EP-4487918-B1 - AMPHIPHILIC POLYMERS AND THEIR USE FOR IMPROVED PRODUCTION OF NANOPARTICLES FOR THE TARGETED DELIVERY OF ANTIGENS

Inventors

• DIGIGOW, Reinaldo
• MUNGALPARA, Disha
• POHLNER, JOHANNES
• SELECI, Muharrem

Dates

Publication Date

20260513

Application Date

20210216

Claims (11)

1. A pharmaceutical composition for use in suppressing a specific immune response, wherein the composition comprises a nanoparticle comprising a) a micelle comprising an amphiphilic polymer with a number average molecular weight (Mn) of 20,000 g/mol or less, and b) at least one peptide comprising at least one T cell epitope.
2. The pharmaceutical composition for use in suppressing a specific immune response of claim 1, wherein the nanoparticle further comprises a solid hydrophobic core which is at least partially coated by the micelle, wherein the core comprises a traceable inorganic material selected from the group comprising iron oxide, CdSe/CdS/ZnS, silver and gold.
3. The pharmaceutical composition for use in suppressing a specific immune response of claims 1 or 2, wherein the peptide is associated with the outside of the micelle.
4. The pharmaceutical composition for use in suppressing a specific immune response of the preceding claims, wherein the amphiphilic polymer has a number average molecular weight (Mn) of 10,000 g/mol or less, preferably 6,000 g/mol or less, most preferably 6,000 to 1,000 g/mol.
5. The pharmaceutical composition for use in suppressing a specific immune response of the preceding claims, wherein the amphiphilic polymer comprises the following building block wherein R is a hydrocarbyl group or a substituted hydrocarbyl group, preferably R is a C 4 to C 22 alkyl group, preferably C 8 to C 20 alkyl group.
6. The pharmaceutical composition for use in suppressing a specific immune response of claim 5, wherein R is a linear alkyl group, preferably a linear C 11 to C 17 alkyl group, most preferably R is a linear pentadecyl group.
7. The pharmaceutical composition for use in suppressing a specific immune response of any of the preceding claims, wherein the amphiphilic polymer is selected from the group comprising poly(maleic acid-alt-1-octadecene) , poly(maleic acid-alt-1-dodecene) and poly(maleic acid-alt-1-tetradecene), preferably the polymer is poly(maleic acid-alt-1-octadecene), and the number average molecular weight of the polymer is from 6,000 to 1,000 g/mol.
8. The pharmaceutical composition for use in suppressing a specific immune response of any of the preceding claims, wherein the peptide is covalently linked to the micelle or non-covalently associated.
9. The pharmaceutical composition for use in suppressing a specific immune response of any of the preceding claims, wherein the nanoparticle is negatively charged at a pH of 6 to 7.
10. The pharmaceutical composition for use in suppressing a specific immune response of any of the preceding claims, wherein the nanoparticle has a hydrodynamic diameter between 100 and 10 nm, preferably between 50 and 10 nm, more preferably between 20 and 40 nm as measured by dynamic light scattering.
11. The pharmaceutical composition for use in suppressing a specific immune response of one of claims 1 to 10, wherein said response is associated with an autoimmune disease, preferably with an autoimmune disease selected from the group comprising Pemphigus vulgaris, Pemphigus foliaceus, Epidermolysis bullosa Acquisita, Bullous pemphigoid, Cicatricial pemphigoid, Goodpasture syndrome, Microscopic polyangiitis, Granulomatosis with polyangiitis (Granulom. Wegener), Thrombotic thrombocytopenic purpura, Immune thrombocytopenic purpura, Uveitis, HLA-B27-associated acute anterior uveitis, Multiple sclerosis, Neuromyelitis optica, Type I diabetes, Narcolepsy with or without cataplexy, Celiac disease, Dermatitis herpetiformis, Allergic airways disease/Asthma, Myasthenia gravis, Hashimoto thyreoiditis, Autoimmune thyroid disease, Graves disease, Autoimmune thyroid disease, Autoimmune Hypoparathyroidism, Autoimmune thyroid disease, Antiphospholipid syndrome, Autoimmune Addison's Disease, Autoimmune haemolytic anaemia, Chronic inflammatory demyelinating, Polyneuropathy, Guillain-Barré syndrome, Autoimmune neutropenia, Linear morphea, Batten disease, Acquired hemophilia A, Relapsing polychondritis, Isaac's syndrome (acquired neuro-myotonia), Rasmussen encephalitis, Morvan syndrome, Stiff-person syndrome, Pernicious anaemia, Vogt-Koyanagi-Harada syndrome, Primary biliary cirrhosis, Autoimmune hepatitis type I, Autoimmune hepatitis type II, Systemic lupus erythematosus, Rheumatoid arthritis, Polymyositis/ Dermatomyositis, Sjögren syndrome, Scleroderma, Vitiligo and Alopecia areata.

Description

FIELD OF THE INVENTION The present invention provides nanoparticles for use in the prevention and treatment of autoimmune diseases, allergies or other chronic inflammatory conditions, and for generation of regulatory T cells. In particular, the present invention relates to nanoparticles comprising a micelle comprising an amphiphilic polymer with a number average molecular weight (Mn) of 20,000 g/mol or less, rendering the nanoparticle water-soluble, and at least one peptide comprising at least one T cell epitope. The present invention relates to a pharmaceutical composition comprising the nanoparticles for use in generating regulatory T cells specific to at least one T cell epitope in a subject for treating or preventing a disease wherein suppression of a specific immune response is beneficial. BACKGROUND OF THE INVENTION Autoimmune diseases represent a substantial burden for patients and healthcare systems. Current therapies rely mostly on immunosuppressive drugs with considerable side effects. Autoantigen-specific immunotherapies that exclusively target disease-specific immune pathologies leaving the general immune status untouched represent an unmet medical need. Immune tolerance to self-antigens is maintained by multiple mechanisms that control potentially pathogenic autoreactive lymphocytes, including deletion, clonal anergy or suppression by regulatory T cells. Autoimmune disease may thus result from insufficient control of autoreactive lymphocytes, and a major goal of immunotherapy for autoimmune diseases is the induction of tolerance to autoantigens by restoring regulation. A particularly promising way to restore self-tolerance seems to be the manipulation of autoantigen-specific CD4+CD25+FOXP3+ regulatory T cells. The adoptive transfer of these cells can prevent autoimmune or inflammatory conditions. The liver plays a central role in the suppression of unwanted immune responses against blood-borne antigens, e.g. food antigens, entering the circulation. This fundamental mechanism of the liver can be employed to specifically downregulate detrimental immune responses against external protein antigens or autoantigens. Antigenic peptides derived from such proteins, when coupled to nano-sized carriers and administered intravenously, mimic food antigens triggering uptake by specific liver cells, the liver sinusoidal endothelial cells (LSECs), followed by a tolerogenic immune response. Peptide-specific immune tolerance can thus be induced for defined immune disease-causing antigens, leading to the amelioration or even eradication of detrimental immune reactions. This approach can thus be used to treat ongoing diseases and may also be used to prevent the respective diseases in a preventive setting. For example, ectopic expression of a neuroantigen in the liver can prevent autoimmune neuroinflammation in mice with experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). This finding can be explained by the capacity of the liver to generate neuroantigen-specific regulatory T cells (Tregs) that have a profound ability to control and suppress autoimmune responses. LSECs play a crucial role for achieving this effect. LSECs express MHC/HLA class I and class II molecules on their surface and thus have the capacity to present peptides to both, CD8+ (via cross-presentation) and CD4+ T cells, respectively. Peptide-antigen presentation by LSECs converts naive and T effector cells to Tregs in an antigen-specific way in vitro. This is apparently the physiological mechanism by which LSECs can establish tolerance against blood-borne antigens. Nanoparticles conjugated with a disease-specific antigenic peptide to the particle surface, like blood-borne antigens, target the liver after intravenous injection. Upon uptake by LSECs, presumably by pinocytosis, the nanoparticles accumulate in the endosomal compartment where the peptide antigens are released from the surface of the particles. This leads to the presentation of those antigenic peptides at the LSEC surface, mediated by MHC/HLA molecules. There is evidence that the subsequent generation of Tregs confers immune tolerance specific for the respective autoantigen based on its antigenic peptide epitopes. WO 2009/067349 discloses a pharmaceutical composition comprising a biocompatible nanoparticle linked to an aryl hydrocarbon receptor (AHR) transcription factor ligand for use in the treatment of autoimmune disorders by increasing the number and/or activity of regulatory T cells. WO 2013/072051 discloses a pharmaceutical composition for use in generating regulatory T cells specific to at least one T cell epitope in a subject for treating or preventing a disease wherein suppression of a specific immune response is beneficial. The nanoparticle comprises a micelle comprising an amphiphilic polymer rendering the nanoparticle water-soluble, and a peptide comprising at least one T cell epitope associated with the outside of the micelle. It is g