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WO2025168658A1 - Activateur de lymphocytes t régulateurs destiné à être utilisé dans un médicament - Google Patents

Activateur de lymphocytes t régulateurs destiné à être utilisé dans un médicament

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Publication number
WO2025168658A1
WO2025168658A1 PCT/EP2025/053009 EP2025053009W WO2025168658A1 WO 2025168658 A1 WO2025168658 A1 WO 2025168658A1 EP 2025053009 W EP2025053009 W EP 2025053009W WO 2025168658 A1 WO2025168658 A1 WO 2025168658A1
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WO
WIPO (PCT)
Prior art keywords
activator
cells
antibody
disease
epidermal
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Pending
Application number
PCT/EP2025/053009
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English (en)
Inventor
Cathrin Schleussner
Andreas KERSTAN
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T Balance Therapeutics GmbH
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T Balance Therapeutics GmbH
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Filing date
Publication date
Application filed by T Balance Therapeutics GmbH filed Critical T Balance Therapeutics GmbH
Publication of WO2025168658A1 publication Critical patent/WO2025168658A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2812—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics

Definitions

  • the present disclosure relates to the prevention and treatment of inflammatory epidermal diseases, including inflammatory autoimmune epidermal diseases such as lichen planus, that are associated with an inflammatory infiltrate comprising cytotoxic CD8 + T cells causing epidermal damage and particularly epidermal cell apoptosis.
  • inflammatory epidermal diseases including inflammatory autoimmune epidermal diseases such as lichen planus, that are associated with an inflammatory infiltrate comprising cytotoxic CD8 + T cells causing epidermal damage and particularly epidermal cell apoptosis.
  • Autoimmunity is an immune response against the body’s own healthy tissue that usually involves T and B lymphocytes and can cause significant diseases that impact a sufferer’s quality of life, and whose treatment can be challenging for medical professionals. These diseases can be classified based on the system(s) or area(s) of the body that is/are affected, with affected systems including, for example, the gastrointestinal system, the musculoskeletal system, the endocrine system, and the cutaneous system.
  • Non-depleting anti-CD4 antibodies Clenoliximab and TRX1 have previously been suggested for the treatment of many autoimmune disease (e.g., in US 2009/0226430 Al entitled “Recombinant anti-CD4 antibodies for Human Therapy”, and in US 2010/0021460 Al entitled “Methods of treating autoimmune diseases using CD4 antibodies”).
  • TRX1 works by reducing the density of CD4 expressed on T-cell surfaces that can engage in an immune response, thereby decreasing the count of functional CD4 + effector T lymphocytes (htps://www.creativebiolabs.net/Anti-CD4- Therapeuti c- Anti body-32250, htm) .
  • alopecia areata is an autoimmune disease associated with attack of the hair follicle by CD8 + T cells, while in certain forms of vitiligo (a condition causing depigmentation of the skin) melanocytes within the epidermis are similarly attacked.
  • the present invention provides an activator of CD4 + Foxp3 + regulatory T cells for use in treating or preventing an inflammatory epidermal disease in a subject, wherein the disease is characterised by an inflammatory infiltrate comprising cytotoxic CD8 + T cells causing epidermal cell apoptosis, apoptosis of melanocytes in the epidermis, or apoptosis of epidermal appendage cells.
  • the present inventors have surprisingly found that regulatory T cells from patients suffering from lichen planus are capable of being activated by an activator, and once activated are able to control autoreactive CD8 + T cell proliferation. This provides a previously unknown therapeutic mechanism for treating this disease.
  • the ability to control CD8 + T cell proliferation in this context as shown by the work in the present application provides a therapeutic mechanism for treating and preventing other inflammatory epidermal diseases or disorders in which CD8 + T cell driven apoptosis of epidermal cells, apoptosis of melanocytes within the epidermis, or apoptosis of epidermal appendage cells occurs.
  • Fi ure 1 shows the amino acid sequences of the heavy chain and light chain of the antibody designated tregalizumab (BT-061).
  • Figures 2A to 2F provide photographs showing the histology of a skin specimen taken from a lichen planus patient, which illustrate the features of the disease. Specifically, Fig, 2A reveals a bandlike lymphocytic infiltrate where cytotoxic CD8 + T cells come into close contact to basal keratinocytes (KC) to induce apoptosis - boxed section is enlarged in Fig, 2B, with apoptotic cells marked with black asterisks). Figs.
  • KC basal keratinocytes
  • FIG. 5B reveals that the addition of tregalizumab (BT-061) to graded amounts of Tregs of LP patients strongly reconstituted their suppressive MLR activity.
  • Cells were co-cultured for 3 days followed by flow cytometric analysis with the proliferation marker Ki- 67.
  • the dashed line represents mean value of the MLR without any supplements.
  • the present invention is directed to the treatment or prevention of inflammatory epidermal disease in a subject where the disease is associated or characterized by an inflammatory infiltrate (e.g., located in the dermis (dermal infiltrate)) comprising cytotoxic CD8 + T cells, and causing epidermal cell damage, in particular epidermal cell apoptosis, or damage to other cells within the epidermis or in epidermal appendages, such as apoptosis of melanocytes in the epidermis or apoptosis of epidermal cell appendage cells.
  • Epidermal appendages are skin associated structures located within the dermal region of the skin, including certain glands and hair follicles.
  • Such epidermal diseases are characterized by (and can be determined based on) histologic examination of specimens taken from disease areas of the body (e.g. biopsy), which show the presence of the cytotoxic CD8 + T cells attacking and causing apoptosis of epithelial cells (e.g. keratinocytes), apoptosis of melanocytes within the epidermis, or apoptosis of cells of epidermal appendages (such as cells of hair follicles).
  • epithelial cells e.g. keratinocytes
  • melanocytes apoptosis of melanocytes within the epidermis
  • apoptosis of cells of epidermal appendages such as cells of hair follicles.
  • cytotoxic CD8 + T cells can be autoreactive or alloreactive (e.g., as in cutaneous or mucosal graft-versus-host disease after an allogeneic stem-cell transplant) and in some cases may be triggered by an allergic response (e.g., as in severe cutaneous drug reactions).
  • histologic examination shows a lymphocytic infiltrate (e.g., a bandlike lymphocytic infiltrate) that reaches the dermal- epidermal junction and evokes a so-called interface dermatitis in which cytotoxic CD8 + T cells come into close contact with the epidermal cells, such as basal keratinocytes, and numerous apoptotic epidermal cells, and particularly apoptotic keratinocytes, are seen.
  • Example histology taken from a lichen planus patient, are shown in Figures 2A to 2F, and particularly in Figure 2B, where apoptotic cells are marked with black asterisks.
  • the inflammatory epidermal disease may be an autoimmune epidermal disease, an alloreactive epidermal disease, or an allergic skin disease caused e.g., by an adverse reaction to a drug or an infection.
  • the disease is an inflammatory autoimmune skin disease selected from lichen planus, lichen sclerosus, cutaneous lupus erythematosus, and dermatomyositis. More preferably the disease is lichen planus, which is also referred to herein as LP. This covers all the clinically different forms of LP skin/mucosal lesions including oral lichen planus, penile or vulvar lichen planus, lichen planopilaris, lichen unguis, and lichen exanthematicus, which is an eruptive variant of lichen planus.
  • the diseases to be treated are characterised by cytotoxic CD8 + T cells that cause apoptosis of the patient’s keratinocytes. In particular, this occurs despite the presence of regulatory T cells (see Fig. 3A to 3D). See also, for example, Ujiie, H., “Regulatory T cells in autoimmune skin diseases”, Experimental Dermatology, 2019; 28: 642-646.
  • Regulatory T cells are a subpopulation of CD4 + T cells that are known to modulate the immune system, and in particular are known to be important for maintaining tolerance to selfantigens (Sakaguchi et al., Immunological Reviews (2001); 182: 18-32), and in regulating immune homeostasis and inflammation.
  • Tregs The family of Tregs consists of two key subsets: (i) naturally arising Tregs (sometimes known as nTregs), which develop in the thymus; and (ii) peripherally induced Tregs (sometimes known as iTregs) which arise in peripheral circulation from conventional T cells.
  • Tregs are generally characterised by the expression of CD4 and CD25 surface biomarkers, and also by the transcription factor Foxp3.
  • regulatory T cells are referred to as CD4 + Foxp3 + regulatory T cells (although they can also be considered as CD4 + CD25 + Foxp3 + regulatory T cells).
  • Tregs Functional impairment or low numbers of Tregs are known to be associated with certain autoimmune or allergic disease, and also graft-versus host disease (Rivas et al., J Allergy Clin Immunol. 2016 September; 138(3): 639-652; Ohl and Tenbrock, Eur. J. Immunol. 2015. 45: 344-355; Whangbo et al., Expert Review of Hematology, 2020; 13(2): 141-154.) Their impairment in lichen planus can be postulated from their inability to control the cytotoxic CD8 + cells despite being present in lesional skin in significant numbers. As shown in Figure 5A the Tregs from LP patients are unable to suppress CD8 + cell proliferation during a Mixed- Lymphocyte Reaction (MLR).
  • MLR Mixed- Lymphocyte Reaction
  • Tregs are able to be activated with an activation agent (“an activator”) as described herein, and once activated can control CD8 + T cell proliferation.
  • an activation agent an activator
  • the present invention relates to the medical use of an activator of CD4 + Foxp3 + regulatory T cells.
  • the activator is for administration to the subject, i.e., for treatment or prevention of the disease in vivo.
  • CD4 + Foxp3 + regulatory T cells can be isolated from a sample taken from the subject to be treated, such as a blood sample, and activated ex vivo, before being transferred back to the subject to treat or prevent the disease.
  • the activator may be an antibody or antibody fragment such as an anti-CD4 antibody or a fragment thereof (e.g. as described in patent application publication no. WO 2011/064407), or a protein, such as a gpl20 protein or fragment thereof (e.g. as described in patent application publication no. WO 2008/092905), IL-2, or an IL-2 mutein.
  • Some activators that are known to be activators of both regulatory T cells and T effector cells, or that are known to cause undesirable side-effects in vivo are only suitable for use ex vivo where their action can be effectively targeted to isolated regulatory T cells, e.g. some anti-CD3 antibodies or fragments thereof.
  • Other activators including the anti-CD4 antibody tregalizumab discussed below (which is also known in the art and referred to herein as BT-061), are capable of selective activation of regulatory T cells.
  • a testing method for such activity may comprise pre-incubating CD4 + Foxp3 + regulatory T cells obtained from a donor (e.g. a healthy human donor) with the antibody or antibody fragment for a period suitable to activate the cells (e.g., 48 - 72 hours), TCR stimulating a T effector cell culture obtained from the same donor, transferring the pre-incubated CD4 + Foxp3 + regulatory T cells to the T effector cell culture, and measuring the level of the pro-inflammatory cytokine after 72 hours.
  • the T effector cell culture and/or the CD4 + Foxp3 + regulatory T cells may be obtained from a healthy individual, or an individual suffering from a disease according to the present invention as described above.
  • an activator e.g., an anti-CD4 antibody or fragment thereof, that is capable of activating CD4 + Foxp3 + regulatory T cells will lead to reduction in the amount of the pro-inflammatory cytokine detected as compared to a negative control in which the CD4 + Foxp3 + cells have not been pre-incubated with the activator.
  • the activator being tested leads to the same reduction +/- 25%, more preferably +/- 10%, as a positive control with the tregalizumab antibody (BT-061), or an anti-CD4 antibody having the same variable heavy and variable light chain regions as the tregalizumab antibody (BT-061), which is described herein.
  • the ability of the activator to activate CD4 + Foxp3 + regulatory T cells can also be determined by methods described in the art, such as those described in WO2011/064407. For example, the ability can be assayed by examining the suppressive activity of the CD4 + Foxp3 + regulatory T cells after incubation with the activator by co-culturing the CD4 + Foxp3 + regulatory T cells with CD4 + CD25‘ effector T cells.
  • Activated CD4 + Foxp3 + regulatory T cells are able to inhibit proliferation of such effector T cells in effector T cell proliferation assays.
  • the effector T cells can be labelled with CFSE such that any proliferation can be determined.
  • proliferation of effector cells can be determined by [3H] thymidine incorporation.
  • CD137 + CD154‘ expression is a universal Treg activation signature ex vivo, which allows the identification and isolation of antigen-activated Tregs (Nowak et al., Frontiers in Immunology, February 2018, Vol. 9, Article 199). Therefore, as a further alternative, activated CD4 + Foxp3 + regulatory T cells produced in the assay may also be identified based on CD137 + CD154‘ expression.
  • the activator may also be defined as one that does not cause antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC).
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • CDC complement-dependent cytotoxicity
  • This ability can be determined by methods known in the art.
  • the anti-CD4 antibody tregalizumab (BT-061) described herein is known not to cause ADCC or CDC (as described in Helling et al., Immunology and Cell Biology (2015) 93: 396-405).
  • Methods of modulating the effector functions of an antibody or antibody fragment, so as to ablate effector functions are known in the art (Saunders, K.O., June 2019, Frontier in Immunology, Vol. 10, Article No. 1296).
  • Antibodies or antibody fragments that are modified such that they do not cause ADCC or CDC are within the scope of the invention.
  • the activator is preferably an antibody, an antibody fragment, or a multispecific or bispecific antibody that binds to the Tregs.
  • a multispecific or bispecific antibody is one which targets at least one other antigen e.g., an antigen of another target cell such as a CD8+ cell, and can be used to assist in bringing the activated Treg cell into contact with the cells on which it has an effect.
  • the antibody may be a human antibody, a humanized antibody, a chimeric antibody, or a fragment thereof.
  • the antibody is a humanized antibody or a fragment of a humanized antibody.
  • the antibody further comprises a human constant region (Fc).
  • This constant region can be selected among constant domains from any class of immunoglobulins, including IgM, IgG, IgD, IgA and IgE, and any isotype, including IgGl, IgG2, IgG3 and IgG4.
  • Preferred constant regions are selected among constant domains of IgG, in particular IgGl.
  • the antibodies are preferably IgGl antibodies, and/or the antibody or antibody fragment preferably comprises an Fc portion such that the antibody or antibody fragment is capable of binding to an Fc receptor, preferably FcyRI (i.e. CD64). Most preferably the antibody or antibody fragment comprises the Fc portion of an IgGl antibody. In addition, or alternatively, the antibody or antibody fragment is capable of binding to monocytes via an Fc receptor.
  • the present invention also includes any fragment of the antibody including fragments comprising the V regions thereof. This comprises in particular Fab, Fab', F(ab)'2, Fv and scFv fragments.
  • the activator can be an anti-CD4 antibody or antibody fragment thereof, preferably an antihuman CD4 antibody or fragment thereof.
  • the anti-CD4 antibody can be the antibody tregalizumab (also known and referred to herein as BT-061) or one based on or derived from this antibody.
  • BT-061 antibody tregalizumab
  • Such antibodies are nondepleting and are capable of activating regulatory T cells but not effector T cells.
  • the antibody is a humanized anti-CD4 antibody or fragment thereof which is the tregalizumab antibody (BT-061), or a variant or fragment thereof.
  • the tregalizumab antibody (BT-061) has V domains defined by the following polypeptide sequences (and which are described further in the examples below):
  • KPGQPPKLLIYLASILESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQHSRELPWT FG QGTKVEIK (SEQ ID NO: 4).
  • the antibody or antibody fragment may be one which has been produced in a mouse or a human cell line, and in particular in a cell line mentioned herein.
  • Doses may also be calculated based on the body weight of the subject, and may be from 1 to 3mg/kg, preferably 1 to 2.5 mg/kg, and most preferably 1.5 to 2 mg/kg.
  • Example 1 Activation of regulatory T cells in the treatment of lichen planus (LP) patients
  • the anti-CD4 antibody tregalizumab (BT-061) that is used in the examples is a recombinant, humanized IgGl monoclonal antibody comprised of two heavy chains and two light chains.
  • the amino acid sequence for both heavy and light chains has been predicted from the translation of the nucleotide sequence for the gene of tregalizumab (BT-061) and have been confirmed experimentally.
  • Figure 1 displays the predicted amino acid sequences for the heavy and light chains, as well as the most likely disulphide bond assignment.
  • the heavy chain has SEQ ID NO: 1 and the light chain has SEQ ID NO: 2.
  • the BT-061 antibody has been given the generic name tregalizumab.
  • MLR Mixed Lymphocyte Reaction
  • MLR Mixed Lymphocyte Reaction
  • CD8-positive T cells from donor A are mixed with antigen-presenting cells (APC) from donor B and cultivated at 37°C in an incubator. Over the course of 3 days, the cytotoxic CD8 cells recognize the APC as foreign in a nascent immune response and start to proliferate. This proliferative response will be quantified by flow cytometry with the proliferation marker Ki-67.
  • the addition of CD4-positive T lymphocytes (from donor A) to cell culture enables a more physiological approach and ensures measurement of proliferation.
  • the influence of regulatory T cells (Tregs) on the proliferative response of CD8 cells will be addressed by the admixture of Tregs (from donor B) to the cell cultures.
  • Tregs regulatory T cells
  • 5xl0 7 cells from the buffy coat of healthy donors from donor A and 2-3 x 10 7 cells from donor B were thawed from the freezer (-80 °C) and cultured in X-Vivo medium (Gibco) overnight in an incubator at 37°C with 5% CO2.
  • CD8-positive T cells were first isolated from donor A using MACS technology (Miltenyi Biotec, #130-045-201). The initial flow through of the CD8 column was used to purify CD4 cells, from which CD4-positive cells without contaminating Tregs were obtained in a further step using the Tregs isolation kit (Miltenyi Biotec, #130-091-301). In this step, CD25-labelled CD4-positive T cells (Tregs) remain in the MACS column, whereas Treg- depleted CD4-positive cells pass through the column as flow-through. To ensure a high level of Treg-depleted CD4 cells, the procedure was repeated. The CD4 cells were added to the MLR at the above concentration. The Tregs remaining in the column were discarded.
  • APC from donor B e.g. LP patients
  • donor B e.g. LP patients
  • CD3 microbeads e.g. CD3 microbeads
  • Tregs from donor B were isolated using the Tregs isolation kit (Miltenyi Biotec, #130-091-301) according to manufacturer's instructions. Varying concentrations of Tregs, ranging from IxlO 2 to IxlO 4 cells, were used in the MLR assay.
  • the stock solution (120 mg/ml) of tregalizumab (BT-061) was first diluted 1 : 120 in X-Vivo medium (Gibco) and then 1 : 1000 to the final concentration of 1 pg/ml (corresponding to a 1 :120,000 dilution of the stock solution). The same dilution was used for the placebo solution containing the dissolvent of tregalizumab (BT-061).
  • cells were cultured for flow cytometric analysis of proliferation markers for 4 hours with PMA (final concentration 100 ng/ml) and ionomycin (final concentration 1 pg/ml) in the presence of brefeldin A (final concentration 20 pg/ml) in an incubator at 37 °C with 5% CO2. Thereafter, cells were analyzed by flow cytometer (with the markers CD3, CD4, CD8, CD137, CD154, Ki-67, Foxp3, live/dead stain).
  • tregalizumab (BT-061) has the capacity to activate Tregs from healthy donors and inhibit alloreactive proliferation of CD8 + T cells in a MLR (data not shown)
  • MFI mean fluorescence intensity
  • CD137 expression in Treg and Tconv was also analysed by flow cytometry after the 3 days of stimulation in the MLR with tregalizumab (BT-061) or placebo (PL). Gating strategy was performed as in the previous paragraph, followed by sequential gating on Foxp3 + /Foxp3‘ and CD137/CD154. CD137 + cells were CD154' (data not shown). The results are shown in Figure 5E, in which CD137 expression is depicted as the MFI difference (A) between BT-061 and placebo treated MLRs. These results show that tregalizumab (BT-061) has induced CD 137 expression specifically in Tregs but not in Tconv. (CD137 being known as marker for Treg activation.)
  • the MLR model is an accepted model to address alloreactive immune responses. Applying this model, the ex vivo testing of regulatory T cells from patients suffering from the autoimmune skin disease LP revealed that Tregs alone were not capable to suppress the MLR. Strikingly, the addition of the mAb BT-061 to the MLR-Treg-cocultures facilitated a strong Treg-mediated suppression. In contrast, tregalizumab (BT-061) alone or placebo (tregalizumab (BT-061) solvent) did not show a significant effect.
  • Treg cells from the MLR had been activated by tregalizumab (BT-061) - CD4 downmodulation had been induced and the cells were CD137 + and CD 154", a known phenotype of Treg activation (Nowak et al., Frontiers in Immunology, February 2018, Vol. 9, Article 199).
  • the data indicates that the tregalizumab antibody (BT-061) antibody, and T regulatory cell activators in general, can enhance Treg effector functions in LP patients in vivo leading to treatment of the disease.
  • DIVMTQSPDS LAVS L GE RAT INCRASKSVS TSGYSYIYWY QQKPGQPPKL

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Abstract

La présente invention concerne un activateur de lymphocytes T régulateurs CD4+Foxp3+ destinés à être utilisés dans le traitement ou la prévention d'une maladie épidermique inflammatoire chez un sujet, la maladie étant caractérisée par un infiltrat inflammatoire comprenant des lymphocytes T CD8+ cytotoxiques provoquant l'apoptose des cellules épidermiques, l'apoptose de mélanocytes dans l'épiderme, ou l'apoptose de cellules d'appendice épidermique. L'invention concerne en outre un procédé de préparation d'un médicament approprié pour traiter un sujet souffrant, ou pour empêcher un sujet de souffrir, de la maladie épidermique inflammatoire, le procédé comprenant l'activation de lymphocytes T régulateurs CD4+Foxp3+ ex vivo obtenus à partir du sujet avec un activateur de lymphocytes T régulateurs CD4+Foxp3+. En outre, l'invention concerne des lymphocytes T régulateurs CD4+Foxp3+ activés ex vivo destinés à être utilisés dans le traitement ou la prévention de la maladie épidermique inflammatoire.
PCT/EP2025/053009 2024-02-05 2025-02-05 Activateur de lymphocytes t régulateurs destiné à être utilisé dans un médicament Pending WO2025168658A1 (fr)

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