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WO2019010471A1 - Procédés et réactifs pour traiter des maladies auto-immunes et l'allergie - Google Patents

Procédés et réactifs pour traiter des maladies auto-immunes et l'allergie Download PDF

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Publication number
WO2019010471A1
WO2019010471A1 PCT/US2018/041170 US2018041170W WO2019010471A1 WO 2019010471 A1 WO2019010471 A1 WO 2019010471A1 US 2018041170 W US2018041170 W US 2018041170W WO 2019010471 A1 WO2019010471 A1 WO 2019010471A1
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Prior art keywords
antigen
cell
polymer
mhc
drug
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PCT/US2018/041170
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English (en)
Inventor
Tian Xin WANG
Original Assignee
Wang tian xin
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Priority claimed from US15/723,173 external-priority patent/US20180092983A1/en
Application filed by Wang tian xin filed Critical Wang tian xin
Priority to CN201880057516.6A priority Critical patent/CN111132686A/zh
Publication of WO2019010471A1 publication Critical patent/WO2019010471A1/fr

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    • 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
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • 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
    • A61K39/0005—Vertebrate antigens
    • A61K39/0008—Antigens related to auto-immune diseases; Preparations to induce self-tolerance
    • 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
    • A61K39/35—Allergens
    • 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
    • A61K47/61—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 the organic macromolecular compound being a polysaccharide or a derivative thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/645—Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
    • 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
    • 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
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • 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
    • A61K2039/6031—Proteins
    • A61K2039/605—MHC molecules or ligands thereof
    • 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

Definitions

  • the current invention relates to protein, peptide and antigen modification for pharmaceutical applications and reagents to treat disease such as auto immune disease and allergy.
  • the current invention discloses methods to treat auto immune disease and allergy.
  • Immune tolerance is the acquired lack of specific immune responsiveness to an antigen to which an immune response would normally occur. Typically, to induce tolerance, there must be an exposure to a tolerizing antigen, which results in the death or functional inactivation of certain lymphocytes. This process generally accounts for tolerance to self antigens, or self-tolerance.
  • Immunosuppressive agents are useful in prevention or reduction of undesired immune responses, e.g., in treating patients with autoimmune diseases or with allogeneic transplants.
  • Conventional strategies for generating immunosuppression associated with an undesired immune response are based on broad-acting immunosuppressive drugs. Additionally, in order to maintain immunosuppression, immunosuppressant drug therapy is generally a life-long proposition. Unfortunately, the use of broad-acting immunosuppressants is associated with a risk of severe side effects, such as tumors, infections, nephrotoxicity and metabolic disorders. Accordingly, new immunosuppressant therapies would be beneficial.
  • FIG. 1 shows example of general structure of antigen-drug conjugate
  • FIG. 2 shows example of general structure of antigen- alpha gal conjugate
  • FIG. 3 shows an example of antigen- alpha gal conjugate for SLE treatment
  • FIG. 4 shows examples of 3 different formats of the antigen-drug conjugate.
  • FIG. 5 shows examples of an antigen-sialic acid rich polymer conjugate to treat autoimmune disease or allergy or to induce immune tolerance.
  • FIG.6 shows examples of the conjugate containing antigen and sialic acid/siglec ligand.
  • FIG.7 shows schematic example of the structure of the microsphere based agent to induce immune tolerance and treating auto immune diseases or allergy.
  • FIG. 8 shows different formats of using polymer carrier conjugated with antigen, siglec ligand and other immunosuppressant; and both siglec ligand and other immunosuppressant conjugated to the antigen.
  • FIG. 9 shows examples of siglec ligand-antigen conjugate for systemic lupus erythematosus treatment.
  • FIG. 10 shows schematic example of multiple antigens and immunosuppressants with linkers to form a linear polymer.
  • FIG. 11 shows exemplary scheme of antigen containing polymer conjugated to a nano or micro particle encapsulating immune suppressant.
  • FIG. 12 shows exemplary scheme of multiple antigens with linkers to form a linear polymer.
  • FIG. 13 shows exemplary scheme of multiple antigen conjugated to a polymer carrier backbone.
  • FIG. 14 shows exemplary scheme of antigen containing polymer conjugated to a nano or micro particle.
  • FIG. 15 shows exemplary scheme of coating additional T/B regulatory cell stimulating molecule/cytokine to pMHC-NP/MP.
  • FIG. 16 shows exemplary scheme of multiple pMHC is conjugated to or expressed in a polymer instead of being coated on a particle.
  • the current invention discloses a transdermal drug delivery system such as a transdermal patch to treat conditions selected from autoimmune disease, allergy and anti-drug antibody comprising an antigen causing said condition and an immunosuppressant.
  • the antigen can be B cell antigen, T cell antigen in MHC-peptide complex form or the antigen peptide (or its derivative) of T cell antigen that can bind with MHC to form the MHC-peptide complex.
  • Example of immunosuppressant is selected from rapamycin, fujimycin and methotrexate.
  • the current invention also discloses a method to treat autoimmune disease or allergy or inhibit antidrug antibody production or induce antigen specific immune tolerance in a subject by administering to the subject a said transdermal drug delivery system on the skin.
  • the current invention discloses a conjugate in linear polymer form or particle form to treat conditions selected from autoimmune disease, allergy and anti-drug antibody or to inhibit anti-drug antibody production or to induce antigen specific immune tolerance comprising an antigen causing the condition, a first immunosuppressant and an optional second immunosuppressant.
  • the antigen can be B cell antigen, T cell antigen in MHC-peptide complex form or the antigen peptide (or its derivative) that can bind with MHC.
  • the first 80 immunosuppressant is selected from siglec ligand such as sialic acid or poly sialic acid.
  • Example of second immunosuppressant is selected from rapamycin, fujimycin, methotrexate and PD-L1.
  • the current invention also discloses a method to treat autoimmune disease or allergy or inhibit anti-drug antibody production or induce antigen specific immune tolerance in a subject by administering to the subject said conjugate (e.g. subcutaneous or intravenous
  • Antigen-drug conjugate can be used for SLE treatment.
  • DNA-linker-Mertansine DNA sequence adopted from Abetimus, linker/toxin adopted from Kadcyla, linker can be optimized for B/T cells
  • the DNA sequence used are the complex formed with GTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT (SEQ ID NO: 1) and
  • Single strand DNA antigen can also be used to inactivate auto antibody generating cells specific to single strand DNA. It will selectively inactivate the specific B cell clone producing auto antibody against DNA, treat the disease from the source. It can be prepared easily with solid phase synthesis. It can be intravenously injected to the patient having SLE to treat it. Companion test will be performed 100 to increase the efficacy. Patient will be treated with hemopurification to remove the anti-DNA antibody before the first dose ADC administration for better therapeutical index.
  • epitope (antigen)-toxin instead of epitope(antigen)-toxin described, epitope (antigen)- alpha gal(e.g. Galactose-alpha- 1,3 -galactose) can also be used instead, which utilize the endogenous anti gal antibody to inactivate the B cell clone or T cell clone that can selectively bind with the epitope (antigen).
  • epitope (antigen)- alpha gal e.g. Galactose-alpha- 1,3 -galactose
  • the alpha gal can be readily adopted from US patent application US 12/450,384 and other publication.
  • Epitope (antigen)-alpha gal conjugate design has the formula: alpha galactosyl- (optional linker)-epitope (antigen), which will allow the T cell/B cell specific to the epitope (antigen) bind with endogenous anti-Gal antibody and therefore be eliminated/inactivated due to the bound antibody. Examples of its structure are shown in figure 2.
  • the antigen can be insulin or insulin fragment that recognized by autoimmune B cell/T cell, or peptide of pancreatic islets recognized by the auto immune T cell in diabetics or the auto antigen of beta cells (e.g. those described in Clin Immunol. 2004 Oct;113(l):29-37 and Proc Natl Acad Sci U S A. 2003 Jul 8; 100(14): 8384-8388). This conjugate will selectively inactive the autoimmune B cell/T cells causing diabetics.
  • T cell antigen it can be insulin or insulin fragment that recognized by autoimmune B cell/T cell, or peptide of pancreatic is
  • peptide 115 be the MHC-peptide complex form, in which the peptide can be optionally covalently linked
  • the T cell recognize T cell antigen by its TCR receptor.
  • the T cell antigen normally is in the form of MHC-epitope binding complex.
  • the epitope normally is a peptide (sometimes other molecules such as carbohydrate) processed by APC. In some embodiments of the current
  • the antigen for T cells preferably is the formed MHC-epitope complex or its fragment/derivatives/mimics, which has higher specific affinity to TCR than the epitope alone. It can be the monomer form or oligomer (dimer, trimer, tetramer, pentamer or even higher degree oligomer or polymer) form such as the MHC tetramer or dextramer currently used in research. For example, HLA-A2insB10-18 tetramer (described in doi:
  • 125 10.107 ' 3/pnas.0508621102 can be conjugated with the cell inactivating agent with an optional linker to treat Type 1 diabetes by inactivating the auto immune T cell.
  • the epitope e.g. peptide
  • MHC cell containing a cell chromosome
  • the antigen used for B cell in the current invention can also be oligomer or polymer form.
  • the antigen used for B cell can also be oligomer or polymer form.
  • 130 inactivation may not require the MHC component.
  • FIG. 3 An example reagent that can selectively inactivate B cells producing auto antibody against DNA is shown in figure 3, this drug can be used to treat lupus.
  • the patient can receive 500 mg-lg of the said conjugate as weekly i.v. injection to treat his lupus until symptom disappears.
  • a carrier system can be used for the current invention to build the conjugate.
  • the liposome or microparticle or nanoparticle can be used as a carrier.
  • the antigen is immobilized on the surface of the liposome or particles and the effector molecule (e.g. alpha gal, rhamnose, immune suppression cytokine, tregitope peptide, toxin, Si RNA or mi RNA or the like, immune suppressant, antisense molecule) can be either encapsulated inside or co-immobilized 140 on the surface of liposome or particles.
  • the carrier can also be a linear or branched polymer such as dextran. Both antigen and the effector molecule are conjugated to the polymer.
  • Solid phase particle coated with auto antigen or combinations of different auto antigens for the same diseases (because sometimes a patient will have T cells/B cells specific for a groups of different auto antigens) coated on their surface can be used to treat their corresponding auto
  • the solid phase particle can be a mixture of different solid phase particle each coated with different auto antigen for this diseases; or a solid phase particle coated with a mixture of the different auto antigen involved for the diseases.
  • GAD65 a specific auto antigen that is involved
  • insulin a specific auto antigen that is involved
  • preproinsulin a specific auto antigen that is involved
  • the solid phase particle can be a mixture of different solid phase particle each coated with different auto antigen for this diseases; or a solid phase particle coated with a mixture of the different auto antigen involved for the diseases.
  • a solid phase particle coated with a mixture of the different auto antigen involved for the diseases e.g. GAD65, insulin, preproinsulin and etc.
  • 150 single antigen can be used to induce immune tolerance for a group of devise antigens therefore the mixture of different antigen may not be required.
  • An ELISA test can be performed to the patient to identify the antigens involved and use this information to select suitable solid phase adsorbent for treatment.
  • MHC-epitope e.g. peptide
  • the complex can be either covalent or non-covalent
  • MHC-epitope complex such as HLA-A2insB10-18.
  • alpha gal other molecule/peptide/protein can also be used to conjugate with a specific antigen to selectively inactivate the specific B cell clone or T cell clone that binds and 160 reacts with the specific antigen.
  • the resulting agent has the general structure:
  • the agent can be given to the patient (e.g. by i.v. injection) at therapeutic effective amount and in therapeutic acceptable formulation to the patient having autoimmune disease or allergy due to the said antigen to treat said autoimmune disease or allergy or to inhibit anti-drug antibody 165 production or to induce antigen specific immune tolerance.
  • the antigen is a therapeutic drug (e.g. recombinant protein) or its epitope
  • it can be given to the patient (e.g. by i.v. injection) to inhibit/prevent the production of anti drug antibody (ADA). It can be used to induce antigen specific immune tolerance.
  • ADA anti drug antibody
  • Example of cell inactivating molecule include affinity ligand (e.g. antibody or its fragment, aptamer) or their combination against immune 170 cells (e.g.
  • bi specific antibody and triomab for cancer treatment such as a antibody against a T-lymphocyte antigen like CD3, or a bi specific antibody (or a triomab having Fc) against CD3 and CD28, or a fusion protein of B7 with an antibody (or its fragment) against CD3, antigen that already has immuno response in the body (e.g. alpha-gal, L- rhamnose), B7, super antigen (e.g. staphylococcal enterotoxin A, SEA), cytokines (e.g. 175 immuno cell inactivating cytokines) and those described in the previous patent applications by the inventor and references.
  • L-rhamnose can be linked with a PEG 3 by a glycoside bond and the PEG 3 is also conjugated with an auto antigen.
  • affinity ligand such as antibody or its fragment against cytotoxic immune cell activating receptor such as CD3 of T cell or CD16 of NK cell
  • it will 180 recruit/activate cytotoxic immune cell such as T cells or NK cells to inhibit/kill the target B/T cell that can bind with the antigen (preferably the antigen for target T cell will be MHC-peptide complex recognized by its TCR); which is similar to the current bi-specific antibody to kill cancer cell except the auto antigen is used in the conjugate instead of the antibody against cancer cell).
  • an antibody or Fab against CD16A of NK cell (which sequence can be adopted from the TnadAb AFM13 of Affimed) is conjugated with the linker- antigen for SLE shown in figure 1 via its cysteine to form a thiol-maleimide linkage, which is widely used in antibody drug conjugate and the conjugation protocol is well known to the skilled in the art.
  • This antigen-anti CD16A antibody conjugate can be used to treat SLE.
  • the patient e.g. 200mg -lOOOmg i.v. bi weekly
  • it will bind with DNA antigen specific B cells and attract NK cell to kill it, therefore inhibit auto antibody production against DNA antigen.
  • an antibody or Fab against CD3 can be used instead of those against CD 16 to prepare the conjugate.
  • the resulting conjugate can attract cytotoxic T cell to kill the antigen specific B cell to treat corresponding autoimmune diseases.
  • additional affinity ligand can also be introduced into the conjugate to increase the affinity and specificity to B or T cell.
  • antibody against CD20 can also be incorporated in the conjugate via a linker to increase the targeting toward B cell, a scheme similar to tri-specific antibody.
  • co-stimulatory molecules B7.1 can also be used as 200 cell inactivating molecule such as those selected from other B7 family members including B7.2 (CD86), B7-H1 (PD-L1), B7-H2 (B7RP-1 or ICOS-L or B7h or GL-50), B7-H3 (B7RP-2), B7- H4 (B7x or B7S1), B7-DC (PD-L2) and etc., and these proteins having amino acid sequence of more than 70% identity of the natural and man-made variants.
  • B7.2 B7 family members
  • B7-H1 PD-L1
  • B7-H2 B7RP-1 or ICOS-L or B7h or GL-50
  • B7-H3 B7RP-2
  • B7- H4 B7x or B7S1
  • B7-DC PD-L2
  • Co-stimulatory molecules B7.1 (CD80) or other co-stimulatory molecule's role is to stimulate the body's immune response.
  • T cells can also be used as cell inactivating molecule of the present invention.
  • the protocol described in patent application CN102391377A (CN201110338886) can be readily adopted for the current invention.
  • the cytokine of the fusion protein in CN102391377A can be replaced with the auto antigen to generate the conjugate of the current application to inactivate the 210 antigen specific B cell and/or T cells.
  • B7 is a type of peripheral membrane protein found on activated antigen presenting cells (APC) that, when paired with either a CD28 or CD 152 (CTLA-4) surface protein on a T cell, can produce a costimulatory signal or a coinhibitory signal to enhance or decrease the activity of a MHC-TCR signal between the APC and the T cell, respectively.
  • APC activated antigen presenting cells
  • CTL-4 CD 152
  • T cells e.g. B7.1, B7.2
  • B/T cells B7.DC/PD-L2, B7.H1/PD-L1
  • T cell activating B7 it will recruit/activate other T cells or cytotoxic immune cells to inhibit/kill (similar to the current bi-specific antibody to kill cancer cell except the auto antigen is used instead of the antibody against cancer cell) the target B/T cell that can bind with the antigen (preferably the
  • 220 antigen for target T cell will be MHC-peptide complex recognized by its TCR).
  • B/T cell inhibiting B7 When B/T cell inhibiting B7 is used in the conjugate, it will bind with the corresponding receptors on target B/T cell to kill/inactivate the target B/T cells that can bind with the antigen.
  • ligand that can activate the inhibitory immune checkpoint receptors on immune cells such as A2AR, B7-H3, B7-H4, BTL, IDO, KIR, LAG3, PD-1, ⁇ -3 and VISTA, or the 225 ligand (e.g. antibody or its fragment) that can block the activating checkpoint molecules on immune cells
  • 225 ligand e.g. antibody or its fragment
  • CD27, CD 47, CD 28, CD40, CD122, CD137, OX40, GITR, CD52 and ICOS can also be used as cell inactivating molecule.
  • the cell inactivating molecule can be PD-L1 or its derivative/fragment or mimic or other ligand that binds to PD-1 to prevent B or T cell activation, PD-L2 or its derivative /fragment or mimic or other ligand 230 that binds to PD-1 to prevent B or T cell activation and etc.
  • BCR antigen-TCR antigen conjugate can also be used.
  • Optional linker can be added between these functional groups.
  • the B cell antigen binds with the target B cell and the T cell antigen (MHC-antigen peptide complex, which can be covalently linked together) bind with the effector T cell.
  • the antigen for B cell and T cell can 235 be different. The principle is to recruit the existing effector T cell to kill/inactivate the target B cell.
  • the T cell antigen can also be the peptide that can bind with the MHC to form the MHC- peptide complex or its derivative, instead of the full MHC-peptide complex type T cell antigen, in this case the peptide will be taken by APC and then form the MHC-peptide complex in vivo
  • the current invention further discloses methods and regents to treat autoimmune diseases and allergy or to inhibit anti-drug antibody production or to induce antigen specific immune tolerance by applying the combination of antigen and immunosuppressive agent/drug either as a physical mixture or as synthetic conjugate or as nano/micro particles or liposome to the object/patient in need.
  • nano/micro particle means the particle is in either nanometer
  • the nano/micro particle can be in the size range of 50 nm ⁇ 100um.
  • List of exemplary immunosuppressive drugs can be found at
  • immunosuppressive agent/drug suitable for the current application include but are not limited to, statins; mTOR inhibitors, such as rapamycin or a rapamycin analog; TGF- ⁇ signaling agents; TGF- ⁇
  • TLR toll like receptor
  • Pattern recognition receptor inhibitors 250 receptor agonists; TLR (toll like receptor) inhibitors; Pattern recognition receptor inhibitors;
  • NLR NOD-like receptors
  • RIG-I-like receptors inhibitors RIG-I-like receptors inhibitors
  • NOD2 inhibitors RIG-I-like receptors inhibitors
  • histone deacetylase inhibitors such as Trichostatin A; corticosteroids; inhibitors of
  • mitochondrial function such as rotenone; P38 inhibitors; NF- ⁇ inhibitors, such as 6Bio, Dexamethasone, TCPA-1, IKK VII; adenosine receptor agonists; prostaglandin E2 agonists
  • PGE2 such as Misoprostol
  • phosphodiesterase inhibitors such as phosphodiesterase 4
  • PDE4 Peroxisome proliferator-activated receptor antagonists
  • Rolipram such as Rolipram
  • proteasome inhibitors such as Rolipram
  • kinase inhibitors such as Rolipram
  • G-protein coupled receptor agonists such as G-protein coupled receptor agonists
  • G-protein coupled receptor antagonists such as glucocorticoids; retinoids; cytokine inhibitors; cytokine receptor inhibitors; cytokine receptor activators; peroxisome proliferator-activated receptor antagonists; peroxisome proliferator-activated receptor agonists;
  • histone deacetylase inhibitors calcineurin inhibitors; phosphatase inhibitors; PI3 KB
  • Immunosuppressants also include IDO, vitamin D3, cyclosporins, such as cyclosporine A, aryl hydrocarbon receptor inhibitors, resveratrol, azathiopurine (Aza), 6-
  • the immunosuppressant may comprise any of the agents provided herein.
  • the immunosuppressant can be a compound that directly provides the
  • immunosuppressive e.g., tolerogenic
  • APCs can be a compound that provides the immunosuppressive (e.g., tolerogenic) effect indirectly (i.e., after being processed in some way after administration).
  • Immunosuppressants therefore, include prodrug forms of any of the compounds provided herein.
  • the immunosuppressant also include Heme Oxygenase- 1 (HO-1) inducer such as Cobalt protoporphyrin (CoPP), protoporphyrin IX containing a ferric iron ion (Heme B) with a chloride ligand (Hemin), hematin, iron protoporphyrin or heme degradation products as well as those described in PCT/EP2015/074819.
  • HO-1 Heme Oxygenase- 1
  • CoPP Cobalt protoporphyrin
  • protoporphyrin IX containing a ferric iron ion (Heme B) with a chloride ligand (Hemin), hematin, iron protoporphyrin or heme degradation products as well as those described in PCT/EP2015/074819.
  • Siglecs Sialic acid-binding immunoglobulin-type lectins
  • sialic acid or its derivatives is also another type of immunosuppressant
  • PD-L1 is also another type of immunosuppressant that can be used in current invention.
  • PD-L1 can effectively inhibit cytotoxic T cell. Fragment or mimic or derivative of PD-L1 that can bind with PD-1 can also be used instead.
  • Other inhibitory ligands that can bind with inhibitory checkpoint receptor e.g. A2AR, BTLA, CTLA-4, CD 47, KIR, LAG3, TIM-3, VISTA and etc
  • B7-H3, B7-H4 can also be used
  • Molecule that can promote T/B reg expansion e.g. cytokine that can promote T/B reg expansion
  • T/B reg expansion such as IL-2 and TGF- ⁇
  • the immunosuppressant can be a compound that directly provides the immunosuppressive (e.g., tolerogenic) effect on APCs or it can be a compound that provides the immunosuppressive (e.g., tolerogenic) effect on APCs or it can be a compound that provides the immunosuppressive (e.g., tolerogenic) effect on APCs or it can be a compound that provides the immunosuppressive (e.g., tolerogenic) effect on APCs or it can be a compound that provides the
  • Immunosuppressive e.g., tolerogenic
  • Immunosuppressants include prodrug forms of any of the compounds provided herein.
  • Immunosuppressants also include nucleic acids that encode the peptides, polypeptides or proteins provided herein that result in an immunosuppressive (e.g. tolerogenic) immune response.
  • the immunosuppressant is a nucleic acid that encodes a peptide, polypeptide or protein that results in an immunosuppressive (e.g., tolerogenic)
  • the nucleic acid can be coupled to synthetic nanocarrier.
  • the nucleic acid may be DNA or RNA, such as mRNA.
  • the inventive compositions comprise a complement, such as a full-length complement, or a degenerate (due to degeneracy of the genetic code) of any of the nucleic acids provided herein.
  • the nucleic acid is an expression vector that can be transcribed when transfected into a cell line.
  • the expression vector may comprise a plasmid, retrovirus, or an adenovirus amongst others.
  • Nucleic acids can be isolated or synthesized using standard molecular biology approaches, for example by using a polymerase chain reaction to produce a nucleic acid fragment, which is then purified and cloned into an expression vector.
  • the immunosuppressants provided herein are coupled to synthetic nanocarriers or microcarriers.
  • the immunosuppressant is an element that is in addition to the material that makes up the structure of the synthetic nanocarrier or microcarrier.
  • the immunosuppressant is a compound
  • the immunosuppressant is again in addition and coupled to the one or more lipids.
  • the immunosuppressant is an 320 element present in addition to the material of the synthetic nanocarrier or microcarrier that results in an immunosuppressive (e.g., tolerogenic) effect.
  • immunosuppressants include, but are not limited, small molecule drugs, natural products, antibodies (e.g., antibodies against CD20, CD3, CD4), biologies-based drugs,
  • compositions comprising B cell and/or MHC Class II-restricted epitopes and
  • the antigen/epitope is conjugated to the nanocarrier and immunosuppressants is coupled to the nanocarrier.
  • nano/micro particle having antigen/epitope non-covalently adsorbed to its surface and immunosuppressant encapsulated within.
  • the nano/micro particles can be made of biodegradable materials such as PLGA. These kinds of nano/micro particles (e.g. lOnm ⁇ lOum of diameter in size) can be given to the patient in need
  • the surface of the nano/micro particles can have charged groups such as amino or carboxyl group to increase the binding of antigen/epitope to its surface; it can also have a hydrophobic surface to allow binding antigen/epitope via hydrophobic interaction; or
  • Introducing charged groups to the surface can be done by using surface modification or using amine or carboxyl group containing molecules to prepared the nano/micro particles.
  • the antigen/epitope can also be conjugated with a lipid molecule such as fatty acid or cholesterol to increase its binding to nano/micro particles.
  • the adsorption of antigen/epitope to the nano/micro particle surface can be done by incubating antigen/epitope
  • nano/micro particle e.g. 4 degree overnight in aqueous solution buffer such as
  • PLGA nano particle encapsulated with 10% by weight of rapamycin is prepared according to the literature.
  • the PLGA nano particle is mixed with
  • OVA ovalbuproliferative
  • rapamycin is dissolved in DMSO at 50 mg/ml.
  • a total of 50 ⁇ L ⁇ rapamycin is added to 1 ml PLGA (5 mg/ ml) dissolved in dichloromethane.
  • the mixture is homogenized with 0.4 ml 5% OVA solution for 10 min using ultrasoni cation.
  • the o/w emulsion is added to 2.1 ml of a 5%
  • OVA coated nano particles containing rapamycin are obtained after centrifugation at 3,500g for 20 min. Additional washing step can be performed to obtain unbound OVA free particles.
  • This OVA coated particle can be given to the target in need to induce OVA immune tolerance, using the similar protocol described in the publications (e.g. those from Selecta Bio).
  • the OVA can be
  • lipophilic carboxylic acid or lipophilic amine or anionic detergent or cationic detergent e.g. fatty acid such as caprylic acid , lauric acid ; or cationic lipid such as DOTMA, DOTAP, cholesterylamine
  • rapamycin is dissolved in DMSO at 50 mg/ml with lauric acid
  • antigen/epitope can also be encapsulated within the nano/micro particle besides being conjugated or adsorbed to its surface.
  • the preparation of antigen/epitope encapsulation is well known to the skilled in the art and can be adopted from related publications readily, e.g. using a double emulsion water/oil/water system.
  • US patent application 20130287729 Al disclosed antigen-specific, tolerance-inducing microparticles and uses thereof. It disclosed a microparticle (0.5 ⁇ - ⁇ . ⁇ ⁇ in size) for targeting an antigen-presenting immune cell of interest and for inducing antigen-specific immune tolerance, wherein the microparticle comprises an antigen and a therapeutic agent
  • the therapeutic agent is an immunomodulatory agent, an immunosuppressive
  • a further improvement of this method and composition is to use a nano/micro particle having the size of
  • the surface of the nano/micro particle is coated with Fc portion of an antibody or a full antibody with its Fc portion facing outside. This will bind with the FcR to facilitate APC uptake.
  • the surface of the nano/micro particle needs not to have a ligand that targets the antigen-presenting immune cell. In some embodiments, it can have antigen/epitope coated on
  • the inner part of the nano/micro particle contains immunosuppressive agent listed in the current application and optionally antigen/epitope, e.g. by encapsulation.
  • the preparation method is well known to the skilled in the art and can be adopted from related publications readily.
  • a liposome encapsulating an autoantigen wherein the liposome has a size comprised from 500 to 15000 nm and the liposome membrane comprises phosphatydilserine (PS) in an amount comprised from 10 to 40% by weight with respect to the total membrane liposomal composition.
  • PS phosphatydilserine
  • compositions as defined above for use as a medicament, particularly for the treatment of autoimmune diseases are provided liposomes and pharmaceutical or veterinary compositions as defined above for use in the restoration of tolerance to self in a patient suffering from an autoimmune disease.
  • the current invention also discloses antigen-specific, tolerance- inducing liposome and uses thereof.
  • the liposome contains immunosuppressive agent listed in the current application (and optionally antigen/epitope molecule) inside by encapsulation.
  • the surface of the liposome can also have antigen/epitope coated. It can be given to the patient in need as
  • the lipid used for injection or inhaler or applied topically to induce immuno tolerance 420 injection or inhaler or applied topically to induce immuno tolerance.
  • the lipid used for injection or inhaler or applied topically to induce immuno tolerance 420 injection or inhaler or applied topically to induce immuno tolerance.
  • liposome can include but not limited to phosphatydilserine at 10 to 40% by weight of the membrane. It can also use non- phosphatydilserine lipid to prepare the membrane.
  • the antigen/epitope can also be conjugated with a lipid type molecule such as fatty acid or phospholipid or cholesterol derivative to allow it to be inserted to the liposome membrane.
  • Suitable liposome can have a size between 50nm ⁇ 20um.
  • the preparation method and the protocol of its use are well known to the skilled in the art and can be adopted from related publications readily such as those in US20160338953.
  • Example of the lipid molecule suitable for the current invention to prepare liposome includes but is not limited to phospholipid glycerolipid, glycerophospholipid, sphingolipid, ceramide, glycerophosphoethanolamine, sterol
  • lipid molecules can also be used to prepare the antigen/epitope-lipid
  • Membrane anchoring peptide- antigen/epitope conjugate can also be used instead of antigen/epitope-lipid conjugate.
  • T/B reg expansion e.g. IL-2 and/or TGF- ⁇ and 435 PD-L1
  • IL-2 and/or TGF- ⁇ and 435 PD-L1 can also be coated/conjugated to and/or encapsulated within the liposome and
  • the current invention discloses methods and regents to treat autoimmune diseases and allergy by applying the mixture of antigen and immunosuppressive agent topically to the object/patient 440 in need. It can also be used to inhibit the generation of anti drug antibody when the antigen is the drug (e.g. a protein drug) or its epitope. It will induce immune tolerance for the antigen.
  • the formulation suitable for the current application include solid form such as powder, gel, lotion, ointment, solution, spray, suppository, lozenge, tablet and patch that can be topically applied to the skin or mucosa.
  • topical drug delivery include drug delivery
  • the immunosuppressive agent can be in the form of active agent, prodrug form, micro particle or nano particle form or liposome form.
  • the antigen can be either B cell antigen/epitope or T cell antigen/epitope (e.g. MHC-peptide complex or conjugate; or the peptide antigen that can bind
  • the combination can be either B cell antigen/epitope with T cell antigen/epitope; or the combination of several different B cell antigen/epitope and/or several different T cell antigen/epitope targeting the same disease or different diseases.
  • peptide antigen T cell epitope
  • T cell antigen T cell antigen
  • the method is to use a patch containing both antigen/allergen and immune suppressive drug (the drug listed above such as rapamycin or fujimycin or
  • the sialic acid can be either free sialic acid or sialic acid ester, sialic acid -lipid conjugate from.
  • sialic acid can be conjugated to cholesterol to form an ester bond using the -COOH of sialic acid with the -OH of the cholesterol. This conjugate will have better trandermal and cell membrane permeation capability.
  • the fatty acid can also be conjugated
  • the transdermal or transmucosal delivery of both antigen and immunosuppressive drug will induce immune tolerance via DC cells in the skin or mucosa.
  • the skin may be exfoliated to 470 remove stratum corneum layer to increase drug delivery or using a micro needle system. This would be a much easier strategy for food allergy and auto immune diseases treatment than injection.
  • the skin may be intact or may be exfoliated to remove stratum corneum layer to increase drug delivery.
  • Micro needle system can also be used to the skin.
  • the micro needle in the micro needle system can be made of bio degradable material such as PLGA encapsulating
  • a bio degradable implant encapsulating antigen and immunosuppressant can also be used.
  • the size of the implant can be bigger than lOum in diameter, preferably > lOOum, if the implant is a macro particle.
  • a 2mm (length) x 0.3mm (diameter) rod made with PLGA containing 3mg rapamycin and lmg gliadin can be used as an implant underneath the skin to treat gluten intolerance.
  • Other implant format can be used as an implant underneath the skin to treat gluten intolerance.
  • NanoPortal Capsule from Nanoprecision Medical and Medici Drug Delivery System from Intarcia, as long as they can deliver the antigen and immunosuppressant simultaneously.
  • DBV Technologies and other groups are using skin patch
  • the topically patch or other formulation can be readily adopted for the current application.
  • the topical applied formulation such as patch described in US 15/135,914, US6676961, US15/111,204, US8932596B2, US15/184,933A1 and US8202533B2 can be adopted for the current application by adding additional immune suppressive drug in the patch
  • transdermal enhancer e.g. DMSO, Azone, fatty acid, hyaluronic acid and etc, which can be found in the publication readily as
  • transdermal enhancing agent can be added include DMSO (e.g. 10 ⁇ 300mg/patch), azone (e.g. 1% -10% of total drug weight), surfactant, fatty acid (e.g. 1% -10% oleic acid).
  • the skin can also remove for stratum corneum with be exfoliation or other means to enhance the transdermal delivery.
  • the patch contains 500 ug - lOmg
  • 500 gluten e.g. G5004 Gluten from wheat, Sigma
  • O. lmg - 10 mg of rapamycin or 1 mg -50 mg methotrexate e.g., antigen such as gluten and immunosuppressant such as rapamycin and/or methotrexate can be in powder form, which can be simply mixed together physically, they can also be co-dissolved and then dried and then placed in the patch.
  • the patch contains 5 mg gluten (e.g. G5004 Gluten from wheat, Sigma) and 5
  • the patch contains 5 mg gluten (e.g. G5004 Gluten from wheat, Sigma) and 100 mg of sialic acid or sialic acid -cholesterol conjugate or 10 mg methotrexate. This can be used to induce gluten tolerance and treat gluten intolerance. The gluten can be replaced with gliadin instead.
  • the patch can be applied daily for 1-5 weeks. In another example, the
  • peanut antigen ara h2 200ug and 2 mg of rapamycin is in the patch to treat peanut allergy.
  • peanut antigen ara h2 200ug, 2 mg of rapamycin and 50 mg sucrose is dissolved in water and then lyophilized and then placed in the patch.
  • peanut antigen ara h2 200ug, 2 mg of rapamycin, 50mg SDS and 50 mg sucrose is dissolved in water and then lyophilized and then placed in the patch.
  • peanut antigen ara h2 200ug, 2 mg of rapamycin, 50mg SDS and 50 mg sucrose is dissolved in water and then lyophilized and then placed in the patch.
  • the antigen is the double strand DNA (lmg - 10 mg) in the previous figures to treat lupus and the drug is 3mg of rapamycin or fujimycin or Temsirolimus.
  • the nasal spray contains 1 mg gluten (e.g. G5004 from Sigma, Gluten from wheat) and 1 mg of rapamycin or 10 mg methotrexate in a
  • the sublingual lozenge contains 50 mg gluten (e.g. G5004 from Sigma, Gluten from wheat) and lmg of rapamycin or 20 mg methotrexate.
  • the gel contains 50 mg gluten (e.g. G5004 Gluten from wheat, Sigma) and 2 mg of rapamycin or 20 mg methotrexate in each 1ml of gel.
  • the immunosuppressant drug or both the immunosuppressant drug and the antigen can be either in the form of powder or gel or
  • liposome e.g. lOOnm ⁇ 5 um diameter
  • nano/micro particle e.g. lOOnm ⁇ lum
  • antigen and immunosuppressant can also be used 530 in the patch, as long as it can produce satisfactory biological and therapeutical (e.g. immune tolerance) effect, which can be determined experimentally by screening and testing with well- known protocol and methods.
  • the antigen can be either B cell antigen/epitope or T cell antigen/epitope (e.g. MHC-peptide complex or conjugate; or the peptide antigen that can bind with MHC) or their combination. 535 Examples of them can be found in the current application and related publications and patent applications.
  • transdermal delivery of both antigen and immunosuppressive drug will be uptaken by APC in the skin, induce/activate tolerogenic dendritic cell and Treg/Breg, inhibit B cell
  • a skin patch (also called transdermal patch) is a medicated adhesive patch or attachable patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream.
  • transdermal patch A wide variety of pharmaceuticals are now available in transdermal patch form.
  • the Single-layer Drug-in- Adhesive type is that the adhesive layer of this system also contains the drug. In this type of patch the adhesive layer not only serves to adhere the various layers together, along with the entire system to the skin, but is also responsible for the releasing of the drug.
  • the adhesive layer is surrounded by a temporary liner and a backing.
  • the Multi-layer Drug-in- Adhesive type is the
  • multi-layer drug-in-adhesive patch is similar to the single-layer system; the multi-layer system is different, however, in that it adds another layer of drug-in-adhesive, usually separated by a membrane (but not in all cases).
  • One of the layers is for immediate release of the drug and other layer is for control release of drug from the reservoir.
  • This patch also has a temporary liner-layer and a permanent backing. The drug release from this depends on membrane
  • the Reservoir type is unlike the single-layer and multi-layer drug-in-adhesive systems, the reservoir transdermal system has a separate drug layer.
  • the drug layer can be a liquid or gel or powder compartment containing a drug solution or suspension or powder separated by the adhesive layer. This patch is also backed by the backing layer. In this type of system the rate of release is zero order.
  • the Matrix type has a
  • the adhesive layer in this patch surrounds the drug layer, partially overlaying it.
  • the reservoir type and the matrix type can be used for current invention.
  • antigen and immunosuppressant loaded matrix-type transdermal patch is 565 prepared by using solvent casting method. A petri dish with a total area of 50 cm2 is used.
  • Antigen and immunosuppressant are dissolved in 5 mL of water, methanol (1 : 1) solution and mixed until clear solution is obtained. 200 mg polyethylene glycol 400 is used as plasticizer and optional 100 mg propylene glycol or oleic acid or tween 80 is used as permeation enhancer, together with 1 OOmg sucrose they are added to the antigen/immunosuppressant 570 solution. The resulted uniform solution is cast on the petri dish, which is lubricated with
  • glycerin and lyophilized or dried at room temperature for 24 h.
  • the dried patch is placed on a cellulose acetate membrane used as backing membrane.
  • weighed amount of PVA (2.5% w/v) is added to a distilled water and a homogenous solution is made by constant stirring and intermittent heating at 60°C for a few seconds and poured into glass 575 molds already wrapped with aluminium foil around open ends and are kept for drying at 60°C for 6 h, forming a smooth, uniform, and transparent backing membrane.
  • Backing membrane is used as a support for antigen and immunosuppressant containing matrix.
  • the skin patch device used in the method of the invention preferably comprises a backing, the periphery of said backing being adapted to create with the skin a 580 hermetically closed chamber.
  • This backing bears on its skin facing side within the chamber the composition used to decrease the skin reactivity.
  • the periphery of the backing has adhesive properties and forms an airtight joint to create with the skin a hermetically closed chamber.
  • the composition allergens and immunosuppressants are maintained 585 on the backing by means of electrostatic and/or Van der Waals forces.
  • electrostatic force generally designates any non- covalent force involving electric charges.
  • Van der Waals forces designates non- 590 covalent forces created between the surface of the backing and the solid allergen, and may be of three kinds: permanent dipoles forces, induced dipoles forces, and London- Van der Waals forces. Electrostatic forces and Van der Waals forces may act separately or together.
  • the patch device comprises an electrostatic backing.
  • electrostatic backing denotes any backing made of a material
  • the electrostatic backing typically includes a surface with space charges, which may be dispersed uniformly or not.
  • the charges that appear on one side or the other of the surface of the backing may be positive or negative, depending on the material constituting said backing, and on the method
  • the positive or negative charges distributed over the surface of the backing cause forces of attraction on conducting or non-conducting materials, thereby allowing to maintain the allergen and immunosuppressant.
  • the particles also may be ionized, thereby causing the same type of electrostatic forces of attraction between the particles and the backing. Examples of materials suitable to provide electrostatic backings are glass or a
  • CA cellulose plastics
  • PE polyethylene
  • PET polyethylen terephtalate
  • PVCs polyvinyl chlorides
  • PMMA poly(methyl methacrylate)
  • PTFE fluoropolymers
  • the back of the backing may be covered with a label which may be peeled off just before 610 application.
  • This label makes it possible, for instance, to store the composition allergen in the dark when the backing is at least partially translucent.
  • the intensity of the force between a surface and a particle can be enhanced or lowered by the presence of a thin water film due to the presence of moisture.
  • the patch is made and kept in a dry place.
  • the moisture shall be low enough to allow the active ingredient to be conserved.
  • the moisture rate can be 615 regulated in order to get the maximum adhesion forces. As discussed above, the use of an
  • electrostatic backing is particularly advantageous where the allergen is in a dry form, e.g., in the form of particles.
  • the particle size may be adjusted by the skilled person to improve the efficiency of electrostatic and/or Van der Waals forces, to maintain particles on the support.
  • the patch comprises a polymeric or metal or metal coated polymeric backing and the particles of composition allergens are maintained on the backing essentially by means of Van der Waals forces.
  • the average size of the particles is lower than 60 micrometer.
  • the allergens are maintained on the backing by means of an adhesive coating on 625 the backing.
  • the backing can be completely covered with adhesive material or only in part.
  • occlusive backings can be used such as polyethylene or PET films coated with aluminium, or PE, PVC, or PET foams with an adhesive layer (acrylic, silicone, etc.).
  • patch devices for use in the present invention are disclosed in patent application US11/915,926 or U.S. Pat. No. 7,635,488.
  • An electrospray device uses high voltage to disperse a liquid in the fine aerosol. Allergens and immunosuppressants dissolved in a solvent are then pulverized on the patch backing where the solvent evaporates, leaving allergens and immunosuppressants in particles form.
  • the 635 may be, for instance, water or ethanol, according to the desired evaporation time.
  • solvents may be chosen by the skilled person.
  • This type of process to apply substances on patch backing allows nano-sized and mono-sized particles with a regular and uniform repartition of particles on the backing.
  • This technique is adapted to any type of patch such as patch with backing comprising insulating polymer, doped polymer or polymer recovered with
  • the backing comprises a conductive material.
  • the periphery of the backing is covered with a dry hydrophilic polymer, capable of forming an adhesive hydrogel film by contact with the moistured skin (as described in US 12/680,893).
  • the skin has to be moistured before the application of the patch.
  • the 645 polymer particles absorb the liquid and become adhesive, thereby creating a hermetically
  • hydrogels examples include polyvinylpyrolidone, polyacrylate of Na, copolymer ether methyl vinyl and maleic anhydride.
  • the liquid composition allergen and immunosuppressant is held on the support of the patch in a reservoir of absorbent material.
  • the composition may 650 consist in an allergen + immunosuppressant solution or in a dispersion of the mixture, for example in glycerine.
  • the adsorbent material can be made, for example, of cellulose acetate.
  • the backing may be rigid or flexible, may or may not be hydrophilic, and may or may not be translucent, depending on the constituent material.
  • the support may be made break-resistant by bonding a sheet of plastic to the glass.
  • the backing 655 of the patch contains a transparent zone allowing directly observing and controlling the
  • Suitable transparent materials include polyethylene film, polyester (polyethylene-terephtalate) film, polycarbonate and every transparent or translucent biocompatible film or material.
  • the injection can be given as either subcutaneous injection or intramuscular injections or intradermal injections.
  • the injection contains a viscosity enhancing agent to increase its viscosity after being injected, which acts as a sustained release formulation
  • Molecule that can promote T/B reg expansion e.g. IL-2 and/or TGF- ⁇ and. or PD-L1
  • T/B reg expansion e.g. IL-2 and/or TGF- ⁇ and. or PD-L1
  • Antigen and immunosuppressive agent can be either in free molecule form or in nano/micro particle from including liposome form.
  • the injection has a viscosity greater than 10,000 cps at room temperature.
  • the injection has a viscosity greater than 100,000 cps at room
  • the injection has a viscosity greater than 5,000,000 cps at room temperature. In certain embodiments, the injection has a viscosity of 11,000,000 cps at room temperature.
  • Example of the viscosity enhancing agent can be found readily from known pharmaceutical acceptable excipient such as hyaluronic acid, starch and carbomer. In some
  • the viscosity enhancing agent is biodegradable.
  • injection contains 5 mg/mL gluten (e.g. G5004 Gluten from wheat, Sigma) and 5 mg/mL of rapamycin or 50 mg/mL methotrexate and suitable amount of hyaluronic acid (e.g. 50mg/mL) to reach a viscosity of 5,000,000 cps with optional lmg/mL IL-2.
  • the injection formulation can also be a thermal phase changing formulation. Thermal phase changing formulation is a
  • thermal phase changing injectable formulation that change its phase from liquid at low temperature or room temperature (25C) to semisolid/gel when temperature increases to body temperature (37C), which can use poloxamer as excipient.
  • a thermal phase changing injectable formulation containing both antigen and immunosuppressive agent can be given as either subcutaneous injection or intramuscular injections or intradermal injections to induce antigen specific immune tolerance 685 and treat corresponding auto immune diseases or allergy. It has low viscosity at low or room temperature but high viscosity at body temperature.
  • the preparation of this kind of thermal phase changing injectable formulation can be adopted from related publications readily by the skilled in the art.
  • the immunosuppressive agent can also be conjugated to carbohydrate polymer to form
  • novel prodrugs can be in the form of carbohydrate (or other polymer) drug conjugate in which the drug is conjugated to the carbohydrate (or other polymer) with cleavable linkage. More than one drugs can be conjugated to the polymer backbone.
  • Suitable carbohydrate includes sialic acid containing polymer, hyaluronic acid, ehondroitin sulfate, dextran, carboxyl dextran, cellulose, carboxyi
  • the carbohydrate is selected from sialic acid containing polymer, hyaluronic acid, starch, dextran and ehondroitin sulfate.
  • the sialic acid containing polymer suitable for the current invention include poly sialic acid formed by sialic acid monomer connected with o2,3 or a2,6 or «2,8 or «2,9 linkage or their combination. It also includes graft polymer or branched polymer containing sialic acid. It can
  • 700 also be a linear polymer backbone (e.g. dextra or synthetic polymer such as PVA, PAA).
  • a linear polymer backbone e.g. dextra or synthetic polymer such as PVA, PAA.
  • the immune suppressive drug can also be directly conjugated to antigen or conjugated to the antigen via a linker or carrier and used in the patch.
  • the carrier can be a polymer.
  • the poly sialic acid-rapamycin in figure 8 of US Application 15/723,173 can be used to conjugate to the protein's lysine with EDC coupling (e.g. gluten or antibody
  • the figure 12 shows examples of 3 different formats of the antigen-drug conjugate.
  • the drug or both the antigen and immune suppressive drug can be encapsulated in the liposome.
  • Dendritic cell is abundant in skin, adding DC regulating drug 710 with antigen/allergen in a patch can be effective to induce tolerance.
  • the mixture or conjugate can also be injected or taken orally to induce immune tolerance and to treat auto immune disease /allergy.
  • the topical formulation or implant can contain either antigen + drug or antigen-drug conjugate or encapsulated antigen/drug (e.g. in microsphere or liposome) or their combinations.
  • the 715 antigen can be either in the form of crude antigen (e.g. peanut extract, gluten) or purified antigen (e.g. peanut antigen protein ara h2, gliadin) or antigen-drug conjugate or encapsulated antigen (e.g. in microsphere or liposome) or their mixture.
  • the Epitope(antigen)- Sialic acid rich polymer conjugate or Epitope(antigen)- Siglec ligand rich polymer conjugate can be used to treat
  • the antigen/epitope can be either B cell antigen or T cell antigen or their combination.
  • the lysine group of the antigen can be used to conjugate to the -COOH group of the sialic acid with well known EDC coupling method.
  • the pharmaceutically acceptable amount of conjugate can also be used,
  • Sialic acid rich polymer means a polymer having multiple sialic acids or siglec ligand conjugated to its back bone.
  • the back bone can be a branched or linear polymer or dendrimer such as synthetic polymer PVA, PAA, polyamine, or nature polymer such as polysialic acid,
  • sialic acid or sialic acid containing fragments or siglec ligands are conjugated to the polymer back bone.
  • Sialic acid polymer contains either a2,3 or a2,6 or a2,8 sialoside or sialic acid or their derivatives (e.g. those described in J Immunol. 2006 Sep l;177(5):2994-3003, US patent application US9522183 and US Patent US8357671) that can bind with Siglec.
  • the oligo/poly sialic acid with a2,8 linkage backbone itself is also a sialic
  • the sialic acid rich polymer can also contains the mixture of different sialoside, sialic acid and/or their derivatives on its backbone.
  • the liposome having sialic acid or sialoside attached on its surface can also be regarded as a sialic acid rich polymer (e.g. those described in US patent US9522183).
  • sialic acid/siglec ligand rich polymer suitable for the current application can be 740 readily found in the literature, for example, those described in J Immunol. 2006 Sep l;177(5):2994-3003, Nat Chem Biol. 2014 Jan; 10(1): 69-75, J Am Chem Soc. 2013 Dec 11; 135(49): 18280-18283, J Immunol. 2014 Nov 1;193(9):4312-21, J Allergy Clin Immunol. 2017 Jan;139(l):366-369.e2, Angew Chem Int Ed Engl. 2015 Dec 21; 54(52): 15782-8, Proc Natl Acad Sci U S A. 2009 Feb 24; 106(8): 2500-5, J Exp Med.
  • sialic acid/ siglec ligand rich polymers can be readily adopted for the current inventions.
  • each polymer is conjugated with more than 10 copies of antigen.
  • the antigen will bind with the auto immune T cell or B cell clones, which will guide the conjugated sialic acid rich polymer to inactivate these antigen specific auto immune T cell or B cell clones selectively.
  • Figure 6 shows examples of the conjugate containing sialic acid/siglec ligand suitable for the current inventions.
  • Optional linkers can be added between the antigen and the polymer and/or 755 between siglec ligand and the polymer.
  • each liposome particle can contain 760 pharmaceutical effective amount of rapamycin (e.g. 1% -50% liposome weight of rapamycin).
  • microsphere include particles from nano meter size to micrometers (e.g. 50nm ⁇ 50um in 765 diameter).
  • the microsphere is bio degradable (e.g. made of biodegradable polymer such as poly(lactidecoglycolide)(PLGA) ), the microsphere can further encapsulate immune suppressive drug such as rapamycin ( e.g. 1% ⁇ 80% weight of the microsphere).
  • FIG. 7 shows schematic examples of the structure of the microsphere based agent to induce immune tolerance and treating auto immune diseases/allergy.
  • the microsphere 770 can be biodegradable synthetic polymer such as PLGA.
  • Immune suppressive drug such as rapamycin (e.g. 1% ⁇ 80% weight of the microsphere) is encapsulated.
  • the size of the microsphere is 3 um or 300 nm.
  • Sialic acid rich polymer or other siglec ligand is conjugated to the surface of the microsphere directly or with a linker, antigen is also conjugated to the surface of the microsphere directly or with a linker.
  • the Sialic acid rich polymer is conjugated to the surface of the microsphere directly or with a linker.
  • the antigen 775 is conjugated to the surface of the microsphere directly or with a linker and the antigen is conjugated to the Sialic acid rich polymer.
  • the antigen can also be encapsulated in the microsphere as well.
  • the drug can be conjugated to the surface of the microsphere or conjugated to the sialic acid rich polymer instead of being encapsulated. Examples of microsphere suitable for the current application can be readily
  • Another format suitable for the current application is to use polymer carrier conjugated with antigen, siglec ligand and/or other immunosuppressant, which is shown in the figure 8.
  • both siglec ligand and other immunosuppressant can be conjugated to the
  • the figure 9 shows different formats suitable for the current invention.
  • the polymer conjugated with multiple antigen e.g.1-100
  • multiple siglec ligands e.g. 5-500 copies
  • multiple copies of other immunosuppressant is essentially the previous described polymer conjugated with antigen and siglec ligand, which is further conjugated with multiple
  • immunosuppressant molecules e.g. 5-500 molecules.
  • polymer conjugated with multiple immunosuppressant molecules and multiple siglec ligands can be conjugated to one antigen molecule.
  • multiple immunosuppressant molecules and multiple siglec ligands can be conjugated to one antigen molecule directly or with linker but without polymer carrier.
  • ligands can be conjugated to one antigen molecule.
  • one or more polymer conjugated with multiple immunosuppressant molecules and one or more multiple polymer conjugated with siglec ligands can be conjugated together and then conjugated to one antigen molecule.
  • Other molecule that can promote T/B reg expansion e.g. IL-2 and/or TGF- ⁇ and/or 805 PD-L1 can also be conjugated.
  • conjugates can be used to treat autoimmune disease or allergy or to induce immune tolerance caused by the antigen used to construct these conjugate, which can be either injected or implanted (being encapsulated inside the implant) or applied topically to the subject in need.
  • the pharmaceutically acceptable amount of conjugate in pharmaceutically acceptable formulation 810 can be used, as long as it can produce satisfactory therapeutical (e.g. immune tolerance) effect, which can be determined experimentally by screening and testing with well-known protocol. This method can be used to treat antigen specific autoimmune disease or allergy.
  • Sialic acid rich polymer-Antigen conjugate for systemic lupus erythematosus examples of Sialic acid rich polymer-Antigen conjugate for systemic lupus erythematosus are shown in the figures 9.
  • the sialic acid polymer- Antigen conjugate for SLE treatment has the 815 structure of DNA-linker-Sialic acid polymer.
  • the patient having SLE will receive 200mg ⁇ lg of the said conjugate as weekly i.v. injection to treat SLE.
  • the transdermal delivery system using the combination of antigen and immune suppressant agent are used for allergy, autoimmune diseases and antidrug antibody treatment.
  • immune suppressant agent in the above example and methods is replaced with immune
  • the transdermal delivery system becomes a vaccine or booster for the pathogen antigen.
  • the transdermal delivery system is a skin patch containing co-formulated immune enhancing agent together with pathogen antigen with optional transdermal delivery enhancer (e.g. azone, fatty acid, hyaluronic acid) in Viaskin® patch or similar dermal patch.
  • optional transdermal delivery enhancer e.g. azone, fatty acid, hyaluronic acid
  • Vaccine adjuvant type molecule such as TLR agonists can be used in the current invention such as MPLA, CpG ODNs, imiquimod, poly IC, resiquimod, gardiquimod, R848 and 3M-052.
  • the antigen can be either synthetic or purified or the mixture made of pathogen. For example, it can be HIV gp-120, it can be flu
  • the topical formulations contain 0.1 ⁇ lOOmg antigen, 0.1 ⁇ 50mg TLR agonist in each patch or each mL of gel/lotion/liquid.
  • Transdermal enhancing agent can be any suitable transdermal enhancing agent.
  • the formulations contain 10 mg/mL Flu virus lysate, 5mg/mL imiquimod, 20 mg/mL SDS in IX PBS and 5% sucrose and then being lyophilized.
  • the lyophilized powder can be used to prepare a skin patch and attached to the skin at 10 -500 mg powder/patch.
  • 10 ⁇ 100mg HBV surface antigen, 5-50mg of imiquimod is
  • VIASKIN R like dermal patch 840 mixed together and added to a VIASKIN R like dermal patch. It can be applied to the skin twice every week for 2 weeks, each time for 2 day as a vaccine and then applied for 2 days as a booster after 1 month and 3 month to generate immunity against HBV.
  • lOOmg pathogen antigen, 20mg of poly IC, 20mg of imiquimod and lOOmg of DMSO is mixed together and added within a skin patch. It can be applied to the skin twice every week for 2
  • the pathogen antigen can be the antigen peptide that can bind with MHC to form MHC-peptide complex.
  • Using antigen peptide instead of MHC-peptide complex improves transdermal delivery.
  • Another format is to connect multiple antigen/epitope with linkers to form a linear polymer and 850 the drug (such as sialic acid or other immunosuppressant listed in the current invention
  • the linker can be either a synthetic polymer such as a PEG (e.g. MW 500D - 5KD) or a flexible peptide linker consist of hydrophilic amino acid such as
  • Suitable 855 linker can be found in US patent application 15/373,483; 15/169,640 and 62/517,994 by the current inventor.
  • XTEN polypeptide from Amunix Inc. can also be used as a peptide linker.
  • the linear polymer can be expressed by recombinant technology if the antigen/epitope is also a peptide or protein that can be linked at its N and C terminal with linker.
  • the drug can be conjugated to the linear polymer directly or with a second linker.
  • the 860 drug conjugated can be either as a single molecule form or multiple molecules form such as in a carrier or encapsulated in nano/micro particle form or in liposome form.
  • one or more PD-L1 is fused or conjugated with multiple antigen and linkers to form a fusion protein, which can be constructed by expression.
  • Inhibitory ligand that can bind with inhibitory checkpoint receptor e.g. A2AR, BTLA, CTLA-4, KIR, LAG3, TIM-3, VISTA, 865 CD47 and etc
  • B7-H3, B7-H4 can also be used instead of PD-L1.
  • the number of antigen/epitope in each polymer backbone is more than 6, preferably more than 8. In some embodiments, the number of antigen/epitope conjugated to each polymer backbone is more than 10. In some embodiments, the number of drug conjugated to each polymer backbone is more than 4. In some embodiments, the number of drug
  • the antigen can be either B cell antigen or T cell antigen in MHC-peptide complex form or the antigen peptide (or its derivative) that can bind with MHC or their combination.
  • one or more antigen/epitope containing polymer which each contains one or more antigen/epitope, can be conjugated or coated to a nano/micro particle, which is
  • the drug is not necessary.
  • One format is to connect multiple items
  • the linker can be either a synthetic polymer such as a PEG ( e.g. MW 500D ⁇ 5KD) or a flexible peptide linker consist of
  • hydrophi c amino acid such as -GGEGGGEGEEEGGGEGGEGGEEGGGEEDGG- (SEQ ID NO: 3).
  • suitable linker can be found in US patent application 15/373,483;
  • XTEN polypeptide from Amunix Inc. can also be used as a peptide linker.
  • the linear polymer can be expressed by recombinant technology if the antigen/epitope is also a peptide or protein that can
  • polymer back bone can be polypeptide such as Xten from Amunix, synthetic polymer such as poly acrylic acid, carbohydrate includes sialic acid containing polymer, hyaluronic acid, chondroitin sulfate, dextran, carboxyl dextran,
  • the polymer backbone used in previous described prodrug or in previous drug/antigen conjugate can be readily adopted.
  • the average MW of the carbohydrate or other polymer carrier is between 5K -1000K.
  • the number of antigen/epitope conjugated to each polymer backbone is more than 8, preferably more than 10.
  • the antigen/epitope can be conjugated to the polymer directly 895 or via a linker.
  • the linker can be either covalent or none-covalent.
  • the linker can be avidin conjugated on polymer bind with the biotin conjugated with antigen/epitope.
  • the polymer carrier is soluble in aqueous solution.
  • one or more antigen/epitope containing polymer which each contains one or more antigen/epitope, can be conjugated or coated to a nano/micro particle, which is optionally
  • the antigen can be either B cell antigen/epitope or T cell antigen/epitope (e.g. MHC-antigen peptide complex or conjugate; or the peptide antigen that can bind with MHC) or their combination. Examples of them can be found in the current application and related
  • Parvus' NAVACIM R technology use peptide-MHC coated nanoparticles (pMHC-NPs) to delete the high avidity cytotoxic effector T cells, expand a population of autoregulatory memory T cells to target and kill antigen presenting cells (APCs), expand and/or develop populations of Trl cells and/or B-regulatory cells in subject to treat corresponding auto
  • the antigen/epitope (peptide-MHC complex such as N P-V7-K d or IGRP 206 -2i4- d or both) used in these pMHC-NPs can also be used as antigen/epitope for the current invention to treat corresponding autoimmunity disease such as type 1 diabetes (T1D).
  • T1D type 1 diabetes
  • 920 pMHC can also be used as antigen/epitope for the current invention to treat type 1 diabetes
  • the peptide-MHC complex can be either autoimmune-disease-relevant peptides bound to major histocompatibility complex class II (pMHCII) molecule or autoimmune-disease- relevant peptides bound to major histocompatibility complex class I (pMHCI) molecule or their combinations.
  • pMHCII major histocompatibility complex class II
  • pMHCI major histocompatibility complex class I
  • Examples of these peptide-MHC complex can be found in the prior arts 925 listed above and can be readily used in the current invention to induce corresponding immune tolerance and to prevent/treat corresponding autoimmune disorder listed in the above cited prior arts.
  • Suitable particles can be made of biodegradable material such as PLGA.
  • effector molecule such as immunosuppressant drug (e.g. rapamycin or PD-Ll) can be further conjugated or encapsulated to the pMHC coated nano/micro particle such as peptide-MHC-coated nanoparticles (pMHC-NPs) cited in the
  • the surface of pMHC-NPs or pMHC-MPs can be coated with PD-Ll (or its PD-1 binding domain or other PD-1 agonist). Conjugating PD-Ll can effectively inhibit cytotoxic T/B cell and boost Treg/Breg expansion. As shown in figure 15, coating additional T/B
  • regulatory cell stimulating molecule/cytokine e.g. PD-Ll, IL-2, TGF- ⁇ et.ac.
  • PD-L2 or other ligand for inhibitory immune check point receptor is coated to the surface of pMHC-NP or pMHC-MP.
  • immunosuppressant drug such as rapamycin is conjugated to pMHC-NP/pMHC-MP or
  • avidin coated NP or MP is
  • biotinylated NRP- V7/H-2K d and biotinylated PD-Ll is added to the avidin coated NP/MP in excess of the binding capacity of the coated avidin (e.g. 2 - 5 folds excess) and incubated overnight at 4C.
  • pMHC-NP/pMHC-MP is washed with PBS 3 times to remove unbound protein.
  • Bigger size NP e.g. 100 -500 nm
  • Exemplary ratio of V7/H-2K d vs biotinylated PD-L1 used can be between 10: 1 - 1 :3.
  • Other molecule that can promote T/B reg expansion e.g. T/B reg promoting cytokines such as IL-2 and TGF- ⁇
  • T/B reg promoting cytokines such as IL-2 and TGF- ⁇
  • MHC-peptide complex such as IGRP 206 -214- K d can also be used instead to treat T1D.
  • Other disease related MHC-peptide complex can also be used to treat corresponding disease, for example, pMOG 38-49/IA (disclosed in
  • coated NP or MP can also be encapsulated or coated with immunosuppressant to treat experimental autoimmune encephalomyelitis (EAE).
  • EAE experimental autoimmune encephalomyelitis
  • peptide-MHC-coated micro or nanoparticles 965 In some embodiments of the current invention, peptide-MHC-coated micro or nanoparticles
  • 975 complex includes both none-covalent MHC-peptide complex and covalent MHC-peptide
  • MHC-peptide complex mimetic can also be used in the current invention to replace the MHC-peptide complex as long as it can bind with the corresponding antigen specific TCR receptor.
  • the MHC-peptide complex mimetic can be readily developed with phage display library or other screening
  • Another format is to use polymer based peptide-MHC oligomer/multimer instead of peptide- MHC coated micro/nanoparticle to induce immune tolerance to the antigen of the MHC- peptide complex and to treat the corresponding auto immune diseases.
  • the MHC- peptide complex in each polymer is more than 6 copies.
  • the MHC- 985 peptide complex in each polymer is more than 8 copies.
  • the MHC- peptide complex in each polymer is more than 20 copies.
  • the polymer can be a soluble polymer such as the polymer carrier described above.
  • the soluble polymer can be a linear polymer.
  • MHC multimer can be MHC pentamer, MHC dextramer (e.g.
  • Immudex dextramer Cat no. WB3329 (peptide: VLFGLGFAI; antigen: IGRP allele: HLA-A*0201) can be used to treat diabetes.
  • DX01 is used to mix with biotinylated NRP-V7/H-2K d or the mixture of biotinylated NRP-V7/H-2K d and biotinylated PD-L1 in 995 excess (e.g. 1.2 - 2 folds excess of the binding capacity of the streptavidin) and incubated overnight at 4C.
  • 995 excess e.g. 1.2 - 2 folds excess of the binding capacity of the streptavidin
  • the resulting peptide-MHC polymer is dialyzed in PBS to remove unbound peptide-MHC.
  • Other molecule that can promote T/B reg expansion e.g. IL-2 and/or TGF- ⁇
  • SA-Dextramer e.g.
  • MHC-peptide complex such as IGRP 206 -214- 1000 K d can also be used instead to treat T1D.
  • IGRP 206 -214- 1000 K d can also be used instead to treat T1D.
  • complex/conjugate and MHC-peptide complex mimetic can also be used as T cell antigen to build this kind of polymer for the same application.
  • 1005 streptavidin/avidin-biotin binding can also be used instead to incorporate the MHC-peptide complex to the NP/MP or linear polymer using chemical conjugation or other affinity binding such as Fc-protein A interaction.
  • the site-specific conjugation is well known to the skilled in the art and can be adopted from related publications readily.
  • the surface mirco/nanoparticle(MP/NP) or polymer can be modified/derivatized to have maleimide groups
  • FIG. 1010 to allow the -SH (cysteine) of the peptide-MHC to conjugate to them using the well-known maleimide thiol reaction.
  • the protocol for these kind of modification, derivatization and conjugation are well known to the skilled in the arts and can be readily found in the publications and manual of the related reagents.
  • Figure 16 shows the multiple pMHC is conjugated or expressed in a polymer instead of being coated on particles.
  • 1015 Compounds (e.g. the conjugate, polymer and nano/micro particle disclosed in the current invention) described herein can be administered as a pharmaceutical or medicament formulated with a pharmaceutically acceptable carrier. Accordingly, the compounds may be used in the manufacture of a medicament or pharmaceutical composition.
  • Pharmaceutical compositions of the invention may be formulated as solutions or lyophilized powders for parenteral
  • Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
  • Liquid formulations may be buffered, isotonic, aqueous solutions. Powders also may be sprayed in dry form.
  • suitable diluents are normal isotonic saline solution, standard 5% dextrose in water, or buffered sodium or ammonium acetate solution. Such formulations are especially suitable for parenteral
  • Compounds may be formulated to include other medically useful drugs or biological agents. The compounds also may be administered in conjunction with the administration of other drugs or biological agents useful for the disease or condition to which the invention compounds are directed.
  • the compound can be formulated in
  • pharmaceutically acceptable carrier refers to pharmaceutically acceptable materials, compositions or vehicles, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any supplement or composition, or component thereof, from one organ, or portion of the body, to another organ, or portion of the body, or to deliver an agent to the
  • compositions provided in accordance with the present disclosure are formulated as a solution for delivery into a patient in need thereof, and
  • 1040 are, in some embodiments, focused on injection delivery.
  • Diluent or carriers employed in the compositions can be selected so that they do not diminish the desired effects of the composition.
  • suitable compositions include aqueous solutions, for example, a saline solution, 5% glucose.
  • Other well-known pharmaceutically acceptable liquid carriers such as alcohols, glycols, esters and amides, may be employed.
  • the composition further comprises one or more excipients, such as, but not limited to ionic strength modifying agents, solubility enhancing agents, sugars such as mannitol or sorbitol, pH buffering agent, surfactants, stabilizing polymer, preservatives, and/or co-solvents.
  • a polymer matrix or polymeric material is employed as a pharmaceutically acceptable carrier.
  • the polymeric material described herein may comprise
  • natural or unnatural polymers for example, such as sugars, peptides, protein, laminin, collagen, hyaluronic acid, ionic and non-ionic water soluble polymers; acrylic acid polymers; hydrophilic polymers such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol; cellulosic polymers and cellulosic polymer derivatives such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose,
  • compositions provided herein may be formulated as films, gels, foams, or and other dosage forms.
  • Suitable ionic strength modifying agents include, for example, glycerin, propylene
  • Suitable pH buffering agents for use in the compositions herein include, for example, acetate, borate, carbonate, citrate, and phosphate buffers, as well as hydrochloric acid, sodium hydroxide, magnesium oxide, monopotassium phosphate, bicarbonate, ammonia, carbonic acid, hydrochloric acid, sodium citrate, citric acid, acetic acid, disodium hydrogen
  • the pH buffer system e.g., sodium phosphate, sodium acetate, sodium citrate, sodium borate or boric acid
  • the pH buffer system is added to maintain a pH within the range of from about pH 4 to about pH 8, or about pH 5 to about pH 8, or about
  • the said parenteral composition/formulation further include a viscosity enhancing agent to increase its viscosity before or after being injected, which acts as a sustained release formulation.
  • the injection has a viscosity greater than 10,000 cps at room temperature. In certain embodiments, the injection has a viscosity greater 1075 than 100,000 cps at room temperature. In certain embodiments, the injection has a viscosity greater than 5,000,000 cps at room temperature. In certain embodiments, the injection has a viscosity of 11,000,000 cps at room temperature.
  • Example of the viscosity enhancing agent can be found readily from known pharmaceutical acceptable excipient such as hyaluronic acid, starch and carbomer. In some embodiments, the viscosity enhancing agent is biodegradable.
  • the injection formulation can also be a thermal phase changing formulation.
  • Thermal phase changing formulation is a formulation that change its phase from liquid at low temperature or room temperature (25 C) to semisolid/gel when temperature increases to body temperature (37C), which can use poloxamer as excipient.
  • a thermal phase changing injectable formulation can be given as either subcutaneous injection or intramuscular injections or intradermal
  • an effective amount refers to a dose sufficient to provide concentrations high enough to impart a beneficial effect on the recipient thereof.
  • the specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated, the severity of the disorder, the activity of the specific compound, the route of administration, the rate of clearance of the compound, the
  • a compound can be administered parenterally, such as intravascularly, intravenously, intraarterially, intramuscularly, subcutaneously, or the like. Administration can also be orally, nasally, rectally, transdermally or inhalationally via an aerosol.
  • the compound may be administered as a bolus, or slowly infused.
  • a therapeutically effective dose can be estimated initially from cell
  • 1105 culture assays by determining an IC50 by determining an IC50.
  • a dose can then be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 as determined in cell culture. Such information can be used to more accurately determine useful initial doses in humans. Levels of drug in plasma may be measured, for example, by HPLC.
  • the exact formulation, route of administration and dosage can be chosen by the individual physician in 1110 view of the patient's condition.
  • the compound is injected lmg/kg ⁇ lOmg/kg to a subject in need either IV or SQ once a week for 2 months.
  • the compound is injected lmg/kg ⁇ lOmg/kg either IV or SQ once per two week for 3 months.

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Abstract

La présente invention concerne des compositions pour induire une tolérance immunitaire et des procédés pour modifier l'antigène afin de traiter une maladie telle que des maladies auto-immunes et l'allergie. L'invention concerne des compositions et des procédés associés, comprenant des antigènes présentables par APC, et des immunosuppresseurs qui permettent d'obtenir des réponses immunitaires tolérogènes spécifiques de l'antigène. Les compositions peuvent être des particules contenant un antigène et un immunosuppresseur. Les compositions peuvent également être un polymère linéaire contenant un antigène et un immunosuppresseur.
PCT/US2018/041170 2017-07-07 2018-07-07 Procédés et réactifs pour traiter des maladies auto-immunes et l'allergie WO2019010471A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4370145A1 (fr) * 2021-07-16 2024-05-22 DBV Technologies Procédé immunothérapeutique permettant d'augmenter la tolérance aux noix de cajou chez un sujet

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116115772A (zh) * 2022-11-23 2023-05-16 浙江大学 靶向清除抗原特异性t细胞的核壳结构纳米粒构建与应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013192504A1 (fr) * 2012-06-22 2013-12-27 The Trustees Of Dartmouth College Nouveaux produits de recombinaison vista-ig et leur utilisation dans le traitement des troubles autoimmuns, allergiques et inflammatoires
US20150150996A1 (en) * 2012-06-06 2015-06-04 Northwestern University Compositions and methods for antigen-specific tolerance
US9308280B2 (en) * 2008-10-12 2016-04-12 Massachusetts Institute Of Technology Targeting of antigen presenting cells with immunonanotherapeutics
US20170007684A1 (en) * 2010-06-24 2017-01-12 The University Of Kansas Bifunctional conjugate compositions and associated methods

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TR201000668T1 (tr) * 2007-07-31 2010-06-21 The Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Neoplasti̇k veya enfeksi̇yoz bozukluklara yöneli̇k i̇mmunoprofi̇laksi̇ veya i̇mmünoterapi̇ i̇çi̇n poli̇pepti̇d-nüklei̇k asi̇t konjugati
EP2701737B8 (fr) * 2011-04-29 2024-05-01 Cartesian Therapeutics, Inc. Nanosupports synthétiques tolérogènes pour thérapie d'une allergie
US20170165334A1 (en) * 2015-12-11 2017-06-15 Tianxin Wang Methods to Treat Diseases with Protein, Peptide, Antigen Modification and Hemopurification
WO2018067477A1 (fr) * 2016-10-05 2018-04-12 Wang tian xin Procédés et réactifs pour traiter des maladies auto-immunes et l'allergie

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9308280B2 (en) * 2008-10-12 2016-04-12 Massachusetts Institute Of Technology Targeting of antigen presenting cells with immunonanotherapeutics
US20170007684A1 (en) * 2010-06-24 2017-01-12 The University Of Kansas Bifunctional conjugate compositions and associated methods
US20150150996A1 (en) * 2012-06-06 2015-06-04 Northwestern University Compositions and methods for antigen-specific tolerance
WO2013192504A1 (fr) * 2012-06-22 2013-12-27 The Trustees Of Dartmouth College Nouveaux produits de recombinaison vista-ig et leur utilisation dans le traitement des troubles autoimmuns, allergiques et inflammatoires

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4370145A1 (fr) * 2021-07-16 2024-05-22 DBV Technologies Procédé immunothérapeutique permettant d'augmenter la tolérance aux noix de cajou chez un sujet

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