US20110150826A1 - Agent for the treatment and/or prophylaxis of an autoimmune disease and for the formation of regulatory t cells - Google Patents

Agent for the treatment and/or prophylaxis of an autoimmune disease and for the formation of regulatory t cells Download PDF

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US20110150826A1
US20110150826A1 US12/941,885 US94188510A US2011150826A1 US 20110150826 A1 US20110150826 A1 US 20110150826A1 US 94188510 A US94188510 A US 94188510A US 2011150826 A1 US2011150826 A1 US 2011150826A1
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hil
mutein
cells
amino acid
substitution
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Daniela Paulsen
Nina Brunner
Dorothy Bray
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Aicuris GmbH and Co KG
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Aicuris GmbH and Co KG
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Assigned to AICURIS GMBH & CO. KG reassignment AICURIS GMBH & CO. KG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PAULSEN, DANIELA, BRUNNER, NINA, BRAY, DOROTHY
Publication of US20110150826A1 publication Critical patent/US20110150826A1/en
Priority to US14/752,726 priority Critical patent/US9616105B2/en
Priority to US15/439,845 priority patent/US10086046B2/en
Priority to US15/439,866 priority patent/US20170173117A1/en
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Definitions

  • the present invention relates to an agent for the treatment and/or prophylaxis of an autoimmune disease, an agent for the formation of regulatory T cells (T Reg ) in an organism and various methods in which the agents according to the invention are used.
  • T Reg regulatory T cells
  • Autoimmune diseases are characterized by an excessive reaction of the immune system against endogenous tissue.
  • the immune system erroneously recognizes endogenous tissue as foreign bodies to be combated. This results in severe inflammatory reactions, which lead to damage to organs affected by them.
  • T lymphocytes or T cells which are “trained” in the thymus to dock only onto endogenous cell surface molecules, the so-called MHC molecules, and thus to tolerate endogenous structures. These processes are called “clonal deletion” and “clonal selection”. During the initial selection in the thymus, only those T cells, which are able to recognize MHC molecules on the endogenous cell membranes survive, while the binding is however not so strong that it could lead to activation of the T cells. T cells which cannot bind to or recognize endogenous MHC molecules at all are eliminated.
  • autoimmune diseases a group of the T cells behaves abnormally. In addition to the still functioning defence from exogenous molecules and organisms, they now also attack endogenous structure. Organs or tissues are perceived as exogenous. There can be various consequences: if vital structures are affected, an autoimmune disease will take a fatal course. The immune system directs its defence against these structures, cellular and also humoral defence reactions are set in motion, and autoantibodies are formed, as a result of which the organs affected in the course of time cease to function. Most commonly, the immune system is weakened and the body becomes susceptible to all kinds of diseases.
  • the immune system consists of various cells which are capable of combating infectious agents which have invaded the body.
  • the mechanism of the immune response includes the activation of specialized cells and the acquisition of effector functions, such as the cytotoxicity of certain T cells, which express the so-called CD8 transmembrane glycoprotein and which are therefore described as CD8 + T cells.
  • T Reg Regulatory T cells
  • Autoimmune diseases are treated according to the organ affected.
  • the basic principle of the causal therapy is to suppress the activity of the immune system by administration of immunosuppressants, e.g., cortisone.
  • immunosuppressants e.g., cortisone.
  • These substances are characterized by multiple systemic side-effects and interactions, owing to which attempts have been made to develop new drugs which specifically influence the mechanisms involved in the disease event. Examples of this are natalizumab and infliximab.
  • Natalizumab is a monoclonal antibody and selective inhibitor of IgG4, an adhesion molecule which is located on the surface of white blood cells. Natalizumab inhibits the migration of white blood cells into inflammation foci and is used for the treatment of particularly aggressive forms of plaque progressive multiple sclerosis.
  • Infliximab is a chimeric monoclonal antibody against tumour necrosis factor a (TNF ⁇ ), which plays a key part in autoimmune inflammatory reactions. Infliximab is used in rheumatoid arthritis, Crohn's disease, Bechterew disease and psoriasis.
  • TNF ⁇ tumour necrosis factor a
  • TCR T-cell receptor
  • the purpose of the present invention is to provide a new pharmaceutical composition for the treatment and/or prophylaxis of an autoimmune disease, with which the disadvantages due to the state of the art are as far as possible avoided.
  • a pharmaceutical composition which is characterized by good tolerance and low toxicity should be provided.
  • a further purpose of the present invention is to provide an agent for the formation of regulatory T cells (T Reg ) in an organism.
  • hIL-2 mutein human interleukin 2
  • a section or fragment thereof which is numbered in accordance with the hIL-2 wild type and has an amino acid substitution in at least one of the positions 20, 88 or 126.
  • hIL-2 mutein or a fragment thereof has high therapeutic potential which can be utilized for the treatment and prophylaxis of autoimmune diseases.
  • the hIL-2 mutein selectively induces the formation of regulatory T cells such as CD4 + CD25 + Foxp3 + and CD4 + CD25 ⁇ Foxp3 + in an organism.
  • the hIL-2 mutein according to the invention displays markedly higher activity on the regulatory T cells than hIL-2 wild type. This is particularly apparent at high concentrations.
  • the hIL-2 mutein it is disclosed in WO 99/60128 that it binds more strongly to the triple-chain IL-2 receptor (IL-2R ⁇ ) than to the double-chain IL-2 receptor (IL-2R ⁇ ).
  • the hIL-2 mutein according to the invention induces, but surprisingly also intensifies, the formation of those regulatory T cells which lack the a subunit of the IL-2 receptor (CD25) (CD4 + CD25 ⁇ Foxp3 + ).
  • This subpopulation in addition contributes to the suppression of the activation of the immune system and thereby to the regulation of the self-tolerance of the immune system.
  • the hIL-2 mutein according to the invention displays considerably higher potency as an active substance for the treatment of autoimmune diseases than the hIL-2 wild type.
  • the inventors were also able to demonstrate that a hIL-2 mutein induces the formation of CD8 positive regulatory T cells, such as CD3 + CD4 ⁇ CD25 + Foxp3 + and CD3+CD4 ⁇ CD25 ⁇ Foxp3 + (data not shown) which play a decisive role in the suppression of autoimmune diseases.
  • CD8 positive regulatory T cells such as CD3 + CD4 ⁇ CD25 + Foxp3 + and CD3+CD4 ⁇ CD25 ⁇ Foxp3 + (data not shown) which play a decisive role in the suppression of autoimmune diseases.
  • the hIL-2 mutein according to the invention has the further advantage compared to hIL-2 wild type that it selectively activates T cells as opposed to natural killer cells (NK cells) and as a result displays a reduced toxicity profile and an increased therapeutic index.
  • NK cells natural killer cells
  • the hIL-2 mutein according to the invention is considerably better tolerated than the hIL-2 wild type; see WO 99/60128.
  • the hIL-2 mutein according to the invention surprisingly has no or only a slight effect on the proliferation of CD8-positive cytotoxic T cells which are also described as “na ⁇ ve, central memory, early differentiated” and “late differentiated” CD8 T cells.
  • CD8 + -cytotoxic T cells are held to be responsible for persistent, chronic inflammatory processes in autoimmune diseases; cf. Liu et al. (2007), Multiple Sclerosis, 13, p. 149, and Haegele et al. (2007), Neuroimmunol, 183, p. 168).
  • the hIL-2 mutein according to the invention prevents a further intensification of this inflammatory reaction caused by the CD8 + T cells, which represents a further tolerance advantage.
  • the hIL-2 mutein according to the invention also stimulates the antigen-specific activity of the immune cells.
  • This has the advantage that, by means of the hIL-2 mutein, disease-specific immune cells are selectively stimulated and thereby the systemic effect of the immune therapy is limited. As a result, induction of other diseases due to the administration of the hIL-2 mutein is also prevented.
  • the inventors were able to show that the onset of an autoimmune disease can be prevented by the treatment with the hIL-2 mutein according to the invention.
  • wild type of human interleukin 2 is understood to mean a polypeptide or protein which has the amino acid sequence of 133 amino acids which is present in natural human IL-2 (without the signal peptide which consists of a further 20 N-terminal amino acids) hIL-2 wild type can be expressed both naturally and also recombinantly.
  • the amino acid sequence of hIL-2 wild type is described in Fujita et al. (1983), PNAS USA 80, p. 7437-7441, both with and without an additional N-terminal methionine, which is necessarily present when the protein is expressed in E. coli as an intracellular fraction.
  • the amino acid sequence of the hIL-2 wild type is disclosed in the attached sequence protocol under SEQ ID NO:1.
  • the nucleotide sequence of the cDNA which encodes for hIL-2 is disclosed in the attached sequence protocol under SEQ ID NO:2.
  • a “mutein” of human interleukin 2 is understood to mean a polypeptide or protein in which compared to hIL-2 wild type specific substitutions have been effected.
  • the identification of the positions at which substitutions have been effected is based on the positions of the amino acids in the hIL-2 wild type, which can for example be taken from SEQ ID NO:1. Accordingly, an alanine (A) is located at position 1, a proline (P) at position 2, a threonine (T) at position 133, etc.
  • the aspartic acid residue (D) at position 20 (“D20”) can for example be replaced by an isoleucine residue (I) or a histidine (H), so that IL-2 muteins which are described as hIL-2-D201 and hIL-2-D2OH, respectively, are formed.
  • hIL-2 mutein according to the invention can be substituted at several of the stated positions 20, 88 or 126, so that combination mutants which are particularly suitable for the treatment of an autoimmune disease or for the induction of regulatory T cells are formed.
  • an hIL-2 mutein also includes a modified polypeptide, for example a glycosylated hIL-2 mutein.
  • Glycosylated hIL-2 muteins are for example disclosed in the U.S. patent application Ser. Nos. 09/310,026 and 10/051,657, which are incorporated herein by reference.
  • a “section” or “fragment” of hIL-2 mutein is understood to mean a polypeptide in which compared to the hIL-2 mutein one or more amino acids are missing at the N- and/or C-terminus, but this nonetheless still exhibits sufficient biological activity of the hIL-2 mutein to be used according to the invention for the treatment and/or prophylaxis of autoimmune diseases.
  • This activity is regarded as sufficient if the section or fragment exhibits at least 50%, preferably at least 60%, more preferably at least 70%, more preferably at least 80%, more preferably at least 90% and most preferably at least 95% of the activity of the hIL-2 mutein for the induction of regulatory T cells.
  • the activity of the hIL-2 mutein can easily be measured by methods known to the person skilled in the art. Such a method is for example disclosed in WO 99/60128, examples 3 to 5. By reference, this publication is incorporated into the present disclosure.
  • substitutions at the stated positions are not conservative substitutions whereby one amino acid is exchanged for another with similar biochemical properties.
  • the substitution at position 20 is not one in which the aspartic acid (D) is exchanged for a glutamic acid (E).
  • the substitution at position 88 is not one in which the asparagine (N) is exchanged for an alanine (A), proline (P), glycine (G), glutamine (Q), serine (S) or threonine (T).
  • the substitution at position 126 is preferably not one in which the glutamine (Q) is exchanged for an alanine (A), proline (P), glycine (G), asparagine (N), serine (S) or threonine (T).
  • substitution of the hIL-2 mutein according to the invention at position 20 is preferably not one in which the aspartic acid (D) is exchanged for arginine (R), asparagine (N), aspartic acid (D), cysteine (C), glutamic acid (E), glycine (G), leucine (L), lysine (K), phenylalanine (F), proline (P), threonine (T) or tryptophan (W).
  • the substitution at position 88 is preferably not one in which the asparagine (N) is exchanged for aspartic acid (D), cysteine (C), glutamine (Q), tryptophan (W) or proline (P).
  • the substitution at position 126 is preferably not one in which the glutamine (Q) is exchanged for an alanine (A), histidine (H), tryptophan (W), cysteine (C), glutamine (Q), glutamic acid (E) or lysine (K).
  • the hIL-2 mutein according to the invention can be prepared by any suitable method known in the state of the art. Such methods comprise the construction of a DNA sequence which encodes for the IL mutein according to the invention and for example includes the nucleotide sequence SEQ ID NO:2 and the expression of this sequence in a suitable host. This method leads to the muteins according to the invention in recombinant form.
  • the mutein according to the invention can also be prepared by chemical synthesis or a combination of chemical synthesis and recombinant DNA technology. The preparation of the mutein according to the invention is described in detail in WO 99/60128, embodiments 1 and 2, which are incorporated by reference into the present disclosure.
  • hIL-2-N88R A particularly preferred hIL-2 mutein according to the invention, in which at position 88 the asparagine (N) is exchanged for an arginine (R) (hIL-2-N88R), is available to the person skilled in the art under the name BAY50-4798; see Shanafelt et al. (2000), A T-cell-selective interleukin 2 mutein exhibits potent antitumor activity and is well tolerated in vivo, Nat. Biotechnol. Vol. 18, p. 1197-1202.
  • the amino acid sequence of hIL-2-N88R is disclosed in the appended sequence protocol under SEQ ID NO:3.
  • hIL-2 mutein for the targeted treatment and/or prophylaxis of autoimmune diseases or for the selective activation of regulatory T cells in an organism, is neither described nor rendered obvious in the state of the art.
  • IL-2 administration increases CD4 + CD25 hi Foxp3 + regulatory T cells in cancer patients
  • Blood, Vol. 107, p. 2409-2414 propose improving the therapeutic efficacy of human wild type IL-2 in tumour patients by eliminating the patients' regulatory T cells.
  • this approach turned out not to be promising; see Powell et al. (2007), Inability to mediate prolonged reduction of regulatory T cells after transfer of autologous CD25-depleted PBMC and interleukin-2 after lymphodepleting chemotherapy, J. Immunother. Vol. 30, p. 438-447.
  • hIL-2 mutein can be different depending on the indication and the concentration used.
  • a high concentration of hIL-2 can be advantageous for the treatment of autoimmune diseases, but be contra-indicated in the therapy of tumour diseases.
  • an asparagine is exchanged for an arginine (hIL-2-N88R), or for a glycine (hIL-2-N88G), or for an isoleucine (hIL-2-N88I), and/or through the substitution at position 20 an aspartic acid is exchanged for a histidine (hIL-2-D2OH), or for an isoleucine (hIL-2-D20I), or for a tyrosine (hIL-2-D20Y), or through the substitution at position 126 a glutamine is exchanged for a leucine (hIL-2-Q126L).
  • This measure has the advantage that an hIL-2 mutein according to the invention which is distinguished in that it particularly selectively activates T cells as opposed to natural killer cells and hence exhibits a high therapeutic potential and low toxicity is used.
  • These properties of the preferred hIL-2 muteins according to the invention are described in WO 99/60128, which is incorporated by reference into the present disclosure.
  • the hIL-2 mutein or the fragment thereof has at least one further amino acid substitution in any position except the positions 20, 88 or 126 so that the thus further substituted hIL-2 mutein or the thus further substituted section or fragment thereof has an amino acid sequence which is at least 80%, preferably 85%, more preferably 90%, more preferably 95%, most preferably 99% identical with the amino acid sequence of the hIL-2 mutein or of the section or fragment thereof, which is not further substituted compared to the hIL-2 wild type, apart from in at least one of the positions 20, 88 or 126.
  • the further amino acid substitution in any position except the positions 20, 88 or 126 is a conservative amino acid substitution.
  • the agent according to the invention for the induction of the formation of regulatory T cells in an organism is preferably a pharmaceutical composition which contains a pharmaceutically acceptable carrier.
  • This measure has the advantage that the agent is already provided in a form which enables direct administration to the organism, preferably to a person.
  • compositions are comprehensively described in the state of the art; see Row et al. (2006), Handbook of Pharmaceutical Excipients, 5 th Edition, Pharmaceutical Press and American Pharmacists' Association; Bauer et al. (1999), Lehrbuch der pharmazeutica Technologie,ticianliche Verlagsgesellschaft mbH Stuttgart.
  • a particularly preferred formulation is that which is disclosed in WO 02/00243, which by reference is a component of the present disclosure.
  • This formulation is albumin-free and the stabilization of the hIL-2 mutein or section thereof is effected with histidine.
  • the pharmaceutical composition also contains an immunosuppressant.
  • the pharmaceutical composition can already be used as a monopreparation for the treatment and/or prophylaxis of autoimmune diseases.
  • a monopreparation contains the hIL-2 mutein according to the invention as the only active substance.
  • pharmaceutically acceptable carriers, solvents (buffers, water, etc.), additives, etc. are not active substances.
  • This measure has the advantage that the therapeutic index of the drug according to the invention is further increased by inclusion of a standard immunosuppressant.
  • the immunosuppressant is selected from the group consisting of glucocorticoid, including decortin, prednisol; azathioprine; cyclosporin A; mycophenolate mofetil; tacrolimus; anti-T lymphocyte globulin, anti-CD3 antibodies, including muromonab; anti-CD25 antibodies, including basiliximab and daclizumab; anti-TNF- ⁇ antibodies, including infliximab and adalimumab; azathioprine; methotrexate; cyclosporin; sirolimus; everolimus; fingolimod; CellCept®; myfortic and cyclophosphamide.
  • glucocorticoid including decortin, prednisol
  • azathioprine cyclosporin A
  • mycophenolate mofetil tacrolimus
  • anti-T lymphocyte globulin anti-CD3 antibodies, including muromonab
  • This measure has the advantage that an immunosuppressant which has demonstrably therapeutic activity in autoimmune diseases and is sufficiently available in the state of the art is used.
  • the autoimmune disease is selected from the group consisting of: type I diabetes mellitus, rheumatoid arthritis, multiple sclerosis, chronic gastritis, Crohn's disease, Basedow disease, Bechterew disease, psoriasis, myasthenia gravis, autoimmune hepatitis, APECED, Chrug-Strauss syndrome, ulcerative colitis, glomerulonephritis, Guillain-Barré syndrome, Hashimoto thyroiditis, lichen sclerosus, systemic lupus erythematodes, PANDAS, rheumatic fever, sarcoidosis, Sjorgren syndrome, Stiff-Man syndrome, scleroderma, Wegener's granulomatosis, vitiligo, autoimmune enteropathy, Goodpasture syndrome, dermatomyositis, polymyositis, autoimmune allergy, asthma and autoimmune reaction after organ transplantations.
  • type I diabetes mellitus rheumato
  • This measure has the advantage that a drug which can be used for the treatment and/or prophylaxis of the most important autoimmune diseases is provided.
  • a further subject of the present invention relates to a pharmaceutical composition for the treatment and/or prophylaxis of an autoimmune disease, which contains the hIL-2 mutein according to the invention or a fragment thereof.
  • a further subject of the present invention relates to an agent for the formation of regulatory T cells (T Reg ) in an organism, which contains the hIL-2 mutein according to the invention or a fragment thereof.
  • T Reg regulatory T cells
  • T Reg regulatory T cells
  • the organism is preferably a mammal, more preferably a human organism.
  • a further subject of the present invention relates to a method for the formation of regulatory T cells (T Reg ) in vitro, which comprises the following steps: (a) provision of a mutein of human interleukin-2 (hIL-2 mutein) or of a fragment thereof, (b) contacting of the hIL-2 mutein or of the fragment thereof with peripheral mononuclear blood cells (PBMCs), and (c) if necessary repetition of the steps (a) and (b), where the hIL-2 mutein or the fragment thereof is the hIL-2 mutein according to the invention or a fragment thereof.
  • T Reg regulatory T cells
  • the contacting of hIL-2 or of the fragments thereof with the PBMCs can be effected in any suitable medium for the culturing of the PBMCs.
  • T Reg regulatory T cells
  • a further subject of the present invention relates to a method for the treatment and/or prophylaxis of an autoimmune disease in an organism, which comprises the following steps: (a) provision of a mutein of human interleukin-2 (hIL-2 mutein) or of a fragment thereof, (b) contacting of the hIL-2 mutein or of the fragment thereof with peripheral mononuclear blood cells (PBMCs) deriving from a first organism, (c) incubation of the hIL-2 mutein or of the fragment thereof with the PBMCs, in order to obtain a cell population which contains regulatory T cells (T Reg ), and (d) introduction of the cell population into a second organism, where the hIL-2 mutein or the fragment thereof is the hIL-2 mutein according to the invention or a fragment thereof.
  • PBMCs peripheral mononuclear blood cells
  • the first organism and the second organism preferably have the identical blood group, it being particularly preferred if the first and the second organisms are identical organisms or individuals.
  • FIG. 1 shows that hIL-2-N88R in healthy subjects at equal or lower dosage in comparison to proleukin induces a greater increase in the regulatory CD4 + CD25 + Foxp3 + T cells.
  • FIG. 2 shows that hIL-2-N88R in healthy subjects at equal or lower dosage in comparison to proleukin induces a greater increase in the regulatory CD4 + CD25 ⁇ Foxp3 + T cells.
  • FIG. 3 shows that hIL-2-N88R in melanoma patients at equal or lower dosage in comparison to proleukin induces a greater increase in the regulatory CD4 + CD25 + Foxp3 + T cells.
  • FIG. 4 shows that hIL-2-N88R in melanoma patients at equal or lower dosage in comparison to proleukin induces a greater increase in the regulatory CD4 + CD25 ⁇ Foxp3 + T cells.
  • FIG. 5 shows that hIL-2-N88R in multiple sclerosis patients at equal or lower dosage in comparison to proleukin induces a greater increase in the regulatory CD4 + CD25 + Foxp3 + T cells.
  • FIG. 6 shows that hIL-2-N88R in multiple sclerosis patients at equal or lower dosage in comparison to proleukin induces a greater increase in the regulatory CD4 + CD25 ⁇ Foxp3 + T cells.
  • FIG. 7 shows that hIL-2-N88R in multiple sclerosis patients at equal or higher dosage in comparison to proleukin induces a lower increase in the cytotoxic CFSElow/CD3 + CD8 + CD45RO + T cells.
  • FIG. 8 shows that hIL-2-N88R in healthy subjects at equal or higher dosage in comparison to proleukin induces a lower increase in the cytotoxic CFSElow/CD3 + CD8 + CD45RO + T cells.
  • FIG. 9 shows that hIL-2-N88R in the mouse type I diabetes model in comparison to hIL-2 wild type leads to a higher percentage increase in FoxP3 + cells within the CD4 + cells (A). In addition, these CD4 + FoxP3 + cells exhibit higher expression of CD25 (B).
  • FIG. 10 shows that in the mouse type I diabetes model, in contrast to hIL-2 wild type, hIL-2-N88R prevents the development of diabetes.
  • PBMCs Peripheral mononuclear blood cells
  • melanoma patients or MS patients are separated from the blood by means of lymphocyte separation medium (Histopaque, Sigma Aldrich).
  • lymphocyte separation medium Histopaque, Sigma Aldrich
  • two tubes of blood (7 or 10 ml) from the same subject or patient are transferred into a sterile 50 ml tube and made up to 30 ml with RPMI 1640 (InVitrogen, #14190-69).
  • the number of live leucocytes is determined by exclusion staining using trypan blue (InVitrogen #15250-061) and a haemocytometer (FisherBioblock A2759B).
  • the cells are washed twice in PBS and resuspended in PBS at a concentration of 1 ⁇ 10 6 cells/ml.
  • CFSE InVitrogen #C1157
  • CFSE-labelled cells are washed three times with fresh complete medium at 4° C. and resuspended in complete medium at a concentration of 1 ⁇ 10 6 cells/ml for plating out.
  • the PBMCs either remain unstimulated or are stimulated with hIL-2 wild type (proleukin) or hIL-2-N88R (BAY 50-4798; Lot #PR312C008) with or without a pool of synthetic peptides, which are derived from the melanoma-specific proteins gp100, TRP-2, MART-1 and tyrosinase or from the protein MOG specific for multiple sclerosis (MS), each peptide being added in a final concentration of 2.5 ⁇ M (melanoma peptide) or 30 ⁇ g/ml (MS peptide).
  • hIL-2 wild type proleukin
  • hIL-2-N88R BAY 50-4798; Lot #PR312C008
  • synthetic peptides which are derived from the melanoma-specific proteins gp100, TRP-2, MART-1 and tyrosinase or from the protein MOG specific for multiple sclerosis (MS), each peptide being
  • Stimulator and peptide are added under the following 23 conditions:
  • the staining of the cells with fluorescence-labelled antibodies to cell surface molecules makes it possible to study the proliferation of a specific subgroup of lymphocytes (memory and activation markers, see Tab. 2).
  • the immunostaining with fluorochrome-labelled (PE: phycoerythrin, ECD: PE-Texas Red, APC: allophycocyanin, PC7: PE-Cy7) antibodies is performed before and after six days of culturing with the stimulators.
  • the first two stainings (1 and 1iso) are performed with non-CFSE-labelled cells (CFSE: carboxyfluorescein diacetate succinimidyl ester); the other stainings are performed on CFSE-labelled cells.
  • CFSE carboxyfluorescein diacetate succinimidyl ester
  • CD25-PE, Foxp3-APC and rat IgG2a-APC are from ebiosciences; CD25-APC, CD45RA-APC and CD45RO-APC were purchased from BD Biosciences. All other antibodies are from Beckman-Coulter, France.
  • peripheral mononuclear blood cells PBMCs
  • T cells ⁇ 75% CD4- and CD8-positive
  • B and NK cells ⁇ 25% positive
  • PBMCs from six healthy subjects (10 6 cells/ml) were stimulated with wild type IL-2 (proleukin) or IL-2-N88R [BAY 50-4798, Lot #PR312C008 (“BAY#C008”)] at concentrations which lay between 10 ⁇ 11 and 10 ⁇ 6 M, or in the positive control with the non-specific mitogen phytohaemagglutinin (“PHA”) at a concentration of 5 ⁇ g/ml or with culture medium only (“Med”).
  • PHA phytohaemagglutinin
  • Med culture medium only
  • hIL-2-N88R at concentrations of 10 ⁇ 7 M and 10 ⁇ 6 M leads to marked induction of the subpopulation of the regulatory T cells CD4 + CD25 + Foxp3 + .
  • the induction here is markedly greater than with stimulation of the PBMCs by hIL-2 wild type.
  • hIL-2 mutein according to the invention N88R also stimulates the antigen-specific activity of immune cells.
  • PBMCs (10 6 cells/ml) from three melanoma patients were stimulated with hIL-2-N88R (BAY 50-4798, Lot #PR312C008) or hIL-2 wild type (proleukin) at concentrations which lay between 10 ⁇ 11 and 10 ⁇ 6 M, in the presence or absence of a melanoma-associated peptide pool, with 5 ⁇ g/ml PHA or with culture medium only.
  • hIL-2-N88R BAY 50-4798, Lot #PR312C008
  • hIL-2 wild type proleukin
  • CD4 + CD25 + Foxp3 + and CD4 + CD25 ⁇ Foxp3 + respectively were determined. The result is shown in FIG. 3 and Table 5 and FIG. 4 and Table 6 respectively.
  • hIL-2-88R also leads to a marked increase in the regulatory T cells in melanoma patients.
  • this is markedly greater than with stimulation with corresponding concentrations of wild type-IL-2 (proleukin).
  • hIL-2 mutein according to the invention N88R also stimulates the antigen-specific activity of immune cells.
  • PBMCs (10 6 cells/ml) from two multiple sclerosis patients were stimulated with hIL-2-N88R (BAY 50-4798, Lot #PR312C008) or hIL-2 wild type (proleukin) at concentrations which lay between 10 ⁇ 11 and 10 ⁇ 6 M, in the presence or absence of a multiple sclerosis-associated peptide, with 5 ⁇ g/ml PHA or with culture medium only.
  • hIL-2-N88R BAY 50-4798, Lot #PR312C008
  • hIL-2 wild type proleukin
  • hIL-2-N88R also leads to a marked increase in the T cells in multiple sclerosis patients.
  • this is markedly greater than with stimulation with corresponding concentrations of hIL-2 wild type (proleukin).
  • cytotoxic CD8+ central memory T cells was studied.
  • PBMCs from healthy subjects or multiple sclerosis patients were treated as described in 2.3.
  • the percentage of CFSElow/CD3 + CD8 + CD45RO + T cells was analysed. The result is shown in FIG. 7 and Table 9 and FIG. 8 and Table 10.
  • hIL-2-N88R leads to only a slight proliferation of central memory CD8 + T cells, and this at every concentration studied.
  • FIG. 9 (A) shows that, in contrast to the hIL-2 wild type, hIL-2-N88R treatment in the mouse type I diabetes model prevents the development of the diabetes in all mice in the treatment group.
  • T Reg regulatory T cells
  • the hIL-2 muteins according to the invention and sections thereof are substances which are suitable for the treatment and/or prophylaxis of an autoimmune disease or for the induction of T Reg in an organism and for the formation of T Reg in vitro. This is demonstrated by the inventors not only in vitro but also in vivo.

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