar way.
  • One-package nanocarriers that can target the diseased tissues, while releasing one or multiple therapeutic agents are being investigated for treating cancer.
  • Partially acetylated PAMAM dendrimers (G5) were then conjugated with FITC, FA and MTX, for targeting tumour cells through the folate receptor, while releasing intracellular ⁇ an anti-tumour drug.
  • Yang et al. 6 have also synthesized the FITC-labelled and biotin-linked PAMAM dendrimer (G5) conjugates and further studied its ability for targeting cancer cells.
  • Document WO2015/051247 refers to artificial antigen presenting cells (nanoparticles or microparticles) that are useful in treating disease and have uses, for example, directly in vivo and/or in the expansion of a patients cells for re-introduction ex vivo.
  • Document EP2848255 relates to a method to isolate, stimulate and expand naive cytotoxic T lymphocyte precursors (CTLp) to antigen-specific effectors, capable of lysing tumor cells in vivo.
  • CTLp cytotoxic T lymphocyte precursors
  • the ex vivo protocol produces fully functional effectors.
  • This artificial antigen expression system can be adapted to treat most cancers in a significant majority of the population.
  • Document WO2014/209868 refers to compositions and methods for immunotherapy, which include shelf-stable pharmaceutical compositions for inducing antigen-specific T-cells. Such compositions are employed as components of an artificial antigen presenting cell (aAPC), to provide a patient with complexes for presentation of an antigen and/or a T-cell co-stimulatory molecule.
  • aAPC artificial antigen presenting cell
  • Document US20140370099I relates to compositions and methods comprising asymmetrical artificial antigen presenting cells (aAPCs).
  • aAPCs asymmetrical artificial antigen presenting cells
  • the non-spherical aAPCs more closely mimic endogenous cell-cell interactions and can be used for antigen-specific immunotherapy.
  • Document WO2014/16013 discloses nano-scale Artificial Antigen Presenting Cells (aAPC), which deliver stimulatory signals to lymphocytes, including cytotoxic lymphocytes, for use as a powerful tool for immunotherapy.
  • aAPC artificial antigen presenting cells
  • the aAPC of the present subject matter can be used as an "off the shelf" APC that can be readily designed to expand a T-cell of interest.
  • the aAPC of the present subject-matter may be used identify the stimulatory, co-stimulatory, and any other factors that mediate growth and expansion of a T-cell of interest.
  • Document WO2014/041517 relates to dendrimers composed of hetero- bifunctional moiety and aromatic heterocycle and the methods of synthesizing said dendrimers.
  • the present subject matter also relates to dendrimer-bioactive molecule conjugates, the process of synthesizing the conjugates and pharmaceutical compositions comprising said conjugates.
  • the dendrimer in the conjugates act as a carrier and significantly increases the therapeutic efficacy of the bioactive molecule.
  • Documents EP2600904 and WO 2012/018389 relate to artificial antigen presenting cells, methods of making the same, methods of administering the same, computer systems relating thereto, computer-implemented methods relating thereto, and associated computer program products.
  • Documents CA2777682 and WO2011/059609 refer to dendrimer compounds and methods of synthesizing the same.
  • the present subject-matter may is directed to polyamidoamine (PAMAM) dendrimers, dendrimer branching units, methods for synthesizing such PAMAM dendrimers and functionalized dendrimers, as well as systems and methods utilizing the dendrimers.
  • PAMAM polyamidoamine
  • Document US20110065180 relates to artificial antigen presenting cells to generate specific Cytotoxic T lymphocytes (CTLs) for antigenic peptides derived from IgE molecule.
  • CTLs Cytotoxic T lymphocytes
  • Document WO 2011/028334 and WO/2011/011384 relates to methods of synthesis and isolation of dendrimer systems.
  • Document WO2010/115046 relates to nanoparticle-based vaccines, compositions, kits and methods used for the effective delivery of one or more antigens in vivo for vaccination and antibody production, and for the effective delivery of peptides, proteins, siRNA, RNA or DNA to PAPCs or MHC class II positive cells.
  • Antigens may be, for example, DNA that results in expression of the gene of interest and induction of a robust and specific immune response to the expressed protein in a subject, or may also be immunogenic peptides or polypeptides that are processed and presented.
  • Nanoparticle-based method to deliver antigens in vivo may include injection of a vaccine composed of a DNA encoding at least one antigen, or at least one antigenic peptide or polypeptide conjugated to a charged dendrimer that is also conjugated to a T helper epitope. Alternatively, negatively-charged dendrimers may be used.
  • a vaccine composed of a DNA encoding at least one antigen, or at least one antigenic peptide or polypeptide conjugated to a charged dendrimer that is also conjugated to a T helper epitope.
  • negatively-charged dendrimers may be used.
  • the compositions, kits, vaccines and methods described herein have both prophylactic and treatment applications.
  • the vaccine system described can be used to mount an immune response against any infectious pathogen or cancer.
  • Document WO2010/075423 relates to therapeutic and diagnostic dendrimer based modular platforms.
  • the dendrimer based modular platforms are configured such that two or more dendrimers are coupled together wherein each of the coupled dendrimers is functionalized.
  • the present subject matter provides dendrimer based modular platforms having coupled dendrimers wherein each dendrimer is conjugated to one or more functional groups or the functional groups are conjugated to the dendrimers via a linker and/or a triggering agent.
  • the present subject-matter is directed to methods of synthesizing dendrimer based modular platforms, compositions comprising the dendrimer based modular platforms, as well as systems and methods utilizing the dendrimer based modular platforms.
  • Documents WO2010/039861 and WO/2009/151687 relate to therapeutic and diagnostic dendrimers.
  • the present subject-matter is directed to dendrimer-linker conjugates, methods of synthesizing the same, compositions comprising the conjugates, as well as systems and methods utilizing the conjugates.
  • the dendrimer-linker conjugates may further comprise one or more components for targeting, imaging, sensing, and/or providing a therapeutic or diagnostic material and/or monitoring response to therapy.
  • Documents WO2009/009203, WO2008/008483 and WO 2006/033766 relate to therapeutic and diagnostic dendrimers.
  • Dendrimer based compositions and systems are envisioned for use in disease diagnosis and therapy.
  • the compositions and systems comprise one or more components for targeting, imaging, sensing, and/or providing a therapeutic or diagnostic material and monitoring the response to therapy of a cell or tissue.
  • Document WO2007/149500 concerns to hybrid dendrimers comprising a mixture of at least two dendritic polymers or dendronized polymers that have at least one difference between them.
  • the surfaces of the dendritic polymer or dendronized polymer may be further modified by known methods.
  • Such formulations of hybrid dendrimers may have different guest molecules present at either identical or different loading concentrations but have different release profiles.
  • a method of using a hybrid dendrimer for delivery of a drug or guest moiety in order to provide increased solubility to poorly soluble drugs or guest moieties is provided.
  • Documents US20050079208, US20040224009, US20020122818, EP1123086, CA2345277, WO2000/023053 relate to artificial antigen presenting cells and methods of making artificial antigen presenting cells that may be used in certain methods of isolating and expanding T-cell populations as well as modulating T-cell responses. Provides methods for the identification and isolation of antigen-specific T-cells.
  • the methods provide for the construction of liposomes containing MHC: peptide complexes, accessory molecules, co-stimulatory molecules, adhesion molecules, and other molecules irrelevant to T-cell binding or modulation that are used in the binding of artificial antigen presenting cells to solid support systems that may be used in the retrieval and identification of antigen-specific T-cells.
  • the present subject-matter relates to the design and methods of assembling dendronized polymers conjugated with specific molecules to guide specific T-cell responses that can be used as immunotherapeutic agents in pathological conditions such as cancer, autoimmune disorders and infection where is critical to avoid T-cells "terminal differentiation” or "exhaustion”.
  • the disclosure subject matter refers to the design and method(s) for producing an artificial antigen presentation based on nanoparticles of natural origin dendronized polymers to be loaded with cytokines in their inner core and coated with recombinant molecules at their surface to prime and expand tumour-specific T-cells, acting as artificial antigen presenting cells (aAPCs).
  • aAPCs artificial antigen presenting cells
  • the aAPC systems may be administered by intravenous or direct injection at the tumour site.
  • the developed surface modified dendrimers used to generate the novel aAPC are manipulated in order to carry antibodies or tetramers in their surface (targeted delivery), and molecules such as cytokines in their inner core that are slowly released.
  • the dendrimers-based aAPCs targeted delivery systems are able to promote an efficient and sustained expansion of effector tumour-specific T-cells that attack and lyse tumour cells, leading to a more rapid tumour regression.
  • the created nano- structure is able to promote a sustained response, as this system is not recognized by the host phagocytic system, thus remaining for longer periods of time in vivo.
  • the dendrimers are produced in a way to add a-CD3 and a- CD28 in the surface (external shell).
  • the assembly of this system seems very complex, it is rather simple and promising results regarding cytotoxicity and phagocytosis evaluation have also been obtained, with the assembled system not being considered cytotoxic and with an extremely low phagocytosis rate by macrophages or dendritic cells (data not published).
  • the proposed system is multifunctional, biocompatible, biodegradable and highly permeable, allowing a slow and steady release of cytokines from the inner core and promoting a long lasting activation of cytotoxic T-cell responses.
  • Different molecules may be used to the functionalization of the system of the present subject- matter which allows not only to expand ongoing T-cell responses, but also to modulate their functions by means of preventing the development of their "terminal differentiation” or "exhaustion”.
  • Dendrimers are repetitively branched molecules. Synonymous terms for dendrimer include arborols and cascade molecules. However, dendrimer is currently the internationally accepted term. A dendrimer is typically symmetric around the core, and often adopts a spherical three-dimensional morphology.
  • the present subject-matter is related to dendrimer conjugates with defined and limited numbers of ligand conjugates and high levels of structural uniformity, methods of synthesizing the same, compositions comprising the conjugates, as well as systems and methods utilizing the conjugates.
  • dendrimer conjugates of the present subject matter may further comprise at least two different components for targeting, imaging, sensing, and/or providing a therapeutic or diagnostic material and/or monitoring response to therapy.
  • novel synthesis methods of certain embodiments of the present subject matter provide significant advantages with regard to total reaction time and simplicity.
  • the dendrimeric compositions/nanopackages have certain functionalities, such as specific biofunctionalization, targetability, traceability, drug delivery capacity, or reactivity, which offer new possibilities for diagnose and management of several diseases, namely immunotherapy treatment in particular cancer.
  • An aspect of the present subject matter is a pharmaceutical composition
  • a dendrimer in particular polycationic dendrimer
  • co-stimulatory molecule wherein the co-stimulatory molecule is bound to the linear polymer, in particular wherein the co-stimulatory molecule is a T-cell co-stimulatory molecule.
  • the dendrimer is spherical.
  • the composition may further comprises MHC tetramers, fluorescent probe, or mixtures thereof bounded to the linear polymer.
  • the cytokine can be select from a list consisting of: chemokine, interferon, interleukin, tumour necrosis factor, lymphokine and mixtures thereof.
  • the cytokine is an interleukin, in particular IL-12, IL- 17, IL-23 or mixtures thereof.
  • IL-12 is used which is important for the differentiation of Thl cells that, by their turn help macrophages, natural killer (NK) cells and even CD8 cytotoxic T-cells.
  • IL-12 has been shown to enhance anti- tumour responses by promoting the development of T helper cells with a type 1 phenotype that support the expansion of cytotoxic responses against cancer cells.
  • the molecular weight of the dendrimer is between 3-1000 kDa, preferably 50-500 kDa; more preferably 100-300 kDa.
  • the measured diameter of the dendrimer can be between 29-135 A, preferably 50-100 A, more preferably 70-85 A.
  • the dendrimer diameter (A) may be measured by several methods, namely in five independent images by atomic force microscopy - AFM.
  • the number of functional groups in the dendrimer can vary between 16-4,096, preferably 50-1,000 functional groups; more preferably 400-600 functional groups.
  • the dendrimer is a generation-G5 dendrimer to a generation-G8 dendrimer, in particular G5, G6, G7, G8 or mixtures thereof; more preferably a generation-G7 dendrimer.
  • the dendrimer is select from a list consisting of: 1. poly(phosphorus) dendrimer; 2. poly(amidoamine) (PAMAM) dendrimer; 3. poly(ethyleneoxide) dendrimer (PEO); 4. polypropyleneimine dendrimer (PPI); 5. poly(phosphorhydrazone) (PPH) dendrimer; 6.polyethylenimine (PEI) dendrimer, and mixtures thereof.
  • composition may comprise
  • cytokine 10-50 % m/m of a cytokine, preferably 10-20 % m/m;
  • the molecular weight of the linear polymer may be between 200 Da - 500 kDa, preferably 500 Da-100 KDa; more preferably 1 KDa-10 KDa.
  • the linear polymer may be select from a list consisting of: polyethylene glycol, carboxymethylchitosan, hyaluronan, gellan gum, or mixtures thereof.
  • the antibody may be select from a list consisting of: a-CD3 antibody, or a-CD28 antibody, MHC tetramers or mixtures thereof; in particular a-CD3 antibody, and a-CD28 antibody (see figure 5).
  • the dendrimer may be poly(amidoamine) dendrimer, the cytokine is IL-12.
  • fluorescent probe may be selected from DAPI, FITC, or mixtures thereof.
  • the dendrimer core may further comprise an anti-inflammatory agent, an antiseptic agent, an antipyretic agent, an anaesthetic agent, a therapeutic agent, and mixtures thereof.
  • the functional group that link the linear polymer to the dendrimer is selected from : carboxylic acids, amines, esters, aldehyde, or mixtures thereof.
  • the composition may further comprising adequate amounts of pharmaceutical acceptable excipient.
  • the composition is an injectable formulation.
  • the composition may be use in veterinary or human medicine, namely in mammals.
  • the composition may be use in immunotherapy.
  • cancer diseases in particular solid tumours.
  • breast cancer lymphomas, brain cancer, kidneys cancer, liver cancer, lung cancer, pancreatic cancer.
  • compositions can be administered by various routes, including topical, enteral and parenteral.
  • Parenteral administration routes include intra-arterial, intraarticular, intracavitary, intradermal, intralympathic, intramuscular, intrasynovial, intravenous, or subcutaneous.
  • Enteral routes include oral and gastro-intestinal.
  • Topical routes include application into the skin and mucous membranes.
  • Dosage of the composition can be adapted to the administration route, as well as to the patient profile, including age, gender, condition, disease progression, or any other phenotypic or environmental parameters.
  • the composition may be in a solid form such as an amorphous, crystalline or semi-crystalline powder, granules, flakes, pills, scaffolds, capsules and suppositories.
  • a solid form can be converted into a liquid form by mixing the solid with a physiologically appropriate liquid such as solvents, solutions, suspensions and emulsions.
  • the present invention provides a method of treating a patient with in immunotherapy - namely, for use in the treatment of cancer diseases, in particular solid tumours - the method comprising administering an effective amount of dendrimer-complex of the present disclosure to the patient.
  • the word "comprise” and variations of the word are not intended to exclude other technical features, additives, components, or steps. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention.
  • the following examples and drawings are provided by way of illustration, and they are not intended to be limiting of the present invention.
  • the present invention covers all possible combinations of particular and preferred embodiments described herein.
  • Figure 1 An embodiment of a schematic representation of the aAPC, consisting of a generation 7 polyamidoamine dendrimer loaded with accessory cytokines in its inner core and surface tailored with a different active molecules, such as, MHC tetramer, co-stimulatory molecules and fluorescent probes.
  • FIG. 1 Figure 2 - Tapping mode Atomic force microscopy of generation 7 polyamidoamine dendrimers deposited on the mica surface.
  • Figure 4 Confocal imaging of the bone marrow derived macrophages labelled with DAPI (blue) when placed contact with CMCht/PAMAM generation 7 labelled with FITC (green) dendrimers conjugated to anti-CDllb (in red).
  • FIG. 5 Graphical representation of the indirect quantification of functional grade a-CD3 binding to the dendrimer surface.
  • the present subject-matter relates to functionalized dendrimer-based nanoparticles to obtain effective artificial antigen presenting cells to be used in immunotherapeutic purposes.
  • the present disclosure provides compositions and methods to modify and functionalize the dendronized polymers as efficient artificial antigen presenting cells (aAPCs).
  • the dendrimeric compositions/nanopackages have certain functionalities, such as targetability, traceability, drug delivery capacity, or reactivity, which offer new possibilities for diagnose and management of several diseases, namely immunotherapy treatment in particular cancer.
  • aAPCS consist of an inner core composed of a dendritic polymer (e.g. polyamidoamine dendrimers) and of an outer shell comprising specifically tailored coating groups (e.g. co-stimulatory molecules, antibodies).
  • a dendritic polymer e.g. polyamidoamine dendrimers
  • an outer shell comprising specifically tailored coating groups (e.g. co-stimulatory molecules, antibodies).
  • the schematic image of a aAPC structure is represented in Figure 1.
  • the nanoparticles of the present subject matter are easily manipulated to carry antibodies or tetramers in their surface (targeted delivery), and other molecules such as cytokines in their inner core that are slowly released. Therefore, dendrimers-based aAPCs targeted delivery systems of the present subject- matter promote a more efficient and sustained expansion of effector tumour-specific T-cells that attack and lyse tumour cells, leading to a more rapid regression. Additionally, this combination further creates a nano-structure able to promote a more sustained response, as this system is not recognized by the host phagocytic system, thus being able to remain for longer periods of time in vivo.
  • the advantage of the present subject-matter when compared to autologous DCs immunotherapy for instance, is that the function of the aAPCs of the present subject-matter is not modulated and therefore will not be altered by the tumour microenvironment. Moreover, the relatively long half-life of the dendrimers-based aAPC system together with the flexibility to introduce IL-12 in the inner core makes this approach ideal to expand efficient tumour-specific cytotoxic T-cell responses. Finally, the aAPC of the present subject-matter can also be coated with antibodies that modulate T-cell function, preventing their "terminal differentiation" or "exhaustion", two characteristics that can occur in chronic settings.
  • this aAPC system of the present subject-matter allows the incorporation of antibodies in the surface of the synthetic aAPCs that can block the interaction of PD-1 with its ligands, PD-L1 and PD-L2.
  • the synthetic aAPC of the present subject-matter would not only promote the expansion of ongoing T-cell responses, but also improve the quality of these responses, preventing the development of "terminally differentiated” or "exhausted” T-cells. Therefore, a deep understanding of the aAPC system can: i) help us better understand the biology of the T-cell response in chronic settings and determine what T-cell populations are more efficient at targeting and lyse tumour cells. Once this knowledge is acquired ii) aAPC can be used in the clinic to expand these types of T-cells in vivo for a cost-effective and efficient treatment.
  • Another advantage of the present subject-matter, as compared to other promising strategies is that the system of the present subject-matter is aimed to stimulate T-cell responses in vivo, in opposition of the ex vivo stimulation with the nanoparticles nanoparticles. This approach it is able to circumvent the difficulties faced to induce the T-cells homing to the tumour site after their in vitro expansion. Additionally, it is possible to place the aAPCs of the present subject-matter exactly in the place they are needed, at the tumour site, and also promote re-activation of previously activated T-cells and "de novo" activation of naive T-cells. Additionally, this system can be administered using minimally invasive strategies namely in treatment of different types of cancer.
  • the surface of the PAMAM dendrimers are modified with linear polymers (e.g. polyethylene glycol, carboxymethylchitosan, hyaluronan, and gellan gum), allowing for the development of novel dendronized nanocarriers with improved encapsulation ability, biocompatibility and prolonged bioavailability.
  • linear polymers e.g. polyethylene glycol, carboxymethylchitosan, hyaluronan, and gellan gum
  • the nanoparticles developed by combining the glycodendrimers (inner core) and natural-based polymers (external shell) allow specific biofunctionalization (e.g. T-cell priming).
  • the aAPCs of the present disclosure can be obtained by chemically modifying generation 7 PAMAM dendrimers into PAMAM- methyl ester terminated dendrimers according to the following procedure: the PAMAM dendrimers are induced to react (condensation reaction between the methyl ester groups of the dendrimer and the amine groups of the natural-based polymers) with natural-based polymers (e.g carboxymethylchitosan) to create the outer shell of the aAPC; after the completion of this binding reaction the unreacted methyl ester are capped and the remaining dendrimer precipitated, resulting in spheroidal nanosystems.
  • the obtained nanoparticles were identified by atomic force microscopy (Fig. 2).
  • the dendronized nanoparticle of the present subject- matter may be further tailored by binding a-CD3 and a-CD28 antibodies to the surface, but other antibodies are possible to be linked.
  • This binding reaction can be performed through different methods, such as: i - Covalent binding techniques resorting to carbodiimide crosslinkers (e.g. EDC- NHS chemistry); ii - High affinity non-covalent binding techniques (e.g. streptavidin/avidin and biotin interaction).
  • the conjugation of antibodies to the surface of the nanoparticles improved the in vitro functionality and stabilize the aAPC system by reducing particle/particle interaction as shown in table 1.
  • Table 1 Diameter (nm) and surface charge (mV) of dendrimers conjugates to anti-CD3 and anti-CD28 antibodies evaluated by dynamic light scattering (DLS).
  • the optimal conditions have been established regarding the type and antibodies concentrations, the binding of tetramers to expand tumour-specific T-cell responses.
  • the specific cytokines aimed at generating protective T-cell responses (e.g. IL-12 to generate IFNv-producing T-cells).
  • the inclusion of cytokines in the inner core of the dendrimers is a novelty of this system as the slow release of cytokines promotes sustained T-cell responses.
  • the cytokine release profile comprehends an initial burst until 24 hours, followed by a steady state lasting for nearly 7 days.
  • the assembled aAPCs are able to, for instance expand human T-cells retrovirally transduced to express these TCRs prior to in vitro testing for ability to kill myeloid leukaemia cells. Also, it can possibly prime/boost T-cell responses in vivo in the context of chronic disease such as cancer.
  • This strategy has advantages over those protocols stimulating T-cells in vitro, previous to their administration, since it is well accepted that in vitro stimulated T-cells have a homing pattern distinct of those stimulated in vivo. While in vitro activated T-cells home preferentially to the gut, those stimulated in the draining lymph nodes home preferentially to the region drained by that lymph node.
  • PEC capsules can be subsequently cultured together with the previously described growth medium and kept at 37°C with 5% C0 2 in a standard tissue culture incubator.
  • figure 5 data showed that it is possible to effectively bind the desired functional grade antibody to the surface of the dendrimer in order to create a functional artificial antigen presenting cell system.
  • Generation 7 Polyamidoamine (PAMAM)- Carboxymethylchitosan (CMCht) nanoparticles, and well as, fluorescein isothiocyanate (FITC)-labeled generation 7 PAMAM-CMCht nanoparticles were performed as described by Oliveira et al.(Oliveira, Kotobuki et al. 2008);
  • further surface functionalization of both PAMAM-CMCht and PAMAM-CMCht-FITC systems with anti-CD3 and anti-CD28 antibodies may be achieved through EDC carbodiimide and N-hydroxysulfosuccinimide (NHS) conjugation.
  • EDC carbodiimide and N-hydroxysulfosuccinimide (NHS) conjugation Both anti-CD3 and anti-CD28 antibodies are reacted with EDC/NHS at room temperature for 30min in MES buffer 50mM at pH6,5. Unreacted EDC/NHS molecules are removed through ultracentrifugation.
  • PAMAM-CMCht were incubated overnight at 4 ⁇ C with the previously activated antibodies in a phosphate-buffered saline solution for coupling and the following day unreacted antibodies are removed by ultracentrifugation and sample is freeze-dryed.
  • the composition may comprises the dendrimer-complex discloses in the present subject-matter, in an amount effective to improve the immunotherapy by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, at least 95.7%, at least 98%, or at least 99% in the subject.
  • the composition comprises a dose of 0.1-1000 mg of the dendrimer complex disclosed.
  • the preparation comprises a dose of 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 11 mg/kg, 12 mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18 mg/kg, 19 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 200 mg/kg, 250 mg/kg, 300 mg/kg, 400 mg
  • the preparation comprises a dose of 0.1-10 mg/kg, 0.1-100 mg/kg, 1-10 mg/kg, 1-100 mg/kg, 1-1000 mg/kg, 10-100 mg/kg, 10-1000 mg/kg, 100-1000 mg/kg, 10-50 mg/kg, 10-25 mg/kg, 10-20 mg/kg, 50-100 mg/kg, or 100-250 mg/kg.
  • Preferred routes of administration include but are not limited to oral, parenteral, intramuscular, intravenous, in situ injection, intranasal, sublingual, intratracheal, and inhalation.
  • the dose or dosage form is administered to the subject once a day, twice a day, or three times a day. In other embodiments, the dose is administered to the subject once a week, once a month, once every two months, four times a year, three times a year, twice a year, or once a year. [0085] All references recited in this document are incorporated herein in their entirety by reference, as if each and every reference had been incorporated by reference individually.
  • the invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process.
  • the invention also includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.
  • any particular embodiment of the present invention may be explicitly excluded from any one or more of the claims. Where ranges are given, any value within the range may explicitly be excluded from any one or more of the claims. Any embodiment, element, feature, application, or aspect of the compositions and/or methods of the invention, can be excluded from any one or more claims. For purposes of brevity, all of the embodiments in which one or more elements, features, purposes, or aspects is excluded are not set forth explicitly herein.

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Abstract

La présente divulgation concerne la conception et la production d'un nouveau système de cellules présentatrices d'antigènes artificielles (aAPC) basé sur des nanopolymères dendronisés d'origine naturelle dont le cœur peut être chargé de cytokines et portant sur leur surface des molécules recombinées pour amorcer et expanser les réponses en cellules T spécifiques de tumeurs. La méthodologie de modification et de fonctionnalisation des polymères dendronisés est décrite. Les dendrimères sont multifonctionnels, biocompatibles, biodégradables et extrêmement perméables, ce qui permet l'ingénierie de surface et la fonctionnalisation des systèmes aAPC par le biais de molécules différentes qui servent non seulement à expanser les réponses en lymphocytes T en cours mais aussi à moduler leurs fonctions en prévenant le développement de leur "différenciation terminale" ou leur "épuisement".
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WO2021064678A1 (fr) * 2019-10-04 2021-04-08 Association For The Advancement Of Tissue Engineering And Cell Based Technologies & Therapies A4Tec - Associação Particules de type hydrogel, procédés et utilisations de celles-ci
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Publication number Priority date Publication date Assignee Title
WO2021064678A1 (fr) * 2019-10-04 2021-04-08 Association For The Advancement Of Tissue Engineering And Cell Based Technologies & Therapies A4Tec - Associação Particules de type hydrogel, procédés et utilisations de celles-ci
WO2023079524A3 (fr) * 2021-11-08 2023-07-13 Life Technologies As Conjugués polymère-molécules d'interaction et procédés d'utilisation

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