Methods for Treating Post-Infectious Autoimmune Diabetes Mellitus - Patent application

Abstract

Provided herein are methods for treating type 1 diabetes (T1D) following SARS-CoV-2 infection. In some embodiments, such methods include administering about 9000 μg / m 2 The method may include administering a 12 day course of teplizumab at a total dose of greater than 100 mg / kg.

Description

[Technical field]

[0001] [CROSS REFERENCE TO RELATED APPLICATIONS] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 192,414, filed May 24, 2021, and U.S. Utility Application No. 17 / 752,650, filed May 24, 2022, the disclosures of each of which are incorporated by reference in their entirety herein.

[0002] [Sequence table] This application contains a sequence listing submitted herewith, including a file entitled 178833-011201_ST25.txt, created on May 23, 2022, with a size of 6,078 bytes, the contents of which are incorporated herein by reference.

[0003] [Field] The present disclosure relates generally to methods and dosage regimens for treating post-infectious autoimmune diabetes in a subject in need thereof. [Background technology]

[0004] Type 1 diabetes (T1D) is caused by autoimmune destruction of insulin-producing beta cells in the islets of Langerhans, leading to a dependency on exogenous insulin injections for survival. Approximately 1.6 million Americans have type 1 diabetes, and type 1 diabetes remains one of the most common childhood diseases after asthma. Despite improvements in care, individuals most affected by T1D are unable to consistently achieve the desired target glycemia. There are persistent concerns regarding the increased risk of both morbidity and mortality for individuals with type 1 diabetes. Two recent studies found a 17.7-year reduction in life expectancy for children diagnosed before age 10, and 11 and 13 years of life expectancy reduction for Scottish men and women diagnosed as adults, respectively. Thus, there is a need for improved methods and compositions for treating T1D, including those associated with viral infections. Summary of the Invention

[0005] Some embodiments provide a method of treating type 1 diabetes (T1D) comprising administering to a subject in need thereof about 9000 μg / m 2 In some embodiments, the method includes administering to a subject in need thereof a 12 day course of teplizumab at a total dose of greater than about 9000 μg / m 2 The present invention relates to teplizumab for use in a method comprising administering a 12 day course of teplizumab at a total dose of greater than about 9000 to about 9500 μg / m2, wherein the subject in need thereof is post-viral infection. In some embodiments, the total dose is from about 9000 to about 9500 μg / m2. 2 In some embodiments, the total dose is between about 9000 and about 14000 μg / m 2 It is between.

[0006] Some embodiments include a method of treating type 1 diabetes (T1D) following a viral infection, comprising administering to a subject in need thereof about 9000 μg / m 2 to about 9500 μg / m 2 Some embodiments relate to a method of treating type 1 diabetes (T1D) following a viral infection, comprising administering to a subject in need thereof a 12 day course of teplizumab at a total dose of up to about 9000 μg / m 2 to about 14,000 μg / m 2 The method includes administering a 12 day course of teplizumab for a total dose of up to 12 days.

[0007] In some embodiments, the subject in need thereof is positive for type 1 diabetes-associated autoantibodies. In some embodiments, the subject in need thereof is post-Severe Acute Respiratory Syndrome (SARS)-associated coronavirus (SARS-CoV-2).

[0008] In some embodiments, a subject in need thereof is negative for SARS-CoV-2 infection and positive for type 1 diabetes associated autoantibodies.

[0009] In some embodiments, the subject in need thereof has been diagnosed with T1D within 6-12 weeks prior to the administering step.

[0010] In some embodiments, the total dose for a 12 day course is about 9000 to about 9500 μg / m 2 It is between.

[0011] In some embodiments, a 12 day course includes 106 μg / m 2 1 dose of teplizumab on day 2, 425 μg / m 2 and a second dose of teplizumab at 850 μg / m on each of days 3 to 12. 2 for a total dose of approximately 9031 μg / m 2 It is.

[0012] In some embodiments, a 12 day course includes 211 μg / m 2 The first dose of teplizumab was 423 μg / m on day 2. 2 and a second dose of teplizumab at 840 μg / m on each of days 3 to 12. 2 for a total dose of approximately 9034 μg / m 2 It is.

[0013] In some embodiments, the method can include administering a first and a second 12 day course of teplizumab, hi some embodiments, the first and second 12 day courses are administered about 1-6 months, about 2-5 months, or about 3 months apart.

[0014] In some embodiments, the method comprises administering to a subject in need thereof each course of about 9000 μg / m 2 The method may include administering a third or more 12 day courses of teplizumab at a total dose of greater than or equal to 12 days.

[0015] In some embodiments, a third or more 12-day course of teplizumab includes 106 μg / m 21 dose of teplizumab on day 2, 425 μg / m 2 and a second dose of teplizumab at 850 μg / m on each of days 3 to 12. 2 Each course contains one dose of 9031 μg / m 2 It is.

[0016] In some embodiments, a third or more 12-day course of teplizumab includes 211 μg / m 2 The first dose of teplizumab was 423 μg / m on day 2. 2 and a second dose of teplizumab at 840 μg / m on each of days 3 to 12. 2 Each course contains one dose of 9034 μg / m 2 It is.

[0017] In some embodiments, the third or more 12-day courses of teplizumab are administered about 12 months to about 24 months apart.

[0018] In some embodiments, the method can further include determining a baseline level of TIGIT+KLRG1+CD8+ cells relative to total CD3+ T cells after administration of each 12-day course, monitoring the level of TIGIT+KLRG1+CD8+CD3+ T cells, and administering an additional 12-day course of teplizumab if the level of TIGIT+KLRG1+CD8+CD3+ T cells returns to baseline levels.

[0019] In some embodiments, the step of determining TIGIT+KLRG1+CD8+CD3+ T cells is by flow cytometry.

[0020] In some embodiments, the step of monitoring TIGIT+KLRG1+CD8+CD3+ T cells is by flow cytometry.

[0021] In some embodiments, the step of determining TIGIT+KLRG1+CD8+CD3+ T cells is about 1-6 months, about 2-5 months, or about 3 months after administration of each 12-day course.

[0022] In some embodiments, if the subject has greater than about 10% TIGIT+KLRG1+CD8+ T cells among total CD3+ T cells, then the monitoring step is once a year.

[0023] In some embodiments, if the subject has less than about 10% TIGIT+KLRG1+CD8+ T cells among total CDCD8+ T cells, then the monitoring step is about every 3-6 months.

[0024] In some embodiments, the administering step results in at least a 10% decrease in insulin use, HbA1c levels, low blood glucose episodes, or a combination thereof, compared to pre-treatment levels.

[0025] In some embodiments, each dose is administered parenterally.

[0026] In some embodiments, each dose is administered by intravenous infusion.

[0027] In some embodiments, a subject in need thereof has a peak C-peptide level of 0.2 pmol / mL or greater during a mixed meal tolerance test (MMTT).

[0028] In some embodiments, subjects receiving teplizumab have higher mean C-peptide values ​​compared to controls receiving a placebo.

[0029] In some embodiments, the method may further comprise assessing the area under the curve (AUC) of C-peptide after a mixed meal tolerance test (MMTT) at 78 weeks.

[0030] In some embodiments, the subject in need thereof has at least 20% beta cell function prior to administration of the first dose.

[0031] In some embodiments, the reduction in insulin use, HbA1c levels, low blood glucose episodes, or a combination thereof, is over a period of 12 months or greater. [Brief description of the drawings]

[0032] [Figure 1] FIG. 1 shows simulated concentrations for three dosing regimens: population predictions for a typical male patient with WT=60 kg, age=18 years, BSA=1.67 m2 and no detectable ADA. [Diagram 2] FIG. 13 shows a comparison of concentrations for dosing regimens 1 and 2: model-based simulation for a typical male patient with WT=60 kg, age=18 years, BSA=1.67 m2 and no detectable ADA. [Diagram 3] FIG. 13 shows a comparison of concentrations for Herold dosing regimen and dosing regimen 1: model-based simulation for a typical male patient with WT=60 kg, age=18 years, BSA=1.67 m2 and no detectable ADA. [Figure 4] FIG. 13 shows a comparison of concentrations on the last dosing day for Herold dosing regimen and dosing regimen 1: model-based simulation for a typical male patient with WT=60 kg, age=18 years, BSA=1.67 m2 and no detectable ADA. [Diagram 5] FIG. 13 shows simulated concentrations for three dosing regimens: population predictions for a typical male patient with WT=60 kg, age=18 years, BSA=1.67 m2 and detected high levels of ADA. [Figure 6] FIG. 13 shows a comparison of concentrations for dosing regimens 1 and 2: A model-based simulation for a typical male patient with WT=60 kg, age=18 years, BSA=1.67 m2 and high levels of ADA detected. [Figure 7] FIG. 13 shows a comparison of concentrations for Herold dosing regimen and dosing regimen 1: model-based simulation for a typical male patient with WT=60 kg, age=18 years, BSA=1.67 m2 and high levels of ADA detected. [Figure 8] FIG. 13 shows a comparison of concentrations on the last dosing day for Herold dosing regimen and dosing regimen 1: A model-based simulation for a typical male patient with WT=60 kg, age=18 years, BSA=1.67 m2 and high levels of ADA detected. [Figure 9] FIG. 13 shows simulated concentrations for three dosing regimens: population predictions for a typical male patient with WT=45 kg, age=13 years, BSA=1.33 m2 and no detectable ADA. [Figure 10] FIG. 13 shows a comparison of concentrations for dosing regimens 1 and 2: model-based simulation for a typical male patient with WT=45 kg, age=13 years, BSA=1.33 m2 and no detectable ADA. [Figure 11] FIG. 13 shows a comparison of concentrations for Herold dosing regimen and dosing regimen 1: model-based simulation for a typical male patient with WT=45 kg, age=13 years, BSA=1.33 m2 and no detectable ADA. [Figure 12] FIG. 13 shows a comparison of concentrations on the last dosing day for Herold dosing regimen and dosing regimen 1: model-based simulation for a typical male patient with WT=45 kg, age=13 years, BSA=1.33 m2 and no detectable ADA. [Figure 13] FIG. 1 shows simulated concentrations for three dosing regimens: population predictions for a typical male patient with WT=45 kg, age=13 years, BSA=1.33 m2 and detected high levels of ADA. [Figure 14]FIG. 13 shows a comparison of concentrations for dosing regimens 1 and 2: A model-based simulation for a typical male patient with WT=45 kg, age=13 years, BSA=1.33 m2 and high levels of ADA detected. [Figure 15] FIG. 13 shows a comparison of concentrations for Herold Dosing Regimen and Dosing Regimen 1: Model-based simulation for a typical male patient with WT=45 kg, Age=13 years, BSA=1.33 m2 and high levels of ADA detected. [Figure 16] FIG. 13 shows a comparison of concentrations on the last dosing day for Herold dosing regimen and dosing regimen 1: A model-based simulation for a typical male patient with WT=45 kg, age=13 years, BSA=1.33 m2 and high levels of ADA detected. [Figure 17] FIG. 13 shows a comparison of concentrations for Herold Regimen and Dosing Regimen 2: Model-based simulation (42 days) for a male patient with WT=60 kg, age=18 years, BSA=1.67 m2 and no detectable ADA. [Figure 18] FIG. 13 shows a comparison of median concentrations for Herold Regimen and Dosing Regimen 2: Model-based simulation (35 days) for a male patient with WT=60 kg, age=18 years, BSA=1.67 m2 and no detectable ADA. [Figure 19] FIG. 13 shows a comparison of concentrations for Herold Regimen and Dosing Regimen 2: Model-based simulation (42 days) for a male patient with WT=60 kg, age=18 years, BSA=1.67 m2, and high levels of ADA detected. [Figure 20] FIG. 13 shows a comparison of median concentrations for Herold Regimen and Dosing Regimen 2: Model-based simulation (35 days) for a male patient with WT=60 kg, age=18 years, BSA=1.67 m2, and high levels of ADA detected. [Figure 21]FIG. 13 shows a comparison of concentrations for Herold Regimen and Dosing Regimen 2: Model-based simulation (42 days) for a male patient with WT=45 kg, age=13 years, BSA=1.33 m2 and no detectable ADA. [Figure 22] FIG. 13 shows a comparison of median concentrations for Herold Regimen and Dosing Regimen 2: Model-based simulation (35 days) for a male patient with WT=45 kg, age=13 years, BSA=1.33 m2 and no detectable ADA. [Diagram 23] FIG. 13 shows a comparison of concentrations for Herold Regimen and Dosing Regimen 2: Model-based simulation (42 days) for a male patient with WT=45 kg, age=13 years, BSA=1.33 m2, and high levels of ADA detected. [Figure 24] FIG. 13 shows a comparison of median concentrations for Herold Regimen and Dosing Regimen 2: Model-based simulation (35 days) for a male patient with WT=45 kg, age=13 years, BSA=1.33 m2, and high levels of ADA detected. [Diagram 25] FIG. 25 is a diagram illustrating a study design according to one embodiment. [Figure 26] FIG. 1 shows the predicted mean difference between teplizumab and control in change from baseline in C-peptide AUC (nmol / L) at 1-year follow-up in a meta-analysis of supportive trials. [Figure 27] FIG. 1 shows the predicted mean difference between teplizumab and control in change from baseline in C-peptide AUC (nmol / L) at 2-year follow-up in a meta-analysis of supportive trials. [Figure 28] FIG. 1 shows C-peptide AUC (nmol / L) in patients with TN-10:T1D. [Figure 29] FIG. 1 shows the average insulin use at each visit. [Diagram 30] FIG. 1 shows predicted mean teplizumab serum concentration versus time profiles following a 14-day regimen across different body weights. [Diagram 31] Plot of Emax model: expected C-peptide change vs. AUC, 2 years. The Protege trial was conducted in newly diagnosed (stage 3) T1D patients and with three teplizumab dosing regimens studied (full 14 days [approximately 9,030 mg / m2 cumulative dose], one-third [1 / 3] of the 14-day regimen, and shortened to 6 days [first 6 days of the full 14-day regimen]). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] <Type 1 diabetes> Type 1 diabetes usually occurs during childhood and adolescence, but can be present, albeit very infrequently, in adulthood around the fifth or sixth decade of life (Atkinson 2014, Bluestone 2010, Streisand 2014). In addition to being more susceptible to some short-term and long-term complications, there are differences in the clinical course and response to immunotherapy between children / young adults and older adults. In the days or weeks before initial diagnosis, children and adolescents often suffer from severe diabetic symptoms, including polydipsia, polyuria, and weight loss, which lead to the clinical picture of DKA and shock requiring hospitalization (Atkinson 2014, Bluestone 2010, Streisand 2014, Mittermayer 2017). Children and young adults with new-onset T1D usually have an urgent need for exogenous insulin.

[0034] This is in stark contrast to the experience of adults who develop T1D, who often have nonspecific symptoms for months or years or are asymptomatic from routine blood glucose screening. These individuals can often be managed for extended periods (months or years) with diet or oral hypoglycemic agents before there is a demonstrable need for insulin. More conclusive studies have shown differential rates of beta-cell decline according to age (Greenbaum 2012; Ludvigsson 2013). After decades of research, the Diabetes TrialNet network concluded that "age is the most important factor influencing the rate of decline in C-peptide after diagnosis," in that a significantly more rapid rate of decline occurs in children and adolescents compared to young adults and older adults with newly onset disease. This more rapid decline is likely due to a much more virulent and aggressive autoimmune process in children compared to adults, ostensibly supporting the existence of important differences in T1D immunopathogenesis in younger versus older individuals (Greenbaum 2012, Campbell-Thompson 2016). Due to these fundamental differences, it is reasonable to expect that adults and children may respond differently to immune-based disease-modifying therapies: in other words, a treatment may be highly effective in children but completely ineffective in adults, or vice versa (Rigby 2014).

[0035] Children and adolescents are at highest risk of developing the disease, suffering the most from substantial short-term and long-term morbidity, and death, and therefore this group would benefit most from disease-modifying therapies (Wherrett 2015). This is now reinforced by large-scale studies showing that individuals diagnosed with T1D in childhood and adolescence have a seven-fold increased risk of death from cardiovascular disease and a four- to six-fold increased lifetime mortality risk compared to their counterparts without T1D. This mortality risk contrasts sharply with individuals diagnosed with T1D in adulthood, who have an approximately three-fold increased risk of all-cause mortality and cardiovascular disease-related mortality compared to their otherwise healthy counterparts (Rawshani 2017, Rawshani 2018). Recent reports indicate that individuals with T1D have a life expectancy approximately 11 to 13 years shorter than other healthy age-matched individuals (Lind 2014, Huo 2016). Although the goal in T1D research is to reduce morbidity and mortality for all individuals with T1D, it is clear that the most urgent need is for those who developed T1D during childhood and adolescence.

[0036] <Infection-associated type 1 diabetes> Infection (eg, viral infection) of beta cells and other pancreatic cells has been shown to be associated with T1D (eg, Coxsackie B virus, enterovirus, adenovirus, rubella, cytomegalovirus, Epstein-Barr virus).

[0037] Coronaviruses (CoVs) are within the largest known group of RNA viruses in the Coronaviridae family and the Nidovirales order. Coronaviruses are responsible for 15-30% of common colds in humans and respiratory and digestive infections in animals. In 2019, a new coronavirus was isolated, named SARS-CoV-2, which causes COVID-19.

[0038] It is believed that viral infections, such as SARS-CoV-2 infection, can induce T1D by infecting beta cells and breaking immune tolerance and / or altering the immune response in presymptomatic T1D patients. Viral infections can result in dysregulation of immune and vascular responses, including endothelial injury, hypercoagulation, and cytokine storm, which can lead to beta cell injury and / or insulin resistance. Some studies have shown that SARS-CoV-2 infection is associated with a significant downregulation of insulin expression (Michalakis et al.,World J Diabetes 2021 May 15;12(5):642-650).

[0039] Metabolic dysregulation, such as increased hyperglycemia, ketoacidosis, and new-onset T1D in the absence of autoantibodies, has been shown in patients infected with SARS-CoV-2. Although it is not yet clear how infection with SARS-CoV-2 leads to beta cell injury, it has been demonstrated that the pancreas, especially beta cells, are targets of SARS-CoV-2 infection and can cause metabolic dysregulation in patients with COVID-19 (see Muller et al., Nature Metabolism, volume 3, pages 149-165, 2021). In addition, recent studies support that ACE2 (the receptor for SARS-CoV-2) is found in the pancreas and pancreatic islets, specifically in the endothelium and ducts.

[0040] Without being bound by theory, it is hypothesized that infectious diseases such as SARS-CoV-2 may induce or cause clinical autoimmune diabetes (T1D or TlD-like) in subjects with or without pre-onset diabetes by one or more of the following: (1) potentially infecting pancreatic cells and breaking immune tolerance to beta cells in subjects with no history or pre-onset disease (pre-diabetes), (2) potentially altering the immune response of pre-onset T1D patients leading to irreversible clinical T1D in subjects with pre-existing autoimmune diabetes, and (3) inducing beta cell dysfunction / injury and / or insulin resistance with subsequent hyperglycemia as a result of cytokine storm resulting from infection-derived inflammation and / or immune modulating therapy (e.g., the steroid dexamethasone) in subjects without history or pre-onset (pre-diabetic) disease and in subjects with pre-existing autoimmune diabetes.

[0041] In addition, COVID-19 patients with type 1 diabetes have been shown to have a significantly higher risk of hospitalization, intubation, sepsis and death compared to patients without type 1 diabetes (see Barron et al, The Lancet, Vol. 8, p. 813-822, 2020).

[0042] Thus, there is a need to develop therapies for patients with newly diagnosed type 1 diabetes who have evidence of or are suspected of having a bacterial or viral infection, such as SARS-CoV-2.

[0043] Provided herein are methods to preserve beta cell function and improve clinical management of T1D in patients relative to the natural history of the disease and current standard of care, including exogenous insulin therapy. Preservation of beta cell function is expected to translate into clinical and / or metabolic benefits consistent with improved ability to maintain glycemic control and short-term and / or long-term outcomes.

[0044] [Definition] Certain terms are defined herein below: Additional definitions are provided throughout this application.

[0045] As used herein, the articles "a" and "an" refer to one or more than one, e.g., at least one, of the grammatical object of the article. The use of the word "a" or "an" when used in conjunction with the term "comprising" can mean "one" herein, but is also consistent with the meaning of "one or more," "at least one," and "one or more than one."

[0046] As used herein, "about" and "approximately" generally refer to an acceptable degree of error for the measured quantity given the nature or precision of the measurement. Exemplary degrees of error are within 20 percent (%), typically within 10%, and more typically within 5% of a given value range. The term "substantially" refers to greater than 50%, preferably greater than 80%, and most preferably greater than 90% or 95%.

[0047] As used herein, the terms "comprising" or "comprises" are used in reference to compositions, methods, and their respective component(s) present in a given embodiment, but are open to the inclusion of non-specified elements.

[0048] As used herein, the term "consisting essentially of" refers to those elements required in a given embodiment. The term permits the presence of additional elements that do not materially affect the basic and novel or functional characteristic(s) of that embodiment of the disclosure.

[0049] The term "consisting of" refers to compositions, methods, and their respective components described herein, excluding any element not recited in the description of that embodiment.

[0050] The term "antibody" is used herein in the broadest sense and encompasses a variety of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity.

[0051] "Antibody fragment" refers to a molecule other than an intact antibody that contains a portion of an intact antibody that binds to the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv); and multispecific antibodies formed from antibody fragments.

[0052] As used herein, the term "development" of a disease associated with type 1 diabetes refers to a patient meeting the criteria established by the American Diabetes Association for the diagnosis of type 1 diabetes (see Mayfield et al., 2006, Am. Fam. Physician 58:1355-1362).

[0053] As used herein, a "protocol" includes a dosing schedule and a dosing regimen. A protocol herein is a method of use and includes a treatment protocol. A "dosing regimen," "dosage regimen," or "course of treatment" can include administration of a therapeutic agent in several doses over a period of 1-20 days.

[0054] As used herein, the terms "subject" and "patient" are used interchangeably. As used herein, the terms "subject" and "subjects" refer to animals, preferably mammals, including non-primates (e.g., cows, pigs, horses, cats, dogs, rats, and mice) and primates (e.g., monkeys or humans), more preferably humans. In some embodiments, the patient population includes children. In some embodiments, the patient population includes children newly diagnosed with T1D. In some embodiments, the patient population is treated within 6 weeks of T1D diagnosis. In some embodiments, the patient population includes children who are positive for at least one T1D-associated autoantibody and have a peak stimulatory C-peptide of 0.2 pmol / mL or greater at screening.

[0055] As used herein, the term "child" (and variations thereof) includes those approximately 8 to 17 years of age.

[0056] As used herein, the term "effective amount" refers to an amount of teplizumab sufficient to result in delaying or preventing the onset, recurrence or development of one or more symptoms of T1D.

[0057] As used herein, the terms "treat", "treatment" and "treating" refer to the amelioration of one or more symptoms associated with T1D resulting from administration of one or more CD3 binding molecules. In some embodiments, such terms refer to a reduction in the average number of low blood glucose episodes in a human. In other embodiments, such terms refer to the maintenance of a reference level of C-peptide in peripheral blood.

[0058] In some embodiments, an effective amount reduces one or more symptoms of T1D by at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%.

[0059] Various aspects of the disclosure are described in further detail below. Additional definitions are set forth throughout the specification.

[0060] <Anti-CD3 antibody and pharmaceutical composition> The terms "anti-CD3 antibody" and "antibody that binds CD3" refer to an antibody or antibody fragment that can bind cluster of differentiation 3 (CD3) with sufficient affinity such that the antibody is useful as a prophylactic, diagnostic and / or therapeutic agent in targeting CD3. In some embodiments, the extent of binding of an anti-CD3 antibody to unrelated, non-CD3 proteins is less than about 10% of the binding of the antibody to CD3, e.g., as measured by radioimmunoassay (RIA). In some embodiments, the dissociation constant (Kd) of an antibody that binds CD3 is <1 μM, <100 nM, <10 nM, <1 nM, <0.1 nM, <0.01 nM, or <0.001 nM (e.g., 10 -8 M or less, e.g., 10 -8 M to 10 -13 Up to M, for example, 10 -9 M~10 -13 In some embodiments, the anti-CD3 antibody binds to an epitope of CD3 that is conserved among CD3 from different species.

[0061] In some embodiments, the anti-CD3 antibody can be ChAglyCD3 (otelixizumab). Otelixizumab is a humanized Fc-unbinding anti-CD3 that was first evaluated in a phase 2 study by the Belgian Diabetes Registry (BDR), then developed by Tolerx, which then partnered with GSK to conduct the phase 3 DEFEND new-onset T1D study (NCT00678886, NCT01123083, NCT00763451). Otelixizumab is administered IV as an infusion over 8 days. See, e.g., Wiczling et al., J. Clin. Pharmacol. 50(5) (May 2010) 494-506; Keymeulen et al., N Engl J Med. 2005; 352:2598-608; Keymeulen et al., Diabetologia. 2010; 53:614-23; Hagopian et al., Diabetes. 2013; 62:3901-8; Aronson et al., Diabetes Care. 2014; 37:2746-54; Ambery et al., Diabet Med. 2014; 31:399-402; Bolt et al., Eur. J. Immunol. 1YY3.23: 403-411; Vlasakakis et al., Br J Clin Pharmacol(2019)85 704-714;Guglielmi et al,Expert Opinion on Biological Therapy,16:6,841-846;Keymulen et al.,N Engl J Med 2005;352:2598-608;Keymulen et al.,BLOOD 2010,VOL 115,No.6;Sprangers et al. See Daifotis et al., Clinical Immunology (2013) 149, 268-278.

[0062] In some embodiments, the anti-CD3 antibody can be vicilizumab (also called HuM291; Nuvion). Vicilizumab is a humanized anti-CD3 monoclonal antibody characterized by a mutant IgG2 isotype, lack of binding to Fcγ receptors, and the ability to selectively induce apoptosis in activated T cells. Vicilizumab has been evaluated in patients with graft-versus-host disease (NCT00720629; NCT00032279) as well as ulcerative colitis (NCT00267306) and Crohn's disease (NCT00267709). See, for example, Sandborn et al., Gut 59(11) (Nov 2010) 1485-1492, which is incorporated herein by reference.

[0063] <Teplizumab> In some embodiments, the anti-CD3 antibody can be teplizumab. Teplizumab, also known as hOKT3yl(Ala-Ala) (containing alanine at positions 234 and 235), is an anti-CD3 antibody engineered to alter the function of T lymphocytes that mediate the destruction of insulin-producing beta cells of pancreatic islets. Teplizumab binds to an epitope on the CD3ε chain expressed on mature T cells, thereby altering their function. Circulating T cells (and other lymphocytes) are temporarily reduced after teplizumab treatment in a process that may include margination and exhaustion (Long 2017, Sherry 2011). In addition to reducing T cell effector function, teplizumab appears to increase both the number and function of regulatory T cells (TRegs) (Ablamunits 2010, Bisikirska 2005, Long 2017, Waldron-Lynch 2012). More recent studies indicate that teplizumab induces immunological “exhaustion” in a subset of effector CD8+ T cells, possibly rendering them more susceptible to regulation or depletion (Long 2016, Long 2017). Taken together, these mechanistic data suggest that teplizumab not only exhibits an “inhibitory” effect on the immune destruction process of β cells, but rather is an immune “modulator” that favors a rebalancing of the effector and regulatory arms involved in T1D autoimmunity, supporting the idea that teplizumab may have the capacity to contribute to the reintroduction of β cell self-tolerance (Lebastchi 2013).

[0064] The sequence and composition of teplizumab are disclosed in U.S. Patent Nos. 6,491,916; 8,663,634; and 9,056,906, each of which is incorporated herein by reference in its entirety. The molecular weight of teplizumab is approximately 150KD. The complete sequences of the light and heavy chains are listed below. The bolded parts are the complementarity determining regions. Teplizumab light chain (SEQ ID NO: 1): [ka] Teplizumab heavy chain (SEQ ID NO:2): [ka]

[0065] In some embodiments, pharmaceutical compositions are provided herein. Such compositions include an effective amount of an anti-CD3 antibody and a pharma- ceutically acceptable carrier. In some embodiments, the term "pharma- ceutically acceptable" means approved by a federal or state regulatory agency for use in animals, more particularly in humans, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias. The term "carrier" refers to a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like (see, e.g., Handbook of Pharmaceutical Excipients, Arthur H. Kibbe (ed., 2000, incorporated herein by reference in its entirety); Am. Pharmaceutical Association, Washington, DC).

[0066] If desired, the compositions may also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions may take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained release formulations, and the like. Oral formulations may contain standard carriers, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by EW Martin. Such compositions contain a therapeutically effective amount of the therapeutic agent, preferably in purified form, together with a suitable amount of carrier to provide the form for proper administration to the patient. The formulation should be compatible with the mode of administration. In some embodiments, the pharmaceutical compositions are sterile and in a form suitable for administration to subjects, preferably animal subjects, more preferably mammalian subjects, and most preferably human subjects.

[0067] In some embodiments, it may be desirable to administer the pharmaceutical composition locally to the area in need of treatment, which can be achieved, for example and without limitation, by local injection or by using an implant, which can be a membrane, such as a silastic membrane, or a porous, non-porous, or gelatinous material, including fibrous materials. Preferably, when administering an anti-CD3 antibody, care must be taken to use a material to which the anti-CD3 antibody does not absorb.

[0068] In some embodiments, the compositions can be delivered as vesicles, in particular liposomes (Langer, Science 249:1527-1533 (1990); Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally ibid.).

[0069] In some embodiments, the composition can be delivered in a controlled release or sustained release system. In some embodiments, pumps can be used to achieve controlled release or sustained release (see Langer, supra; Sefton, (1987), CRC Crit. Ref. Biomed. Eng. 14:20; Buchwald et al., 1980, Surgery 88:507; Saudek et al., 1989, N. Engl. J. Med. 321:574). In some embodiments, polymeric materials can be used to provide controlled or sustained release of the antibodies or fragments thereof of the present disclosure (see, e.g., Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, (1983), J., Macromol. Sci. Rev. Macromol. Chem. 23:61; also Levy et al., 1985, Science 228:190; During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989, Ann. Neurol. 25:351; al., 1989, J. Neurosurg. 71:105); U.S. Patent No. 5,679,377; U.S. Patent No. 5,916,597; U.S. Patent No. 5,912,015; U.S. Patent No. 5,989,463; U.S. Patent No. 5,128,326; PCT Publication No. WO 99 / 15154; and PCT Publication No. WO 99 / 20253).Examples of polymers used in sustained release formulations include, but are not limited to, poly(2-hydroxyethyl methacrylate), poly(methyl methacrylate), poly(acrylic acid), poly(ethylene-co-vinyl acetate), poly(methacrylic acid), polyglycolide (PLG), polyanhydrides, poly(N-vinyl pyrrolidone), poly(vinyl alcohol), polyacrylamide, poly(ethylene glycol), polylactic acid (PLA), poly(lactide-co-glycolide) (PLGA), and polyorthoesters. In some embodiments, the polymers used in sustained release formulations are inert, free of impurities that may leach out, stable during storage, sterile, and biodegradable. In some embodiments, controlled or sustained release systems can be placed in the vicinity of the therapeutic target, i.e., the lungs, and thus only a fraction of the systemic dose is required (see, for example, Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)).

[0070] Controlled release systems are discussed in the review by Langer (1990, Science 249:1527-1533). Any technique known to those of ordinary skill in the art can be used to prepare sustained release formulations containing one or more antibodies or fragments thereof of the present disclosure. See, e.g., U.S. Pat. No. 4,526,938; PCT Publication No. WO 91 / 05548; PCT Publication No. WO 96 / 20698; Ning et al., 1996, Radiotherapy & Oncology 39:179-189; Song et al., 1995, PDA Journal of Pharmaceutical Science & Technology 50:372-397; Cleek et al., 1997, Pro. Int'l. Symp. Control. Rel. Bioact. Mater. 24:853-854; and Lam et al., 1997, Proc. Int'l. Symp. Control Rel. Bioact. Mater. 24:759-760, each of which is incorporated by reference herein in its entirety.

[0071] A pharmaceutical composition can be formulated to suit its intended route of administration. Examples of routes of administration include, but are not limited to, parenteral administration, such as intravenous administration, intradermal administration, subcutaneous administration, oral administration, intranasal administration (e.g., inhalation), transdermal (topical) administration, transmucosal administration, and rectal administration. In some embodiments, the composition is formulated according to routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to humans. In some embodiments, the pharmaceutical composition is formulated according to routine procedures for subcutaneous administration to humans. In general, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. If necessary, the composition may also include a solubilizing agent and a local anesthetic, such as lignocaine, to ease pain at the site of injection.

[0072] The composition can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. The preparation for injection can be provided in unit dosage form, for example, in ampoules or in multi-dose containers, with added preservatives. The composition can take the form of a suspension, solution or emulsion in an oily or aqueous vehicle, and can contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.

[0073] In some embodiments, the present disclosure provides dosage forms (e.g., in conjunction with a pump or other device for such delivery) that allow for the administration of anti-CD3 antibodies continuously over a period of several hours or days, e.g., 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 20 hours, 24 hours, 30 hours, 36 hours, 4 days, 5 days, 7 days, 10 days, or 12 days. ...06 μg / m 2 / day to 850 μg / m 2 / day or 211 μg / m 2 / day to 840 μg / m 2 Dosage forms are provided that allow administration over a period of 24 hours, 30 hours, 36 hours, 4 days, 5 days, 7 days, 10 days or 12 days, increasing the dose to 100 mg / day.

[0074] The composition can be formulated as a neutral or salt form. Pharmaceutically acceptable salts include salts formed with anions, such as those derived from hydrochloric acid, phosphoric acid, acetic acid, oxalic acid, tartaric acid, etc., and salts formed with cations, such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxide, isopropylamine, triethylamine, 2-ethylaminoethanol, histidine, procaine, etc.

[0075] In general, the components of the compositions disclosed herein are supplied either separately or mixed together in unit dosage form, for example as dry lyophilized powder or water-free concentrate, in a sealed container such as an ampoule or sachet indicating the quantity of active agent.When the composition is administered by injection, it can be dispensed using an infusion bottle containing sterile pharmaceutical grade water or saline.When the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the components can be mixed before administration.

[0076] In particular, the present disclosure provides an anti-CD3 antibody or pharmaceutical composition thereof that can be packaged in a sealed container, such as an ampoule or sachet, indicating the quantity of agent. In some embodiments, the anti-CD3 antibody or pharmaceutical composition thereof is provided as a dry, sterile, lyophilized powder or water-free concentrate in a sealed container, which can be reconstituted, for example, with water or saline, to a concentration suitable for administration to a subject. The anti-CD3 antibody or pharmaceutical composition thereof is preferably provided as a dry, sterile, lyophilized powder in a sealed container in a unit dosage of at least 5 mg, more preferably at least 10 mg, at least 15 mg, at least 25 mg, at least 35 mg, at least 45 mg, at least 50 mg, at least 75 mg, or at least 100 mg. The lyophilized agent or pharmaceutical composition herein should be stored in its original container between 2° C. and 8° C., and the therapeutic agent or pharmaceutical composition of the present disclosure should be administered within one week, preferably within five days, within 72 hours, within 48 hours, within 24 hours, within 12 hours, within 6 hours, within 5 hours, within 3 hours, or within one hour after reconstitution. In some embodiments, the pharmaceutical composition is provided in liquid form in a sealed container indicating the quantity and concentration of the drug. The liquid form of the composition to be administered is preferably provided in a sealed container at least 0.25 mg / ml, more preferably at least 0.5 mg / ml, at least 1 mg / ml, at least 2.5 mg / ml, at least 5 mg / ml, at least 8 mg / ml, at least 10 mg / ml, at least 15 mg / ml, at least 25 mg / ml, at least 50 mg / ml, at least 75 mg / ml or at least 100 mg / ml. The liquid form should be stored in its original container at between 2°C and 8°C.

[0077] In some embodiments, the disclosure provides a composition of the disclosure packaged in a hermetically sealed container, such as an ampoule or sachet indicating the quantity of anti-CD3 antibody.

[0078] The compositions can, if desired, be presented in a pack or dispenser device which can contain one or more unit dosage forms containing the active ingredient. The pack includes, for example, metal or plastic foil, such as a blister pack.

[0079] The amount of the composition of the present invention that is effective in preventing or ameliorating one or more symptoms associated with T1D can be determined by standard clinical techniques.The exact dose to be used in the formulation also depends on the route of administration and the severity of the condition, and should be determined according to the judgment of the practitioner and each patient's circumstances.Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0080] Methods and Use In some embodiments, the disclosure encompasses administration of an anti-human CD3 antibody, such as teplizumab, to a patient suspected of infection, such as type 1 diabetes (T1D) associated with coronavirus infection. In some embodiments, the coronavirus infection is a SARS-CoV-2 infection. In some embodiments, the patient has a past COVID-19 infection. In some embodiments, the coronavirus infection can be detected in a patient's biological sample using a nucleic acid amplification or antigen detection assay. In some embodiments, the detection of the presence or absence of SARS-CoV-2 is a PCR assay (RT-PCR). Other assays known in the art can be used to detect the presence or absence of SARS-CoV-2 infection. In some embodiments, the sample can be saliva and nasopharyngeal secretions. In some embodiments, the virus sample can be collected from the patient using a nasal or pharyngeal swab.

[0081] In some embodiments, the patient is diagnosed with T1D diabetes, as determined by detection of type 1 diabetes associated autoantibodies by the methods disclosed herein or known in the art.

[0082] In some embodiments, assays for the presence or absence of SARS-CoV-2 and the presence of type 1 diabetes associated autoantibodies (AA) can be performed in the same biological sample. In some embodiments, assays for the presence or absence of SARS-CoV-2 and the presence of type 1 diabetes associated autoantibodies can be performed simultaneously in the same biological sample. In some embodiments, the biological sample includes blood, serum, saliva, or any other bodily fluid or any other cell or tissue.

[0083] In some embodiments, if a patient tests positive for type 1 diabetes associated autoantibodies and has a prior infection (e.g., a negative SARS-CoV-2 test, such as a PCR test), the patient is administered an anti-human CD3 antibody, such as teplizumab, as described herein. In some embodiments, the anti-human CD3 antibody, such as teplizumab, can be administered on the same day that the patient tests negative for infection (e.g., a negative SARS-CoV-2 test, such as a PCR test) and positive for type 1 diabetes associated autoantibodies. In some embodiments, the anti-human CD3 antibody, e.g., teplizumab, can be administered 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 6 months, 12 months, or any interval between 1 day and 1 year after the patient tests negative for infection (e.g., a negative SARS-CoV-2 test, such as a PCR test) and positive for type 1 diabetes associated autoantibodies.

[0084] In some embodiments, the subject or patient in need thereof is an adult. In some embodiments, the subject or patient in need thereof is a child. In some embodiments, the subject or patient in need thereof is between 8 and 17 years old. In some embodiments, the subject does not have an active viral infection. In some embodiments, the subject or patient in need thereof has a previous viral infection. In some embodiments, the subject has a previous SARS-CoV-2 infection.

[0085] In some embodiments, the method includes diagnosing a patient with T1D and administering a first course of a 12-day daily dose of teplizumab to patients with a history of viral infection and within 6-12 weeks of diagnosis. In some embodiments, the method further includes assessing the area under the curve (AUC) of C-peptide after a mixed meal tolerance test (MMTT) at 78 weeks (18 months or 1.5 years) and / or evaluating clinical endpoints such as insulin use, HbA1c levels, and low blood glucose episodes.

[0086] In some embodiments, the disclosure encompasses administration of an anti-human CD3 antibody, such as teplizumab, to a post-viral infection patient with a peak C-peptide level of 0.2 pmol / mL or greater during a mixed meal tolerance test (MMTT). In some embodiments, the peak C-peptide level at screening ranges from 0.2 pmol / mL (inclusive) to 0.7 pmol / mL (inclusive).

[0087] In some embodiments, T1D diagnosis follows American Diabetes Association (ADA) criteria. As defined by the American Diabetes Association (ADA) for a clinical diagnosis of diabetes, an individual must meet one of the following four criteria:

[0088] Fasting plasma glucose (FPG) ≥ 126 mg / dL (7.0 mmol / L). Fasting is defined as no caloric intake for at least 8 hours.

[0089] A 2-hour plasma glucose of 200 mg / dL (11.1 mmol / L) or greater during an oral glucose tolerance test (OGTT). The test should be performed as described by the World Health Organization (WHO) using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.

[0090] Hemoglobin A1C (HbA1c) greater than or equal to 6.5% (48 mmol / mol). Testing must be performed in a laboratory that is National Glycohemoglobin Standardization Program (NGSP) accredited and standardized to the Diabetes Control and Complications Trial (DCCT) assay.

[0091] A random PG of 200 mg / dL (11.1 mmol / L) or greater in patients with classic symptoms of hyperglycemia or a hyperglycemic emergency.

[0092] For the diagnosis of clinical type 1 diabetes (T1D), the ADA suggests that plasma glucose rather than HbA1C should be used to diagnose acute onset of T1D in individuals with symptoms of hyperglycemia.

[0093] According to the ADA, a patient with standard symptomatic plasma glucose measures is sufficient to diagnose clinical diabetes (symptoms of hyperglycemia or hyperglycemic urgency and random plasma glucose of 200 mg / dL [11.1 mmol / L] or greater). In these cases, it is important to know the plasma glucose level, as it informs management decisions in addition to confirming that the symptoms are attributable to diabetes. Some providers may also want to know the HbA1C to determine how long the patient has had hyperglycemia. In addition, T1D, formerly called "insulin-dependent diabetes" or "juvenile-onset diabetes," accounts for 5-10% of diabetes and is caused by cell-mediated autoimmune destruction of pancreatic β cells. Autoimmune markers include islet cell autoantibodies and autoantibodies against GAD (GAD65), insulin, tyrosine phosphatases IA-2 and IA-2β, and ZnT8. T1D is defined by the presence of one or more of these autoimmune markers.

[0094] In some embodiments, a diagnosis of T1D is made by use of a continuous glucose monitoring system (CGM) revealing high sensor mean glucose levels (≧110 mg / dL), or high blood glucose variability (CV≧15), or lower time in range (TIR) ​​(≧10% time above 140 mg / dL).

[0095] In some embodiments, a patient diagnosed with clinical T1D has a positive result in testing for at least one of the following T1D-related autoantibodies: glutamic acid decarboxylase (GAD65) autoantibody, islet antigen 2 (IA-2) autoantibody, zinc transporter 8 (ZnT8) autoantibody, islet cytoplasmic autoantibody (ICA) or insulin autoantibody (if the test is obtained within the first 14 days of insulin treatment). In some embodiments, the presence of autoantibody is detected by ELISA, electrochemiluminescence (ECL), radioassay (see, for example, Yu et al., 1996, J. Clin. Endocrinol. Metab. 81:4264-4267), agglutination PCR (Tsai et al, ACS Central Science 2016 2(3),139-147), or any other method for immunospecific detection of antibody as described herein or known to those skilled in the art.

[0096] It is recognized that beta cells continue to be lost following T1D diagnosis. To maximize the benefits of beta cell preservation in patients with recoverable levels of endogenous insulin production, patients treated will be within 6 weeks of T1D diagnosis and have peak C-peptide levels of 0.2 pmol / mL or greater during a mixed meal tolerance test (MMTT).

[0097] In some embodiments, the methods provided herein prevent or delay the need to administer insulin to a patient.

[0098] The beta cell function before, during and after treatment can be evaluated by the methods described herein or by any method known to those skilled in the art.For example, the Diabetes Control and Complications Trial (DCCT) research group established the monitoring of percentage glycosylated hemoglobin (HA1 and HA1c) as the standard for evaluating blood glucose control (DCCT, (1993), N. Engl. J. Med. 329: 977-986). Alternatively, characterization of daily insulin requirements, C-peptide levels / response, low blood glucose episodes, and / or FPIR can be used as markers of beta cell function or to establish a therapeutic index (see Keymeulen et al., 2005, N. Engl. J. Med. 352:2598-2608; Herold et al., 2005, Diabetes 54:1763-1769; U.S. Patent Application Publication No. 2004 / 0038867 A1; and Greenbaum et al., 2001, Diabetes 50:470-476, respectively). For example, FPIR is calculated as the sum of insulin values ​​at 1 and 3 minutes after an IGTT performed according to the Islet Cell Antibody Register User's Study protocol (see, e.g., Bingley et al., 1996, Diabetes 45:1720-1728 and McCulloch et al., 1993, Diabetes Care 16:911-915).

[0099] In some embodiments, an effective amount is between 106 and 850 micrograms per square meter (μg / m 2 ) for a 12-day course of subcutaneous intravenous (IV) infusion of an anti-CD3 antibody (e.g., teplizumab). In some embodiments, the total dose administered over the duration of the regimen is about 14,000 μg / m 2 , 13,500 μg / m 2 , 13000μg / m 2 , 12500μg / m 2 , 12000μg / m 2, 11,500 μg / m 2 , 11000μg / m 2 , 10,500 μg / m 2 , 10000μg / m 2 , 9500μg / m 2 , 9000μg / m 2 , 8000μg / m 2 , 7000μg / m 2 , 6000μg / m 2 and 5000 μg / m 2 , 4000μg / m 2 , 3000μg / m 2 , 2000μg / m 2 , or 1000 μg / m 2 In some embodiments, the total dosage administered over the duration of the regimen is about 9030 μg / m 2 to about 14,000 μg / m 2 up to about 9030 μg / m 2 to about 13,500 μg / m 2 up to about 9000 μg / m 2 to about 13,000 μg / m 2 up to about 9000 μg / m 2 to about 12,500 μg / m 2 up to about 9000 μg / m 2 to about 12,000 μg / m 2 up to about 9000 μg / m 2 to about 11,500 μg / m 2 up to about 9000 μg / m 2 to about 11,000 μg / m 2 up to about 9000 μg / m 2 to about 10,500 μg / m 2 up to about 9000 μg / m 2 to about 10,000 μg / m 2 up to about 9000 μg / m 2 to about 9500 μg / m 2 In some embodiments, the total dose administered over the duration of the regimen is about 9030 μg / m 2 to about 14,000 μg / m 2 up to about 9030 μg / m 2 to about 13,500 μg / m 2 up to about 9030 μg / m2 to about 13,000 μg / m 2 up to about 9030 μg / m 2 to about 12,500 μg / m 2 up to about 9030 μg / m 2 to about 12,000 μg / m 2 up to about 9030 μg / m 2 to about 11,500 μg / m 2 up to about 9030 μg / m 2 to about 11,000 μg / m 2 up to about 9030 μg / m 2 to about 10,500 μg / m 2 up to about 9030 μg / m 2 to about 10,000 μg / m 2 up to about 9030 μg / m 2 to about 9500 μg / m 2 That is until now.

[0100] Without being bound by theory, approximately 9,000 μg / m 2 Cumulative doses of teplizumab above 1,500 mg are expected to have comparable efficacy in terms of C-peptide preservation, as shown for approximately 9,000 mg. This is because the exposure / response curve reaches a plateau above which escalating doses surprisingly do not result in increased efficacy. Evaluation of C-peptide preservation was performed utilizing the Protege study data. The model predicted AUC of teplizumab versus change from baseline in C-peptide was plotted and an Emax analysis was performed. These data demonstrate that the Emax model describes the relationship between teplizumab exposure and change in C-peptide at 2 years. As shown in Figure 31, teplizumab AUC levels higher than approximately 1500 ng×hr / mL (1,789 ng×hr / mL at approximately 9,000 μg / m 2 No additional improvement in C-peptide was observed with increasing teplizumab exposure at doses below the lowest AUC predicted for that dose. Thus, these data suggest that doses above about 9,000 mg teplizumab have comparable efficacy in terms of C-peptide preservation as shown for about 9,000 mg.

[0101] In some embodiments, the effective amount is 106 μg / m on day 1. 2 1 dose of teplizumab on day 2, 425 μg / m 2 and a second dose of teplizumab at 850 μg / m on each of days 3 to 12. 2 In some embodiments, the effective amount comprises a 12-day course of IV infusion of teplizumab at a dose of 211 μg / m on day 1. 2 The first dose of teplizumab was 423 μg / m on day 2. 2 and a second dose of teplizumab at 840 μg / m on each of days 3 to 12. 2 In some embodiments, the effective amount comprises a 12-day course of IV infusion of teplizumab at a dose of approximately 100 μg / m on day 1. 2 The first dose of teplizumab was approximately 400 μg / m on day 2. 2 A second dose of teplizumab at approximately 850 μg / m on day 3 2 and a third dose of approximately 1,200 μg / m on each of days 4 through 12. 2 In some embodiments, the effective amount comprises a 12-day course of teplizumab administered IV at 100 μg / m 2 The first dose of teplizumab was approximately 400 μg / m on day 2. 2 A second dose of teplizumab, approximately 850 μg / m on day 3 2 and a third dose of approximately 1,300 μg / m on each of days 4 through 12. 2 In some embodiments, the effective amount comprises a 12-day course of teplizumab administered IV at 100 μg / m 2 The first dose of teplizumab was approximately 400 μg / m on day 2. 2 A second dose of teplizumab, approximately 850 μg / m on day 3 2 and a third dose of approximately 1,400 μg / m on each of days 4 through 12. 2 In some embodiments, each 12-day course may include a 2-day escalation step, and a 10-day fixed maximum dosing period. 2of teplizumab was administered on day 1 and 425 μg / m 2 of teplizumab was administered on day 2, 850 μg / m 2 of teplizumab will be administered on days 3 through 12.

[0102] In some embodiments, the effective amount is approximately 200 μg / m on day 1. 2 The first dose of teplizumab was approximately 400 μg / m on day 2. 2 A second dose of teplizumab at approximately 850 μg / m on day 3 2 and a third dose of approximately 1,200 μg / m on each of days 4 through 12. 2 In some embodiments, the effective amount comprises a 12-day course of teplizumab IV infusion at approximately 200 μg / m on day 1. 2 The first dose of teplizumab was approximately 400 μg / m on day 2. 2 A second dose of teplizumab, approximately 850 μg / m on day 3 2 and a third dose of approximately 1,300 μg / m on each of days 4 through 12. 2 In some embodiments, the effective amount comprises a 12-day course of teplizumab IV infusion at approximately 200 μg / m on day 1. 2 The first dose of teplizumab was approximately 400 μg / m on day 2. 2 A second dose of teplizumab at approximately 850 μg / m on day 3 2 and a third dose of approximately 1,400 μg / m on each of days 4 through 12. 2 The study included a 12-day course of teplizumab administered IV at 4°C for 12 days.

[0103] Provided herein are dosing regimens that include two or more courses of dosing with an anti-CD3 antibody (e.g., teplizumab), including a first course dosing at week 1 and a second course dosing at week 26. In some embodiments, teplizumab is administered by IV infusion in two courses, with the first course beginning on day 1 (week 1) and the second course beginning on about day 182 (week 26), and each course of treatment being administered at a dose of 9000 μg / m for each course of treatment. 2In some embodiments, teplizumab is administered by IV infusion in two courses, with the first course starting on day 1 (week 1) and the second course starting on about day 182 (week 26), with each course of treatment comprising a daily infusion of 9500 μg / m for 12 days with a cumulative teplizumab dose of 9500 μg / m for each course of treatment. 2 In some embodiments, teplizumab is administered by IV infusion in two courses, the first course beginning on day 1 (week 1) and the second course beginning on about day 182 (week 26), with each course of treatment comprising a daily infusion of 10,000 μg / m for each course of treatment. 2 In some embodiments, teplizumab is administered by IV infusion in two courses, the first course beginning on day 1 (week 1) and the second course beginning on about day 182 (week 26), with each course of treatment comprising a daily infusion of 10,500 μg / m for 12 days with a cumulative teplizumab dose of 10,500 μg / m for each course of treatment. 2 In some embodiments, teplizumab is administered by IV infusion in two courses, the first course beginning on day 1 (week 1) and the second course beginning on about day 182 (week 26), with each course of treatment consisting of 11,000 μg / m2 daily infusions for 12 days with a cumulative teplizumab dose of 11,000 μg / m2 for each course. 2 In some embodiments, teplizumab is administered by IV infusion in two courses, the first course beginning on day 1 (week 1) and the second course beginning on about day 182 (week 26), with each course of treatment comprising a daily infusion of 11,500 μg / m for 12 days with a cumulative teplizumab dose of 11,500 μg / m for each course of treatment. 2 In some embodiments, teplizumab is administered by IV infusion in two courses, the first course beginning on day 1 (week 1) and the second course beginning on about day 182 (week 26), with each course of treatment comprising a daily infusion of 12000 μg / m for each course of treatment. 2In some embodiments, teplizumab is administered by IV infusion in two courses, the first course beginning on day 1 (week 1) and the second course beginning on about day 182 (week 26), with each course of treatment comprising a daily infusion of 12,500 μg / m for each course of treatment. 2 In some embodiments, teplizumab is administered by IV infusion in two courses, the first course beginning on day 1 (week 1) and the second course beginning on about day 182 (week 26), with each course of treatment comprising a daily infusion of 13,000 μg / m for 12 days with a cumulative teplizumab dose of 13,000 μg / m for each course of treatment. 2 In some embodiments, teplizumab is administered by IV infusion in two courses, with the first course starting on day 1 (week 1) and the second course starting on about day 182 (week 26), with each course of treatment comprising a daily infusion of 13,500 μg / m for 12 days with a cumulative teplizumab dose of 13,500 μg / m for each course of treatment. 2 In some embodiments, teplizumab is administered by IV infusion in two courses, the first course beginning on day 1 (week 1) and the second course beginning on about day 182 (week 26), with each course of treatment comprising a daily infusion of 14,000 μg / m for each course of treatment. 2 In some embodiments, the 12-day course includes a daily infusion of a cumulative teplizumab dose of 106 μg / m 2 of teplizumab was administered on day 1 and 425 μg / m 2 of teplizumab was administered on day 2, 850 μg / m 2 of teplizumab will be administered on days 3 through 12.

[0104] In other embodiments, the course of dosing can be repeated at intervals of 2 months, 4 months, 5 months, 6 months, 8 months, 9 months, 10 months, 12 months, 15 months, 18 months, 24 months, 30 months, or 36 months. In some embodiments, the efficacy of treatment with an anti-CD3 antibody (e.g., teplizumab) is determined as described herein or known in the art 2 months, 4 months, 5 months, 6 months, 9 months, 12 months, 15 months, 18 months, 24 months, 30 months, or 36 months after the previous treatment.

[0105] In some embodiments, a subject is administered about 5-1200 μg / m to treat, slow the progression of, or reverse one or more symptoms of T1D. 2 , preferably 106 to 850 μg / m 2 One or more, preferably 12 daily doses of a dose of anti-CD3 antibody (e.g., teplizumab) are administered.

[0106] In some embodiments, the subject is administered a treatment regimen comprising two courses of daily doses of an effective amount of an anti-CD3 antibody (e.g., teplizumab), where the course of treatment is administered over 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 days. In some embodiments, the treatment regimen comprises administering an effective amount of a dose every day, every other day, every third day, every third day, or every fourth day.

[0107] In some embodiments, the subject is administered a treatment regimen comprising one or more doses of a prophylactically effective amount of an anti-CD3 antibody (e.g., teplizumab), where the prophylactically effective amount is 200 μg / kg / day, 175 μg / kg / day, 150 μg / kg / day, 125 μg / kg / day, 100 μg / kg / day, 95 μg / kg / day, 90 μg / kg / day, 85 μg / kg / day, 80 μg / kg / day, 75 μg / kg / day, 70 μg / kg / day, 65 μg / kg / day, 60 μg / kg / day, 55 μg / kg / day, 50 μg / kg / day, 45 μg / kg / day, 40 μg / kg / day , 35 μg / kg / day, 30 μg / kg / day, 26 μg / kg / day, 25 μg / kg / day, 20 μg / kg / day, 15 μg / kg / day, 13 μg / kg / day, 10 μg / kg / day, 6.5 μg / kg / day, 5 μg / kg / day, 3.2 μg / kg / day, 3 μg / kg / day, 2.5 μg / kg / day, 2 μg / kg / day, 1.6 μg / kg / day, 1.5 μg / kg / day, 1 μg / kg / day, 0.5 μg / kg / day, 0.25 μg / kg / day, 0.1 μg / kg / day, or 0.05 μg / kg / day; and / or the prophylactically effective amount is 1200 μg / m 2 / day, 1150μg / m 2 / day, 1100μg / m 2 / day, 1050μg / m 2 / day, 1000μg / m 2 / day, 950 μg / m 2 / day, 900μg / m 2 / day, 850 μg / m 2 / day, 800μg / m 2 / day, 750 μg / m 2 / day, 700 μg / m 2 / day, 650 μg / m 2 / day, 600μg / m 2 / day, 550μg / m 2 / day, 500μg / m 2 / day, 450μg / m 2 / day, 400μg / m 2 / day, 350μg / m 2 / day, 300μg / m 2 / day, 250μg / m 2 / day, 200μg / m 2 / day, 150μg / m 2 / day, 100μg / m 2 / day, 50μg / m 2 / day, 40μg / m 2 / day, 30μg / m 2 / day, 20μg / m 2 / day, 15μg / m 2 / day, 10μg / m 2 / day or 5μg / m 2 / day.

[0108] In some embodiments, 1200 μg / m 2 Below, 1150μg / m 2 Below, 1100μg / m 2 Below, 1050μg / m 2 Below, 1000μg / m 2 Below, 950μg / m 2 Below, 900μg / m 2 Below 850μg / m 2 Below 800μg / m 2 Below, 750μg / m 2 Below, 700μg / m 2 Below, 650μg / m 2 Below, 600μg / m 2 Below, 550μg / m 2 Below, 500μg / m 2 Below, 450μg / m 2 Below 400μg / m 2 Below 350μg / m 2 Below 300μg / m 2 Below 250μg / m 2 Below, 200μg / m 2 Below 150μg / m 2 Below, 100μg / m 2 Below, 50μg / m 2 Below, 40μg / m 2 Below, 30μg / m 2 Below, 20μg / m 2 Below, 15μg / m 2 Below, 10μg / m 2 or less than 5 μg / m 2The following intravenous doses of anti-CD3 antibody (e.g., teplizumab) are administered over about 24 hours, about 22 hours, about 20 hours, about 18 hours, about 16 hours, about 14 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1.5 hours, about 1 hour, about 50 minutes, about 40 minutes, about 30 minutes, about 20 minutes, about 10 minutes, about 5 minutes, about 2 minutes, about 1 minute, about 30 seconds, or about 10 seconds. The total dose over the duration of the regimen totals about 14,000 μg / m 2 Less than 13,500 μg / m 2 Less than 13,000 μg / m 2 Less than 12,500 μg / m 2 Less than 12,000 μg / m 2 Less than 11,500 μg / m 2 Less than 11,000 μg / m 2 Less than 10,500 μg / m 2 Less than 10,000 μg / m 2 Less than 9500 μg / m 2 Less than 9000 μg / m 2 Less than 8000 μg / m 2 Less than 7000 μg / m 2 Less than 6000 μg / m 2 Preferably less than 5000 μg / m 2 Less than 4000 μg / m 2 Less than 3000 μg / m 2 Less than 2000 μg / m 2 Less than or equal to 1000 μg / m 2 In some embodiments, the daily dosage administered in the regimen is about 100 μg / m 2 ~about 200μg / m 2 , about 100μg / m 2 ~about 500μg / m 2 , about 100μg / m 2 ~Approx. 1000μg / m 2 , or about 500 μg / m 2 ~Approx. 1000μg / m 2 It is.

[0109] In some embodiments, the dose is titrated over the first third, first quarter, or first 3 days of a 12-day regimen of one dose per day until an effective daily dose of the anti-CD3 antibody (e.g., teplizumab) is achieved. In some embodiments, the subject is administered a treatment regimen that includes one or more doses of an effective amount of an anti-CD3 antibody (e.g., teplizumab), where the effective amount is, for example, 0.01 μg / kg, 0.02 μg / kg, 0.04 μg / kg, 0.05 μg / kg, 0.06 μg / kg, 0.08 μg / kg, 0.1 μg / kg, 0.2 μg / kg, 0.25 μg / kg, 0.5 μg / kg, 0.75 μg / kg, 1 μg / kg, 1.5 μg / kg, 2 μg / kg, daily as treatment progresses. or by increasing the dose by, for example, 100 μg / m daily. 2 Each, 150μg / m 2 Each, 200μg / m 2 Each, 250μg / m 2 Each, 300μg / m 2 Each, 350μg / m 2 Each, 400μg / m 2 Each, 450μg / m 2 Each, 500μg / m 2 Each, 550μg / m 2 Each, 600μg / m 2 or 650μg / m 2In some embodiments, a subject is administered a treatment regimen comprising one or more doses of an effective amount of an anti-CD3 antibody (e.g., teplizumab), where the effective amount is increased by 1.25-fold, 1.5-fold, 2-fold, 2.25-fold, 2.5-fold, or 5-fold until an effective daily dose of the anti-CD3 antibody (e.g., teplizumab) is achieved.

[0110] In some embodiments, a subject is administered 200 μg / kg or less, preferably 175 μg / kg or less, 150 μg / kg or less, 125 μg / kg or less, 100 μg / kg or less, 95 μg / kg or less, 90 μg / kg or less, 85 μg / kg or less, 80 μg / kg or less, 75 μg / kg or less, 70 μg / kg or less, 65 μg / kg or less, 60 μg / kg or less, 55 μg / kg or less, ... One or more of the following doses of an anti-CD3 antibody (e.g., teplizumab) are administered intramuscularly: 0 μg / kg or less, 45 μg / kg or less, 40 μg / kg or less, 35 μg / kg or less, 30 μg / kg or less, 25 μg / kg or less, 20 μg / kg or less, 15 μg / kg or less, 10 μg / kg or less, 5 μg / kg or less, 2.5 μg / kg or less, 2 μg / kg or less, 1.5 μg / kg or less, 1 μg / kg or less, 0.5 μg / kg or less, or 0.2 μg / kg or less.

[0111] In some embodiments, a subject is administered 200 μg / kg or less, preferably 175 μg / kg or less, 150 μg / kg or less, 125 μg / kg or less, 100 μg / kg or less, 95 μg / kg or less, 90 μg / kg or less, 85 μg / kg or less, 80 μg / kg or less, 75 μg / kg or less, 70 μg / kg or less, 65 μg / kg or less, 60 μg / kg or less, 55 μg / kg or less, ... One or more of the following doses of an anti-CD3 antibody (e.g., teplizumab) are administered subcutaneously: 0 μg / kg or less, 45 μg / kg or less, 40 μg / kg or less, 35 μg / kg or less, 30 μg / kg or less, 25 μg / kg or less, 20 μg / kg or less, 15 μg / kg or less, 10 μg / kg or less, 5 μg / kg or less, 2.5 μg / kg or less, 2 μg / kg or less, 1.5 μg / kg or less, 1 μg / kg or less, 0.5 μg / kg or less, or 0.2 μg / kg or less.

[0112] In some embodiments, a subject is administered 100 μg / kg or less, preferably 95 μg / kg or less, 90 μg / kg or less, 85 μg / kg or less, 80 μg / kg or less, 75 μg / kg or less, 70 μg / kg or less, 65 μg / kg or less, 60 μg / kg or less, 55 μg / kg or less, 50 μg / kg or less, 45 μg / kg or less, 40 μg / kg or less, or 50 μg / kg or less to treat or ameliorate one or more symptoms of T1D. In one embodiment, one or more of the following doses of an anti-CD3 antibody (e.g., teplizumab) are administered intravenously: ≤35 μg / kg, ≤30 μg / kg, ≤25 μg / kg, ≤20 μg / kg, ≤15 μg / kg, ≤10 μg / kg, ≤5 μg / kg, ≤2.5 μg / kg, ≤2 μg / kg, ≤1.5 μg / kg, ≤1 μg / kg, ≤0.5 μg / kg, or ≤0.2 μg / kg. In some embodiments, 100 μg / kg or less, 95 μg / kg or less, 90 μg / kg or less, 85 μg / kg or less, 80 μg / kg or less, 75 μg / kg or less, 70 μg / kg or less, 65 μg / kg or less, 60 μg / kg or less, 55 μg / kg or less, 50 μg / kg or less, 45 μg / kg or less, 40 μg / kg or less, 35 μg / kg or less, 30 μg / kg or less, 25 μg / kg or less, 20 μg / kg or less, An intravenous dose of up to, 15 μg / kg or less, 10 μg / kg or less, 5 μg / kg or less, 2.5 μg / kg or less, 2 μg / kg or less, 1.5 μg / kg or less, 1 μg / kg or less, 0.5 μg / kg or less, or 0.2 μg / kg or less of an anti-CD3 antibody (e.g., teplizumab) is administered over about 6 hours, about 4 hours, about 2 hours, about 1.5 hours, about 1 hour, about 50 minutes, about 40 minutes, about 30 minutes, about 20 minutes, about 10 minutes, about 5 minutes, about 2 minutes, about 1 minute, about 30 seconds, or about 10 seconds.

[0113] In some embodiments, a subject is administered 100 μg / kg or less, preferably 95 μg / kg or less, 90 μg / kg or less, 85 μg / kg or less, 80 μg / kg or less, 75 μg / kg or less, 70 μg / kg or less, 65 μg / kg or less, 60 μg / kg or less, 55 μg / kg or less, 50 μg / kg or less, 45 μg / kg or less, 40 μg / kg or less, or 50 μg / kg or less to treat or ameliorate one or more symptoms of T1D. In one embodiment, one or more of the following doses of anti-CD3 antibody (e.g., teplizumab) are orally administered: g / kg or less, 35 μg / kg or less, 30 μg / kg or less, 25 μg / kg or less, 20 μg / kg or less, 15 μg / kg or less, 10 μg / kg or less, 5 μg / kg or less, 2.5 μg / kg or less, 2 μg / kg or less, 1.5 μg / kg or less, 1 μg / kg or less, 0.5 μg / kg or less, or 0.2 μg / kg or less. In some embodiments, 100 μg / kg or less, 95 μg / kg or less, 90 μg / kg or less, 85 μg / kg or less, 80 μg / kg or less, 75 μg / kg or less, 70 μg / kg or less, 65 μg / kg or less, 60 μg / kg or less, 55 μg / kg or less, 50 μg / kg or less, 45 μg / kg or less, 40 μg / kg or less, 35 μg / kg or less, 30 μg / kg or less, 25 μg / kg or less, 20 μg / kg or less, An oral dose of up to, 15 μg / kg or less, 10 μg / kg or less, 5 μg / kg or less, 2.5 μg / kg or less, 2 μg / kg or less, 1.5 μg / kg or less, 1 μg / kg or less, 0.5 μg / kg or less, or 0.2 μg / kg or less of an anti-CD3 antibody (e.g., teplizumab) is administered over about 6 hours, about 4 hours, about 2 hours, about 1.5 hours, about 1 hour, about 50 minutes, about 40 minutes, about 30 minutes, about 20 minutes, about 10 minutes, about 5 minutes, about 2 minutes, about 1 minute, about 30 seconds, or about 10 seconds.

[0114] In some embodiments where escalating doses are administered over the first few days of a dosing regimen, the dose on day 1 of the regimen is 100 to 250 μg / m 2 / day, preferably 106 μg / m 2 / day, titrated up to the daily dose listed immediately above by days 2 and 3. For example, subjects are administered approximately 106 μg / m 2 / day and approximately 425 μg / m on day 2 2 / day and 850 μg / m on subsequent days of the regimen (e.g., days 3–12). 2 In some embodiments, on day 1, the subject is administered approximately 211 μg / m 2 / day and on day 2, approximately 423 μg / m 2 / day, approximately 840 μg / m on day 3 and on subsequent days of the regimen (e.g., days 3-12) 2 Administered at 100 mg / day.

[0115] In some embodiments, the first one, two, or three or all doses of the regimen are administered more slowly via intravenous administration to reduce the potential for cytokine release and other adverse effects. 2 The daily dose can be administered over about 5 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, and about 22 hours. In some embodiments, the dose is administered by slow infusion, for example, over a period of 20 to 24 hours. In some embodiments, the dose is infused by pump, preferably with increasing concentrations of antibody administered as the infusion progresses.

[0116] In some embodiments, the 106 μg / m 2 / day to 850 μg / m 2 Administer escalating doses of the indicated fractions of the dose for the / day regimen.

[0117] In some embodiments, the anti-CD3 antibody (e.g., teplizumab) is administered by infusion in a continuous manner over 4, 6, 8, 10, 12, 15, 18, 20, 24, 30, or 36 hours, rather than administered in a daily dose over many days. The infusion can be constant, e.g., starting at a low dose for the first 1, 2, 3, 5, 6, or 8 hours of the infusion, and then increasing to a higher dose. Over the course of the infusion, the patient receives a dose equivalent to that administered in the 5-20 day regimen described above. For example, approximately 150 μg / m 2 , 200 μg / m 2 , 250 μg / m 2 , 500 μg / m 2 , 750 μg / m 2 , 1000μg / m 2 , 1500μg / m 2 , 2000μg / m 2 , 3000μg / m 2 , 4000μg / m 2 , 5000μg / m 2 , 6000μg / m 2 , 7000μg / m 2 , 8000μg / m 2 , 9000μg / m 2 , 9500μg / m 2 , 10000μg / m 2 , 10,500 μg / m 2 , 11000μg / m 2 , 11,500 μg / m 2 , 12000μg / m 2 , 12500μg / m 2 , 13000μg / m 2 , 13,500 μg / m 2 or 14,000 μg / m 2A dose of 100 mg / mL can be administered. In particular, the speed and duration of the infusion is designed to minimize the level of free anti-CD3 antibody (e.g., teplizumab) in the subject after administration. In some embodiments, the level of free anti-CD3 antibody (e.g., teplizumab) should not exceed 200 ng / mL of free antibody. Furthermore, the infusion is designed to achieve a combination of at least 50%, 60%, 70%, 80%, 90%, 95% or 100% T cell receptor coating and modulation.

[0118] In some embodiments, an anti-CD3 antibody (e.g., teplizumab) is administered chronically to treat, slow the progression of, or reverse one or more symptoms of type 1 diabetes. For example, in some embodiments, an anti-CD3 antibody (e.g., teplizumab) is administered at a lower dose once a month, twice a month, three times a month, once a week, or even more frequently, either as an alternative to the 6-14 day dosing regimen described above, or to enhance or maintain the effect following such a regimen. Such a low dose can be as low as 1 μg / m 2 to 100 μg / m 2 Any dose up to about 5 μg / m 2 , 10μg / m 2 , 15 μg / m 2 , 20 μg / m 2 , 25 μg / m 2 , 30 μg / m 2 , 35 μg / m 2 , 40 μg / m 2 , 45 μg / m 2 , or 50 μg / m 2 And so on.

[0119] In some embodiments, a subject may be re-dosed, or may be re-dosed, at some time after administration of a two-course anti-CD3 antibody (e.g., teplizumab) dosing regimen, for example, based on one or more physiological or biomarker parameters. Such re-dosing and / or assessment of the need for such re-dosing may occur 2 months, 4 months, 6 months, 8 months, 9 months, 1 year, 15 months, 18 months, 2 years, 30 months, or 3 years after administration of the dosing regimen, and may include administering a course of treatment every 6 months, 9 months, 1 year, 15 months, 18 months, 2 years, 30 months, or 3 years indefinitely.

[0120] In some embodiments, the level (or relative amount) of phenotypically exhausted T cells, e.g., TIGIT+KLRG1+CD8+CD3+ cells, relative to total CD3+ T cells, is determined, e.g., by flow cytometry, before and / or after administration of a 12-day course of teplizumab (e.g., at 1-6 month intervals, or 2-5 month intervals, or about 3 month intervals). In some embodiments, the level of TIGIT+KLRG1+CD8+CD3+ T cells can be monitored, e.g., by flow cytometry. In some embodiments, when the level of TIGIT+KLRG1+CD8+CD3+ T cells corresponds to (e.g., returns to) baseline levels, an additional 12-day course of anti-CD3 antibody (e.g., teplizumab) is administered. In some embodiments, the step of determining TIGIT+KLRG1+CD8+CD3+ T cells is about 3 months (or about 1-6 months) after administration of the second 12-day course. In some embodiments, if the subject has more than about 10% TIGIT+KLRG1+CD8+ T cells among total CD3+ T cells, the monitoring step can be annually. In some embodiments, if the subject has less than about 10% TIGIT+KLRG1+CD8+ T cells among total CDCD3+ T cells, the monitoring step can be about every 3-6 months.

[0121] In some embodiments, re-doses are about 9000 μg / m each as described herein. 2 In some embodiments, the additional 12-day course of teplizumab includes administering an additional (e.g., a second, third, or more) 12-day course of teplizumab at a total dose of 106 μg / m on day 1 or greater. 2 1 dose of teplizumab on day 2, 425 μg / m 2 and a second dose of teplizumab at 850 μg / m on each of days 3 to 12. 2 for a total dose of approximately 9031 μg / m 2 In another embodiment, an additional 12-day course of teplizumab is administered at 211 μg / m 2 The first dose of teplizumab was 423 μg / m on day 2. 2 and a second dose of teplizumab at 840 μg / m on each of days 3 to 12. 2 for a total dose of approximately 9034 μg / m 2 It is.

[0122] In some embodiments, an additional (e.g., second, third, or more) 12-day course of an anti-CD3 antibody (e.g., teplizumab) can be administered about 12 months to about 24 months, e.g., 12, 13, 14, 15, 16, 17, 19, 20, 21, 22, 23, or 24 months, after the previous 12-day course.

[0123] In some embodiments, an anti-CD3 antibody (e.g., teplizumab) is administered to achieve or maintain a level of glycosylated hemoglobin (HA1 or HA1c) of less than 8%, less than 7.5%, less than 7%, less than 6.5%, less than 6%, less than 5.5%, or less than 5%. At the start of treatment, the patient has a HA1 or HA1c level of less than 8%, less than 7.5%, less than 7%, less than 6.5%, less than 6%, or more preferably 4% to 6% (preferably measured in the absence of other treatments for diabetes, e.g., administration of exogenous insulin). Such patients preferably retain at least 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, or 20% of beta cell function prior to the start of treatment. In some embodiments, administration of an anti-CD3 antibody prevents damage, thereby slowing disease progression and reducing the need for insulin administration. In some embodiments, the methods of treatment provided herein result in levels of HA1 or HA1c that are 7% or less, 6.5% or less, 6% or less, 5.5% or less, or 5% or less 6, 9, 12, 15, 18, or 24 months after the previous treatment. In some embodiments, administration of an anti-CD3 antibody according to the methods provided herein reduces the average levels of HA1 or HA1c in a patient by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70% compared to pre-treatment levels 6, 9, 12, 15, 18, or 24 months after the previous treatment. In some embodiments, administration of an anti-CD3 antibody according to the methods provided herein results in the average levels of HA1 or HA1c in the patient increasing by about 0.5%, about 1%, about 2.5%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% compared to pre-treatment levels 6, 9, 12, 15, 18, or 24 months after the prior treatment.

[0124] In some embodiments, administration of an anti-CD3 antibody, particularly teplizumab, according to the methods provided herein delays beta cell loss and / or preserves beta cell function (e.g., as evidenced by C-peptide levels, episodes of hypo- or hyperglycemia, time in (glycemic) range, insulin use, or assessment methods known in the art) for 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 2 months, 24 months, or longer in children and adolescents ages 8-17 who have been diagnosed with T1D within the past 6 weeks. In some embodiments, administration of an anti-CD3 antibody, particularly teplizumab, according to the methods provided herein delays beta cell loss and / or preserves beta cell function for 18 months (78 weeks) in children and adolescents ages 8-17 who have been diagnosed with T1D within the past 6 weeks.

[0125] Some embodiments provide a method of treating clinical type 1 diabetes, comprising administering to a subject in need thereof about 9000 μg / m 2 In some embodiments, the method comprises administering to a subject in need thereof a 12 day course of teplizumab at a total dose of greater than about 9000 μg / m 2 The present invention relates to teplizumab for use in a method comprising administering a 12 day course of teplizumab at a total dose of greater than about 9000 to about 9500 μg / m2, wherein the subject in need thereof is post-viral infection. In some embodiments, the total dose is from about 9000 to about 9500 μg / m2. 2 In some embodiments, the total dose is between about 9000 and about 14000 μg / m 2 Some embodiments include a method of treating clinical type 1 diabetes following viral infection, comprising administering to a subject in need thereof between about 9000 μg / m 2 to about 9500 μg / m 2 Some embodiments relate to a method of treating clinical type 1 diabetes following a viral infection, comprising administering to a subject in need thereof a 12 day course of teplizumab with a total dose of up to about 9000 μg / m 2to about 14,000 μg / m 2 The method includes administering a 12 day course of teplizumab for a total dose of up to 12 days. EXAMPLES

[0126] [Example 1: Pharmacokinetic simulation of teplizumab population] <Introduction> Teplizumab is a 150 kD monoclonal antibody that binds to the CD3-ε epitope of the T-cell receptor (TCR) complex. The primary mechanism of action of the antibody involves binding of the CD3 antigen target on T cells. A population pharmacokinetic (PK) model was developed to describe teplizumab concentrations following IV administration. Teplizumab PK was described by the quasi-steady-state (QSS) approximation of the target-mediated drug disposition (TMDD) model. The goal of this study was to use the model to simulate and compare the concentration-time profiles of teplizumab following several dosing regimens of interest.

[0127] <Purpose> The objectives of the analysis were: To apply a previously developed population PK model that simulates the following three dosing regimens: - "Herold Dosing Regimen": Day 1: 51 μg / m 2 Day 2: 103 μg / m 2 Day 3: 207 μg / m 2 Day 4: 413 μg / m 2 Days 5-14: 826 μg / m 2 ; - Regimen 1: Day 1: 211 μg / m 2 Day 2: 423 μg / m 2 ;3rd to 12th day: 840μg / m 2 ; - Regimen 2: Day 1: 106 μg / m 2 Day 2: 425 μg / m 2 Days 3-12: 850 μg / m 2 . To demonstrate and compare the concentration-time curves of teplizumab for the three dosing regimens listed above.

[0128] <Subjects and methods> Medication Regimen The Herold regimen consisted of 51 μg / m on days 1 to 4 of the study. 2 , 103 μg / m 2 , 207 μg / m 2 , 413 μg / m 2 daily intravenous (IV) infusion (over at least 30 minutes) of 826 μg / m on each of study days 5 through 14. 2 The total dose for the 14-day course is approximately 9034 μg / m 2 It is 1.92m 2 For a subject with a body surface area (BSA) of 100, this dosing schedule delivers approximately 17 mg of teplizumab. The maximum amount of drug delivered at steady state was designed to provide 50%-80% coating of available CD3 on T cells with no large excess of free, unbound drug (estimated to be less than 200 ng / mL at steady state).

[0129] New Regimen 1 was 211 μg / m on days 1 and 2 of the study. 2 and 423 μg / m 2 daily intravenous (IV) infusion (over at least 30 minutes), and 840 μg / m on each of study days 3 through 12. 2 The total dose for the 12-day course is approximately 9034 μg / m 2 It is.

[0130] New Regimen 2 was 106 μg / m on days 1 and 2 of the study. 2 and 425 μg / m 2 daily intravenous (IV) infusion (over at least 30 minutes), and 850 μg / m on each of study days 3 through 12. 2 The total dose for the 12-day course is approximately 9031 μg / m 2 It is.

[0131] As is apparent, the same total dose should be delivered by all three regimens, but in regimens 1 and 2, delivery is over 12 days rather than the 14 days of the original Herold regimen.

[0132] simulation The final model from the previous analysis was used for the simulation. Concentration-time curves were simulated for 40 days (days 0 to 40) at 10 time points each day. The model included the effect of the study because patients from the Protege Encore study were found to have higher clearance and central volume than patients from the Protege study. Therefore, the simulation was performed separately for these two studies. Specifically, the following four typical patient covariate values ​​were used for the simulation: Adult patients with no detectable anti-drug antibodies (ADA): 1.67m aged 18 years 2 60 kg male with a BSA of; Adult patients with high levels of ADA: 1.67m aged 18 years 2 60 kg male with a BSA of; Pediatric patient with undetectable ADA: 1.33m at 13 years 2 45 kg male with a BSA of; Pediatric patients with high levels of ADA: 1.33m aged 13 years 2 A 45kg male with a BSA of

[0133] For each of these patients, the population prediction of concentration over time was computed for each of the three dosing regimens, and then compared graphically.The parameters of 1000 similar patients were then simulated using the model-estimated individual variability, and individual concentration-time curves were computed using the model.The median and 90% prediction interval of the simulated concentration at each time point were computed for each regimen, and compared graphically.In addition, the mean and standard deviation of the simulated values ​​one day after the last dose were computed and compared.

[0134] software Simulations were performed using NONMEM software, version 7.4.1 (ICON Development Solutions). Computer resources included a personal computer with an Intel® processor, Windows 7 Professional or successor operating system, and the Intel® Visual Fortran Professional compiler (version 11.0). Graphics and all other statistical analyses, including evaluation of NONMEM output, were performed using R version 3.4.4 for Windows (R project, www.r-project.org / ).

[0135] <Result> The results of the simulation for a typical adult patient without ADA detection are shown in Figure 1. Concentrations in the Protege study were predicted to be higher than in the Encore study for all dosing regimens. Concentrations in dosing regimens 1 and 2 were almost indistinguishable, except for slight differences during the first 2 days of dosing. During the first 12 days of dosing, concentrations in the Herold dosing regimen were lower compared to dosing regimens 1 and 2, but they were nearly identical after the last dose (day 14 for the Herold regimen and day 12 for regimens 1 and 2). Simulations including individual differences (Figures 2-4, Table 1) confirmed these observations. Table 1 shows the mean and standard deviation of predicted concentrations (ng / mL) across 1000 simulated subjects from the Protege study.

[0136] [Table 1]

[0137] The results of the simulation for a typical adult patient with detected high levels of ADA are shown in Figures 5-8. As expected, the overall teplizumab levels were extremely low in patients with very high immunogenic responses, but the conclusions about the differences between the three investigated dosing regimens still held up.

[0138] The results of the simulation for a typical pediatric patient are shown in Figures 9-16. They are very similar to those for adult patients, indicating that BSA proportional dosing provides similar exposures for pediatric and adult populations.

[0139] Figures 17-24 show the concentration profiles comparing the Herold regimen and regimen 2 over time, and Tables 2-3 summarize the Cmax and AUC from days 0 to 42 in the simulation. The figures show that concentrations were very low until day 42, and therefore the AUC 0-42 The values ​​of AUCinfinity are essentially the same as AUCinfinity. Table 2 shows the mean and standard deviation of predicted maximum concentrations (ng / mL) across 1000 simulated subjects using Protege model 205. Table 3 shows the mean and standard deviation of predicted AUC from day 0 to day 42 across 1000 simulated subjects using Protege model 205.

[0140] [Table 2]

[0141] [Table 3]

[0142] <Conclusion> Simulations have shown that: · The predicted concentrations of teplizumab are nearly identical for the two proposed dosing regimens (regimen 1 and regimen 2), except on the first day of dosing; · Predicted teplizumab concentrations increase more rapidly during dosing for regimens 1 and 2 compared with the Herold regimen, but they are nearly identical for all regimens on the last day of dosing; · Predicted teplizumab concentrations 1 day after the last dose were nearly identical for all three regimens; ·BSA proportional dosing provides uniform exposure levels for adult and pediatric subjects with different body size scales.

[0143] Example 2: A Phase 3, Randomized, Double-Blind, Multinational, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Teplizumab (PRV-031), a Humanized, FcR-Nonbinding Anti-CD3 Monoclonal Antibody, in Children and Adolescents With Newly Diagnosed Type 1 Diabetes (T1D). Teplizumab (also known as PRV-031, hOKT3γ1[Ala-Ala], and MGA031) is a humanized 150 kilodalton monoclonal antibody (mAb) that binds to the CD3-ε epitope of the T cell receptor. Teplizumab was developed when preclinical studies demonstrated that targeting T cells (cells involved in initiating and orchestrating the autoimmune process that causes type 1 diabetes [T1D]) through this mechanism altered the immunopathogenesis of diabetes and prevented and reversed the disease in relevant animal models. The goal of this trial is to evaluate teplizumab in children and adolescents very recently diagnosed with T1D. Teplizumab is expected to be the first disease-modifying therapy available to improve both medical management and overall outlook in those suffering from the most devastating short-term and long-term effects of the disease.

[0144] <Hypothesis> The hypothesis of this study is that teplizumab is safe, well tolerated, and effective in slowing beta-cell loss and maintaining clinically relevant levels of beta-cell function in newly diagnosed children and adolescents with T1D, while improving important aspects of T1D clinical management over an 18-month period.

[0145] <Purpose> The main objectives are to: To determine whether two courses of teplizumab administered six months apart slows beta-cell loss and preserves beta-cell function over 18 months (78 weeks) in children and adolescents aged 8 to 17 years who have been diagnosed with T1D in the past six weeks.

[0146] The secondary objectives are: To assess participants' improvements in key clinical parameters of diabetes management, including insulin use, glycemic control (including hemoglobin A1c [HbA1c] and time in glycemic target range [TIR]), and clinically significant low blood glucose episodes To determine the safety and tolerability of two courses of teplizumab administered intravenously (IV) six months apart To evaluate the pharmacokinetics (PK) and immunogenicity of two courses of IV teplizumab

[0147] The exploratory objectives are to: To assess β-cell function and clinical parameters focused on T1D Evaluating immunological, endocrinological, molecular, and genetic markers

[0148] <endpoint> 1.The primary endpoints are: Area under the curve (AUC) of C-peptide following a 4-hour mixed meal tolerance test (MMTT), a measure of endogenous insulin production and beta-cell function, at 78 weeks. 2. Secondary endpoints are: A. Key Clinical Endpoints: Exogenous insulin use: defined as the daily average of units per kilogram per day (U / kg / d) at week 78 HbA1c levels: at 78 weeks, expressed as % and mmol / mol TIR: Participant's blood glucose (BG), expressed as a daily average of the percentage of time over a 24-hour period, is greater than 70 mg / dL and less than 180 mg / dL (greater than 3.9 mmol / L and less than 10.0 mmol / L) at week 78, as assessed using a continuous glucose monitoring system (CGM). Clinically significant low blood glucose episodes: defined as the total number of episodes of BG readings <54 mg / dL (3.0 mmol / L) and / or episodes of severe cognitive impairment requiring external assistance for recovery from randomization through Week 78 B. Safety Endpoints: Occurrence of treatment-emergent adverse events (TEAEs), adverse events of special interest (AESIs), and serious adverse events (SAEs) - Patients with, but not limited to, tuberculosis, infections requiring IV antimicrobial therapy or hospitalization, Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections, or significant viremia (i.e., viral load of 1 mL or 10 6 Of particular note were the emergence of treatment-emergent infections, including varicella-zoster syndrome (>10,000 copies per cell) and herpes zoster. The occurrence and severity of immediate or delayed investigational product infusion-related reactions, such as hypersensitivity reactions, pain requiring interruption or cessation of the infusion, cytokine release syndrome, and serum sickness C. PK and Immunogenicity Endpoints: Teplizumab serum concentration -Appearance and titer of anti-teplizumab antibodies after treatment 3.Exploratory endpoints are as follows: A. Assessment of beta cell function and health throughout the study: C-peptide AUC in 4-hour MMTT Participants with a recognized clinically significant stimulated peak C-peptide of 0.2 pmol / m or greater during the 4-hour and 2-hour MMTT Proinsulin to C-peptide ratio, a measure of beta cell endoplasmic reticulum stress and dysfunction B. T1D-focused clinical endpoints during the study unless otherwise noted: Exogenous insulin use (U / kg / day) HbA1c level Participants with poor glycemic control, defined as HbA1c ≥ 9% The number of participants who are able to achieve local, regional, or national age-based glycemic control targets for HbA1c and / or daily blood glucose levels and therefore do not require exogenous insulin Assessment of glycemic control based on BG values ​​obtained from intermittent (i.e., spot checks, finger stick) glucose meter readings Assessment of glycemic control based on BG values ​​obtained from CGM readings, including but not limited to: TIR; time in hyperglycemic and hypoglycemic ranges; daily, midday, and overnight average BG levels and estimated HbA1c; and glycemic variability. Clinically significant hypoglycemic episodes from randomization through 39 weeks and from 39 weeks through 78 weeks "Classic" episodes of hypoglycemia, defined as BG levels ≥ 54 mg / dL (3.0 mmol / L) but < 70 mg / dL (3.9 mmol / L) and / or non-severe clinical episodes The emergence of diabetic ketoacidosis (DKA) requiring medical attention resulting in an outpatient or emergency department visit or hospitalization, defined as a hyperglycemic episode accompanied by an elevation of serum or urinary ketones above the upper limit of normal (ULN) along with serum bicarbonate <15 mmol / L or blood pH <7.3, or both. Patient-reported outcomes measured by instruments such as the Quality of Life Inventory™ (PedsQL) Diabetes Module, the Hypoglycemia Fear Scale (HFS), and the Diabetes Treatment Satisfaction Questionnaire (DTSQ) · Parent-reported impacts on home life as measured by the PedsQL Family Impact Questionnaire C. Composite Clinical Endpoint: Participants with both an HbA1c in the American Diabetic Association (ADA) target range (i.e., <7.5%) and exogenous insulin doses in specific ranges (<0.25, ≥0.25 <0.50, ≥0.50 <0.75, ≥0.75 <1.0, ≥1.0 <1.25, and ≥1.25 U / k / d) Participants with both HbA1c < 6.5% and < 7.0% and exogenous insulin dose < 0.5 U / kg / day or 0.25 U / kg / day D. Other endpoints during the study: Number, type, and titer of T1D autoantibodies -Human leukocyte antigen (HLA) typing with clinical, metabolic and immunological assessment

[0149] <Study design overview> This is a phase 3 randomized, double-blind, placebo-controlled, multinational, multicenter study that will enroll approximately 300 patients and randomly assign them in a 2:1 ratio to either the teplizumab group (N=200) or the placebo group (N=100).

[0150] To minimize bias in treatment allocation, potential confounding factors, and to enhance the validity of statistical analyses, participants will be randomized in a 2:1 ratio using randomly permuted blocks and stratification based on the following criteria: Peak C-peptide levels at screening: in the range of 0.2 (inclusion criteria) to 0.7 pmol / mL (cutoff limit included) vs. >0.7 pmol / mL Age at randomization: 8 to 12 years (inclusive) vs. >12 to 17 years

[0151] Teplizumab or matching placebo will be administered by IV infusion in two courses, the first course beginning on day 1 (week 1) and the second course beginning approximately 6 months later on day 182 (week 26). Each course of treatment will include daily infusions for 12 days.

[0152] The total study duration for each participant will be up to 84 weeks, including a screening period of up to 6 weeks and a post-randomization period of 78 weeks. The treatment period will include two 12-day treatment courses, 6 months apart, and a post-treatment observation period of approximately 52 weeks.

[0153] <Test group> The study will enroll male and female participants aged 8-17 years with new-onset T1D who are able to be randomized and begin study treatment within 6 weeks of their diagnosis. To be eligible for randomization, participants must test positive for at least one T1D-associated autoantibody and have a peak stimulatory C-peptide of 0.2 pmol / mL or greater at screening. Participants must also meet all of the specific inclusion criteria and not meet any exclusion criteria.

[0154] Dosage and Administration On the day of randomization (Day 1), each participant will receive their first dose of study medication for the first 12-day treatment course, as shown in the table below. On approximately Day 182, each participant will receive their first dose of the second 12-day course. Study medication (teplizumab or placebo) will be administered by IV infusion at the study site, or another site certified by study-approved personnel. Study medication doses will be calculated based on the participant's body surface area (BSA), measured on the first day of each treatment course. No dose adjustments will be permitted.

[0155] [Table 4]

[0156] <Critical Evaluation> MMTT: To quantify endogenous beta cell function, participants undergo a standardized provocative metabolic test for C-peptide (a 1:1 by-product of insulin production). Participants ingest a fixed amount of a beverage containing known amounts of carbohydrate, fat, and protein. After ingestion, BG, insulin, and C-peptide levels are measured over time. A 2-hour MMTT is performed at screening, and a 4-hour MMTT is performed at randomization and at weeks 26, 52, and 78 to assess primary endpoints.

[0157] HbA1c: This is the percentage of red blood cells (measured as hemoglobin) that are non-enzymatically glycated in proportion to blood glucose levels. On average, it represents approximately a three-month average of blood glucose values. It is an important clinical target in the management of T1D.

[0158] Insulin use: to quantify exogenously injected insulin, as average data over 7 days collected prior to each designated visit.

[0159] Hypoglycemia: Clinically significant and potentially life-threatening hypoglycemia is a consequence of insulin therapy and is likely to occur in patients attempting to achieve glycemic control goals. The study will ask participants to record information about BG levels below 70 mg / dL (3.9 mmol / L) and / or events consistent with hypoglycemia. In particular, we will focus on clinically significant hypoglycemic events, defined as a reliable glucose reading below 54 mg / dL (3.0 mmol / L) and / or severe cognitive impairment and / or a physical condition requiring external assistance for recovery.

[0160] Glucose monitoring: Intermittent glucose monitoring (e.g., spot checks or finger sticks) performed by the participant or caregiver multiple times per day as a necessary part of glycemic management to accurately measure insulin dosing and support diet and activity. All participants should bring their glucose meter to every visit for review. In addition to data on glycemic control, at designated times during the study, participants will report daily premeal and bedtime BG readings and have glucose levels assessed at 2-week intervals using a CGM.

[0161] Quality of Life Questionnaires: Surveys will be used to assess participants' general health and well-being, as well as the effects of teplizumab, including the PedsQL diabetes module, HFS, DTSQ, and parent-reported PedsQL family impact module.

[0162] Pharmacokinetic and Immunogenicity Assessment: Teplizumab concentrations will be analyzed in blood samples collected at designated time points throughout the study. Anti-teplizumab antibodies, including those that are neutralizing antibodies (NAbs), will be determined.

[0163] A diagram of the study design is provided in FIG.

[0164] The study will focus on individuals with a significant amount of beta cell functional capacity. It is recognized that beta cells continue to be lost following T1D diagnosis. To maximize the effect of beta cell preservation in patients with recoverable levels of endogenous insulin production, the study will recruit participants who are within 6 weeks of T1D diagnosis and have peak C-peptide levels of 0.2 pmol / mL or greater during a mixed meal tolerance test (MMTT). The value of 0.2 pmol / mL was chosen because it is a critical and acceptable threshold for C-peptide that correlates with clinically significant lower rates of T1D-related short- and long-term complications (Lachin 2014, Palmer 2001, Palmer 2009).

[0165] The total study duration for each participant will be up to 84 weeks. This will include a screening period of up to 6 weeks, and a post-randomization period of 78 weeks. The post-randomization period will include two 12-day treatment courses, 6 months apart, and a post-treatment observation period of approximately 52 weeks. The final visit will occur at week 78.

[0166] The overall study length and time points for critical assessments were chosen due to the natural history of residual β-cell loss following a diagnosis of T1D, and the study goals to demonstrate durability of efficacy and confirm the post-treatment safety profile of teplizumab. At the time of diagnosis, there may be substantial β-cell reserve, often estimated at 10-20%, but occasionally >40% of normal β-cell mass (Matveyenko 2008, Campbell-Thompson 2016). At the time of T1D diagnosis, most of this reserve appears to be functionally impaired due to metabolic or immunological (i.e., cytokine-induced) stress. With exogenous insulin treatment, and correction of the pH, electrolyte, and fluid disturbances (i.e., DKA) often present at the time of diagnosis, some β-cell function may return for days, weeks, or months. This observation, often referred to as the "honeymoon period," can result in a substantial reduction in insulin requirements and, at times, independence from exogenous insulin can be achieved. These effects are temporary and over time, usually within the first year of diagnosis, inevitable full insulin replacement becomes necessary due to autoimmune elimination of these remaining β-cells. Due to known individual differences in the natural history of β-cell loss, it is difficult to distinguish the effects of disease-modifying therapies intended to preserve β-cell function from the effect of a honeymoon period during the first 12 months after T1D diagnosis.

[0167] The 18-month time point for the primary and key secondary clinical endpoints provides the critical data necessary to accept teplizumab into routine medical practice as a T1D disease-modifying therapy and is consistent with existing guidelines for endpoints recommended by the EMA and FDA. Data from T1D natural history studies and interventional trials indicate that beta cell loss in those with T1D can be highly variable, especially within weeks to months after diagnosis. Because the study is enrolling younger participants proximal to T1D diagnosis (i.e., within 6 weeks), there may be an added complication of considering the honeymoon phenomenon (or spontaneous, temporary partial remission), which can last up to about a year in the study population (Abdul-Rasoul 2006). The 18-month timing of the primary and key secondary clinical endpoints allows for a substantial amount of inherent natural metabolic variation due to different trajectories of β-cell loss and / or temporarily enhanced β-cell function resulting from the honeymoon phenomenon to be minimized, thereby allowing the true effect of teplizumab on β-cell function and clinical parameters to be distinguished from chance.

[0168] Other key assessments will be performed at randomization, week 26 (6 months), and week 52 (12 months) to better understand the natural history of beta-cell decline and the effect of teplizumab in this particular study population.

[0169] In addition, the primary and key clinical endpoints will be assessed approximately 1 year after the last dose of study drug. Length of effect is recognized as an important attribute of intermittent disease-modifying therapies for T1D. A 12-month off-treatment period while maintaining positive metabolic and clinical effects can currently be considered a reasonable time frame to substantiate claims of sustained metabolically and clinically relevant benefit.

[0170] Throughout the study, participants will be regularly assessed via in-person interviews and physical examinations, self-reports, and laboratory tests. Assessments will be performed daily during the two 12-day treatment courses, as well as periodically during the 6-month interval between courses and 12 months after the second treatment course. The on-treatment and off-treatment observation times in this study are well within, if not significantly beyond, the time periods traditionally used to assess safety and side effects for immunotherapies approved for other autoimmune conditions, including those for pediatric indications. At doses and regimens similar to those used in this study, teplizumab was generally well tolerated with minimal side effects and no signals of significant short- or long-term adverse effects. With additional confirmatory data from this study, it is expected that the side effect profile of teplizumab will continue to be considered acceptable for integration into care plans for children and adolescents newly diagnosed with T1D.

[0171] In some embodiments, T1D diagnosis is according to ADA criteria. In some embodiments, a patient diagnosed with T1D has a positive result in a test for at least one of the following T1D-associated autoantibodies: glutamic acid decarboxylase (GAD65) autoantibodies, islet antigen 2 (IA-2) autoantibodies, zinc transporter 8 (ZnT8) autoantibodies, islet cytoplasmic autoantibodies (ICA), or insulin autoantibodies (if the test is obtained within the first 14 days of insulin treatment).

[0172] At the start of each 12-day course of study drug administration (Day 1 and Day 182), the participant's current BSA will be calculated using the Mosteller formula, BSA = square root [height (cm) × weight (kg) / 3600], using height and weight obtained on that day.

[0173] Teplizumab and placebo will be prepared according to the pharmacy manual provided to the site.

[0174] Polyvinyl chloride (PVC) infusion bags and tubing and normal saline should be used for preparation and administration of investigational medication.

[0175] 2 mL of investigational drug should be withdrawn from the investigational drug vial and slowly reconstituted in 18 mL of 0.9% sodium chloride solution for injection by gentle mixing. The resulting 20 mL of 1:10 dilution is used as the initial investigational drug solution containing either placebo or teplizumab at a concentration of 100 μg / mL. This initial drug solution should then be added to a PVC infusion bag containing 25 mL of 0.9% sodium chloride solution. Finally, this resulting preparation should be gently mixed before administration to the participant.

[0176] The study requires two courses of intravenous infusions and blood draws over 12 days. It is recognized that intravenous access (for infusions and blood draws for test sample collection) in the pediatric population that is the focus of this study can pose challenges. Children have smaller veins than adults, veins can be more difficult to catheterize, and they can have greater resistance to catheterization and / or phlebotomy.

[0177] In recognition of the above, in addition to the use of "standard" intravenous peripheral catheters, this study will permit the use of temporary, intermediate-term approaches for vascular access. Specifically, "midline" or peripherally inserted central catheter (PICC) lines may be used for investigational drug infusions and blood withdrawals (where appropriate according to the characteristics of the access line and local, regional, or national guidance).

[0178] All enrolled participants should receive intensive diabetes management of T1D using approved therapies in accordance with American Diabetes Association (ADA) recommendations or local, regional, or national recommendations, with the assistance of their health care provider, to achieve glucose levels that are likely to reduce some of the short-term or long-term sequelae of T1D. Currently, ADA glycemic targets focus on management strategies to achieve HbA1c levels of less than 7.5% (58 mmol / mol) for individuals 17 years of age or younger and less than 7.0% (53 mmol / mol) for those 18 years of age or older, while minimizing severe or frequent hypoglycemic events.

[0179] Glycemic goals should be attempted through appropriate blood glucose monitoring, administration of exogenous insulin, and monitoring of activity levels and meals. Exogenous insulin may include rapid-, intermediate-, and / or long-acting insulin, administered intermittently or via the use of a personal insulin pump. Blood glucose levels should be measured at least four times a day, including before meals and before bedtime.

[0180] Insulin use, including product type, dosage, and dosing schedule, is expected to change over the course of the study. As part of routine T1D clinical care, participants' insulin doses may be increased, decreased, or even discontinued as deemed clinically appropriate by the caring physician.

[0181] If a participant is not meeting glycemic goals, the study team should contact the participant's primary clinical care team regarding possible adjustments in insulin regimen, referral to a registered dietitian, or other approaches that may improve glucose control.

[0182] <Discontinuing insulin> Insulin therapy may be discontinued when participants achieve HbA1c levels of 6.5% or less with insulin use of 0.25 U / kg / day or less. Participants' blood glucose and HbA1c levels should continue to be monitored per protocol, and urinary ketones should be monitored once daily. If, during routine blood glucose monitoring, participants' blood glucose levels exceed 200 mg / dL (11.1 mmol / L) and / or urinary ketones are moderate or greater, participants should consult with their primary care physician and / or clinical site staff for further evaluation. If fasting blood glucose exceeds 126 mg / dL (7 mmol / L) or HbA1c exceeds 6.5%, as documented by repeat testing, resumption of insulin therapy should be considered.

[0183] Dosing of study medication (teplizumab or placebo) will be based on height and weight obtained at this visit and BSA using the Mosteller formula (BSA = square root [height (cm) x weight (kg) / 3600]).

[0184] <First week test visit> Patients will be premedicated with an NSAID (e.g., ibuprofen) (or acetaminophen if NSAIDs are contraindicated) and an antihistamine (e.g., diphenhydramine) for at least the first 5 days of the treatment course unless contraindicated by drug allergy or sensitivity. At least 30 minutes following administration of the premedication, the infusion of the study drug can begin. Because there are no preservatives and drug loss can occur over time, administration of the study drug should begin as soon as possible after preparation and no later than 2 hours after preparation. The study drug should be scheduled to be administered intravenously over 30 minutes as per standard practice, although this may be delayed if there are signs or symptoms of intolerance. Once the contents of the infusion bag have been completely administered, an additional volume of saline equal to the volume contained in the infusion tube is infused at the same constant rate to ensure that all study drug is cleared from the infusion tube. Start and end times for the infusion should be recorded.

[0185] Days 2-12: Continued treatment course 1 infusion In the absence of clinical or laboratory concerns, the patient may proceed with the next infusion as described above at least 30 minutes after administration of a prophylactic NSAID (or acetaminophen if an NSAID is contraindicated) and an antihistamine. Close monitoring should be performed during and for 60 minutes after the infusion for signs or symptoms of tolerance or infusion reactions.

[0186] Days 2-11 On days 2-11, patients are allowed to leave the facility and return the next day for their next study drug infusion.

[0187] Day 12 On day 12, following completion of the final infusion of the course and at least 30 minutes of observation, a continuous glucose monitoring (CGM) sensor will be applied and participants should be given instructions for the care and use of CGM monitoring.

[0188] <Study visits at weeks 4, 8, 12, and 20> The visit window for these study visits is ±4 days from the target visit date. During these visits, participants will return to the facility for their scheduled visit and clinical and / or laboratory assessments will be performed. Of note at week 12, a CGM sensor will be applied and participants should receive instructions for the care and use of CGM monitoring.

[0189] At the week 20 visit, participants will be given instructions for the 4-hour MMTT at week 26, including overnight fasting and insulin dosing prior to the MMTT.

[0190] <Study visit at week 26: 4-hour MMTT and treatment course 2> The visit window for these study visits is ±3 days from the target visit date.

[0191] Days 182-193 For clinical and laboratory assessments (including a 4-hour MMTT) on Day 182 and for the initiation of the second course of study drug administration.

[0192] Of particular note, height and weight should be obtained at this visit and used for BSA-based dosing calculations for Course 2. As per guidance for study drug in Course 1, patients should be premedicated with an oral NSAID (or acetaminophen if NSAIDs are contraindicated) and an antihistamine at least 30 minutes before the first 5 study drug infusions are started (and as needed for subsequent infusions), study drug administration should begin as soon as possible after preparation but within 2 hours after preparation, and an additional volume of saline equal to the volume contained in the infusion tubing should be infused. Participants should be monitored for signs or symptoms of infusion reactions during and for an additional 60 minutes after the infusion.

[0193] On any given day, two blood draws for teplizumab serum levels will be performed, one within 30 minutes prior to study drug infusion and one within 30 minutes after study drug infusion and flush.

[0194] Days 183-192 (Days 2-11 of Course 2) On days 183-192, participants may leave the site and return the next day for their next study drug infusion.

[0195] Day 193 (12th day of course 2) Following completion of the final injection of this course and at least 30 minutes of observation, a CGM sensor should be applied and the patient should be given instructions for the care and use of CGM monitoring.

[0196] <Study visits at weeks 30, 34, 39, 52 and 65> The visit window for these study visits is ±4 days from the target visit date. At the 52 week visit, a 4 hour MMTT will be performed.

[0197] At the end of the 39, 52, and 65 week visits, a CGM sensor should be applied and, if necessary, additional training and updated instructions for the care and use of the CGM will be given.

[0198] <Study visits at weeks 39 and 65> Patients will be given instructions for a 4-h MMTT at weeks 52 and 78, respectively, including overnight fasting and insulin dosing prior to the MMTT. At the week 65 visit, patients will be dispensed a CGM device for home use starting around week 76.

[0199] <Study visit at week 78> The visit window for this study visit is ±7 days from the target visit date. During this visit, a 4-hour MMTT will be performed.

[0200] <Mixed meal challenge test> A 2-hour MMTT is performed at screening (based on peak C-peptide levels) to determine study eligibility. A 4-hour MMTT is performed at randomization and at weeks 26, 52, and 78 to obtain 4-hour C-peptide AUC and other data. A 4-hour MMTT is used at and after randomization because it has been shown to be more accurate and reliable than a 2-hour MMTT in assessing MMTT-induced C-peptide AUC (Boyle 2015, Rigby 2013, Rigby 2016). Alternatively, a 2-hour MMTT is used at screening because it is sufficient to capture the peak C-peptide levels required for study entry. Samples from these assessments are assessed for C-peptide, serum glucose, and insulin. Samples are stored for potential future evaluations, including but not limited to proinsulin levels. Measurements of C-peptide and glucose are performed in serum samples. MMTTs should be monitored between approximately 7:00 AM and 10:00 AM after an overnight fast due to strict guidance against insulin use. A 2-hour MMTT takes approximately 130 minutes to administer, and a 4-hour MMTT takes approximately 250 minutes.

[0201] <Hemoglobin A1c> HbA1c will be assessed as a blood test at the selection study visit.

[0202] <Insulin use> Patients' daily insulin use will be documented by participants in the eDiary for 7 days prior to randomization and at selected times at approximately week 12, 26, 39, 52, 65, and 78 visits. Patients will record use of all short-acting, intermediate-acting, and long-acting insulin administered as intermittent injections or with an "insulin pump" during this period. Insulin use data will not be recorded the day before or the day of the study visit. If patients forget to record insulin use on one or more days prior to the visit, patients should continue to record insulin use for up to 72 hours after dosing to obtain a maximum of 7 days of data. Because patients will return their eDiary at their final visit, every effort should be made to collect a total of 7 days of insulin use data for all of the aforementioned visits except week 78 (final visit).

[0203] <Hypoglycemic episode> Clinically significant hypoglycemic episodes, and other non-severe and non-serious hypoglycemic episodes, will be recorded by participants throughout the study through evaluation of glucometer readings.

[0204] <Glucose monitoring> (1) Intermittent blood glucose monitoring (fingerstick) Blood glucose levels other than MMTT and CGM are recorded and analyzed as endpoints at various times. As part of routine care, BG levels are typically measured by fingerstick glucometer at least four times a day, including before each meal and at bedtime. At screening, participants are provided with the study-provided glucometer and glucometer strips, but participants are allowed to use their own glucometer if they choose, in which case glucose monitoring strips are not provided. Each participant is instructed to bring their glucometer (or multiple glucometers if the participant uses more than one, e.g., at home and at school) to each visit for review. In addition, approximately seven times throughout the study, participants record BG levels in their study eDiary before breakfast, lunch, and dinner, and at bedtime for seven consecutive days before the randomization visit and the 12th, 26th, 39th, 52nd, 65th, and 78th week visits. Similar to the recording of insulin use data, BG data for the day before and the day of the study visit are not recorded. If a participant forgets to record a fingerstick glucose measurement prior to a visit, the participant should record it for the 72 hours immediately following the visit. Because participants will return their eDiary at their final visit, every effort should be made to collect a total of 7 days of BG data for all of the aforementioned visits except week 78 (final visit).

[0205] (2) Continuous glucose monitoring "Continuous" glucose monitors record continuous glucose levels (which closely approximate blood glucose values) at regular intervals, e.g., every 5-15 minutes depending on the device. A growing number of clinical trials support that such measurements and their assessment provide valuable and unique insights into glycemic control in diabetes. In this study, CGM assessments were performed to provide data for important secondary clinical and exploratory endpoints to address whether and how teplizumab affects glycemic control, e.g., glucose exposure, time in selected glucose ranges, and average daily glucose levels (Steck 2014, Helminen 2016, Danne 2017). A recent international consensus statement on CGM monitoring supported the use of percentage of time in range (target, hypoglycemia, and hyperglycemia) and measurements of glycemic variability as key diabetes control indicators in clinical trials (Danne 2017).

[0206] Glycemic control will be assessed approximately seven times throughout the study using CGM (at randomization and after completion of the 26-week treatment course; after visits at 12, 39, 52, and 65 weeks; and prior to the 78-week visit). CGM sensors will be placed by qualified study staff, who will provide education and training in the use and care of CGM. The sensors will remain in place for a maximum of two weeks. If the sensor becomes dislodged during that two-week period, it may be replaced by the participant, a knowledgeable family member / guardian, or a qualified medical professional.

[0207] To reduce any confounding of glucose measurements during study drug infusion, CGM sensors will be placed in participants after study drug administration is completed for Course 1 and Course 2 and other clinical and laboratory assessments are performed on the dates specified in the schedule of events table. At the 12, 39, 52, and 65 week visits, sensors will be placed in participants after all clinical and laboratory assessments and MMTT are completed.

[0208] Although reading the study CGM is not intended to be medical management of participants' diabetes, it can be done under the supervision of the participants' health care team. Of note, routine use of a personal CGM is permitted under the guidance of participants' regular health care providers.

[0209] Spot checks and CGM blood glucose assessments are expected to include, but are not limited to, mean BG, glycemic variability (BG standard deviation [SD]), highest and lowest BG values ​​over time, and occurrence and / or percent of time of BG >70 mg / dL and <180 mg / dL (>3.9 mmol / L and <10.0 mmol / L), Level 1 (>180 mg / dL and <250 mg / dL (>10 mg / dL and <13.9 mmol / L)) and Level 2 hyperglycemia (>250 mg / dL (>13.9 mmol / L)), as well as Level 1 (<70 mg / dL and <54 mg / dL (>3.9 mmol / L and <3.0 mmol / L)) and Level 2 (<54 mg / dL (<3.0 mmol / L)) hypoglycemia (Seaquist 2013, International Hypoglycaemia Study Group [IHSG] 2017, Agiostratidou 2017).

[0210] Example 3: Meta-analysis of C-peptide in five stage 3 T1D trials <Summary> Confirmatory evidence in the form of a meta-analysis was performed using pooled C-peptide data from five supportive trials, all of which were randomized clinical trials: Protege, Encore, Study 1, AbATE, and Delay. These five trials compared teplizumab to either placebo or standard of care in patients with newly diagnosed stage 3 clinical T1D and had similar designs allowing comparisons between trials (Table 5).

[0211] The meta-analysis evaluated the change from baseline in C-peptide AUC during a 4-h mixed meal tolerance test (MMTT). Analysis of covariance (ANCOVA) was used to estimate mean C-peptide values ​​(least squares means) and individual treatment differences. The meta-analysis had two components: the first was performed in all five studies with 1-year follow-up, and the second was performed in the three studies that had 2-year follow-up.

[0212] In a meta-analysis of 1-year (Figure 26) and 2-year (Figure 27) C-peptide data, patients treated with teplizumab had significantly higher C-peptide levels compared to controls (p<0.001 for both). This effect was consistent for both 1- and 2-year observational and imputed data, as well as for sensitivity analyses that assigned control data to missing data in the teplizumab group.

[0213] To assess whether C-peptide differed between those who were T1D-free and those who developed T1D, separate plots of mean C-peptide over time were generated. As can be seen in Figure 28, those treated with teplizumab who remained T1D-free or eventually developed T1D during the study had higher mean C-peptide values ​​compared to their respective controls.

[0214] <Study design> Confirmatory evidence in the form of a meta-analysis was performed using pooled C-peptide data from five supportive randomized clinical trials: Protege, Encore, Study 1, AbATE, and Delay. C-peptide AUC levels were obtained from 4-hour MMTTs.

[0215] Table 5 shows the study design features across these five trials in stage 3 T1D patients. These trials were selected because they were representative of all randomized trials conducted with teplizumab in stage 3 T1D and used either placebo or standard of care as controls. A similar 14-day escalating dose regimen was used throughout the studies. In Study 1, the 14-day weight-based dosing regimen was subsequently modified to a 12-day BSA-based dosing regimen. However, a 14-day regimen with a 4-day escalation step was adopted in subsequent clinical trials, apparently due to the occurrence of more AEs during the earlier dosing period in the 12-day regimen with a 2-day escalation step. Patients received two 14-day treatment courses in Protege, Encore, and AbATE, and a single treatment course at baseline in Delay and Study 1. The Protege and Encore trials enrolled patients with newly diagnosed stage 3 T1D into four treatment arms: placebo and three teplizumab dosing regimens (full dose for 14 days [9.0 mg / m2 cumulative dose], one-third dose for 14 days [approximately 3.0 mg / m2 cumulative dose], and shortened by 6 days [approximately 2.5 mg / m2 cumulative dose]). In the meta-analysis, we used C-peptide data from the full dose, 14-day regimen. Study 1, AbATE, and Delay trials all used the full dose, 14-day regimen (cumulative dose 9.0 mg / m2).

[0216] [Table 5]

[0217] Patients enrolled in these studies (Table 6) were representative of the newly diagnosed T1D patient population, excluding those with significant medical history, clinical abnormalities, or active infections. Key inclusion criteria were similar across studies. C-peptide levels at study entry were ≥0.2 nmol / L in AbATE, Delay, and Study 1, and detectable levels in Protege and Encore.

[0218] [Table 6]

[0219] The primary endpoint of the meta-analysis was the change from baseline in C-peptide AUC during the 4-hour MMTT. Each study calculated the C-peptide AUC using the same sample collection time points during the MMTT.

[0220] <Meta-analysis of change from baseline in C-peptide AUC during 4-hour MMTT> Patients in the teplizumab group had higher C-peptide preservation (i.e., smaller decline from baseline) at 1- and 2-year follow-up. This effect was consistent for observational and imputed data (p<0.0001 for both analyses). Furthermore, a conservative sensitivity analysis applying control-based imputation (assigning control data to missing teplizumab data) was also significant (p<0.0001).

[0221] The results for the 1-year and 2-year meta-analyses are shown in the forest plots in Figure 26 and Figure 27, respectively. Both forest plots show that the observed (existing) and imputation analyses gave a consistent effect of teplizumab in preserving C-peptide AUC levels. In the 1-year forest plots, teplizumab treatment was consistently more effective than placebo in all studies except Encore. The results in the Encore study were expected since the companion phase 3 study, Protege, did not meet its 1-year primary endpoint, leading to a revision of the study before its completion, resulting in a large amount of missing data that required the largest amount of imputation. Approximately 75% (93 / 125) of the MMTTs were missing. The primary endpoint of the Protege study was a novel, unvalidated composite endpoint focused on metabolic parameters (HbA1c and insulin use).

[0222] In a forest plot of the 2-year data (Figure 27), teplizumab treatment significantly preserved C-peptide AUC levels compared to placebo in all three studies with 2-year data.

[0223] Example 4: Insulin use in five stage 3 T1D trials In the same five studies included in the C-peptide meta-analysis in Example 3, exogenous insulin use was assessed individually in each study. Mean insulin use across time points in each study was numerically lower in teplizumab-treated patients compared to placebo (Figure 29). In two studies (AbATE, Study 1), the differences were statistically significant.

[0224] Specifically, in all five studies, mean insulin use across time points was lower in teplizumab patients compared to placebo patients (Figure 29). Three studies (AbATE, Delay, and Study 1) showed that teplizumab treatment consistently resulted in statistically significant lower levels of insulin requirement compared to placebo (Herold et al., 2013a; Herold et al., 2005; Herold et al., 2013b). Insulin use in the teplizumab group was also lower compared to the placebo group, although statistical significance was not achieved in the Protege and Encore studies. Thus, teplizumab treatment preserves C-peptide levels as reflected by higher endogenous insulin production and lower exogenous insulin requirement.

[0225] Overall, these data support that teplizumab preserves beta cell function as measured by C-peptide levels and, correspondingly, endogenous insulin production, resulting in a lower need for exogenous insulin.

[0226] Example 5: Clinical Pharmacokinetics and Pharmacodynamics Mechanism of action: Teplizumab is a humanized monoclonal antibody that targets the cluster of differentiation 3 (CD3) antigen, which is co-expressed with the T cell receptor (TCR) on the surface of T lymphocytes. The mechanism of action of teplizumab for the proposed indication has not been confirmed but appears to involve weak agonist activity on signaling through the TCR-CD3 complex, which may expand regulatory T cells and re-establish immune tolerance.

[0227] Pharmacokinetics: Figure 30 shows plots of predicted mean teplizumab concentrations over time using a 14-day intravenous (IV) dosing regimen with a 4-day increment followed by a repeat dose of 826 μg / m2 on days 5-14. The left panel represents a typical 60 kg male subject and the right panel represents a typical 40 kg and 90 kg male subject. Dosing based on body surface area (BSA) normalizes exposure across body sizes.

[0228] Repeated IV infusions resulted in increasing serum teplizumab levels, but steady-state PD was not reached at the end of dosing (day 14 within this dosing regimen). The mean accumulation ratio for the area under the curve (AUC) between days 5 and 14 was 3.4. The predicted mean (±SD) total AUC for the 14-day dosing regimen was 6421±1940 ng·day / mL, with Cmax and Cmin of 826±391 and 418±225 ng / mL, respectively, on day 14.

[0229] Distribution: Central and peripheral volumes of distribution from population PK analysis were 3.4 L and 6.9 L, respectively.

[0230] Elimination: Teplizumab clearance is not dose proportional and may be driven by its saturable binding to the CD3 receptor on the surface of T cells. Teplizumab is expected to be degraded to smaller peptide fragments by catabolic pathways. The clearance of teplizumab after a 14-day dosing regimen was estimated from population PK analysis to be 2.3 L / day with a terminal half-life of approximately 4 days.

[0231] The planned commercial formulation was manufactured at a different facility from the clinical trial product and was not used in the clinical trials submitted to support efficacy and safety. A single-dose PK bridging study evaluating the biocomparability of the commercial and clinical trial formulations was performed in healthy volunteers. The mean AUC0-inf for the commercial product was less than half (48.5%, 90% CI: 43.6-54.1) of the AUC0-inf for the product used in the pivotal efficacy study. The reason for this difference is likely a faster clearance of the drug from the circulation rather than differences in product strength, since similar concentrations were observed immediately after IV infusion (Cmax of the commercial product was 94.5% (90% CI; 84.5-106) of the Cmax observed in the clinical trial formulation).

[0232] Example 6: Adverse Events Adverse events associated with teplizumab administration have also been studied. Notably, teplizumab has no overall infection safety signal to date, but based on data from completed trials, patients who received the 12-day dosing regimen (1 or 2 cycles) instead of the 14-day regimen appear to report fewer infection adverse events (Table 7).

[0233] [Table 7]

[0234] Modifications and variations of the methods and compositions described in the present disclosure will be apparent to those skilled in the art without departing from the scope and spirit of the present disclosure.Although the present disclosure has been described in connection with specific embodiments, it should be understood that the present disclosure as claimed should not be unduly limited to such specific embodiments.Indeed, various modifications of the described modes for carrying out the present disclosure are intended to fall within the scope of the present disclosure as represented by the following claims, and will be understood by those skilled in the relevant fields to which the present disclosure pertains.

[0235] [Incorporation by reference] All patents and publications mentioned in this specification are herein incorporated by reference to the same extent as if each individual patent and publication was specifically and individually indicated to be incorporated by reference.

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Claims

1. 1. A pharmaceutical composition comprising teplizumab for use in a method for treating new-onset type 1 diabetes (T1D) induced by a viral infection, said method comprising administering to a subject in need thereof at a dose of about 9000 μg / m 2 to about 14,000 μg / m 2 1. A pharmaceutical composition comprising administering a 12-day course of teplizumab for a total dose of up to 12 days.

2. The total dose of teplizumab is about 9000 μg / m 2 to about 9500 μg / m 2 The pharmaceutical composition of claim 1 , wherein the

3. The 12-day course is 106 μg / m on day 1 2 a first dose of teplizumab of 425 μg / m on day 2 2 a second dose of teplizumab, and 850 μg / m on each of days 3 to 12 2 One dose of teplizumab and a total dose of teplizumab of approximately 9031 μg / m 2 The pharmaceutical composition of claim 1, wherein

4. 10. The pharmaceutical composition of claim 1, wherein the method comprises administering two identical 12-day courses of teplizumab.

5. The pharmaceutical composition according to claim 4, wherein the two courses are administered at an interval of about 6 to about 12 months.

6. 1. A pharmaceutical composition comprising teplizumab for use in a method for treating new-onset type 1 diabetes (T1D) induced by a viral infection, the method comprising administering to a subject in need thereof two 12-day courses of teplizumab about 6 months to about 12 months apart, wherein each 12-day course comprises: 106 μg / m on day 1 2 a first dose of teplizumab of 425 μg / m on day 2 2 a second dose of teplizumab, and 850 μg / m on each of days 3 to 12 2 One dose of teplizumab The total teplizumab dose for each course is approximately 9031 μg / m 2 A pharmaceutical composition comprising:

7. The pharmaceutical composition of any one of claims 1 to 6, wherein each dose is administered parenterally.

8. The pharmaceutical composition of any one of claims 1 to 6, wherein each dose is administered by intravenous infusion.

9. The pharmaceutical composition of any one of claims 1 to 6, wherein the subject in need thereof has been diagnosed with T1D within 6 to 12 weeks prior to the administering step.

10. 1. A pharmaceutical composition comprising teplizumab for use in a method for treating new-onset type 1 diabetes (T1D) induced by a viral infection, the method comprising administering to a subject in need thereof two 12-day courses of teplizumab by intravenous infusion about 6 to about 12 months apart, wherein each 12-day course comprises: 106 μg / m on day 1 2 a first dose of teplizumab of 425 μg / m on day 2 2 a second dose of teplizumab, and 850 μg / m on each of days 3 to 12 2 One dose of teplizumab The total teplizumab dose for each course is approximately 9031 μg / m 2 wherein the subject has been diagnosed with T1D within six weeks prior to the administering step.

11. 11. The pharmaceutical composition of any one of claims 5, 6 and 10, wherein two courses of teplizumab are administered about six months apart.

12. 11. The pharmaceutical composition of any one of claims 5, 6 and 10, wherein two courses of teplizumab are administered about 12 months apart.

13. The method further comprises administering to the subject one or more additional 12-day courses of teplizumab, each additional course being about 9000 μg / m 2 to about 14,000 μg / m 2 11. The pharmaceutical composition of any one of claims 1-6 and 10, further comprising administering at a total teplizumab dose of up to 100 mg / kg.

14. Each additional 12-day course of teplizumab 106 μg / m on day 1 2 a first dose of teplizumab of 425 μg / m on day 2 2 a second dose of teplizumab, and 850 μg / m on each of days 3 to 12 2 One dose of The total teplizumab dose for each course is approximately 9031 μg / m 2 The pharmaceutical composition of claim 13, wherein

15. 14. The pharmaceutical composition of claim 13, wherein each additional 12-day course of teplizumab is administered about 12 months to about 24 months after the previous course.

16. The method comprises: determining the baseline level of TIGIT KLRG1 CD8 T cells relative to total CD3 T cells before and after administration of each 12-day course; monitoring the level of TIGIT+KLRG1+CD8+CD3+ T cells; administering an additional 12-day course of teplizumab if the level of TIGIT+KLRG1+CD8+CD3+ T cells returns to the baseline level. The pharmaceutical composition according to any one of claims 1 to 6 and 10, comprising:

17. 17. The pharmaceutical composition of claim 16, wherein said determining TIGIT+KLRG1+CD8+CD3+ T cells is by flow cytometry.

18. 17. The pharmaceutical composition of claim 16, wherein said determining TIGIT+ KLRG1+ CD8+ CD3+ T cells is about 1 to 6 months, about 2 to 5 months, or about 3 months after administration of each 12-day course.

19. 17. The pharmaceutical composition of claim 16, wherein if the subject has more than about 10% TIGIT+KLRG1+CD8+ T cells among total CD3+ T cells, then the subsequent monitoring step is once a year.

20. 17. The pharmaceutical composition of claim 16, wherein if the subject has less than about 10% TIGIT+KLRG1+CD8+ T cells among total CD3+ T cells, then the subsequent monitoring step is about every 3 to 6 months.

21. 11. The pharmaceutical composition of any one of claims 1-6 and 10, wherein the administering step results in a decrease in insulin use, HbA1c levels, low blood glucose episodes, or a combination thereof compared to pre-treatment levels.

22. 22. The pharmaceutical composition of claim 21, wherein the reduction in insulin use, HbA1c levels, low blood glucose episodes, or a combination thereof is over a period of 12 months or more.

23. 11. The pharmaceutical composition of any one of claims 1 to 6 and 10, wherein the subject in need thereof has a peak C-peptide level of 0.2 pmol / mL or greater during a mixed meal tolerance test (MMTT).

24. 11. The pharmaceutical composition of any one of claims 1 to 6 and 10, wherein the subjects receiving teplizumab have higher mean C-peptide levels compared to controls receiving a placebo.

25. The pharmaceutical composition of any one of claims 1 to 6 and 10, comprising a step of assessing the area under the C-peptide time concentration curve (AUC) after a mixed meal tolerance test (MMTT) at 78 weeks.

26. 11. The pharmaceutical composition of any one of claims 1 to 6 and 10, wherein the subject in need thereof has at least 20% beta cell function prior to administration of the first dose.

27. The pharmaceutical composition of any one of claims 1 to 6 and 10, wherein the subject in need thereof is positive for type 1 diabetes-associated autoantibodies.

28. said subject in need thereof for at least the first 5 days of a course of treatment; nonsteroidal anti-inflammatory drugs (NSAIDs), optionally ibuprofen, acetaminophen, and / or Antihistamines, sometimes diphenhydramine The pharmaceutical composition according to any one of claims 1 to 6 and 10, wherein the compound is administered as a premedication.

29. The method according to any one of claims 1 to 6 and 10, wherein the viral infection is an infection caused by severe acute respiratory syndrome (SARS)-associated coronavirus (SARS-CoV-2). Pharmaceutical composition.

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