Pharmaceutical combination containing anti-CD3 antibody and CXCR3 antagonist

Abstract

The present invention relates to a method for treating CXCR3-associated leukemia (LE) ... and its use in the prevention and / or treatment of (auto-)immune / inflammatory mediated disorders including type 1 diabetes (T1D) (particularly autoimmune T1D), multiple sclerosis, organ transplant rejection (particularly renal and cardiac allograft rejection), thyroid eye disease, rheumatoid arthritis, ulcerative colitis, Crohn's disease, celiac disease, atherosclerosis, psoriasis, pneumonia and psoriatic arthritis.

Description

[Technical Field]

[0001] The present invention relates to a CXCR3 antagonist, 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone (1-{(R)-2-(2-Hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-tri and uses of the pharmaceutical combination in the prevention and / or treatment of (auto-)immune / inflammatory mediated disorders, including type 1 diabetes (T1D) (particularly autoimmune T1D), multiple sclerosis, organ transplant rejection (particularly renal and cardiac allograft rejection), thyroid eye disease, rheumatoid arthritis, ulcerative colitis, Crohn's disease, celiac disease, atherosclerosis, psoriasis, lung inflammation, and psoriatic arthritis. [Background technology]

[0002] Chemokine receptors are a group of G protein-coupled receptors (GPCRs) that bind with high affinity to peptide chemokine ligands. Their primary function is to guide the trafficking of leukocytes to lymphoid organs and tissues under resting and inflammatory conditions, but some chemokine receptors are also known to have roles on non-hematopoietic cells and their precursor cells.

[0003] The chemokine receptor CXCR3 is a G protein-coupled receptor that binds the inflammatory chemokines CXCL9 (originally called MIG, interferon-γ [INF-γ]-induced monokine), CXCL10 (IP-10, INF-γ-induced protein 10), and CXCL11 (I-TAC, INF-γ-induced T cell alpha chemoattractant). CXCR3 is primarily expressed on activated T helper type 1 (Th1) lymphocytes, but is also present on natural killer cells, macrophages, dendritic cells, and subsets of B lymphocytes. The three CXCR3 ligands are primarily expressed under inflammatory conditions, with very low expression in healthy tissues. Cells that can express CXCR3 ligands after exposure to inflammatory cytokines, such as interferon-γ or TNF-α, include various stromal cells, such as endothelial cells, fibroblasts, epithelial cells, and keratinocytes, as well as hematopoietic cells, such as macrophages and monocytes. The interaction between CXCR3 and its ligands (hereinafter referred to as the CXCR3 axis) is involved in guiding receptor-bearing cells to specific sites in the body, particularly sites of inflammation, immune disorders, and immune dysfunction, and is also associated with tissue damage, apoptosis induction, cell growth, and angiogenesis inhibition (angiostasis). CXCR3 and its ligands are highly upregulated in various pathological conditions, including autoimmune disorders, inflammation, infection, transplant rejection, fibrosis, neurodegeneration, and cancer. As described in more detail in WO2022 / 162017 / PCT / EP2022 / 051786, the CXCR system is involved in a variety of diseases, including rheumatoid arthritis, multiple sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, lupus nephritis, sarcoidosis, systemic sclerosis, psoriasis, psoriatic arthritis, interstitial cystitis, celiac disease, myasthenia gravis, type 1 diabetes, vitiligo, uveitis, dry eye, transplant rejection, acute and / or chronic graft-versus-host disease, acute lung injury, acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, atherosclerosis, myocarditis, influenza, cerebral malaria, cirrhosis of the liver, Alzheimer's disease, neurodegeneration, Huntington's chorea, neuromyelitis optica, It is involved in various diseases, such as chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, brain tumors, colorectal cancer, breast cancer, and / or metastatic spread of cancer. The CXCR3 system is also associated with intracerebral hemorrhage (ICH). In a prospective cohort study completed by 115 patients, Landreneau et al. reported that elevated serum CXCL10 concentrations 24 and 72 hours after ICH were associated with worse functional outcomes 90 days after ICH (Landreneau et al., Annals of Clinical and Translational Neurology 2018;5(8):962-970). Furthermore, Leung et al. studied the outcome of experimental intracerebral hemorrhage in CXCR3 knockout mice and concluded that "CXCR3 knockout mice had better motor function, especially in the first week after ICH. The degree of demyelination in CXCR3 knockout mice was less severe compared to wild-type mice" (Leung et al., 28th Annual Scientific Meeting of The Hong Kong Neurosurgical Society: Updates on Traumatic Brain Injury and Neurocritical Care, Virtual Meeting, Hong Kong, November 26-27, 2021, Abstract, http: / / hdl.handle.net / 10722 / 309045).

[0004] T1D is characterized by hyperglycemia and destruction of insulin-producing beta cells. T1D is classified into two subtypes: a common (85-90%), strongly HLA-linked, immune-mediated form with the presence of autoantibodies against one or more of the following autoantigens: islet cell (ICA), GAD, insulin, IA-2, and ZnT8; and a less common, highly inherited, non-HLA-linked, idiopathic form with no evidence of beta cell autoimmunity. Destruction of islet beta cells leads to insulin deficiency, which causes life-threatening impaired glucose regulation. Hyperglycemia contributes to the development of debilitating microvascular complications, which are associated with a significantly higher risk of mortality compared with unaffected populations (Laing SP et al., Stroke 2003a 34(2):418-21; Laing SP et al., Diabetologia 2003b 46(6):760-5). T1D can be controlled with subcutaneous administration of exogenous insulin, but it is not curative and requires lifelong management. The autoimmune process associated with T1D is thought to begin years before clinical diagnosis and involves humoral and cellular immune responses, as evidenced by the appearance of anti-islet autoantibodies. At the time of diagnosis, most individuals with T1D appear to retain some functional β-cells, as indicated by the presence of circulating C-peptide, a by-product of endogenous insulin processing, and further supported by histological analyses of patients recently diagnosed with T1D who died of causes unrelated to diabetes. Preservation of these functional β-cells is associated with reduced clinical complications, and maintaining or enhancing the functional β-cell compartment is of great medical and pharmaceutical interest. That T1D is a bona fide autoimmune disease is indicated by the presence of autoantibodies secreted by B cells even in the pre-symptomatic stages of the disease, the detection of autoreactive T cell receptors on both CD4+ and CD8+ T cell subtypes in the pancreas of patients with recent-onset T1D, and the fact that genetic risk factors for T1D are enriched for immune-related genes (Katsarou et al., Nat Rev Dis Primers. 2017, 3:17016).

[0005] The first evidence that inhibiting the autoimmune response results in preservation of the β-cell compartment and is associated with improved metabolic control in patients with recently diagnosed T1D came from studies with the calcineurin inhibitor cyclosporine (Stiller 2014). CR et al., Science 1984 223(4643):1362-7). However, the benefits of this treatment were outweighed by its safety issues, which prevented its clinical use. No general immunosuppressant has been approved for T1D to date, primarily due to a generally poor safety profile in the pediatric target population (C hatenoud L. Diabetologia 2019 62(4):578~81).

[0006] To avoid chronic immunosuppression, new strategies have emerged to induce immune tolerance to self-antigens using antigen-based immunotherapy and immunomodulatory agents (Jacobsen LM et al., Curr Diab Rep 2018 18(10):90). Clinical trials of several drugs aimed at preventing or delaying the onset of T1D have shown only temporary and modest efficacy, preventing regulatory approval of these therapies (Chatenoud L. Diabetologia 2019 62(4):578-81). For example, although continuous administration of abatacept (CTLA4Ig) slowed disease progression over two years, this treatment only delayed, but did not prevent, the decline in beta-cell function, with kinetics similar to placebo (Orban T et al., Lancet 2011 378(9789):412-9).

[0007] The first successful attempt to block the progression of T1D using a more specific immunomodulatory agent was reported in a preclinical model of T1D (the non-obese diabetic (NOD) mouse model) using a mouse-specific anti-CD3 mAb (clone 145-2C1) (Chatenoud L et al., Proc Natl Acad Sci USA 1994 91(1):123-7). This therapeutic anti-CD3 mAb binds to the epsilon chain of the CD3 / TCR complex found on T lymphocytes. Specifically, Chatenoud et al. showed that intravenous treatment of diabetic NOD mice with anti-CD3 mAb (5 μg / day) for 5 days induced rapid and long-lasting remission from T1D. Treatment with anti-CD3 mAb suppressed immune responses to syngeneic pancreatic islet grafts but did not impair the typical rejection observed with skin allografts (Chatenoud L et al., Proc Natl Acad Sci USA 1994 91(1):123-7). Therefore, it was proposed that the efficacy of transient targeting of the CD3 / T cell receptor by anti-CD3 mAb treatment is due to the restoration of immune tolerance to self-antigens through preferential killing of activated effector T cells and / or proliferation of regulatory T cells (Chatenoud L et al., Proc Natl Acad Sci USA 1994 91(1):123-7). This discovery led to the initiation of several preclinical studies demonstrating the potential use of intravenous anti-CD3 mAb treatment, alone or in combination, for tolerance induction in autoimmune diseases and other immune-mediated conditions (Chatenoud L and Waldmann H. Rev Diabet Stud 2012 9(4):372-81), T1D (Chatenoud L et al., Proc Natl Acad Sci USA 1994 91(1):123-7), multiple sclerosis (Tran GT et al., Int Immunol 2001 13(9):1109-20), inflammatory bowel disease (IBD) (Ludviksson BR et al., J Immunol 1997 159(7):3622-8), rheumatoid arthritis (Hughes C et al., J Immunol 1994 153(7):3319-25), graft-versus-host disease (Blazar BR et al., J Immunol 1994 152(7):3665-74), organ transplant rejection (Nicholls MR et al., Transplantation 1993 55(3):459-68), and atherosclerosis (Kita T et al., Cardiovascular Res 2014 102(1):107-17). Notably, Kuhn et al. also reviewed the efficacy of orally or intranasally administered anti-CD3 mAb in experimental animal autoimmunity models (Kuhn C and Weiner HL. Immunotherapy 2016 8(8):889-906).

[0008] The first anti-CD3 mAb on the market was marketed under the trade name muromonab (Orthoclone OKT3), a mouse model approved by the US Food and Drug Administration (FDA) in 1986 for the prevention of acute allograft rejection in solid organ transplantation. Muromonab is a mouse IgG2a antibody (Hooks MA et al., Pharmacotherapy 1991 11(1):26-37). However, when administered once daily for several days, muromonab induces high titers of anti-mouse antibodies in humans. Furthermore, because it is a potent mitogen, it induces large amounts of cytokines, causing a wide range of side effects, including severe side effects such as encephalopathy, meningitis, graft thrombosis, and renal failure (Sgro C. Toxicology 1995 105(1):23-9). Because muromonab's immunogenicity stems from its rodent origin, next-generation anti-CD3 mAbs have been humanized and their mitogenicity reduced by introducing mutations that reduce the antibody's affinity for Fc receptors (FcRs) on antigen-presenting cells. To date, four humanized anti-human CD3 mAbs, including humanized versions of rodent anti-human CD3 mAbs (otelixizumab, teplizumab, and visilizumab) and a fully human mAb (foralumab), have been investigated in human clinical trials (Kuhn C and Weiner HL. Immunotherapy 2016 8(8):889-906). To overcome the undesirable effects observed with muromonab, all four antibodies have reduced or no FcR binding affinity.

[0009] Visilizumab and foralumab have been primarily studied in inflammatory bowel disease (Dean Y et al., Swiss Med Wkly 2012 142:w13711), otelixizumab and teplizumab have been evaluated in several clinical trials and have independently shown efficacy in patients with recent-onset T1D (Chatenoud L. Diabetologia 2019 62(4):578-81).

[0010] Otelixizumab, also known as ChAglyCD3, TRX4, and GSK2136525, is a chimeric mAb derived from the rat antibody YTH12.5 and a humanized IgG1 antibody with a single mutation in the γ1 Fc region. The potential efficacy of otelixizumab in the treatment of T1D has been extensively investigated in human clinical trials (Guglielmi C et al., Expert Opinion on Biological Therapy 2016 16(6):841-6). Specifically, intravenous treatment with otelixizumab was tested in a large, randomized, placebo-controlled phase II clinical trial in patients with new-onset T1D. A total of 48–64 mg of otelixizumab was administered over six consecutive days (8 mg / day; the first nine patients received 24 mg on day 1, followed by 8 mg / day thereafter). The study demonstrated efficacy as demonstrated by sustained C-peptide levels and reduced insulin requirements. Further analysis showed that efficacy was more pronounced in younger patients with higher residual beta-cell function at baseline (Keymeulen B et al., N Engl J Med 2005 352(25):2598-608; Keymeulen B et al., Diabetologia 2010 53(4):614-23). ​​However, otelixizumab administration was associated with an increased rate of symptomatic Epstein-Barr virus (EBV) reactivation and a moderate "flu-like" syndrome (Keymeulen B et al., N Engl J Med 2005 352(25):2598-608). A follow-up phase III trial was designed to evaluate whether a lower dose of otelixizumab (3.1 mg total dose over 8 days) would reduce these side effects while maintaining efficacy. However, treatment with this dose of otelixizumab, although very well tolerated, did not meet the primary endpoint.

[0011] Teplizumab, also known as hOKT3γ1(Ala-Ala), MGA031, PRV-031, teplizumab-mzwv, and Tzield, is a humanized IgG1 antibody engineered with two point mutations in the Fc portion for FcR non-binding. Teplizumab is currently approved for the treatment of patients with recent-onset type 1 diabetes and individuals at risk for developing T1D. It is currently under development as a treatment for type 1 diabetes (Herold KC et al., N Engl J Med 2019 381(7):603-13). The efficacy of teplizumab was evaluated in phase I-II clinical trials in patients with recent-onset T1D (Herold KC et al., N Engl J Med 2002 346(22):1692-8; Herold KC et al., Diabetes 2005 54(6):1763-9). After 14 days of intravenous administration of tetezumab to 21 patients with recent-onset T1D (diagnosis within 6 weeks), 15 patients maintained or improved their C-peptide response at 1 year, compared with 4 of 19 patients in the control group. Additionally, this study demonstrated reduced insulin use and improved glycated hemoglobin levels in the treated cohort. Furthermore, teplizumab was well tolerated. Subsequently, the randomized, open-label, phase 2 AbATE trial demonstrated the beneficial effect of the anti-CD3 monoclonal antibody teplizumab on maintaining insulin secretion in patients with newly diagnosed T1D (Herold KC et al., Diabetes 2013 62(11):3766-74). Patients receiving the drug received teplizumab once daily for 14 days in an increasing dose regimen (Day 1, 51 μg / m 2 Day 2, 103 μg / m 2 Day 3, 206 μg / m 2 Day 4, 413 μg / m 2 Days 5-14: 826 μg / m 2Patients received intravenous teplizumab according to the body surface area (BSA) and median cumulative dose of 11.6 mg. One year later, patients were eligible for a second treatment cycle. Two years after the start of the study, patients treated with teplizumab had a mean C-peptide area under the curve (AUC) that was 75% higher than those in the control group (Herold KC et al., Diabetes 2013 62(11):3766-74). The clinical benefit provided by teplizumab was clinically meaningful and valuable, but was only transient, and not all patients responded to treatment (Herold KC et al., Diabetes 2013 62(11):3766-74; Perdigoto AL et al., Diabetologia 2019 62(4):655-64). Approximately 45% of treated subjects were classified as responders, defined as patients with a baseline C-peptide loss of less than 40%. In these patients, the effect of teplizumab was robust and durable, whereas the effect of teplizumab was modest in non-responders. Notably, non-responders had increased baseline blood IFN-γ-producing CD8+ T cell counts compared with responders (Herold KC et al., Diabetes 2013 62(11):3766-74). In November 2022, teplizumab-mzwv was approved by the U.S. Food and Drug Administration for delaying the onset of stage 3 type 1 diabetes (T1D) in adults and pediatric patients aged 8 years and older with stage 2 T1D. According to the prescribing information, teplizumab-mzwv is intended to be administered by intravenous infusion (over at least 30 minutes) once daily for 14 consecutive days at a body surface area-based dose as follows: Day 1, 65 μg / m 2 ;2nd day, 125μg / m 2 Day 3, 250 μg / m 2 ;4th day, 500μg / m 2 Days 5 to 14: 1030 μg / m 2 .

[0012] Clinically, anti-CD3 mAbs have also shown beneficial effects in several indications, such as organ transplant rejection, thyroid eye disease, rheumatoid arthritis, ulcerative colitis, Crohn's disease, psoriasis, and psoriatic arthritis (Dean Y et al., Swiss Med Wkly 2012 142:w13711).

[0013] Visilizumab, also known as Nuvion and HuM291, is a humanized IgG2 antibody engineered with two point mutations in the Fc region for FcR non-binding. The efficacy and safety of visilizumab were evaluated in a phase I study in patients with severe, corticosteroid-refractory ulcerative colitis. An initial dose of 15 μg / kg / day produced promising results, with 84% of patients demonstrating clinical response; however, this dose had to be reduced to 10 μg / kg / day to alleviate persistent lymphopenia (Plevy S et al., Gastroenterology 2007 133(5), 1414-1422). However, in a follow-up study, treatment with visilizumab was associated with: It was discontinued early due to safety and efficacy concerns, including increased rates of cytokine release syndrome and infection, possibly due to enhanced activation of CD3 signaling (Sandborn WJ et al., Gut 2010 59(11), 1485~1492; Dean Y et al., Swiss Med. 2012 Wkly 142, w13711).

[0014] Foralaumab, also known as NI-0401, is the only fully human IgG1 monoclonal anti-CD3 antibody currently being developed for the treatment of neurodegenerative diseases such as Crohn's disease and secondary progressive MS. The efficacy and safety of foralaumab were evaluated in a phase I / II clinical trial in patients with moderately to severely active Crohn's disease (Van der woude CJ et al., Inflamm. Bowel Dis 2010 16(10):1708-1716). Patients treated with foralaumab (1 mg intravenously daily for 5 days) experienced a reduction in Crohn's Disease Endoscopic Severity Index at week 6 compared with the placebo group. Additionally, a pilot study evaluated intranasal administration of foralaumab (100 μg daily for 10 days) in non-hospitalized patients with mild to moderate COVID-19. Subjects treated with foralumab showed a decrease in serum IL-6 and C-reactive protein, and a more rapid resolution of pulmonary infiltrates (Moreira TG et al., Front Immunol 2021 12, 709861). Furthermore, when patients with secondary progressive multiple sclerosis were treated with intranasal administration of foralumab for six months, suppression of microglial activation, downregulation of inflammatory cytokines, and stabilization of disease were observed (Tiziana, press release on March 10, 2022: "Tiziana Announces Positive Clinical Data from A Secondary Progressive Multiple Sclerosis Patient Treated for Six Months with Intranasally Administered Foralumab, A" "Fully Human Anti-CD3 Monoclonal Antibody" https: / / ir.tizianalifesciences.com / news-releases / news-release-details / tiziana-announces-positive-clinical-data-secondary-progressive. Tiziana announced that it will study intranasal administration of foralaumab in additional diseases, including Alzheimer's disease, long COVID, early-onset type 1 diabetes, amyotrophic lateral sclerosis, and intracerebral hemorrhage.

[0015] T1D is a pathophysiologically complex disease, and the clinical therapeutic effect of anti-CD3 mAbs diminishes over time. There may be individual factors, such as inflammatory mediators, that lead to evasion from the effectiveness of immunotherapy, including anti-CD3 therapy.

[0016] Inflammatory mediators are involved in the pathogenesis of T1D. In particular, the pathological role of the CXCR3 system in T1D is well documented. CXCR3 is a cell surface chemokine receptor expressed on adaptive and innate immune cells, and is found on subsets of naive and activated CD4+ and CD8+ T lymphocytes, as well as regulatory T cells, B cells, natural killer cells, myeloid cells, and plasmacytoid dendritic cells (Groom et al., 2014). (Groom JR, Luster AD.; Immunol Cell Biol. 2011a;89(2):207-15). This receptor is activated by three IFN-γ-inducible chemokine ligands: CXCL9 (IFN-γ-induced monokine, also known as MIG), CXCL10 (IFN-γ-inducible protein, IP-10), and CXCL11 (IFN-γ-inducible T cell alpha chemoattractant, ITAC) (Groom JR, Luster AD.; Exp Cell Res. 2011b;317(5):620-31). Binding of these chemokines to CXCR3 triggers intracellular signaling, initiating T cell activation and their recruitment to sites of inflammation along the gradient of these chemokines (Khan IA et al.; Immunity. 2000;12(5):483-94; Groom JR, Luster AD.; Exp Cell Res. s.2011b;317(5):620-31; Xie JH et al., J Leukoc Biol.2003;73(6):771-80). CXCR3 signaling is also involved in T cell proliferation, polarization, and tissue retention (Alanio C et al., J Immunol.2018;200(1):139-46).

[0017] CXCR3 and its ligands are significantly upregulated in inflamed tissues of patients with various autoimmune diseases (Steinmetz OM et al.; J Immunol. 2009;183(7):4693-704). As mentioned above, T1D is an autoimmune disease involving the destruction of insulin-producing pancreatic islet β cells by autoreactive T cells, particularly CD8+ T cells. Many chemokines, particularly those associated with type 1 T cell responses (Th1, Tc1), such as the CXCR3 ligands CXCL9 and CXCL10, have been found to be elevated in the sera of T1D patients, especially those newly diagnosed with T1D, compared with healthy controls (Nicoletti F et al., Diabetologia 2002 45(8):1107-10; Hakimizadeh E et al., Clin Lab 2013 59(5-6):531-7). Antonelli et al. showed that serum levels of CXCL10 decreased over time in newly diagnosed children with T1D but remained elevated 16 months after diagnosis compared with healthy controls (Antonelli A et al., Cytokine Growth Factor Rev 2014 25(1):57-65). In addition, elevated levels of both CXCR3 and CXCL10 were observed in pancreatic islets from patients with recent T1D, particularly those with residual functional β cells, suggesting that both autoreactive T cells and the CXCR3 / CXCL10 axis play a detrimental role in the pathogenesis of T1D (Uno S et al., Endocr J. 2010;57(11):991-6; Roep BO et al., Clin Exp Immunol. 2010;159(3):338-43; Tanaka S et al., Diabetes. 2009;58(10):2285-91). Uno et al. identified beta cells as the primary source of CXCL10, and CXCR3 was primarily expressed on T cells in the islet environment (Uno S et al.; Endocr J. 2010;57(11):991-6).These findings are consistent with observations in pancreatic sections from mice with T1D, where CXCL10 was found to be produced primarily by β cells, and CXCR3 was present on infiltrating leukocytes, including CD8+ T cells (Bender C et al., Diabetes 2017 66(1):113-26; Carrero JA et al., PLoS One 2013 8(3):e59701; Sarkar SA et al., Diabetes 2012 61(2):436-46).

[0018] Furthermore, whereas blockade of CXCL9 with neutralizing antibodies did not affect the incidence or development of T1D in previous studies, blockade of CXCL10 with neutralizing anti-CXCL10 antibodies or genetic deletion of its receptor, CXCR3, significantly delayed T1D in preclinical animal models (Christen U et al., J Immunol 2003 171(12):6838-45; Frigerio S et al., Nature Medicine 2002 8(12):1414-20).

[0019] Specifically, in a virus-induced T1D model, prophylactic administration of anti-CXCL10 antibodies reduced the incidence of T1D in mice by 70%, associated with reduced insulitis, reduced infiltration of antigen-specific T cells within the islets, and preserved insulin production (Christen U et al., J Immunol 2003 171(12):6838-45). However, when this treatment was initiated late, i.e., in mice that already had diabetes, anti-CXCL10 antibody treatment only resulted in a small, non-significant reduction in the incidence of T1D (Lasch S et al., Diabetes 2015 64(12):4198-211). Consistent with these results, Coppieters et al. demonstrated that anti-CXCL10 antibodies and CXCL10 deficiency in a similar virus-induced T1D model reduced the incidence of T1D. The effect on the onset of diabetes mellitus was shown to be very limited (Coppieters KT et al., Diabetes 2013 62(7):2492-2499).

[0020] Frigerio et al. suggested that CXCR3 antagonists might be a promising approach to inhibit lymphocyte migration to the islets of Langerhans because the onset of T1D was significantly delayed in CXCR3-deficient mice (Frigerio S et al., Nature Medicine 2002 8(12):1414-20). However, these results were refuted by other researchers who showed that CXCR3 deficiency (Coppieters KT et al., Diabetes 2013 62(7):2492-2499) and administration of a small molecule CXCR3 antagonist (NIBR2130) had little or no effect on disease development in a virus-induced T1D model (Christen S et al., Clin Exp Immunol 2011 165(3):318~28).

[0021] Taken together, these mixed efficacy results suggest that blocking the CXCR3 / CXCL10 axis alone is insufficient to suppress the destructive autoimmune process in T1D. Therefore, it was hypothesized that neutralization of this chemokine axis would be more appropriate as part of a combination therapy, such as with anti-CD3 mAb, resulting in partial T cell depletion and thus immune resetting (Christen U and Kimmel R. Front Endocrinol (Lausanne) 2020 11:591083, doi.org / 10.3389 / fendo.2020.591083).

[0022] Furthermore, it was hypothesized that combining anti-CD3 mAb treatment, which leads to the destruction of aggressive T cells within pancreatic islets, with agents that block the CXCL10 / CXCR3 pathway might prevent reinfiltration of autoreactive T cells into the islets, thereby enhancing the duration and magnitude of the therapeutic effect achieved with anti-CD3 mAb treatment alone. Indeed, the addition of a CXCL10-neutralizing monoclonal antibody immediately after anti-CD3 mAb treatment improved efficacy compared with anti-CD3 antibody treatment alone in two different T1D mouse models. Importantly, the observed remissions were long-lasting, and none of the cured mice developed T1D by the end of the experiment, 6 months after the start of treatment (Lasch S et al., Diabetes 2015 64(12):4198-211, WO2015 / 154795). The combined use of CXCR3 neutralizing antibodies with various immunosuppressants, including the anti-CD3 antibody muromonab, for the prevention or treatment of T1D is described in WO2013 / 109974. Furthermore, a combined therapy of CXCL10 neutralization with an immunomodulator such as an anti-CD3 antibody was proposed by Shigihara et al. (Shigihara T et al., J Immunology 2005 175(12):8401-08).

[0023] CXCL10 neutralizing antibodies have been tested in human clinical trials for autoimmune diseases, but the results have been mixed. For example, the CXCL10 neutralizing antibody, eldelumab, showed favorable data in a phase II trial for patients with rheumatoid arthritis (Yellin et al., 2013). Although studies in inflammatory bowel disease have shown a trend toward efficacy, they have only been limited to patients exposed to high circulating concentrations of CXCL10 antibodies (Sandborn WJ et al., J Crohns Colitis 2016 10(4):418-28; Sandborn WJ et al., J Crohns Colitis 2017 11(7):811-9). These data suggest that the high concentration and production rate of CXCL10 in inflamed tissues necessitates high doses and frequent administration of anti-CXCL10 antibodies to achieve clinical efficacy. Such dosing regimens are unlikely to translate into a viable and clinically successful treatment for chronic diseases requiring long-term or lifelong therapy. This hypothesis is supported by the failure of a trial using a different CXCL10-neutralizing antibody (NI-0801) in primary biliary cholangitis. The study authors concluded that "CXCL10 production "Due to its rapid release, it is difficult to achieve drug levels that sustainably neutralize this chemokine, thereby limiting its targeting potential" (De Graaf KL et al., Hepatol Commun 2018 2(5):492-503). Because CXCL10 is elevated in the circulation of T1D patients and highly expressed in pancreatic islets, it is unlikely that CXCL10-neutralizing antibody therapy will achieve meaningful suppression of the CXCR3 system over the long term using an acceptable dosing regimen.

[0024] Another approach to inhibiting the CXCR3 pathway in clinical settings is to use small molecule CXCR3 receptor antagonists. Ideally, CXCR3 antagonists would exhibit the characteristic of insurmountability, meaning that they suppress the maximal response of the natural agonist and that this inhibitory effect is unaffected by increasing agonist concentrations (Neubig RR et al., Pharmacol Rev 2003 55(4):597-606). Such CXCR3 antagonists would be able to block the CXCR3 pathway even in the presence of high concentrations of CXCL10. Andrews et al. recently reviewed identified and described small molecule CXCR3 antagonists (Andrews SP and Cox RJ. J Med Chem 2016 59(7):2894-917). Of the more than 15 chemical classes identified, only one small molecule CXCR3 antagonist has been studied to Phase IIa in clinical trials, but failed to demonstrate efficacy as monotherapy in patients with psoriasis, likely due to variable exposure (Berry K. et al.; Inflamm. Res. 2004(Suppl. 3), S222). Summary of the Invention

[0025] Surprisingly, it was found that combination therapy of the "compound" with an anti-CD3 monoclonal antibody was not only effective in two different T1D mouse models, but also showed improved efficacy compared to the combination of an anti-CD3 antibody and an anti-CXCL10 antibody (Christen U. et al., Clinical and Experimental Immunology, 2023;uxad083, https: / / doi.org / 10.1093 / cei / uxad083). [Brief explanation of the drawings]

[0026] [Figure 1]Effect of Compound on BAL CXCR3+CD8+ T Cells in an LPS-Induced Lung Inflammation Model. Figure 1 shows the dose-dependent effect of Compound on CXCR3-expressing CD8+ T cells recruited to the BAL in an LPS-induced lung inflammation model. Mice were treated with different doses of Compound (mg (Compound) / g (Food), x-axis) mixed with diet starting on day -3 and stimulated with nebulized LPS on day 0. BAL CXCR3+CD8+ T cells were quantified by flow cytometry 3 days after LPS stimulation. Data are expressed as a percentage of the LPS-stimulated group treated with control diet (positive control group) (y-axis), where the LPS-stimulated group treated with control diet was set to 100%. Data are shown as medians with interquartile ranges; n = 11–24 per group. *p<0.05, ****p<0.0001 vs. mice treated with control diet (Kruskal-Wallis test followed by Dunn's multiple comparisons test). [Figure 2] Effect of treatment on blood glucose levels over an 84-day study in the RIP-LCMV-GP mouse model. Figure 2 shows the effect of anti-CD3 antibody monotherapy, the combination of anti-CD3 antibody and anti-CXCL10 antibody, and the combination of anti-CD3 antibody and "compound" on blood glucose levels in RIP-LCMV-GP mice. Data are shown as mean + SEM. n = 11–14 per group. *p < 0.05, **p < 0.01, ****p < 0.0001 (using two-way ANOVA followed by Tukey's multiple comparisons test). The gray area is the background growth vector (BGV), representing the stages of diabetes. [Figure 3]Effect of treatment on BGV in NOD mice. Figure 3 shows the effect of treatment with "compound" monotherapy, anti-CD3 antibody monotherapy, their combination, and the combination of anti-CD3 antibody and anti-CXCL10 antibody on blood glucose levels in NOD mice. Treatment was initiated at the onset of T1D, defined as the first measurement of BGV ≥ 300 mg / dL. Data are shown as mean + SEM. n = 14–17 / group. ***p < 0.001, ****p < 0.0001 (Mixed-effects analysis followed by Tukey's multiple comparison test). The gray area indicates BGV, representing diabetes stage. [Figure 4] Effect of Treatment on Disease Progression from Treatment Initiation in NOD Mice. Figure 4 shows the therapeutic effects of "compound" monotherapy, anti-CD3 antibody monotherapy, their combination, and the combination of anti-CD3 antibody and anti-CXCL10 antibody on T1D disease progression in NOD mice. Disease progression is expressed as the percentage increase in BGV for each mouse at 40 weeks of age compared to the BGV at the start of treatment, which was set at 100%. Data are shown as mean + SEM. n = 14-17 per group. ***p < 0.001 (using one-way ANOVA followed by Tukey's multiple comparison test). [Figure 5] Effect of treatment on BGV in non-severely diabetic NOD mice at the start of treatment. Figure 5 shows the effect of treatment with "compound" monotherapy, anti-CD3 antibody monotherapy, their combination, and the combination of anti-CD3 antibody and anti-CXCL10 antibody on BGV in non-severely diabetic NOD mice. Non-severely diabetic NOD mice were defined as mice in which treatment was initiated when BGV was between 300 and 400 mg / dL. Data are shown as mean + SEM. n = 7-11 / group. *p < 0.05, ***p < 0.001, ****p < 0.0001 (using mixed-effects analysis followed by Tukey's multiple comparison test). The gray area indicates BGV, representing the diabetic stage. [Figure 6]Effect of Treatment on Disease Progression from Treatment Initiation in Non-Severely Diabetic NOD Mice. Figure 6 shows the therapeutic effects of "compound" monotherapy, anti-CD3 antibody monotherapy, their combination, and the combination of anti-CD3 antibody and anti-CXCL10 antibody on T1D disease progression in non-severely diabetic NOD mice. Non-severely diabetic NOD mice were defined as mice in which treatment was initiated when their BGV was between 300 and 400 mg / dL. Disease progression is expressed as the percentage increase in BGV for each mouse at 40 weeks of age compared to the BGV at the start of treatment, which was set as 100%. Data are shown as mean + SEM. n = 7-11 per group. *p < 0.05, **p < 0.01, ***p < 0.001 (using one-way ANOVA followed by Tukey's multiple comparison test). DETAILED DESCRIPTION OF THE INVENTION

[0027] Description of the Invention : 1) In a first aspect, the present invention relates to a pharmaceutical combination having a first active pharmaceutical ingredient which is 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone (hereinafter also referred to as "the compound") or a pharmaceutically acceptable salt thereof, and a second active pharmaceutical ingredient which is an anti-CD3 monoclonal antibody.

[0028] The "compounds" are potent, insurmountable, and selective CXCR3 receptor antagonists. The "compounds" are useful in treating diseases or disorders associated with dysfunction of the CXCR3 receptor and / or its ligands CXCL9, CXCL10, and CXCL11, such as (auto-)immune / inflammatory-mediated disorders, pulmonary diseases, cardiovascular diseases, infectious diseases, fibrosis, neurodegenerative diseases, and oncological diseases, in particular rheumatoid arthritis, multiple sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, lupus nephritis, sarcoidosis, systemic sclerosis, psoriasis, psoriatic arthritis, interstitial leukemia, and the like. The compounds have been described as useful for the prevention and / or treatment of cystitis, celiac disease, myasthenia gravis, type 1 diabetes, vitiligo, uveitis, inflammatory myopathies, dry eye, thyroiditis including Grave's disease, transplant rejection, acute and / or chronic graft-versus-host disease, acute lung injury, acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, atherosclerosis, myocarditis, influenza, cerebral malaria, liver cirrhosis, Alzheimer's disease, neurodegeneration, Huntington's disease, neuromyelitis optica, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, brain tumors, colon cancer, breast cancer, and / or metastatic spread of cancer (WO2016 / 113344; PCT / EP2022 / 051786). The compounds may be prepared according to the procedures disclosed in WO2016 / 113344.

[0029] The present invention is intended to encompass any form of the Compound, including amorphous and crystalline forms of the Compound. Furthermore, crystalline forms of the Compound encompass all types of crystalline forms of the Compound, including polymorphs of single molecules, solvates and hydrates, molecular salts, and co-crystals (where the same molecule can form co-crystals with different co-crystal formers), that are suitable for pharmaceutical administration.

[0030] 2) A further embodiment of the present invention relates to a pharmaceutical combination according to embodiment 1), wherein the first active pharmaceutical ingredient is 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone (i.e., the Compound in free, non-salt form).

[0031] 3) A further aspect of the invention relates to a pharmaceutical combination according to aspect 1) or 2), wherein said second active pharmaceutical ingredient is a humanized or fully human anti-CD3 monoclonal antibody.

[0032] 4) A further aspect of the invention relates to a pharmaceutical combination according to any one of aspects 1) or 2), wherein said second active pharmaceutical ingredient is a humanized anti-CD3 monoclonal antibody (in particular otelixizumab, teplizumab or visilizumab).

[0033] 5) A further aspect of the invention relates to a pharmaceutical combination according to any one of aspects 1) or 2), wherein said second active pharmaceutical ingredient is a fully human anti-CD3 monoclonal antibody (in particular foralamuab).

[0034] 6) A further aspect of the present invention relates to a pharmaceutical combination according to any one of aspects 1) or 2), wherein the second active pharmaceutical ingredient is selected from the group consisting of otelixizumab, teplizumab, visilizumab and foralumab.

[0035] 7) A further aspect of the present invention relates to a pharmaceutical combination according to any one of aspects 1) or 2), wherein the second active pharmaceutical ingredient is selected from the group consisting of otelixizumab and teplizumab.

[0036] 8) A further embodiment of the present invention relates to a pharmaceutical combination according to any one of embodiments 1) or 2), wherein the second active pharmaceutical ingredient is selected from the group consisting of teplizumab and foralumab.

[0037] 9) A further embodiment of the present invention relates to a pharmaceutical combination according to any one of embodiments 1) or 2), wherein said second active pharmaceutical ingredient is teplizumab.

[0038] 10) A further embodiment of the present invention relates to a pharmaceutical combination according to any one of embodiments 1) or 2), wherein said second active pharmaceutical ingredient is foralamuab.

[0039] 11) A further embodiment of the present invention relates to a pharmaceutical combination according to any one of embodiments 1) or 2), wherein said second active pharmaceutical ingredient is otelixizumab.

[0040] 12) A further embodiment of the present invention relates to a pharmaceutical combination according to any one of embodiments 1) or 2), wherein said second active pharmaceutical ingredient is visilizumab.

[0041] Teplizumab is being studied in clinical trials for the prevention or treatment of type 1 diabetes, particularly in patients with recent-onset type 1 diabetes or at risk. Teplizumab may be administered orally, intranasally, subcutaneously, or intravenously (particularly subcutaneously or intravenously; especially intravenously). Pharmaceutical compositions for intravenous infusion typically contain teplizumab and 0.9% aqueous sodium chloride. Teplizumab is not administered chronically, but may be administered once daily or every other day (particularly once daily) for a treatment period of 6 to 20 days (particularly 10 to 18 days, especially 12 to 14 days), with or without a dose-escalation regimen (i.e., a stepwise increase in the daily dose until a target dose is reached), especially using a dose-escalation regimen. Dose escalation may be achieved by using 3 to 10 (particularly 4 to 6, more particularly 5) different doses of teplizumab, with the dose on each treatment day being equal to or greater than the dose on the preceding day, with the maximum dose of said escalation being equal to the target dose intended and / or administered by the end of the treatment period. Preferably, the administration scheme consists of administering increasing doses (i.e., 5 different doses that successively increase) every day from day 1 (the first day of treatment) to day 5 until the target dose is reached, and then administering a constant dose, which is the target dose, from day 5 until the end of treatment on days 10 to 18 (particularly day 14). The dose of teplizumab intended and / or administered is expressed in square meters [m 2 The cumulative dose of teplizumab may be calculated based on each patient's body surface area (BSA) (measured by the MRI). 2 BSA to 15.0 mg / m 2 BSA (especially 7.0 mg / m 2 BSA to 11.0 mg / m 2 BSA up to approximately 9.0 mg / m 2 Alternatively, the cumulative dose of teplizumab may be 10.0 mg / m 2BSA to 12.0 mg / m 2 The daily dose of teplizumab (in the absence of a dose-escalation regimen) or the target dose (in the case of a dose-escalation regimen) is 1300 μg / m 2 BSA or less (especially 600 μg / m 2 BSA to 1000 μg / m 2 BSA up to approximately 826 μg / m 2 Alternatively, the daily dose or target dose may be about 1030 μg / m 2 An example of a preferred dosing scheme is about 51 μg / m on day 1 of treatment. 2 BSA, approximately 103 μg / m on day 2 2 BSA, approximately 207 μg / m on day 3 2 BSA, approximately 413 μg / m on day 4 2 BSA, approximately 826 μg / m on each of days 5–14 2 Another example of a preferred dosing scheme is to administer about 65 μg / m BSA on the first day of treatment. 2 BSA, approximately 125 μg / m on day 2 2 BSA, approximately 250 μg / m on day 3 2 BSA, approximately 500 μg / m on day 4 2 BSA, approximately 1030 μg / m on each of days 5–14 2 The administration of BSA is preferred. The treatment with teplizumab may be repeated for one or two (particularly one) additional treatment periods, and the administration scheme in the second or third treatment period may be the same as or different from that in the previous treatment period. Preferably, the administration scheme is the same in the different treatment periods. The interval between two treatment periods is at least 5 months (particularly 6 to 12 months).

[0042] BSA may be measured or calculated by any formula commonly used to calculate body surface area, in particular the Mosteller formula: BSA[m 2 ]=((Height [cm] x Weight [kg]) / 3600) 1 / 2 Preferably, BSA is calculated using the Mosteller formula on the first day of treatment of the treatment period (particularly immediately prior to the first treatment) and is based on the patient's height and weight on that first day of treatment.

[0043] Foralaumab may be administered orally, nasally, subcutaneously, or intravenously (particularly orally, nasally, or subcutaneously; especially orally or nasally). Foralaumab may be administered once daily or every other day (particularly once daily) for a treatment period of 3 to 30 days (particularly 4 to 12 days, especially 5 to 10 days), with or without a dose escalation regimen (i.e., a stepwise increase in the daily dose until a target dose is reached), especially using a dose escalation regimen. Dose escalation may be achieved by using 3 to 10 (particularly 4 to 6, especially 5) different doses of foralaumab, with the dose on each treatment day being equal to or greater than the dose on the preceding day, and the maximum dose of the escalations being equal to the target dose intended and / or administered by the end of the treatment period. The daily dose of foralarumab (if no dose-escalation regimen is used) or the target dose (if a dose-escalation regimen is used) may be between 0.1 mg / 60 kg (patient's body weight) and 10 mg / 60 kg (patient's body weight), particularly between 0.5 mg / 60 kg (patient's body weight) and 5.0 mg / 60 kg (patient's body weight). A preferred oral dose range is 0.1 mg to 5.0 mg per day. A preferred intranasal dose range is 0.05 mg to 1.0 mg per day. A preferred subcutaneous dose range is 0.2 mg to 5.0 mg per day. Treatment with foralarumab may be repeated for one or two (particularly one) additional treatment periods, and the administration scheme in this second or third treatment period may be the same or different from that in the previous treatment period. Preferably, the administration scheme is the same in the different treatment periods. Pharmaceutical compositions for oral, nasal or subcutaneous administration containing foralaumab are described in US Pat. No. 10,688,186.

[0044] Otelixizumab may be administered orally, intranasally, subcutaneously, or intravenously (particularly intravenously). Otelixizumab may be administered once daily or every other day (particularly once daily) for a treatment period of 3 to 20 days (particularly 4 to 12 days, more particularly 6 to 10 days), with or without a dose escalation regimen (i.e., stepwise increases in the daily dose until a target dose is reached). Dose escalation may be achieved by using 3 to 10 (particularly 4 to 8) different doses of otelixizumab, with the dose on each treatment day being equal to or greater than the dose on the preceding day, and the maximum dose of the escalation being equal to the target dose intended and / or administered by the end of the treatment period. The daily dose of otelixizumab (when there is no escalation regimen) or the target dose (when there is an escalation regimen) may be between 0.5 mg and 5.0 mg (particularly between 1.0 mg and 3.75 mg; more particularly between 1.5 mg and 3.0 mg). The cumulative dose of otelixizumab may be between 4.0 mg and 27.0 mg (particularly between 6.0 mg and 18.0 mg; more particularly about 9.0 mg). Treatment with otelixizumab may be repeated for one or two (particularly once) additional treatment periods, and the administration scheme in this second or third treatment period may be the same or different from that in the previous treatment period. Preferably, the administration scheme is the same in different treatment periods.

[0045] Visilizumab may be administered orally, intranasally, subcutaneously, or intravenously (particularly intravenously). Visilizumab may be administered once daily or every other day (particularly once daily) for a treatment period of 2 to 10 days (particularly 2 to 5 days, more particularly 2 days), with or without a dose escalation regimen (i.e., a stepwise increase in the daily dose until a target dose is reached). Dose escalation may be achieved by using 2 to 5 different doses of visilizumab, with the dose on each treatment day being equal to or greater than the dose on the preceding day, and the maximum dose of the escalation being equal to the target dose intended and / or administered by the end of the treatment period. The daily dose (if no dose escalation regimen) or target dose (if a dose escalation regimen) of visilizumab may be between 3 μg / kg (patient's body weight) and 15 μg / kg (patient's body weight), particularly between 4 μg / kg (patient's body weight) and 12.5 μg / kg (patient's body weight); especially about 5 μg / kg (patient's body weight). The cumulative dose of visilizumab may be between 6 μg / kg (patient's body weight) and 30 μg / kg (patient's body weight), especially about 8 μg / kg (patient's body weight). The dose may be between 10 μg / kg (patient's body weight) and 25 μg / kg (patient's body weight); in particular about 10 μg / kg (patient's body weight). Treatment with visilizumab may be repeated for one or two (in particular one) further treatment periods, and the administration scheme in this second or third treatment period may be the same or different from the administration scheme in the previous treatment period. Preferably, the administration scheme is the same in the different treatment periods.

[0046] 13) A further aspect of the present invention relates to a pharmaceutical combination according to any one of aspects 1) to 12), comprising the Compound or a pharmaceutically acceptable salt thereof in a pharmaceutical dosage form for oral or intravenous administration, particularly oral administration, of the Compound or a pharmaceutically acceptable salt thereof.

[0047] 14) A further embodiment of the invention relates to a pharmaceutical combination according to embodiment 13) having the Compound in a pharmaceutical dosage form as defined above in a unit dose of between 4.0 mg and 100 mg.

[0048] When the Compound is administered and / or intended to be administered at one unit dose per day (once a day), the lower limits of the unit dose of the Compound are, in particular, 10 mg, 15 mg, and 20 mg, and the upper limits are 100 mg, 80 mg, and 60 mg. It is understood that each lower limit can be combined with each upper limit. Thus, all combinations of lower and upper limits are specifically disclosed herein. In particular, the unit dose is between 10 mg and 100 mg.

[0049] When the Compound is administered and / or intended to be administered in two separate unit doses per day (twice daily), the lower limits of the unit dose of the Compound are, in particular, 4.0 mg, 8.0 mg, 15 mg, and 20 mg, and the upper limits are 50 mg, 40 mg, and 30 mg. It is understood that each lower limit may be combined with each upper limit. Thus, all combinations of lower and upper limits are specifically disclosed herein. In particular, the unit dose is between 8.0 mg and 50 mg; more particularly, the unit dose is 20 mg.

[0050] 15) A further aspect of the present invention relates to a pharmaceutical combination according to any one of aspects 1) to 14), comprising the anti-CD3 monoclonal antibody in a pharmaceutical dosage form for oral, nasal, subcutaneous or intravenous administration of the anti-CD3 monoclonal antibody.

[0051] 16) A further aspect of the present invention relates to a pharmaceutical combination according to any one of aspects 1) to 14), comprising the anti-CD3 monoclonal antibody in a pharmaceutical dosage form for intravenous administration of the anti-CD3 monoclonal antibody.

[0052] 17) A further aspect of the present invention relates to a pharmaceutical combination according to any one of aspects 1) to 14), comprising the anti-CD3 monoclonal antibody in a pharmaceutical dosage form for oral or nasal administration of the anti-CD3 monoclonal antibody.

[0053] 18) A further aspect of the present invention is a method for administering the anti-CD3 monoclonal antibody (particularly teplizumab) at a dose of 50 μg / m2 BSA to 1000 μg / m 2 The present invention relates to a pharmaceutical combination according to any one of aspects 15) to 17), having a pharmaceutical dosage form of a unit dose of between 100 mg / kg and 150 mg / kg BSA.

[0054] The lower limit of the unit dose of the anti-CD3 monoclonal antibody (particularly teplizumab) is 50 μg / m 2 BSA, 100 μg / m 2 BSA, 400 μg / m 2 BSA and 600 μg / m 2 BSA, the upper limit is 1000 μg / m 2 BSA, 900 μg / m 2 BSA and 826 μg / m 2 BSA. Each lower limit may be combined with each upper limit. Thus, all combinations of lower and upper limits are specifically disclosed herein. In particular, the unit dose is about 826 μg / m 2 Alternatively, the unit dose is 80 0 μg / m 2 BSA to 1200 μg / m 2 BSA, especially at approximately 1030 μg / m 2 It is BSA.

[0055] (square meters [m 2 Body surface area (BSA) (measured by [masculine or feminine name]) may be measured or calculated by any formula commonly used to calculate BSA, in particular the Mosteller formula.

[0056] 19) A further aspect of the present invention relates to a pharmaceutical combination according to any one of aspects 15) to 17), which comprises an anti-CD3 monoclonal antibody (in particular otelixizumab, teplizumab and foralumab) in the above-mentioned pharmaceutical dosage form in a unit dose of between 0.1 mg and 10 mg.

[0057] The lower limits of the unit dose of the anti-CD3 monoclonal antibodies (particularly otelixizumab, teplizumab, and foralumab) are 0.1 mg, 0.5 mg, 1.0 mg, and 1.5 mg, and the upper limits are 10 mg, 5.0 mg, 3.0 mg, and 2.0 mg. Each lower limit may be combined with each upper limit. Accordingly, all combinations of lower and upper limits are specifically disclosed herein.

[0058] 20) A further aspect of the present invention relates to a pharmaceutical combination according to any one of aspects 1) to 19), comprising the first and second pharmaceutically active ingredients in a single pharmaceutical composition.

[0059] The single pharmaceutical composition comprises, as active pharmaceutical ingredients, the Compound or a pharmaceutically acceptable salt thereof and the anti-CD3 monoclonal antibody, and further comprises at least one pharmaceutically acceptable carrier material.

[0060] In the special case of embodiment 20) where one active pharmaceutical ingredient is intended to be and / or is administered more frequently than the other active pharmaceutical ingredient, only one or several (up to the administration frequency of the less frequently administered active pharmaceutical ingredient) of the pharmaceutical compositions required per day contain both the first and second active pharmaceutical ingredients. For example, in the case where one of the two active pharmaceutical ingredients is administered once a day and the other active pharmaceutical ingredient is administered twice a day, only one of the two pharmaceutical compositions required per day contains both the first and second active pharmaceutical ingredients, and the other contains only the active pharmaceutical ingredient administered twice a day.

[0061] Furthermore, in the case of a pharmaceutical combination according to embodiment 20) in which the first and / or the second active pharmaceutical ingredient are intended and / or are administered according to a dose escalation regimen, the pharmaceutical composition required for said dose escalation comprises the active pharmaceutical ingredients in the amounts required for the different stages of the dose escalation regimen.

[0062] 21) A further aspect of the present invention relates to a pharmaceutical combination according to any one of aspects 1) to 19), wherein the first and second pharmaceutically active ingredients are contained in separate pharmaceutical compositions.

[0063] One of the separate pharmaceutical compositions comprises the Compound or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient, and further comprises at least one pharmaceutically acceptable carrier material. The other of the separate pharmaceutical compositions comprises the anti-CD3 monoclonal antibody as an active pharmaceutical ingredient, and further comprises at least one pharmaceutically acceptable carrier material.

[0064] When the first and second active pharmaceutical ingredients are contained in separate pharmaceutical compositions, they can be administered simultaneously, sequentially or separately; preferably, the separate pharmaceutical compositions are administered simultaneously or sequentially, in particular sequentially. For example, the first active pharmaceutical ingredient is administered twice a day and the second active pharmaceutical ingredient is administered once a day. When administered, the separate pharmaceutical compositions are preferably administered simultaneously or sequentially, particularly sequentially, once a day. When administered sequentially or separately, the separate pharmaceutical compositions may be administered in either order. The number of times per day may be the same or different for the separate pharmaceutical compositions. For example, one pharmaceutical composition may be administered twice a day, and the other pharmaceutical composition may be administered once or twice a day. Preferably, the pharmaceutical composition having the "compound" or a pharmaceutically acceptable salt thereof is intended to be and / or is administered once or twice a day (particularly twice a day), and the pharmaceutical composition having the second pharmaceutically active ingredient is intended to be and / or is administered once a day. Furthermore, the separate pharmaceutical compositions may be administered by the same or different administration routes, preferably by different administration routes. Most preferably, the pharmaceutical composition comprising the "compound" is intended to be and / or is administered orally, and the pharmaceutical composition comprising the second pharmaceutically active ingredient is intended to be and / or is administered intravenously. The first and / or second pharmaceutically active ingredients may be administered independently to their respective target doses according to a dose escalation regimen; the pharmaceutical composition comprising the first and / or second pharmaceutically active ingredients required for dose escalation has the amounts of the pharmaceutically active ingredients required for different stages of the dose escalation regimen. The two separate pharmaceutical compositions may be administered for the same or different treatment periods. Preferably, the pharmaceutical composition comprising the "compound" or a pharmaceutically acceptable salt thereof is intended to be and / or is administered for a longer treatment period (e.g., longer than 30 days, particularly longer than 1 year, especially chronically) than the pharmaceutical composition comprising the second pharmaceutically active ingredient. Preferably, the pharmaceutical composition comprising the second pharmaceutically active ingredient is intended to be and / or is administered for a treatment period of 2 to 30 days. The lower limits of the treatment duration for the anti-CD3 monoclonal antibodies (particularly otelixizumab, teplizumab, and foralumab) are 2, 4, 6, and 10 days, and the upper limits are 30, 20, 18, and 14 days. Each lower limit may be combined with each upper limit.Therefore, all combinations of the lower and upper limits are specifically disclosed herein. Most preferably, the treatment period for the anti-CD3 monoclonal antibody (particularly teplizumab) is 12 to 14 days. The first administration of the pharmaceutical composition containing the "compound" to a patient may be on the first day of the treatment period with the pharmaceutical composition containing the second active pharmaceutical ingredient (the anti-CD3 monoclonal antibody); or on any of the remaining days of the treatment period (particularly, the second day or any other day in the first half of the treatment period); or on any day after the last administration of the pharmaceutical composition containing the second active pharmaceutical ingredient, i.e., after the end of the treatment period (but within 60 days after the end of the treatment period). Preferably, the first administration of the pharmaceutical composition containing the "compound" to a patient may be on any day during the treatment period with the pharmaceutical composition containing the second active pharmaceutical ingredient; or within 30 days (particularly 14 days, especially 1 day) thereafter. Most preferably, the first administration of the pharmaceutical composition having the Compound to the patient may be on the first day of the treatment period with the pharmaceutical composition having the second active pharmaceutical ingredient (the anti-CD3 monoclonal antibody).

[0065] 22) A further embodiment of the invention relates to a pharmaceutical combination according to any one of embodiments 1) to 21) for use as a medicament.

[0066] 23) A further aspect of the invention relates to a pharmaceutical combination according to any one of aspects 1) to 21) for use in the prevention and / or treatment of a disease or disorder associated with dysfunction of the CXCR3 receptor and / or dysfunction of ligands that signal via CXCR3 (CXCL9, CXCL10 and CXCL11).

[0067] Such diseases or disorders associated with dysfunction of the CXCR3 receptor or its ligand are diseases or disorders for which a modulator of the human CXCR3 receptor is indicated. The above diseases or disorders may be defined to include, inter alia, (auto-)immune / inflammatory mediated disorders; pulmonary diseases; cardiovascular diseases; infectious diseases; fibrosis; neurodegenerative diseases; and oncological diseases.

[0068] (Auto-)immune / inflammatory mediated disorders include rheumatoid arthritis (RA); multiple sclerosis (MS); inflammatory bowel disease (IBD; including Crohn's disease and ulcerative colitis); primary biliary cirrhosis (PBC); autoimmune hepatitis; systemic lupus erythematosus (SLE); lupus nephritis; antiphospholipid syndrome; Sjogren's syndrome; sarcoidosis; systemic sclerosis; spondyloarthritis; psoriasis; psoriatic arthritis; interstitial cystitis; celiac disease; Hashimoto's thyroiditis, lymphocytic thyroiditis, gray thyroiditis, and thyroiditis. thyroiditis, such as Behcet's disease; myasthenia gravis; type 1 diabetes (particularly autoimmune T1D); uveitis; episcleritis; scleritis; Kawasaki disease; retinal uveitis; posterior uveitis; Behcet's disease-associated uveitis; uveomeningocele syndrome; vitiligo; allergic encephalomyelitis; atopic diseases, such as rhinitis, conjunctivitis, and dermatitis; post-infectious autoimmune diseases, including rheumatic fever and post-infectious glomerulonephritis; myopathies (including inflammatory myopathies); obesity; and transplant-related disorders. Transplant-related disorders may be defined to include transplant rejection, such as rejection of transplanted organs, such as kidney, liver, heart, lung, pancreas, cornea, and skin; acute and / or chronic graft-versus-host disease; and chronic allograft vasculopathy.

[0069] Pulmonary disease may be defined to include acute lung injury; acute respiratory distress syndrome; asthma; and chronic obstructive pulmonary disease (COPD).

[0070] Cardiovascular disease may be defined to include atherosclerosis; and myocarditis.

[0071] Infectious diseases may be defined to include diseases and their complications caused by a variety of infectious agents such as malaria, cerebral malaria, leprosy, tuberculosis, influenza, toxoplasmosis, dengue fever, hepatitis B and C, herpes simplex, leishmaniasis, Chlamydia trachomatis, Lyme disease, and West Nile virus.

[0072] Fibrosis may be defined to include liver cirrhosis, idiopathic pulmonary fibrosis, renal fibrosis, endomyocardial fibrosis, systemic sclerosis and arthrofibrosis.

[0073] Neurodegenerative diseases may be defined to include conditions involving neurodegeneration and neuronal death such as multiple sclerosis (including relapsing-remitting multiple sclerosis and progressive multiple sclerosis), Alzheimer's disease, Parkinson's disease, Huntington's chorea, HIV-associated dementia, prion-mediated neurodegeneration, epilepsy, stroke, cerebral ischemia, cerebral palsy, neuromyelitis optica, clinically isolated syndrome, Alpers' disease, amyotrophic lateral sclerosis (ALS), senile dementia, dementia with Lewy bodies, Rett syndrome, spinal cord trauma, traumatic brain injury, trigeminal neuralgia, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, narcolepsy, glossopharyngeal neuralgia, mild cognitive impairment, cognitive decline, spinal muscular atrophy, and cerebral malaria. Stroke specifically includes intracerebral hemorrhage (ICH); subarachnoid hemorrhage (including aneurysmal subarachnoid hemorrhage); and inflammation and complications associated with any of the above.

[0074] Neoplastic disease may be defined to include colorectal cancer, rectal cancer, breast cancer, lung cancer, non-small cell lung cancer, prostate cancer, esophageal cancer, gastric cancer, liver cancer, bile duct cancer, spleen cancer, kidney cancer, bladder cancer, uterine cancer, ovarian cancer, cervical cancer, testicular cancer, thyroid cancer, pancreatic cancer, brain tumor, hematoma, basophilic adenoma, prolactinoma, hyperprolactinemia, adenoma, endometrial cancer, colon cancer; all types of cancer such as chronic lymphocytic leukemia (CLL); and (in particular) metastatic spread of cancer.

[0075] 24) A further aspect of the present invention is directed to the treatment of type 1 diabetes (T1D) (particularly autoimmune T1D), multiple sclerosis, vitiligo, organ transplant rejection (particularly kidney and cardiac allograft rejection), thyroid eye disease, rheumatoid arthritis, ulcerative colitis, Crohn's disease, celiac disease, atherosclerosis, psoriasis, pneumonia, psoriatic arthritis, and hemorrhage (including intracerebral hemorrhage (ICH)). age); subarachnoid hemorrhage (including aneurysmal subarachnoid hemorrhage); and inflammation and complications associated with any of the above.

[0076] 25) A further aspect of the invention relates to a pharmaceutical combination according to any one of aspects 1) to 21) for use in the prevention and / or treatment of a disease or disorder selected from type 1 diabetes (T1D) (in particular autoimmune T1D), multiple sclerosis, vitiligo, organ transplant rejection (in particular kidney and cardiac allograft rejection), thyroid eye disease, rheumatoid arthritis, ulcerative colitis, Crohn's disease, celiac disease, atherosclerosis, psoriasis, pneumonia and psoriatic arthritis.

[0077] 26) A further aspect of the invention relates to a pharmaceutical combination according to any one of aspects 1) to 21) for use in the prevention and / or treatment of a disease or disorder selected from type 1 diabetes (T1D) (in particular autoimmune T1D), multiple sclerosis, organ transplant rejection (in particular renal and cardiac allograft rejection), thyroid eye disease, rheumatoid arthritis, ulcerative colitis, Crohn's disease, celiac disease, atherosclerosis, psoriasis, pneumonia and psoriatic arthritis.

[0078] 27) A further embodiment of the invention relates to a pharmaceutical combination according to any one of embodiments 1) to 21) for use in the prevention and / or treatment of vitiligo.

[0079] 28) A further aspect of the invention relates to a pharmaceutical combination according to any one of aspects 1) to 21) for use in the prevention and / or treatment of type 1 diabetes (in particular autoimmune T1D).

[0080] In a first sub-embodiment of embodiment 28), the present invention relates to a pharmaceutical combination according to any one of embodiments 1) to 21) for use in the prevention and / or treatment (in particular the prevention) of type 1 diabetes (in particular autoimmune T1D) in patients at risk.

[0081] The term "at-risk patient" (or "at-risk individual") as used herein in connection with type 1 diabetes refers to an individual with a lifetime risk of at least 50% (particularly at least 65%, and especially at least 80%) of developing stage 3 type 1 diabetes. In particular, an "at-risk patient" is an individual with two or more T1D-associated and / or islet-specific (particularly islet-specific) autoantibodies. The most important T1D-associated and / or islet-associated autoantibodies are anti-glutamic acid decarboxylase 65 (GAD65), anti-islet cell antibody 512 (ICA512), micro-insulin autoantibody (mIAA), zinc transporter 8 (ZnT8), and anti-islet cell antibody (ICA). According to their clinical characteristics, at-risk patients can be classified into stage 1 or stage 2. At-risk patients are particularly those with close relatives with T1D (especially first-degree relatives such as siblings, parents, and children, and second-degree relatives such as grandparents, grandchildren, half-siblings, aunts, and uncles; especially first-degree relatives such as siblings, parents, and children), individuals with two or more T1D-associated and / or islet-associated (especially islet-associated) autoantibodies; or individuals with two or more T1D-associated and / or islet-associated (especially islet-associated) autoantibodies and (e.g., a 75g oral glucose tolerance test (OGRT)). or an individual with two or more T1D-related and / or islet-associated (particularly islet-associated) autoantibodies and dysglycemia (e.g., diagnosed by an OGTT) who has a close relative with T1D (particularly first-degree relatives such as siblings, parents, and children, and second-degree relatives such as grandparents, grandchildren, half-siblings, aunts, and uncles; especially first-degree relatives such as siblings, parents, and children). Dysglycemia is defined as a blood glucose level of ≥ 100 mg / dL (≥ 5.6 mmol / L) or ≥ 110 mg / dL ( fasting plasma glucose of ≥ 6.2 mmol / L (particularly fasting plasma glucose between 100 and 125 mg / dL (≥ 5.6-6.9 mmol / L)), 2-h plasma glucose during OGTT between 140 and 199 mg / dL (7.8-11.0 mmol / L), high blood glucose levels midway through the OGTT (30, 60, or 90-minute plasma glucose of ≥ 200 mg / dL (≥ 11.1 mmol / L)), and / or HbA 1c ≥ 5.7% (≥ 39 mmol / mol).

[0082] In a second sub-embodiment of embodiment 28), the present invention relates to a pharmaceutical combination according to any one of embodiments 1) to 21) for use in the prevention and / or treatment (in particular the treatment) of type 1 diabetes (in particular autoimmune T1D) in patients with recent onset T1D.

[0083] As used herein, the term "patient with recent-onset type 1 diabetes (T1D)" or "patient with recent-onset type 1 diabetes (T1D)" refers to a patient who has been clinically diagnosed with type 1 diabetes within a maximum of 150 days (or a maximum of 105 days; or a maximum of 56 days; in particular a maximum of 150 days) prior to the start of treatment (in particular, prior to the start of treatment with a pharmaceutical combination according to any one of aspects 1) to 21). Symptoms and signs of type 1 diabetes may include polyuria, polydipsia, weight loss, asthenia, diabetic ketoacidosis (DKA), and others (in particular, polyuria, polydipsia, weight loss, asthenia, and diabetic ketoacidosis (DKA)). Patients with recent-onset type 1 diabetes require repeated administration of exogenous insulin (even though for certain patients, administration of exogenous insulin may be discontinued for a certain period of time (up to several days or weeks)).

[0084] In a third sub-embodiment of embodiment 28), the present invention relates to a pharmaceutical combination according to any one of embodiments 1) to 21) for use in the prevention and / or treatment of type 1 diabetes, in particular autoimmune T1D, in patients at risk and in patients with recent-onset T1D.

[0085] The progression of T1D can be described in three stages (Insel RA et al., Diabetes Care 2015 38(10):1964-74): - Stage 1 (asymptomatic stage) refers to individuals who have developed two or more of the type 1 diabetes-associated islet autoantibodies but are normoglycemic; - Stage 2 (pre-symptomatic stage) refers to individuals with two or more islet autoantibodies and whose disease has progressed from loss of functional beta cell mass to the development of glucose intolerance or dysglycemia; - Stage 3 (symptomatic or clinical stage) refers to individuals whose remaining beta cell capacity is insufficient to maintain glycemic control and who require exogenous insulin. Stage 3 exhibits typical clinical symptoms and signs of diabetes, which may include polyuria, polydipsia, weight loss, fatigue, diabetic ketoacidosis (DKA), and others.

[0086] The term "prevention and / or treatment" when used in relation to the diseases and disorders defined herein refers in particular to the treatment of said disease and disorder; in relation to progressive diseases and disorders (particularly for type 1 diabetes, and especially for type 1 diabetes in recent-onset T1D patients), the term "treatment" refers in particular to reducing the rate of progression of said disease or disorder (particularly for type 1 diabetes, especially for type 1 diabetes in recent-onset T1D patients) or slowing the worsening of one or more symptoms of said disease or disorder (particularly for type 1 diabetes, especially for type 1 diabetes in recent-onset T1D patients). In another aspect, the term "prevention or treatment" when used in relation to the diseases and disorders defined herein refers in particular to the prevention of said disease and disorder (particularly for type 1 diabetes, especially for type 1 diabetes in patients at risk), and in particular to the prevention of said disease or disorder (particularly for type 1 diabetes, especially in patients at risk) and in particular to the prevention of said disease or disorder (particularly for type 1 diabetes, especially in patients at risk) and in particular to the prevention of said disease or disorder (particularly for type 1 diabetes). "prevention" means preventing or delaying (especially delaying) the onset of a disease or disorder (particularly type 1 diabetes) in a patient diagnosed with that disease or disorder, or preventing or delaying (especially delaying) the onset of one or more symptoms of that disease or disorder (especially type 1 diabetes, especially type 1 diabetes in patients at risk of T1D). In the particular case of type 1 diabetes (especially type 1 diabetes in patients at risk), the term "prevention" as used herein may also mean preventing or delaying (especially delaying) the progression from an earlier stage of T1D to a later stage of T1D (e.g., from stage 1 T1D to stage 2 T1D, or from stage 2 T1D to stage 3 T1D; particularly, from stage 2 T1D to stage 3 T1D).

[0087] The present invention also relates to a method for the prevention and / or treatment of a disease or disorder according to any one of aspects 23) to 28), comprising administering to a subject (preferably a human subject) in need thereof a pharmaceutically effective amount of a pharmaceutical combination according to any one of aspects 1) to 21).

[0088] 29) A further aspect of the invention relates to a pharmaceutical combination for use according to any one of aspects 22) to 28), wherein the Compound or a pharmaceutically acceptable salt thereof (in particular the Compound) is intended to be and / or is administered to a patient by oral or intravenous administration.

[0089] 30) A further aspect of the invention relates to a pharmaceutical combination for use according to any one of aspects 22) to 28), wherein the Compound or a pharmaceutically acceptable salt thereof (in particular the Compound) is intended to be and / or is administered to a patient by oral administration.

[0090] 31) A further embodiment of the present invention relates to a pharmaceutical combination for use according to any one of embodiments 22) to 30), wherein the Compound or a pharmaceutically acceptable salt thereof (particularly the Compound) is intended to be and / or is administered to a patient once or twice daily (particularly twice daily).

[0091] 32) A further embodiment of the invention relates to a pharmaceutical combination for use according to embodiment 31), wherein the Compound or a pharmaceutically acceptable salt thereof (particularly the Compound) is intended to be and / or has been administered to a patient for a treatment period of at least 1 year (particularly at least 5 years, more particularly at least 10 years).

[0092] 33) A further embodiment of the invention relates to a pharmaceutical combination for use according to embodiment 31), wherein the Compound or a pharmaceutically acceptable salt thereof (in particular the Compound) is intended to be and / or is administered chronically to a patient.

[0093] The term "chronic treatment" (or "chronically") refers to a treatment period starting from the first day of treatment with the respective active pharmaceutical ingredient and continuing until further continuation of the patient's treatment with the respective active pharmaceutical ingredient is no longer possible or indicated. Treatment of the patient with the active pharmaceutical ingredient may, for example, no longer be possible or indicated due to side effects of the treatment, changes in the subject's health status (e.g., the need for a different drug treatment), changes in other relevant circumstances in the subject's life, death of the subject, etc. In particular, the term "chronic treatment" (or "chronically") refers to a treatment period of at least 10 years starting from the first day of treatment with the respective active pharmaceutical ingredient and continuing until further continuation of the patient's treatment with the respective active pharmaceutical ingredient is no longer possible or indicated.

[0094] 34) A further aspect of the present invention is directed to a method for treating a patient in which the amount of Compound or a pharmaceutically acceptable salt thereof (particularly Compound) intended and / or administered to a patient is 800 mg / day or more. The pharmaceutical combination for use according to any one of aspects 22) to 33) relates to a dosage of 0.0 mg to 100 mg per day.

[0095] When the Compound is administered and / or intended to be administered once daily, the lower limits of the amount of Compound intended and / or administered to a patient per day are 10 mg, 15 mg, and 20 mg, and the upper limits are 100 mg, 80 mg, and 60 mg. It is understood that each lower limit can be combined with each upper limit. Thus, all combinations of lower and upper limits are specifically disclosed herein. The amount of Compound per day is specifically between 10 mg and 100 mg.

[0096] When the Compound is administered and / or intended to be administered twice daily, the lower limits of the amount of Compound intended and / or administered to a patient per day are 8.0 mg (particularly 4.0 mg twice), 16 mg (particularly 8.0 mg twice), 30 mg (particularly 15 mg twice), and 40 mg (particularly 20 mg twice), and the upper limits are 100 mg (particularly 50 mg twice), 80 mg (particularly 40 mg twice), and 60 mg (particularly 30 mg twice). Each lower limit may be combined with each upper limit. Accordingly, all combinations of lower and upper limits are specifically disclosed herein. The daily amounts of Compound are particularly 16 mg (particularly 8.0 mg twice) and 100 mg (particularly 50 mg twice).

[0097] For the avoidance of doubt, in the context of the present invention, any amount / unit dose of "Compound" expressed in mg means an amount / unit dose appropriate for administration of "Compound" in free base form having a molecular weight of 550.48 g / mol at such amount / unit dose. Such amount / unit dose may need to be adjusted in pharmaceutical compositions if "Compound" is present in such compositions in a form other than the anhydrous free base, such as a pharmaceutically acceptable salt; and / or a solvate form such as a hydrate.

[0098] 35) A further aspect of the invention relates to a pharmaceutical combination for use according to any one of aspects 22) to 34), wherein the anti-CD3 monoclonal antibody (in particular otelixizumab, teplizumab or foralumab) is intended to be and / or is administered to a patient by oral, nasal, subcutaneous or intravenous administration (in particular by oral, nasal or intravenous administration).

[0099] 36) A further embodiment of the invention relates to a pharmaceutical combination for use according to any one of embodiments 22) to 34), wherein the anti-CD3 monoclonal antibody (in particular otelixizumab, teplizumab or foralumab) is intended to be and / or is administered to a patient by oral or nasal administration.

[0100] 37) A further embodiment of the invention relates to a pharmaceutical combination for use according to any one of embodiments 22) to 34), wherein the anti-CD3 monoclonal antibody (in particular otelixizumab, teplizumab or foralumab) is intended to be and / or is administered to a patient by intravenous administration.

[0101] 38) A further embodiment of the invention relates to a pharmaceutical combination for use according to any one of embodiments 22) to 34), wherein the anti-CD3 monoclonal antibody is teplizumab, and the anti-CD3 monoclonal antibody is intended to be and / or is administered to a patient by intravenous administration.

[0102] 39) A further embodiment of the invention is any of embodiments 22) to 38), in which the anti-CD3 monoclonal antibody (in particular otelixizumab, teplizumab or foralumab) is intended and / or is administered to the patient once or twice a day (in particular once a day). 1 relates to a pharmaceutical combination for use according to

[0103] 40) A further embodiment of the invention relates to a pharmaceutical combination for use according to any one of embodiments 22) to 38), wherein the anti-CD3 monoclonal antibody is teplizumab, and wherein the anti-CD3 monoclonal antibody is intended to be and / or is administered to a patient once a day.

[0104] 41) A further embodiment of the invention relates to a pharmaceutical combination for use according to any one of embodiments 22) to 40), wherein the anti-CD3 monoclonal antibody (in particular otelixizumab, teplizumab or foralumab) is intended to be and / or is administered to a patient for a treatment period of 2 to 30 days.

[0105] The lower limits of the treatment period with the anti-CD3 monoclonal antibody (particularly otelixizumab, teplizumab, or foralumab) are 2 days, 4 days, 6 days, and 10 days, and the upper limits are 30 days, 20 days, 18 days, and 14 days. Each lower limit can be combined with each upper limit. Thus, all combinations of lower and upper limits are specifically disclosed herein. Most preferably, the treatment period with the anti-CD3 monoclonal antibody (particularly teplizumab) is 12 to 14 days.

[0106] 42) A further embodiment of the present invention relates to a pharmaceutical combination for use according to any one of embodiments 22) to 40), wherein the anti-CD3 monoclonal antibody is teplizumab, and wherein the anti-CD3 monoclonal antibody is intended to be and / or has been administered to a patient for a treatment period of 6 to 20 days.

[0107] The lower limits of the teplizumab treatment period are 6 days, 8 days, 10 days, and 12 days, and the upper limits are 20 days, 18 days, 16 days, and 14 days. Each lower limit can be combined with each upper limit. Thus, all combinations of lower and upper limits are specifically disclosed herein. Most preferably, the teplizumab treatment period is 12 to 14 days.

[0108] 43) A further embodiment of the invention relates to a pharmaceutical combination for use according to any one of embodiments 22) to 42), wherein said anti-CD3 monoclonal antibody (in particular otelixizumab, teplizumab or foralaumab) is intended to be and / or is administered to the patient using an escalating dose regimen (i.e. by stepwise increasing the daily dose until the target dose is reached).

[0109] The dose escalation may be achieved by using 3 to 10 (particularly 4 to 6, more particularly 5) different doses of an anti-CD3 monoclonal antibody (particularly otelixizumab, teplizumab or foralarumab), with the dose on each treatment day being equal to or greater than the dose on the preceding day, and with the maximum dose of the escalation being equal to the target dose intended and / or administered by the end of the treatment period.

[0110] Preferably, the dose on each treatment day during the dose increase is greater than the dose on the preceding day.

[0111] 44) A further embodiment of the invention relates to a pharmaceutical combination for use according to any one of embodiments 22) to 42), wherein the anti-CD3 monoclonal antibody is teplizumab; and the anti-CD3 monoclonal antibody is intended to be and / or is administered to a patient using an escalating dose regimen, the dose on each treatment day being equal to or higher than the dose on the preceding day, and the maximum dose of the escalation being equal to the target dose.

[0112] Preferably, the dose on each treatment day during the dose increase is greater than the dose on the preceding day.

[0113] 45) A further embodiment of the invention relates to a pharmaceutical combination for use according to any one of embodiments 22) to 42), wherein the anti-CD3 monoclonal antibody is teplizumab; and the administration scheme consists of administering increasing doses every day from day 1 (first day of treatment) to day 5 (i.e. five different doses that increase successively) until the target dose is reached, and administering a constant dose (target dose) from day 5 until the end of treatment on days 10 to 18 (in particular days 12 to 14).

[0114] 46) A further embodiment of the invention is characterized in that the anti-CD3 monoclonal antibody is teplizumab; and the administration scheme is about 51 μg / m on day 1 of the treatment. 2 BSA, approximately 103 μg / m on day 2 2 BSA, approximately 207 μg / m on day 3 2 BSA, approximately 413 μg / m on day 4 2 BSA and approximately 826 μg / m on days 5 to 14, respectively. 2 The pharmaceutical combination for use according to any one of embodiments 22) to 42) comprises administering BSA.

[0115] Alternatively, the dosing scheme may be about 65 μg / m on day 1 of the treatment. 2 BSA, approximately 125 μg / m on day 2 2 BSA, approximately 250 μg / m on day 3 2 BSA, approximately 500 μg / m on day 4 2 BSA and approximately 1030 μg / m on days 5 to 14, respectively. 2 It consists of administering teplizumab to BSA.

[0116] 47) A further embodiment of the invention relates to a pharmaceutical combination for use according to any one of embodiments 22) to 45), wherein the amount of the anti-CD3 monoclonal antibody (in particular otelixizumab, teplizumab or foralumab) intended to be and / or administered to a patient is between 0.1 mg per day and 10 mg per day.

[0117] The lower limits of the amount of the anti-CD3 monoclonal antibody (particularly otelixizumab, teplizumab, or foralarumab) intended and / or administered to a patient are 0.1 mg per day, 0.5 mg per day, 1.0 mg per day, and 1.5 mg per day, and the upper limits are 10 mg per day, 5.0 mg per day, 3.0 mg per day, and 2.0 mg per day. Each lower limit may be combined with each upper limit. Accordingly, all combinations of lower and upper limits are specifically disclosed herein.

[0118] 48) A further embodiment of the invention relates to a pharmaceutical combination for use according to any one of embodiments 22) to 45), wherein the anti-CD3 monoclonal antibody is teplizumab; and the amount of the anti-CD3 monoclonal antibody intended to be and / or administered to the patient is between 0.1 mg per day and 4.0 mg per day.

[0119] The lower limits of the amount of teplizumab intended and / or administered to a patient are 0.1 mg per day, 0.5 mg per day, and 1.0 mg per day, and the upper limits are 4.0 mg per day, 3.0 mg per day, and 2.0 mg per day. It is understood that each lower limit may be combined with each upper limit. Accordingly, all combinations of lower and upper limits are specifically disclosed herein.

[0120] 49) A further embodiment of the invention relates to the use according to any one of embodiments 22) to 45), in which the amount of said anti-CD3 monoclonal antibody (in particular otelixizumab, teplizumab or foralumab) intended to be and / or administered to the patient is between 1.5 μg / kg (of the patient's body weight) per day and 200 μg / kg (of the patient's body weight) per day. This invention relates to a pharmaceutical combination for the treatment of

[0121] The lower limits of the amount of the anti-CD3 monoclonal antibody (particularly otelixizumab, teplizumab, or foralarumab) intended and / or administered to a patient are 1.5 μg / kg (patient's body weight) per day, 7.5 μg / kg (patient's body weight) per day, and 15 μg / kg (patient's body weight) per day, and the upper limits are 200 μg / kg (patient's body weight) per day, 100 μg / kg (patient's body weight) per day, 60 μg / kg (patient's body weight) per day, and 40 μg / kg (patient's body weight) per day. Each lower limit may be combined with each upper limit. Accordingly, all combinations of lower and upper limits are specifically disclosed herein.

[0122] 50) A further embodiment of the invention is characterized in that the anti-CD3 monoclonal antibody is teplizumab; and the amount of the anti-CD3 monoclonal antibody intended to be and / or administered to the patient is 50 μg / m per day. 2 BSA to 1000 μg / m per day 2 The pharmaceutical combination for use according to any one of aspects 22) to 45) is between 1) and 2) and BSA.

[0123] Alternatively, the amount of teplizumab intended to be and / or administered to a patient is 50 μg / m per day. 2 BSA to 1200 μg / m per day 2 Until BSA.

[0124] The lower limit of the amount of teplizumab intended and / or administered to patients is 50 μg / m per day. 2 BSA, 100 μg / m per day 2 BSA, 400 μg / m per day 2 BSA and 600 μg / m per day 2 BSA, with an upper limit of 1200 μg / m per day 2 BSA, 1030 μg / m per day 2 BSA, 1000 μg / m per day 2 BSA, 900 μg / m per day 2 BSA and 826 μg / m per day2 BSA (specifically, 1000 μg / m per day) 2 BSA, 900 μg / m per day 2 BSA and 826 μg / m per day 2 BSA). It is intended that each lower limit may be combined with each upper limit. Accordingly, all combinations of lower and upper limits are specifically disclosed herein. In particular, the amount of teplizumab intended to be and / or administered to a patient is about 826 μg / m per day. 2 Alternatively, the amount of teplizumab intended to be and / or administered to a patient is about 1030 μg / m 2 It is BSA.

[0125] (square meters [m 2 Body surface area (BSA) (measured by [masculine or feminine name]) may be measured or calculated by any formula commonly used to calculate BSA, in particular the Mosteller formula.

[0126] 51) A further embodiment of the invention relates to a pharmaceutical combination for use according to any one of embodiments 22) to 50), wherein the cumulative dose of the anti-CD3 monoclonal antibody (in particular otelixizumab, teplizumab or foralumab) intended to be and / or administered to a patient is between 5.0 mg and 40 mg.

[0127] The lower limits of the cumulative doses intended and / or administered to a patient are 5.0 mg, 7.5 mg, and 10 mg, and the upper limits are 40 mg, 30 mg, and 25 mg. Each lower limit may be combined with each upper limit. Accordingly, all combinations of lower and upper limits are specifically disclosed herein.

[0128] 52) A further embodiment of the present invention is characterized in that the anti-CD3 monoclonal antibody is teplizumab; the anti-CD3 monoclonal antibody is intended to be administered to a patient and / or is administered to a patient. The cumulative dose to the body is 5.0 mg / m 2 BSA to 15 mg / m2 The present invention relates to a pharmaceutical combination for use according to any one of aspects 22) to 50), wherein the compound is selected from the group consisting of hydroxybenzoates, ...

[0129] The lower limit of the cumulative dose intended and / or administered to a patient is 5.0 mg / m 2 BSA, 6.5 mg / m 2 BSA and 8.0 mg / m 2 BSA, the upper limit is 15 mg / m 2 BSA, 12 mg / m 2 BSA and 10 mg / m 2 BSA. It is intended that each lower limit may be combined with each upper limit. Accordingly, all combinations of lower and upper limits are specifically disclosed herein. Preferably, the cumulative dose of teplizumab intended to be and / or administered to a patient is about 9.0 mg / m 2 Alternatively, the cumulative dose of teplizumab intended to be and / or administered to the patient is 8.0 mg / m 2 BSA to 12.0 mg / m 2 Until BSA.

[0130] 53) A further embodiment of the invention relates to a pharmaceutical combination for use according to any one of embodiments 22) to 52), in which the anti-CD3 monoclonal antibody (in particular otelixizumab, teplizumab or foralumab) is intended to be and / or is administered to a patient for one treatment period.

[0131] 54) A further embodiment of the invention relates to a pharmaceutical combination for use according to any one of embodiments 22) to 52), wherein said anti-CD3 monoclonal antibody (in particular otelixizumab, teplizumab or foralumab; especially teplizumab) is intended to be and / or has been administered to a patient during a first treatment period and a second treatment period.

[0132] The administration scheme and length of the first and second treatment periods may be the same or different, preferably the administration scheme and length of the first and second treatment periods are the same.

[0133] 55) A further embodiment of the invention relates to a pharmaceutical combination for use according to embodiment 54), wherein the interval between the first and second treatment periods is at least 5 months (particularly about 6 to 12 months, more particularly about 6 months or about 12 months).

[0134] For the avoidance of doubt, the interval is calculated from the first day of treatment in the first treatment period to the first day of treatment in the second treatment period. For example, if the first day of treatment in the first treatment period is February 21st and the first day of treatment in the second treatment period is August 21st of the same year, the interval is six months.

[0135] 56) A further embodiment of the invention relates to a pharmaceutical combination for use according to any one of embodiments 54) or 55), wherein said anti-CD3 monoclonal antibody (in particular otelixizumab, teplizumab or foralumab; especially teplizumab) is intended to be and / or has been administered to the patient for a third treatment period, and wherein the interval between said second and third treatment periods is equal to or longer than the interval between said first and second treatment periods.

[0136] 57) A further embodiment of the present invention relates to a pharmaceutical combination for use according to any one of embodiments 22) to 56), wherein the disease is (autoimmune) type I diabetes (in patients (individuals) with stage 2 type I diabetes), and wherein in at least 75% of said patients, the progression from stage 2 type I diabetes to stage 3 type I diabetes is delayed by at least 24 months (particularly at least 36 months, more particularly at least 48 months) compared to untreated patients.

[0137] 58) A further aspect of the present invention is a method for treating type 1 diabetes, wherein the disease is a type 1 diabetes mellitus (stage 2). The present invention relates to a pharmaceutical combination for use according to any one of aspects 22) to 56), wherein the progression of stage 2 type 1 diabetes to stage 3 type 1 diabetes in a patient (individual) is delayed on average (arithmetic mean) by at least 24 months (particularly at least 36 months, more particularly at least 48 months) compared to untreated patients (individuals) with (autoimmune) type 1 diabetes.

[0138] As used herein, the term "untreated patient" refers to a patient (individual) who is not receiving prophylaxis or treatment for (autoimmune) type 1 diabetes (particularly, who is not receiving prophylaxis or treatment approved for the treatment of type 1 diabetes by a health authority, such as the U.S. Food and Drug Administration (FDA)).

[0139] Treatment of patients with stage 2 type 1 diabetes (particularly autoimmune T1D) with a pharmaceutical combination according to any one of aspects 1) to 21) may delay the progression of stage 2 type 1 diabetes to stage 3 type 1 diabetes by at least 1 month (particularly at least 6 months, more particularly at least 12 months) on average (arithmetic mean) compared to patients treated with the anti-CD3 monoclonal antibody (particularly teplizumab) alone.

[0140] Treatment of (autoimmune) type 1 diabetes in patients (particularly in patients with recent-onset type 1 diabetes or in patients at risk) with a pharmaceutical combination according to any one of aspects 1) to 21) may delay the decline in C-peptide levels in said patients (particularly when compared to untreated patients and / or patients treated with said anti-CD3 monoclonal antibody (particularly teplizumab) alone).

[0141] Furthermore, treatment of type 1 diabetes (particularly autoimmune T1D) in a patient (particularly in a patient with recent-onset type 1 diabetes or in a patient at risk) with a pharmaceutical combination according to any one of aspects 1) to 21) may result in higher (particularly statistically significantly higher) C-peptide levels in the patient 1, 2, and / or 3 years after the first administration of the anti-CD3 monoclonal antibody (particularly teplizumab) compared to C-peptide levels in untreated patients and / or patients treated with the anti-CD3 monoclonal antibody (particularly teplizumab) alone. For example, the C-peptide levels may be at least 10%, at least 20%, or at least 30% higher.

[0142] C-peptide is separated from proinsulin during insulin synthesis and is released from the pancreas simultaneously with insulin and in the same amount. Measurement of C-peptide levels can be used to indirectly measure endogenous insulin production in T1D patients. C-peptide levels can be measured, for example, by two-site immunoenzymometric assay, two-site fluoroimmunoassay, and other methods. C-peptide levels can be measured using a fluoroimmunometric assay (Greenbaum CJ et al., Diabetes Care 2008 31:1966-1971 and supplementary materials), or by any other method known to those skilled in the art. Preferably, C-peptide levels are expressed as the area under the curve (AUC) response to a 2-hour mixed meal tolerance test (MMTT) or an oral glucose tolerance test (OGTT).

[0143] Treatment of type 1 diabetes (particularly autoimmune T1D) in a patient (particularly in a patient with recent-onset type 1 diabetes or in a patient at risk) with a pharmaceutical combination according to any one of aspects 1) to 21) may result in lower exogenous insulin usage (particularly statistically significantly lower exogenous insulin usage) in the patient within at least one year, at least two years, or at least three years after the first administration of the anti-CD3 monoclonal antibody (particularly teplizumab) when compared to exogenous insulin usage in untreated patients and / or patients treated with the anti-CD3 monoclonal antibody (particularly teplizumab) alone. For example, the exogenous insulin usage may be at least 10%, at least 20%, or at least 30% lower. That's fine.

[0144] 59) A further aspect of the invention relates to a pharmaceutical composition having (in particular containing) 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone or a pharmaceutically acceptable salt thereof as an active ingredient and further comprising (in particular containing) at least one pharmaceutically inactive excipient, which is intended to be and / or is administered in combination with a second pharmaceutical composition having (in particular containing) an anti-CD3 monoclonal antibody as an active ingredient (in particular otelixizumab, teplizumab or foralaumab) and further comprising (in particular containing) at least one pharmaceutically inactive excipient.

[0145] 60) A further aspect of the invention relates to a pharmaceutical composition having (in particular containing) 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone as an active ingredient and further comprising (in particular containing) at least one pharmaceutically inactive excipient, which is intended to be and / or is administered in combination with a second pharmaceutical composition having (in particular containing) teplizumab as an active ingredient and further comprising (in particular containing) at least one pharmaceutically inactive excipient.

[0146] 61) A further embodiment of the invention relates to a pharmaceutical composition according to embodiment 59) or 60) for use as a medicament.

[0147] 62) A further aspect of the invention relates to a pharmaceutical composition according to aspect 59) or 60) for use in the prevention and / or treatment of a disease or disorder according to any one of aspects 23) to 28).

[0148] 63) A further aspect of the invention relates to a pharmaceutical composition having (in particular containing) an anti-CD3 monoclonal antibody (in particular otelixizumab, teplizumab or foralaumab) as an active ingredient and further comprising (in particular containing) at least one pharmaceutically inactive excipient, which is intended to be and / or is administered in combination with a second pharmaceutical composition having (in particular containing) 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone or a pharmaceutically acceptable salt thereof as an active ingredient and further comprising (in particular containing) at least one pharmaceutically inactive excipient.

[0149] 64) A further aspect of the invention relates to a pharmaceutical composition having (in particular comprising) teplizumab as an active ingredient and further comprising (in particular comprising) at least one pharmaceutically inactive excipient, said pharmaceutical composition being intended to be and / or being administered in combination with a second pharmaceutical composition having (in particular comprising) 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone as an active ingredient and further comprising (in particular comprising) at least one pharmaceutically inactive excipient.

[0150] 65) A further embodiment of the invention relates to a pharmaceutical composition according to embodiment 63) or 64) for use as a medicament.

[0151] 66) A further aspect of the invention relates to a pharmaceutical composition according to aspect 63) or 64) for use in the prevention and / or treatment of a disease or disorder according to any one of aspects 23) to 28).

[0152] 67) A further aspect of the invention relates to a kit of parts comprising a first pharmaceutical composition having (in particular containing) 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone or a pharmaceutically acceptable salt thereof as an active ingredient and further comprising (in particular containing) at least one pharmaceutically inactive excipient; and a second pharmaceutical composition having (in particular containing) an anti-CD3 monoclonal antibody (in particular otelixizumab, teplizumab or foralaumab) as an active ingredient and further comprising (in particular containing) at least one pharmaceutically inactive excipient.

[0153] 68) A further aspect of the invention relates to a kit comprising a first pharmaceutical composition having (particularly comprising) 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone as an active ingredient and further having (particularly comprising) at least one pharmaceutically inactive excipient; and a second pharmaceutical composition having (particularly comprising) teplizumab as an active ingredient and further having (particularly comprising) at least one pharmaceutically inactive excipient.

[0154] 69) A further embodiment of the invention relates to a kit according to embodiment 67) or 68), further comprising instructions for the simultaneous, sequential or separate administration of said pharmaceutical compositions.

[0155] 70) A further embodiment of the invention relates to a kit according to any one of embodiments 67) to 69) for use as a medicament.

[0156] 71) A further aspect of the invention relates to a kit according to any one of aspects 67) to 69) for use in the prevention and / or treatment of a disease or disorder according to any one of aspects 23) to 28).

[0157] 72) A further aspect of the invention relates to the use of a first active pharmaceutical ingredient which is 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone or a pharmaceutically acceptable salt thereof, and a second active pharmaceutical ingredient which is an anti-CD3 monoclonal antibody (in particular otelixizumab, teplizumab, or foralumab), for the manufacture of a pharmaceutical composition for use according to any one of aspects 22) to 58), comprising the first and second active pharmaceutical ingredients.

[0158] 73) A further aspect of the present invention relates to the use of a first active pharmaceutical ingredient which is 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone or a pharmaceutically acceptable salt thereof, and a second active pharmaceutical ingredient which is an anti-CD3 monoclonal antibody (in particular otelixizumab, teplizumab or foralumab), comprising the preparation of two separate pharmaceutical compositions comprising the first active pharmaceutical ingredient in the first pharmaceutical composition and the second active pharmaceutical ingredient in the second pharmaceutical composition, for use according to any one of aspects 22) to 58). Use for manufacturing.

[0159] 74) A further embodiment of the invention relates to the use of a first active pharmaceutical ingredient that is 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone and a second active pharmaceutical ingredient that is teplizumab, for the manufacture of a pharmaceutical composition comprising the first and second active pharmaceutical ingredients for use according to any one of embodiments 22) to 58).

[0160] 75) A further aspect of the invention relates to the use of a first active pharmaceutical ingredient that is 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone and a second active pharmaceutical ingredient that is teplizumab, for the manufacture of two separate pharmaceutical compositions having the first active pharmaceutical ingredient in the first pharmaceutical composition and the second active pharmaceutical ingredient in the second pharmaceutical composition, for use according to any one of aspects 22) to 58).

[0161] 76) A further aspect of the invention is the use of 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in combination with a second medicament comprising an anti-CD3 monoclonal antibody (in particular otelixizumab, teplizumab or foralarumab), wherein the use of the medicament is according to any one of aspects 22) to 58).

[0162] 77) A further embodiment of the invention is the use of 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone for the manufacture of a medicament for use in combination with a second medicament having teplizumab, wherein the use of said medicament is according to any one of embodiments 22) to 58).

[0163] 78) A further embodiment of the invention is the use of an anti-CD3 monoclonal antibody (in particular otelixizumab, teplizumab or foralumab) for the manufacture of a medicament for use in combination with a second medicament comprising 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone or a pharmaceutically acceptable salt thereof, wherein the use of the medicament is according to any one of embodiments 22) to 58).

[0164] 79) A further embodiment of the invention is the use of teplizumab for the manufacture of a medicament for use in combination with a second medicament having 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone, wherein the use of the medicament is according to any one of embodiments 22) to 58).

[0165] of a disease or disorder as defined herein (in particular according to any one of embodiments 22) to 58) Any aspect relating to a pharmaceutical combination for use in the prevention and / or treatment may include: - a method for the prevention and / or treatment of said diseases or disorders, comprising administering to a patient in need thereof an effective amount of the Compound or a pharmaceutically acceptable salt thereof, wherein the Compound is administered and / or is intended to be administered in combination with an effective amount of an anti-CD3 monoclonal antibody (in particular otelixizumab, teplizumab or foralumab, especially teplizumab); - a method for the prevention and / or treatment of said diseases or disorders, comprising administering to a patient in need thereof an effective amount of an anti-CD3 monoclonal antibody (in particular otelixizumab, teplizumab or foralumab, especially teplizumab), said anti-CD3 monoclonal antibody being administered and / or intended to be administered in combination with an effective amount of the Compound or a pharmaceutically acceptable salt thereof; - a method for the prevention and / or treatment of said disease or disorder, comprising administering to a patient in need thereof an effective amount of a pharmaceutical combination comprising the Compound or a pharmaceutically acceptable salt thereof and an anti-CD3 monoclonal antibody (in particular otelixizumab, teplizumab or foralumab, especially teplizumab); This also relates to:

[0166] Thus, the following preferred embodiments are possible and contemplated, depending on the various embodiments 1)-79) disclosed above, and are specifically disclosed herein as individual embodiments (other embodiments are possible and contemplated, depending on the various embodiments 1)-79): 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+23、54+38+34+31+30+27、54+38+34+31+30+28、55+54+30+22、55+54+30+23、55+54+30+27、55+54+30+28、55+54+34+30+22、55+54+34+30+23、55+54+34+30+27、55+54+34+30+28、55+54+34+31+30+22、55+54+34+31+30+23、55+54+34+31+30+27、55+54+34+31+30+28、55+54+38+22、55+54+38+23、55+54+38+27、55+54+38+28、55+54+38+30+22、55+54+38+30+23、55+54+38+30+27、55+54+38+30+28、55+54+38+34+30+22、55+54+38+34+30+23、55+54+38+34+30+27、55+54+38+34+30+28、55+54+38+34+31+30+22、55+54+38+34+31+30+23、55+54+38+34+31+30+27、55+54+38+34+31+30+28、 56+54+30+22、56+54+30+23、56+54+30+27、56+54+30+28、56+54+34+30+22、56+54+34+30+23、56+54+34+30+27、56+54+34+30+28、56+54+34+31+30+22、56+54+34+31+30+23、56+54+34+31+30+27、56+54+34+31+30+28、56+54+38+22、56+54+38+23、56+54+38+27、56+54+38+28、56+54+38+30+22、56+54+38+30+23、56+54+38+30+27、56+54+38+30+28、56+54+38+34+30+22、56+54+38+34+30+23、56+54+38+34+30+27、56+54+38+34+30+28、56+54+38+34+31+30+22、56+54+38+34+31+30+23、56+54+38+34+31+30+27、56+54+38+34+31+30+28、56+55+54+30+22、56+55+54+30+23、56+55+54+30+27、56+55+54+30+28、56+55+54+34+30+22、56+55+54+34+30+23、56+55+54+34+30+27、56+55+54+34+30+28、56+55+54+34+31+30+22、56+55+54+34+31+30+23、56+55+54+34+31+30+27、56+55+54+34+31+30+28、56+55+54+38+22、56+55+54+38+23、56+55+54+38+27、56+55+54+38+28、56+55+54+38+30+22、56+55+54+38+30+23、56+55+54+38+30+27、56+55+54+38+30+28、56+55+54+38+34+30+22、56+55+54+38+34+30+23、56+55+54+38+34+30+27、56+55+54+38+34+30+28、56+55+54+38+34+31+30+22、56+55+54+38+34+31+30+23、56+55+54+38+34+31+30+27、56+55+54+38+34+31+30+28、57+30+22、57+30+23、57+30+27、57+30+28、57+34+30+22、57+34+30+23、57+34+30+27、57+34+30+28、57+34+31+30+22、57+34+31+30+23、57+34+31+30+27、57+34+31+30+28、57+38+22、57+38+23、57+38+27、57+38+28、57+38+30+22、57+38+30+23、57+38+30+27、57+38+30+28、57+38+34+30+22、57+38+34+30+23、57+38+34+30+27、57+38+34+30+28、57+38+34+31+30+22、57+38+34+31+30+23、57+38+34+31+30+27、57+38+34+31+30+28、 58+30+22、58+30+23、58+30+27、58+30+28、58+34+30+22、58+34+30+23、58+34+30+27、58+34+30+28、58+34+31+30+22、58+34+31+30+23、58+34+ 31+30+27、58+34+31+30+28、58+38+22、58+38+23、58+38+27、58+38+28、58+38+30+22、58+38+30+23、58+38+30+27、58+38+30+28、58+38+34+30+22、58+38+34+30+23、58+38+34+30+27、58+38+34+30+28、58+38+34+31+30+22、58+38+34+31+30+23、58+38+34+31+30+27、58+38+34+31+30+28、59、60、61+59、61+60、62+59、62+60、63、64、65+63、65+64、66+63、66+64、67、68、69+67、69+68、70+67、70+68、70+69+67、70+69+68、71+67、71+68、71+69+67、71+69+68、72、73、74、75、76、77、78、79。

[0167] In the above table, the numbers refer to the embodiments corresponding to the numbers, and "+" indicates a dependency on other embodiments. The various embodiments are individually separated by commas. In other words, for example, "4+2+1" means embodiment 4), which is dependent on embodiment 2) and dependent on embodiment 1), i.e., embodiment "4+2+1" corresponds to a pharmaceutical combination of embodiment 1) further limited by the characteristics of embodiments 2) and 4).

[0168] The definitions set forth herein are uniformly applicable to the subject matter as defined in any one of embodiments 1) to 79) and apply mutatis mutandis throughout the present specification and claims unless a broader or narrower definition is given by a special definition. It should be understood that a definition or preferred definition of a term or expression may independently (and in combination with) define and replace the respective term or expression in any or preferred definition of any or all other terms or expressions defined herein.

[0169] Any reference to an active pharmaceutical ingredient defined in any one of aspects 1) to 79) is intended to also refer, where appropriate and appropriate, to pharmaceutically acceptable salts of such active pharmaceutical ingredient.

[0170] As used herein, the term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxic effects. Such salts include inorganic or organic acid and / or base addition salts, depending on the presence of basic and / or acidic groups in the subject compound. For reference, see, for example, "Handbook of See "Pharmaceutical Salts. Properties, Selection and Use." P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008; and "Pharmaceutical Salts and Co-crystals," Johan Wouters and Luc Quere (Eds.), RSC Publishing, 2012.

[0171] As used herein, the term "pharmaceutical combination" means a combination of two or more (especially two) different active pharmaceutical ingredients, said active pharmaceutical ingredients being contained in a single pharmaceutical composition or in separate pharmaceutical compositions.

[0172] As used herein, "active pharmaceutical ingredient" means a The term "pharmaceutically active ingredient" refers to the pharmaceutically active component of a pharmaceutical composition. Examples of active pharmaceutical ingredients used herein are, in the first group, 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-hydroxy-2-methyl-4-thiazol-5-yl)-piperazin-1-yl}- -methyl-[1,2,4]triazol-1-yl)-ethanone ("the Compound") or a pharmaceutically acceptable salt thereof, and in a second group, anti-CD3 monoclonal antibodies (in particular otelixizumab, teplizumab, visilizumab and / or foralumab; especially teplizumab).

[0173] When used in connection with the administration of active pharmaceutical ingredients or pharmaceutical compositions, the term "simultaneous" or "concurrently" means that the administration of a first active pharmaceutical ingredient (or first pharmaceutical composition) is still ongoing when the administration of a second active pharmaceutical ingredient (or second pharmaceutical composition) begins. In particular, the term "simultaneous" or "concurrently" means that two active pharmaceutical ingredients (or two pharmaceutical compositions) are administered at the same time, i.e., with the same start and finish times, such as in the case of administration of two active pharmaceutical ingredients contained in a single pharmaceutical composition.

[0174] The terms "continuous" or "sequentially," when used in reference to the administration of active pharmaceutical ingredients or pharmaceutical compositions, mean that the administration of a second active pharmaceutical ingredient (or second pharmaceutical composition) begins less than one hour after the completion of the administration of a first active pharmaceutical ingredient (or first pharmaceutical composition).

[0175] When used in connection with the administration of active pharmaceutical ingredients or pharmaceutical compositions, the term "separately" or "separately" means that the administration of a second active pharmaceutical ingredient (or second pharmaceutical composition) begins at least one hour (and up to about 12 hours, or up to about 24 hours, particularly up to about 12 hours) after the end of the last preceding administration of a first active pharmaceutical ingredient (or first pharmaceutical composition).

[0176] The phrases "intended to be administered in combination" or "for use in combination" refer to the simultaneous, sequential or separate administration of active pharmaceutical ingredients or pharmaceutical compositions.

[0177] The term "route of administration" as used herein refers to the route by which a pharmaceutically active ingredient (e.g., in the form of a pharmaceutical composition in a particular dosage form) enters the body. The pharmaceutically active ingredient may be administered enterally (particularly orally) or parenterally (including intravenous, subcutaneous, nasal, or topical application, particularly intravenous application). Examples of dosage forms that may be used to administer the pharmaceutically active ingredient include tablets, capsules, pills, granules, powders, solutions, suspensions, emulsions, injectable aqueous or oily solutions or suspensions, suppositories, creams, gels, ear or eye drops, nasal sprays, skin patches, and aerosols. Oral dosage forms such as tablets, capsules, pills, solutions, or suspensions are preferred. When the two pharmaceutically active ingredients are contained in separate pharmaceutical compositions, the separate pharmaceutical compositions may be administered by the same or different routes of administration using the same or different dosage forms (particularly, orally, especially in the form of tablets or capsules, for the "compound," and intravenously, especially in the form of a solution, for the anti-CD3 monoclonal antibody).

[0178] The manufacture of pharmaceutical compositions can be carried out in a manner well known to any person skilled in the art (see, for example, Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins]) by combining the "compound" or a pharmaceutically acceptable salt thereof and / or a second active pharmaceutical ingredient, optionally with other therapeutically valuable substances, with suitable non-toxic, inert, therapeutically acceptable solid or liquid carrier materials and, if necessary, conventional pharmaceutical adjuvants, to form a pharmaceutical dosage form.

[0179] The term "unit dose" as used herein means the amount of a pharmaceutical active ingredient administered and / or intended to be administered to a patient in a single dose. For example, if a single tablet or capsule is administered and / or intended to be administered to a patient per administration, the unit dose is the amount of pharmaceutical active ingredient in a tablet or capsule for oral administration.

[0180] As used herein, the term "target dose" means the final (highest) daily dose of an escalation regimen.

[0181] The term "cumulative dose" as used herein (particularly in relation to anti-CD3 monoclonal antibodies) refers to the total dose administered and / or intended to be administered to a patient during one treatment period, i.e., the sum of the doses administered on days 1, 2, and 3 of said treatment, through the last day of treatment in each treatment period. For example, if the treatment period for each anti-CD3 monoclonal antibody is 10 days, the cumulative dose is the sum of the doses administered during those 10 days of treatment.

[0182] The term "treatment period" as used herein (particularly in relation to anti-CD3 monoclonal antibodies) means the period from the first day of treatment with the active pharmaceutical ingredient, pharmaceutical composition and / or medicament to the last day of uninterrupted treatment; treatment is "continuous" if it follows a regular repeated administration scheme, e.g., twice daily, once daily, or every other day. For example, if an anti-CD3 monoclonal antibody is administered and / or is intended to be administered once daily for a 14-day treatment period, this means that the anti-CD3 monoclonal antibody is administered and / or is intended to be administered once on day 1, once on day 2, once on day 3, once on day 4, once on day 5, once on day 6, once on day 7, once on day 8, once on day 9, once on day 10, once on day 11, once on day 12, once on day 13, and once on day 14 of treatment (and without any treatment with the anti-CD3 monoclonal antibody on day 15); if treatment with the anti-CD3 monoclonal antibody is resumed any day after day 15 (e.g., 6 or 12 months after day 1), a new treatment period will begin.

[0183] The term "anti-CD3 monoclonal antibody" as used herein refers to a monoclonal antibody or antibody fragment (e.g., a Fab fragment antibody, a VHH antibody (also called nanobody), or a single-chain variable fragment (scFv) antibody) (particularly a monoclonal antibody) that binds to and / or recognizes the human CD3 (cluster of differentiation 3) surface antigen. In particular, such an anti-CD3 monoclonal antibody binds to and / or recognizes the epsilon chain of the CD3 / TCR (T cell receptor) complex. Preferably, such an anti-CD3 monoclonal antibody has only low or no binding affinity to Fc receptors (especially human Fc receptors) (especially compared to non-human anti-CD3 monoclonal antibodies such as muromonab-CD3). Fc receptor binding may be reduced in a monoclonal antibody by introducing one, two, three, or more (especially one or two) mutations into the Fc portion of the antibody.

[0184] As used herein, the term "humanized anti-CD3 monoclonal antibody" refers to an anti-CD3 monoclonal antibody in which the portions of the complementarity-determining regions that bind to and / or recognize the human CD3 (cluster of differentiation 3) surface antigen are derived from a non-human species and grafted onto a human IgG backbone.

[0185] As used herein, the term "fully human anti-CD3 monoclonal antibody" refers to an anti-CD3 monoclonal antibody composed of human immunoglobulins derived from human immunoglobulin genes. Fully human anti-CD3 monoclonal antibodies can be produced by transgenic animals expressing human immunoglobulins, bacteriophage display of human antigen-binding fragments, or human immunoglobulins. The antibodies may be produced by yeast display of immunoglobulins, or by other methods (particularly transgenic animals expressing human immunoglobulins, bacteriophage display of human antigen-binding fragments, or yeast display of human immunoglobulins).

[0186] As used herein, the term "patient" refers to a mammalian patient, and in particular a human patient.

[0187] When not used in reference to temperature, the term "about" (or "in the vicinity of") before a numerical value "X" in this application means between 10% of XX and 10% of X + X, preferably between 5% of XX and 5% of X + X. Particularly preferred is between 1% of XX and 1% of X + X. In the specific case of temperature, the term "about" (or "in the vicinity of") before a temperature "Y" in this application means between Y - 10°C and Y + 10°C, preferably between Y - 5°C and Y + 5°C. As used herein, the term "room temperature" means a temperature of about 25°C.

[0188] Whenever the word "between" (or "to") is used to describe a numerical range, the endpoints of the stated range are expressly included in that range. For example: if a temperature range is stated to be between 40°C and 80°C (or stated to be from 40°C to 80°C), it is meant that the endpoints 40°C and 80°C are included in the range; or, if a variable is defined as an integer between 1 and 4 (or from 1 to 4), it is meant that the variable is the integer 1, 2, 3, or 4.

[0189] The present invention also provides isotopically labeled, especially 2 The present invention also includes an isotopically labeled active pharmaceutical ingredient, which is identical to the active pharmaceutical ingredient defined in any one of embodiments 1) to 79) except that one or more atoms have been replaced by atoms having the same atomic number but an atomic mass different from that normally found in nature. 2 H (deuterium) labeled active pharmaceutical ingredients and pharmaceutically acceptable salts thereof are included within the scope of the present invention. 2 Substitution with H (deuterium) increases metabolic stability, resulting in, for example, a longer in vivo half-life, a reduced required dose, or reduced inhibition of cytochrome P450 enzymes, thereby improving, for example, the safety profile. In one embodiment, only one of the two active pharmaceutical ingredients of the pharmaceutical combination is isotopically labeled. In a preferred embodiment of the present invention, the active pharmaceutical ingredients are not isotopically labeled, or one active pharmaceutical ingredient is not isotopically labeled and the other active pharmaceutical ingredient is labeled only with one or more deuterium atoms, or both active pharmaceutical ingredients are labeled only with one or more deuterium atoms. In the most preferred embodiment, none of the active pharmaceutical ingredients are isotopically labeled. Isotopically labeled active pharmaceutical ingredients may be prepared in a manner similar to that described for non-isotopically labeled active pharmaceutical ingredients, except for using appropriate isotopic species of appropriate reagents or starting materials.

[0190] Experimental section Abbreviation The following abbreviations are used throughout the specification and examples: Area under the AUC curve BAL (bronchoalveolar lavage) BGV Blood glucose value BSA body surface area Fig. h time ip intraperitoneal iv intravenous LCMV-GP Lymphocytic choriomeningitis virus glycoprotein LPS lipopolysaccharide mAb Monoclonal antibody min MMTT Mixed meal tolerance test NOD Non-Obese Diabetes n number of animals ns non-significant OGTT Oral glucose tolerance test qd (quaque die): also known as qd; once a day RIP rat insulin promoter SEM Standard error of the mean T1D type I diabetes

[0191] The Compound may be prepared according to the procedures disclosed in WO2016 / 113344.

[0192] Examples of therapeutic uses of the Compounds as monotherapy or in combination with anti-CD3 monoclonal antibodies The therapeutic effect can be modeled in multiple animal models representing diseases and disorders (particularly T1D disease) in which both CXCR3 expression or its ligands play a pathogenic role and treatment with anti-CD3 antibodies has been shown to have some therapeutic effect.

[0193] 1) Dose-finding experiments The efficacy of a compound in inhibiting the migration of CXCR3-expressing CD8+ T cells to sites of inflammation can be determined in pilot experiments to assess the dose-effect relationship of the compound on pulmonary inflammatory T cell infiltration into bronchoalveolar lavage (BAL) in a mouse model of lipopolysaccharide (LPS)-induced pneumonia.

[0194] Male DBA / 1 mice are exposed to nebulized LPS for 30 minutes (day 0).

[0195] Starting 3 days before LPS challenge and continuing throughout the experiment, groups of 11 to 22 mice are fed food admixed with different concentrations of the compound. The study consists of seven treatment groups: 1. Control mixed diet (no compound), n=22 2. Mixed diet containing 0.006 mg of the compound per gram of diet, n=12 3. Mixed diet containing 0.02 mg of the compound per gram of diet, n=12 4. Mixed diet containing 0.06 / 0.07 mg of the compound per gram of diet, n=24 5. Mixed diet containing 0.2 mg of the compound per gram of diet, n=12 6. Mixed diet containing 0.6 mg of the compound per gram of diet, n=11 7. Mixed diet containing 2 mg of the compound per gram of diet, n=11 The experiment is terminated on day 3, 72 hours after LPS stimulation. BAL is collected and the number of CXCR3-expressing T cells is quantified by flow cytometry as described in Pouzol et al., Front Pharmacol 2021, 12(2991), doi:10.3389 / fphar.2021.748740. Plasma samples are collected for measurement of compound concentrations.

[0196] The results of the efficacy study are shown in Figure 1. The prophylactically administered Compounds inhibited BAL CXCR 3 + CD8 +It showed dose-dependent efficacy as indicated by a dose-dependent reduction in T cells, and efficacy was associated with a dose-dependent increase in plasma concentrations of the Compound.

[0197] Based on the above pilot experiments, CXCR3 + CD8 + The one dose of Compound that significantly and maximally reduces T cell migration is selected for combination effect experiments (dose: 0.6 mg Compound / g bait).

[0198] 2) Combination effect experiments in T1D animal models The efficacy of the Compounds and anti-CD3 monoclonal antibodies, alone or in combination, or the combination of anti-CD3 and anti-CXCL10 monoclonal antibodies, can be determined in mouse models of induced and spontaneous T1D. Anti-CD3 (monoclonal Armenian hamster anti-mouse CD3ε antibody 145-2C11 F(ab')2 fragment, pepsin digest, BioXCell, ref. BE0001-1FAB 4294 / 0212) and anti-CXCL10 (monoclonal Armenian hamster anti-mouse CXCL10 monoclonal antibody (clone 1F11) (Khan et al., Immunity 2000, 12:483-494) and the doses selected for the combination efficacy experiments described below have shown efficacy in a similar T1D animal model (Lasch S et al., Diabetes 2015, 64:4198-4211). An isotype control Armenian hamster F(ab')2 fragment of anti-CD3 antibody used as a control in the experiments described below was obtained from BioXCell (ref. BE0091-FAB).

[0199] a) Inducible T1D model The first mouse model was an inducible T1D model, called the RIP-LCMV-GP model, in which transgenic C57BL / 6 mice express lymphocytic choriomeningitis virus glycoprotein (LCMV-GP) under the control of the rat insulin promoter (RIP) in β-cells (Oldstone MBA et al., Cell 1991, 65:319-331). RIP-LCMV-GP transgenic mice were injected intraperitoneally (ip) with LCMV Armstrong clone 53b, as previously described (Lasch S et al., Diabetes 2015, 64:4198-4211).

[0200] Blood glucose concentrations can be measured using a dynaValeo blood glucose meter from dynamiCARE. RIP-LCMV-GP mice with blood glucose values ​​(BGV) of 300 mg / dL or higher are considered diabetic (Christen U et al., J Immunol 2001, 166:7023-7032).

[0201] Groups of 11 to 14 mice will be treated when they begin to develop diabetes between days 10 and 14 after infection. The study will consist of four treatment groups: Group 1: Isotype control iv from day 10 to day 12, control diet (isotype / vehicle) from day qd+1 to day 84 Group 2: Anti-CD3 antibody (3 μg) iv from day 10 to day 12, control diet (anti-CD3 / vehicle) qd+1 to day 84 Group 3: anti-CD3 antibody (3 μg) iv from days 10 to 12, anti-CXCL10 antibody (100 μg) ip from days +13 to 28 (on days 13, 15, 17, 19, 21, 24, 26, and 28); control diet (anti-CD3 / anti-CXCL10) from days 1 to 84 Group 4: anti-CD3 antibody (3 μg) iv from days 10 to 12, qd + chow mixed with "compound" (0.6 mg / g chow) from days 13 to 84; control chow (anti-CD3 / "compound") from days 1 to 12

[0202] BGV was monitored weekly throughout the 12-week study period and compared between isotype / vehicle mice (Group 1) and mice treated with anti-CD3 antibody monotherapy (Group 2) or different combinations of anti-CD3 antibody and anti-CXCL10 antibody or "compound" (Groups 3 and 4). The study was terminated 84 days after LCMV infection. Results of the combination efficacy study are shown in Figure 2. Overall, both combination treatments were significantly superior to anti-CD3 antibody monotherapy in lowering blood glucose, with mean BGVs below the diabetic threshold of 300 mg / dL at the end of the study period (297 mg / dL for the anti-CD3 / anti-CXCL10 group and 234 mg / dL for the anti-CD3 / "compound" group) (Figure 2).

[0203] b) Spontaneous T1D model The efficacy of the compound and anti-CD3 monoclonal antibody, alone or in combination, can be examined in non-obese diabetic (NOD) mice, a spontaneous model for studying T1D (Chen et al., Front Endocrinol 2018, 9:51).

[0204] Blood glucose concentrations can be measured using dynamiCARE's dynaValeo blood glucose meter.

[0205] NOD mice typically develop diabetes, defined as a blood glucose level (BGV) of ≥ 300 mg / dL, between 13 and 30 weeks of age.

[0206] For groups of 14-17 mice, treatment begins on the first measurement of diabetes (BGV ≥ 300 mg / dL) for each mouse in a treatment setting (day 1). Mice are randomized into five treatment groups based on BGV and age at the start of treatment: Group 1: injected iv with isotype from day 1 to day 3, control diet (isotype / vehicle) from day qd+1 until the end of the study Group 2: injected iv with isotype from day 1 to day 3, and chow containing "compound" (0.6 mg / 1 g chow) from day qd+1 until the end of the study (isotype / "compound"). Group 3: anti-CD3 antibody (30 μg) iv from days 1 to 3, control diet (anti-CD3 / vehicle) from day +1 to the end of the study Group 4: Anti-CD3 antibody (30 μg), iv, qd, from days 1 to 3 + Anti-CXCL10 antibody (100 μg), ip (administered every 2 / 3 days, total 8 doses) from days 4 to 19 + Control diet (anti-CD3 / anti-CXCL10) from day 1 to the end of the study Group 5: Anti-CD3 antibody (30 μg) iv from days 1 to 3, qd+1 to the end of the study, followed by chow containing "compound" (0.6 mg / 1 g chow) (anti-CD3 / "compound").

[0207] BGV will be assessed weekly and compared between mice treated with isotype / control diet (Group 1) and mice receiving different treatments. The experiment will be terminated for each mouse once it reaches 40 weeks of age.

[0208] This experiment is suitable to demonstrate whether the addition of the Compound has an additive effect on anti-CD3 antibody monotherapy, and whether the combination of the Compound with anti-CD3 antibody is superior to the combination of anti-CD3 antibody followed by anti-CXCL10 antibody.

[0209] The results of the combination efficacy experiment are shown in Figure 3 and Table 1. Therapeutic administration of Compound and anti-CD3 antibody as monotherapy showed minimal and moderate efficacy against BGV, respectively (Figure 3 and Table 1). When administered in combination, the two treatments showed a synergistic effect against BGV (Figure 3 and Table 1). Additionally, in contrast to each monotherapy, only the combination of anti-CD3 antibody and Compound significantly inhibited and reversed disease progression over the study period (mean 1.5 mg / kg bw). BGV was defined as BGV < the mean BGV at the start of treatment (100%) (Figure 4). The combination of anti-CD3 antibody and anti-CXCL10 antibody was significantly less effective than the combination of anti-CD3 antibody and "compound" (Figure 3 and Table 1).

[0210] Table 1: Effect of treatment on BGV in NOD mice at 40 weeks of age. Table 1 shows the therapeutic effects of compound monotherapy, anti-CD3 antibody monotherapy, their combination, and the combination of anti-CD3 antibody and anti-CXCL10 antibody on BGV in NOD mice. Data are expressed as mean + SEM. n = 14-17 per group.

[0211] [Table 1]

[0212] The results of a sub-analysis of this study are shown in Figure 5 and Table 2. In this sub-analysis, only mice that did not have severe hyperglycemia at the start of treatment (defined as 300 mg / dL ≤ BGV ≤ 400 mg / dL) were included. Therapeutic administration of Compound and anti-CD3 antibody as monotherapy demonstrated minimal and moderate efficacy on BGV, respectively (Figure 5 and Table 2). When administered in combination, the two treatments demonstrated a synergistic effect on BGV (Figure 5 and Table 2). Importantly, T1D was reversed in 100% of NOD mice treated with the combination of anti-CD3 antibody and Compound, in contrast to the individual monotherapies, in which 86% and 45% of mice treated with Compound or anti-CD3 monotherapy, respectively, showed disease progression at the end of the study period (Figure 6). The combination of anti-CD3 antibody and anti-CXCL10 antibody was significantly less effective than the combination of anti-CD3 antibody and "compound" (Figures 5 and 6).

[0213] Table 2: Effect of treatment on BGV in non-severely diabetic NOD mice at 40 weeks of age. Table 2 shows the therapeutic effects of "compound" monotherapy, anti-CD3 antibody monotherapy, their combination, and the combination of anti-CD3 antibody and anti-CXCL10 antibody on BGV in non-severely diabetic NOD mice. Only mice showing non-severe hyperglycemia (defined as 300 mg / dL ≤ BGV ≤ 400 mg / dL) were included in this sub-study analysis. Data are expressed as mean + SEM. n = 7-11 per group.

[0214] [Table 2]

[0215] 3) Combined effect experiment in vitiligo animal model The efficacy of the "compound" and the anti-CD3 monoclonal antibody, alone or in combination, was It can be determined in a mouse model of vitiligo based on transient inoculation of melanoma cells and depletion of CD4+ regulatory T cells (Chen et al., Cell Regeneration 2022, 11, 31). Anti-CD3 (monoclonal Armenian hamster anti-mouse CD3ε antibody 145-2C11 F(ab')2 fragment, pepsin digestion, BioXCell, ref. BE0001-1FAB 4294 / 0212) and "Compound" and their doses selected for the combination efficacy experiments described below have shown efficacy in a T1D animal model (Christen et al., Clinical & Experimental Immunology 2023, doi:10.1093 / cei / uxad083). The Armenian hamster F(ab')2 fragment of anti-CD3 antibody isotype control used as a control in the experiments described below was obtained from BioXCell (reference number BE0091-FAB).

[0216] 2 x 10 female C57BL / 6 mice 5Mice were injected intradermally with 100 μg of B16F10 cells (day 0). On days 4 and 10, mice were injected intraperitoneally with 200 μg of anti-CD4 (Clone GK1.5, BioX Cell, Cat. BE003-1). Tumors were removed on days 11-12, and mice were injected intraperitoneally with 250 μg of anti-PDL1 antibody (Clone 10F.9G2, BioX Cell, Cat. BE0101) on days 12, 14, and 17.

[0217] Mice show signs of depigmentation, and the degree of hair depigmentation is rated on a scale of 0 to 6, where 0 = no signs, 1 = presence of white hair, 2 = at least one white patch >0.5 cm, 3 = at least one white patch >2 cm, 4 = at least one white patch >3 cm, 5 = at least one white patch >3 cm + scattered white hair, and 6 = at least one white patch >3 cm + most (>30%) of the body is white. At the cellular level, immune cell infiltration, including CD8+ T cells, and melanocyte loss are monitored by flow cytometry and histology.

[0218] Treatment in a therapeutic setting in groups of 10-15 mice begins on day 19. Mice are randomized into five treatment groups based on their hypopigmentation status and body weight at the start of treatment: Group 1: Healthy mice Group 2: injected iv with isotype from day 19 to day 21, qd + control diet (isotype / vehicle) from day 19 to the end of the study Group 3: injected iv with isotype from day 19 to day 21, qd + chow containing "compound" (0.6 mg / 1 g chow) from day 19 until the end of the study (isotype / "compound"). Group 4: anti-CD3 antibody (3 μg) iv, qd from day 19 to day 21 + control diet (anti-CD3 / vehicle) from day 19 to the end of the study Group 5: Anti-CD3 antibody (3 μg) from day 19 to day 21, iv, qd + chow containing "compound" (0.6 mg / 1 g chow) from day 19 to the end of the study (anti-CD3 / "compound").

Claims

1. A pharmaceutical combination comprising a first active pharmaceutical ingredient which is 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone or a pharmaceutically acceptable salt thereof, and a second active pharmaceutical ingredient which is an anti-CD3 monoclonal antibody.

2. 2. The pharmaceutical combination according to claim 1, wherein the first active pharmaceutical ingredient is 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone.

3. 3. The pharmaceutical combination according to claim 1, wherein the second active pharmaceutical ingredient is a humanized or fully human anti-CD3 monoclonal antibody.

4. 3. The pharmaceutical combination according to claim 1, wherein the second active pharmaceutical ingredient is teplizumab.

5. 5. The pharmaceutical combination according to any one of claims 1 to 4, comprising 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone or a pharmaceutically acceptable salt thereof in a pharmaceutical dosage form for oral or intravenous administration of 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone or a pharmaceutically acceptable salt thereof.

6. 6. The pharmaceutical combination according to claim 5, having 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone in a unit dose of between 4.0 mg and 100 mg of the pharmaceutical dosage form.

7. 7. The pharmaceutical combination according to claim 1, wherein the anti-CD3 monoclonal antibody is in a pharmaceutical dosage form for intravenous administration of the anti-CD3 monoclonal antibody.

8. The anti-CD3 monoclonal antibody was administered at a concentration of 50 μg / m ２ BSA to 1000 μg / m ２ 8. The pharmaceutical combination according to claim 7, having a pharmaceutical dosage form of unit doses ranging from 0.1 to 0.5 mg / kg BSA.

9. 9. The pharmaceutical combination according to any one of claims 1 to 8, wherein the first and second pharmaceutically active ingredients are contained in separate pharmaceutical compositions.

10. The pharmaceutical combination according to any one of claims 1 to 9 for use as a medicine.

11. 10. The pharmaceutical combination according to any one of claims 1 to 9 for use in the prevention and / or treatment of a disease or disorder selected from type 1 diabetes, multiple sclerosis, organ transplant rejection, thyroid eye disease, rheumatoid arthritis, ulcerative colitis, Crohn's disease, celiac disease, atherosclerosis, psoriasis, pneumonia and psoriatic arthritis.

12. 10. The pharmaceutical combination according to any one of claims 1 to 9 for use in the prevention and / or treatment of type 1 diabetes.

13. 13. The pharmaceutical combination for use according to any one of claims 10 to 12, wherein 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone or a pharmaceutically acceptable salt thereof is intended to be and / or is administered to a patient once or twice daily.

14. 14. The pharmaceutical combination for use according to any one of claims 10 to 13, wherein said anti-CD3 monoclonal antibody is intended to be and / or has been administered to a patient for a treatment period of 2 to 30 days.

15. 15. The pharmaceutical combination for use according to any one of claims 10 to 14, wherein the cumulative dose of the anti-CD3 monoclonal antibody intended to be and / or administered to a patient is between 5.0 mg and 40 mg.

16. 16. The pharmaceutical combination for use according to any one of claims 10 to 15, wherein the disease is type 1 diabetes and in at least 75% of said patients, the progression from stage 2 type 1 diabetes to stage 3 type 1 diabetes is delayed by at least 24 months compared to untreated patients.

17. 1. A pharmaceutical composition comprising 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone or a pharmaceutically acceptable salt thereof as an active ingredient, and further comprising at least one pharmaceutically inactive excipient, wherein said pharmaceutical composition is intended to be and / or is administered in combination with a second pharmaceutical composition comprising an anti-CD3 monoclonal antibody as an active ingredient, and further comprising at least one pharmaceutically inactive excipient.

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