Methods of treating type 1 diabetes

Abstract

Provided herein are methods of treating type 1 diabetes mellitus (T1D). Such methods may comprise administering tilizumab to a subject in need thereof at intervals of about 3 months to about 12 months at a total dose greater than about 9000 [mu] g / m2 for a first 12-day course of treatment and tilizumab at a total dose greater than about 9000 [mu] g / m2 for a second 12-day course of treatment.

Description

Cross-reference to related applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 515,949, filed July 27, 2023, and U.S. Provisional Application No. 63 / 590,883, filed October 17, 2023, the contents of which are incorporated herein by reference in their entirety. sequence list

[0002] This application includes an enclosed sequence list submitted electronically. The electronic file, created on July 23, 2024, is named 122548WO061.xml and is 3,380 bytes in size. The contents of that file are incorporated herein by reference in their entirety. Background Technology

[0003] Type 1 diabetes (T1D) is caused by the autoimmune destruction of insulin-producing beta cells on the island of Langerhans, leading to a dependence on exogenous insulin injections for survival. Approximately 1.6 million Americans have T1D. It is one of the most common childhood diseases. Despite improvements in care, most people with T1D are still unable to consistently achieve their desired blood glucose targets. The increased risk of morbidity and mortality for individuals with T1D remains a significant concern. Two recent studies indicated that children diagnosed before age 10 have a 17.7-year reduced life expectancy, while Scottish men and women diagnosed as adults have 11 and 13 years fewer life expectancy, respectively. Therefore, there is a need for improved treatments and combinations for T1D. Summary of the Invention

[0004] This disclosure relates to a method of treating T1D using tilipizumab, for example, by slowing the loss of β-cell function. The T1D to be treated may be phase 3 or clinical T1D. In some embodiments, the patient has new-onset or recently-onset T1D, for example, the patient was diagnosed with phase 3 or clinical T1D within six weeks prior to receiving tilipizumab treatment. In some embodiments, the subject has at least 20% β-cell function prior to receiving tilipizumab treatment. In some embodiments, the patient has a peak C-peptide level of at least 0.2 pmol / mL during a mixed dietary tolerance test (MMTT) (e.g., a two-hour MMTT) prior to receiving tilipizumab treatment. In some embodiments, the patient is, for example, a child or adolescent aged approximately 8 to 17 years (inclusive).

[0005] In some embodiments, the method includes administering a total dose of approximately 9000 μg / m² to a subject in need. 2 Approximately 9500 μg / m 2The first 12-day course of telizumab, wherein the subject had a peak C-peptide level of at least 0.2 pmol / mL during the MMTT (e.g., two-hour MMTT) prior to administration of the first 12-day course of telizumab; and the subject was administered a total dose of approximately 9000 μg / mL. 2 Approximately 9500 μg / m 2 The second 12-day course of teliximab, wherein the first and second 12-day courses of teliximab are administered at an interval of at least about 3 months, or at an interval of about 6 months to about 12 months.

[0006] In some embodiments, the method includes administering a total dose of approximately 9000 μg / m² to a subject in need. 2 Approximately 14000 μg / m 2 The first 12-day course of telizumab, wherein the subject had a peak C-peptide level of at least 0.2 pmol / mL during the MMTT (e.g., two-hour MMTT) prior to administration of the 12-day course of telizumab; and the subject was administered a total dose of approximately 9000 μg / mL. 2 Approximately 14000 μg / m 2 The second 12-day course of teliximab, wherein the first and second 12-day courses of teliximab are administered at an interval of at least about 3 months, or at an interval of about 6 months to about 12 months.

[0007] This disclosure relates to telizumab for use in a method of treating T1D, the method comprising administering a total dose of approximately 9000 μg / m² to a subject in need. 2 Approximately 9500 μg / m 2 The first 12-day course of telizumab, wherein the subject had a peak C-peptide level of at least 0.2 pmol / mL during the MMTT (e.g., two-hour MMTT) prior to administration of the first 12-day course of telizumab; and the subject was administered a total dose of approximately 9000 μg / mL. 2 Approximately 9500 μg / m 2 The second 12-day course of teliximab, wherein the first and second 12-day courses of teliximab are administered at an interval of at least 3 months, or at an interval of about 6 months to about 12 months.

[0008] This disclosure relates to telizumab for use in a method of treating T1D, the method comprising administering a total dose of approximately 9000 μg / m² to a subject in need. 2 Approximately 14000 μg / m 2The first 12-day course of telizumab, wherein the subject had a peak C-peptide level of at least 0.2 pmol / mL during the MMTT (e.g., two-hour MMTT) prior to administration of the first 12-day course of telizumab; and the subject was administered a total dose of approximately 9000 μg / mL. 2 Approximately 14000 μg / m 2 The second 12-day course of teliximab, wherein the first and second 12-day courses of teliximab are administered at an interval of at least 3 months, or at an interval of about 6 months to about 12 months.

[0009] In some embodiments, the 12-day treatment course includes a first dose of 106 μg / m² on day 1. 2 Teglituzumab, second dose on day 2, 425 μg / m² 2 Teglituzumab, and one dose of 850 μg / mcg daily from day 3 to 12. 2 The total dose of telizumab was approximately 9031 μg / m². 2 .

[0010] In some embodiments, the method further includes administering a third or more 12-day cycles of telizumab to the subject, each cycle containing a total dose greater than about 9000 μg / m². 2 In some embodiments, the third or more 12-day cycles of telixirmab comprise a first dose of 106 μg / m² on day 1. 2 Teglituzumab, second dose on day 2, 425 μg / m² 2 Teglituzumab, and one dose of 850 μg / mcg daily from day 3 to 12. 2 The total dose of telizumab in each cycle is approximately 9031 μg / m². 2 In some embodiments, the third or more 12-day courses of telixirmab are administered at intervals of at least 3 months, or at intervals of about 6 months to about 24 months.

[0011] In some embodiments, the method includes determining the baseline levels of TIGIT+KLRG1+CD8+ T cells relative to all CD3+ T cells and / or PD-1+CD8+ T cells relative to all CD3+ T cells after each 12-day treatment cycle, monitoring the levels of TIGIT+KLRG1+CD8+CD3+ T cells and / or PD-1+CD8+CD3+ T cells, and administering an additional 12-day cycle of telizumab when the levels of TIGIT+KLRG1+CD8+CD3+ T cells and / or PD-1+CD8+CD3+ T cells return to baseline levels. In some embodiments, the baseline levels of TIGIT+KLRG1+CD8+ T cells and / or PD-1+CD8+ T cells are less than approximately 5% of the total CD3+ T cells. In some embodiments, TIGIT+KLRG1+CD8+CD3+ T cells and / or PD-1+CD8+CD3+ T cells are determined by flow cytometry. In some embodiments, TIGIT+KLRG1+CD8+CD3+ T cells and / or PD-1+CD8+CD3+ T cells are monitored by flow cytometry. In some embodiments, TIGIT+KLRG1+CD8+CD3+ T cells and / or PD-1+CD8+CD3+ T cells are measured approximately 1–6 months, approximately 2–5 months, or approximately 3 months after each 12-day treatment cycle. In some embodiments, if the subject has more than approximately 10% TIGIT+KLRG1+CD8+ T cells and / or more than approximately 10% PD-1+CD8+ T cells in all CD3+ T cells, follow-up monitoring is performed annually. In some embodiments, if the subject has less than approximately 10% TIGIT+KLRG1+CD8+ T cells and / or less than approximately 10% PD-1+CD8+ T cells in all CD3+ T cells, follow-up monitoring is performed approximately every 3–6 months.

[0012] In some embodiments, each dose of telizumab is administered parenterally (e.g., via intravenous infusion). Subjects may be pre-administered with (1) a nonsteroidal anti-inflammatory drug (NSAID) or acetaminophen, (2) an antihistamine, and / or (3) an antiemetic three, four, five, six, or seven days before each dose in each cycle of treatment.

[0013] In some embodiments, subjects have peak C-peptide levels in the range of 0.2 pmol / mL to 0.7 pmol / mL during the MMTT (e.g., a two-hour MMTT). In some embodiments, subjects who require peak C-peptide levels of at least 0.7 pmol / mL during the MMTT (e.g., a two-hour MMTT) may have peak C-peptide levels of at least 0.7 pmol / mL.

[0014] In some embodiments, the method includes evaluating the area under the time-concentration curve (AUC) of the C-peptide at 78 weeks or 18 months after MMTT.

[0015] In some embodiments, subjects receiving telizumab had higher mean C-peptide values ​​compared to controls receiving placebo. "Receiving telizumab" means that a subject has been given one or more courses of telizumab. "Controls receiving placebo" are control subjects who did not receive telizumab (i.e., no dose of telizumab).

[0016] In some embodiments, administration of telizumab to subjects resulted in a mean C-peptide value that was 40% to 80% or more higher than that of subjects receiving placebo.

[0017] In some embodiments, subjects receiving telizumab maintain or reduce baseline HbA1c levels and / or maintain or increase the time within range (TIR) ​​with less insulin compared to subjects receiving placebo. For example, subjects receiving telizumab have reduced HbA1c levels compared to pre-treatment levels (i.e., prior to receiving any telizumab treatment).

[0018] In some embodiments, administration of telizumab to subjects resulted in a 10% to 30% or more reduction in insulin dose compared to subjects receiving placebo.

[0019] In some embodiments, administration of telizumab to a subject may reduce the insulin dose by at least 0.1 U / kg / day or maintain the insulin dose.

[0020] In some embodiments, administration of telizumab to subjects resulted in a reduction of HbA1c baseline of 0.1 to 1 point or more compared to subjects receiving placebo.

[0021] In some embodiments, administration of telizumab to a subject may increase the blood glucose TIR (%) assessed using a glucose monitoring system by 3% to 10% or more.

[0022] In some embodiments, administration of telizumab to subjects resulted in fewer grade 3 hypoglycemic episodes (e.g., at least 1, 2, or 3 fewer per year) compared to control subjects receiving placebo.

[0023] This disclosure relates to a method for maintaining or increasing C-peptide levels and / or slowing β-cell dysfunction in a subject with T1D (e.g., stage 3 or clinical T1D). In some embodiments, the method includes administering a total dose of about 9000 μg / m² to the subject. 2 Approximately 9500 μg / m2 The first 12-day course of telizumab was administered, wherein the subject had a peak C-peptide level of at least 0.2 pmol / mL during the MMTT prior to administration of the first 12-day course of telizumab; and the subject was administered a total dose of approximately 9000 μg / mL. 2 Approximately 9500 μg / m 2 The second 12-day course of telizumab, wherein the first and second 12-day courses of telizumab are administered at intervals of approximately 6 months to approximately 12 months, and wherein administration of telizumab results in a 40% to 80% or greater increase in mean C-peptide levels compared to subjects receiving placebo. In some embodiments, the method includes administering a total dose of approximately 9000 μg / m² to the subject. 2 Approximately 14000 μg / m 2 The first 12-day course of telizumab, wherein the subject had a peak C-peptide level of at least 0.2 pmol / mL during the MMTT (e.g., two-hour MMTT) prior to administration of the first 12-day course of telizumab; and the subject was administered a total dose of approximately 9000 μg / mL. 2 Approximately 14000 μg / m 2 The second 12-day course of teliximab, wherein the first and second 12-day courses of teliximab are administered at an interval of at least about 3 months, or at an interval of about 6 months to about 12 months, and wherein, compared with the placebo-receiving subjects, administration of teliximab increases the mean C-peptide value by 40% to 80% or more.

[0024] This disclosure relates to telizumab for use in a method for maintaining or increasing C-peptide levels and / or slowing β-cell dysfunction in subjects with T1D (e.g., stage 3 or clinical T1D), the method comprising administering to the subject a total dose of approximately 9000 μg / m². 2 Approximately 9500 μg / m 2 The first 12-day course of telizumab, wherein the subject had a peak C-peptide level of at least 0.2 pmol / mL during the MMTT (e.g., two-hour MMTT) prior to administration of the first 12-day course of telizumab; and the subject was administered a total dose of approximately 9000 μg / mL. 2 Approximately 9500 μg / m 2 The second 12-day course of teliximab, wherein the first and second 12-day courses of teliximab are administered at an interval of at least about 3 months, or at an interval of about 6 months to about 12 months, and wherein, compared with the placebo-receiving subjects, administration of teliximab increases the mean C-peptide value by 40% to 80% or more.

[0025] This disclosure relates to telizumab for use in a method for maintaining or increasing C-peptide levels and / or slowing β-cell dysfunction in subjects with T1D (e.g., stage 3 or clinical T1D), the method comprising administering to the subject a total dose of approximately 9000 μg / m². 2 Approximately 14000 μg / m 2 The first 12-day course of telizumab, wherein the subject had a peak C-peptide level of at least 0.2 pmol / mL during the MMTT (e.g., two-hour MMTT) prior to administration of the first 12-day course of telizumab; and the subject was administered a total dose of approximately 9000 μg / mL. 2 Approximately 14000 μg / m 2 The second 12-day course of teliximab, wherein the first and second 12-day courses of teliximab are administered at intervals of at least 3 months, or at intervals of about 6 months to about 12 months, and wherein administration of teliximab increases the mean C-peptide value by 40% to 80% or more compared with the placebo-receiving subjects.

[0026] In some embodiments, the 12-day treatment course includes a first dose of 106 μg / m² on day 1. 2 Teglituzumab, second dose on day 2, 425 μg / m² 2 Teglituzumab, and one dose of 850 μg / mcg daily from day 3 to 12. 2 And the total dose was approximately 9031 μg / m 2 .

[0027] In some embodiments, the method further includes administering a third or more 12-day cycles of telizumab to subjects in need, each cycle containing a total dose greater than about 9000 μg / m². 2 In some embodiments, the third or more 12-day cycles of telixirmab include a first dose of 106 μg / m² on day 1. 2 Teglituzumab, second dose on day 2, 425 μg / m² 2 Teglituzumab, and one dose of 850 μg / mcg daily from day 3 to 12. 2 And the total dose for each treatment course is approximately 9031 μg / m². 2 In some embodiments, the third or more 12-day courses of telixirmab are administered at intervals of approximately 6 months to approximately 24 months.

[0028] In some embodiments, the method includes measuring the baseline levels of TIGIT+KLRG1+CD8+ T cells relative to all CD3+ T cells and / or PD-1+CD8+ T cells relative to all CD3+ T cells after each 12-day treatment cycle, monitoring the levels of TIGIT+KLRG1+CD8+CD3+ T cells and / or PD-1+CD8+CD3+ T cells; and administering an additional 12-day cycle of telizumab when the levels of TIGIT+KLRG1+CD8+CD3+ T cells and / or PD-1+CD8+CD3+ T cells return to baseline levels. In some embodiments, the baseline levels of TIGIT+KLRG1+CD8+ T cells and / or PD-1+CD8+ T cells are less than approximately 5% of the total CD3+ T cells. In some embodiments, TIGIT+KLRG1+CD8+CD3+ T cells and / or PD-1+CD8+CD3+ T cells are measured by flow cytometry. In some embodiments, TIGIT+KLRG1+CD8+CD3+ T cells and / or PD-1+CD8+CD3+ T cells are monitored by flow cytometry. In some embodiments, TIGIT+KLRG1+CD8+CD3+ T cells and / or PD-1+CD8+CD3+ T cells are measured approximately 1–6 months, approximately 2–5 months, or approximately 3 months after each 12-day treatment cycle. In some embodiments, if the subject has more than approximately 10% TIGIT+KLRG1+CD8+ T cells and / or more than approximately 10% PD-1+CD8+ T cells in all CD3+ T cells, follow-up monitoring is performed annually. In some embodiments, if the subject has less than approximately 10% TIGIT+KLRG1+CD8+ T cells and / or less than approximately 10% PD-1+CD8+ T cells in all CD3+ T cells, follow-up monitoring is performed approximately every 3–6 months.

[0029] In some embodiments, each dose of telizumab is administered parenterally. In some embodiments, each dose of telizumab is administered via intravenous infusion. Patients may be pre-administered as described herein.

[0030] In some embodiments, the subject has a peak C-peptide level in the range of 0.2 pmol / mL to 0.7 pmol / mL during the MMTT (e.g., a two-hour MMTT). In some embodiments, the subject has a peak C-peptide level of at least 0.7 pmol / mL during the MMTT (e.g., a two-hour MMTT).

[0031] In some embodiments, the method includes assessing the AUC of the C-peptide at 78 weeks or 18 months after MMTT (e.g., four-hour MMTT).

[0032] In some embodiments, subjects given telizumab maintained or reduced baseline HbA1c levels and / or maintained or increased TIR with less insulin compared to subjects given placebo.

[0033] In some embodiments, administration of telizumab to subjects resulted in a 10% to 30% or more reduction in insulin dose compared to subjects receiving placebo.

[0034] In some embodiments, administration of telizumab to a subject may reduce the insulin dose by at least 0.1 U / kg / day or maintain the insulin dose.

[0035] In some embodiments, administration of telizumab to subjects resulted in a reduction of HbA1c baseline of 0.1 to 1 point or more compared to subjects receiving placebo.

[0036] In some embodiments, administration of telizumab to a subject may increase the blood glucose TIR (%) assessed using a glucose monitoring system by 3% to 10% or more.

[0037] Slowing down β-cell function loss includes preserving β-cells, slowing down β-cell loss or destruction, and / or preserving β-cell function (e.g., insulin production). In some embodiments, this administration of telizumab slows down β-cell function loss for at least about 18 months or 78 weeks. Attached Figure Description

[0038] Figure 1 Simulated concentrations for three dosing regimens: WT = 60 kg, age = 18 years, BSA = 1.67 m 2 Furthermore, no population prediction of typical male patients with ADA was detected.

[0039] Figure 2 Concentration comparison between dosing regimens 1 and 2: WT = 60 kg, age = 18 years, BSA = 1.67 m 2 Furthermore, model-based simulations of typical male patients with ADA were not detected.

[0040] Figure 3 Concentration comparison between Herold dosing regimen and dosing regimen 1: WT = 60 kg, age = 18 years, BSA = 1.67 m 2 Furthermore, model-based simulations of typical male patients with ADA were not detected.

[0041] Figure 4 Concentration comparison on the last day of dosing between Herold dosing regimen and dosing regimen 1: WT = 60 kg, age = 18 years, BSA = 1.67 m 2 Furthermore, model-based simulations of typical male patients with ADA were not detected.

[0042] Figure 5 Simulated concentrations for three dosing regimens: WT = 60 kg, age = 18 years, BSA = 1.67 m 2 Furthermore, it provides a high level of detection and predicts a typical male patient population for ADA.

[0043] Figure 6 Concentration comparison between dosing regimens 1 and 2: WT = 60 kg, age = 18 years, BSA = 1.67 m 2 Furthermore, a model-based simulation of typical male patients with high levels of ADA was obtained.

[0044] Figure 7 Concentration comparison between Herold dosing regimen and dosing regimen 1: WT = 60 kg, age = 18 years, BSA = 1.67 m 2 Furthermore, a model-based simulation of typical male patients with high levels of ADA was obtained.

[0045] Figure 8 Concentration comparison on the last day of dosing between Herold dosing regimen and dosing regimen 1: WT = 60 kg, age = 18 years, BSA = 1.67 m 2 Furthermore, a model-based simulation of typical male patients with high levels of ADA was obtained.

[0046] Figure 9 Simulated concentrations for three dosing regimens: WT = 45 kg, age = 13 years, BSA = 1.33 m 2 Furthermore, no population prediction of typical male patients with ADA was detected.

[0047] Figure 10 Concentration comparison between dosing regimens 1 and 2: WT = 45 kg, age = 13 years, BSA = 1.33 mg / L. 2 Furthermore, model-based simulations of typical male patients with ADA were not detected.

[0048] Figure 11 Concentration comparison between Herold dosing regimen and dosing regimen 1: WT = 45 kg, age = 13 years, BSA = 1.33 m 2 Furthermore, model-based simulations of typical male patients with ADA were not detected.

[0049] Figure 12 Concentration comparison on the last day of dosing between Herold dosing regimen and dosing regimen 1: WT = 45 kg, age = 13 years, BSA = 1.33 m 2 Furthermore, model-based simulations of typical male patients with ADA were not detected.

[0050] Figure 13 Simulated concentrations for three dosing regimens: WT = 45 kg, age = 13 years, BSA = 1.33 m 2 Furthermore, it provides a high level of detection and predicts a typical male patient population for ADA.

[0051] Figure 14 Concentration comparison between dosing regimens 1 and 2: WT = 45 kg, age = 13 years, BSA = 1.33 mg / L. 2 Furthermore, a model-based simulation of typical male patients with high levels of ADA was obtained.

[0052] Figure 15 Concentration comparison between Herold dosing regimen and dosing regimen 1: WT = 45 kg, age = 13 years, BSA = 1.33 m 2 Furthermore, a model-based simulation of typical male patients with high levels of ADA was obtained.

[0053] Figure 16 Concentration comparison on the last day of dosing between Herold dosing regimen and dosing regimen 1: WT = 45 kg, age = 13 years, BSA = 1.33 m 2 Furthermore, a model-based simulation of typical male patients with high levels of ADA was obtained.

[0054] Figure 17 Concentration comparison between Herold regimen and dosing regimen 2: WT = 60 kg, age = 18 years, BSA = 1.67 m 2 Model-based simulations (42 days) of male patients in whom ADA was not detected.

[0055] Figure 18 Median concentration comparison between Herold regimen and dosing regimen 2: WT = 60 kg, age = 18 years, BSA = 1.67 m 2 Model-based simulations (35 days) of male patients in whom ADA was not detected.

[0056] Figure 19Concentration comparison between Herold regimen and dosing regimen 2: WT = 60 kg, age = 18 years, BSA = 1.67 m 2 And a high level of ADA was detected in male patients in a model-based simulation (42 days).

[0057] Figure 20 Median concentration comparison between Herold regimen and dosing regimen 2: WT = 60 kg, age = 18 years, BSA = 1.67 m 2 And a high level of ADA was detected in male patients in a model-based simulation (35 days).

[0058] Figure 21 Concentration comparison between Herold regimen and dosing regimen 2: WT = 45 kg, age = 13 years, BSA = 1.33 m 2 Model-based simulations (42 days) of male patients in whom ADA was not detected.

[0059] Figure 22 Median concentration comparison between Herold regimen and dosing regimen 2: WT = 45 kg, age = 13 years, BSA = 1.33 m 2 Model-based simulations (35 days) of male patients in whom ADA was not detected.

[0060] Figure 23 Concentration comparison between Herold regimen and dosing regimen 2: WT = 45 kg, age = 13 years, BSA = 1.33 m 2 And a high level of ADA was detected in male patients in a model-based simulation (42 days).

[0061] Figure 24 Median concentration comparison between Herold regimen and dosing regimen 2: WT = 45 kg, age = 13 years, BSA = 1.33 m 2 And a high level of ADA was detected in male patients in a model-based simulation (35 days).

[0062] Figure 25 : A schematic diagram of a research design according to one embodiment.

[0063] Figure 26 : A modified dosing schedule for participants affected by restrictions imposed by the COVID-19 pandemic, according to one embodiment.

[0064] Figure 27 A graph showing insulin use at different time points (baseline, week 12, week 26, week 39, week 52, week 65, and week 78). Figure 27 The results showed that patients treated with telithrumab had numerically lower insulin usage.

[0065] Figure 28 : A graph showing the percentage of subjects who met the requirements of Hb1Ac ≤ 6.5% and daily insulin dose ≤ 0.25 units / kg / day at different time points (baseline, week 12, week 26, week 39, week 52, week 65, and week 78). Figure 28 The study showed that more patients receiving telizumab met the insulin discontinuation criteria of Hb1Ac ≤ 6.5% and daily insulin dose ≤ 0.25 units / kg / day.

[0066] Figure 29 : A graph showing HbA1c levels at different time points (baseline, week 12, week 26, week 39, week 52, week 65, and week 78). Figure 29 The results showed that both treatment groups achieved the target HbA1c level.

[0067] Figure 30 : A chart showing the percentage of time within a range at different time points (baseline, week 12, week 26, week 39, week 52, week 65, and week 78). Figure 30 The study showed that patients treated with telizumab had a longer time-in-range (TIR).

[0068] Figures 31A-31D : A chart showing the endpoint of therapeutic efficacy. Figure 31A The area under the curve (ln(AUC+1)) of the stimulation C-peptide level over time is shown. Data are expressed as the least squares mean (95% CI). Figure 31B The percentage of patients with a time range (≥70%) is shown. Figure 31C The average daily insulin dose over time is shown to be ≤ 0.25 units / kg / day. Data are expressed as least squares mean (95% CI). Figure 31D This figure shows the proportion of patients who met the clinical remission criteria (HbA1c ≤ 6.5% and daily insulin dose ≤ 0.25 units / kg / day). Estimates were obtained from a mixed model of repeated measures models, with treatment group, visit and randomized age groups, baseline values ​​as fixed effects, and visit-treatment interaction terms. AUC, area under the curve; CGM, continuous glucose monitoring; CI = confidence interval.

[0069] Figure 32 : A graph showing the subgroup analysis of the C-peptide AUC-ITT population (AUC, area under the curve; CI, confidence interval).

[0070] Figure 33: A graph showing the proportion of patients with peak C-peptide ≥ 0.2 pmol / mL over time. ***P < 0.001. Error bars represent 95% confidence intervals. Percentages are based on the number of non-missing observations in each treatment group. Estimates were obtained from a repeated measures generalized linear model using a logit join function, which includes treatment, visits, randomized age groups, and baseline peak C-peptide as fixed effects, and a visit-treatment interaction term.

[0071] Figures 34A-34B : A graph showing HbA1c levels. Figure 34A The data shows HbA1c levels over time, and Figure 34B This shows the proportion of patients with HbA1c < 7% over time. MMRM, repeated measures mixed-effects model. Error bars represent 95% confidence intervals. Baseline was defined as the most recent value collected prior to the first dose of the study drug. Estimates are based on a repeated measures mixed-effects model (MMRM model) with treatment group, visit, randomized age group, screening peak C-peptide category, and visit-treatment interaction term as fixed effects.

[0072] Figure 35 : A graph showing the proportion of patients with insulin doses ≤ 0.25 units / kg / day obtained through study visits. Error bars represent 95% CI.

[0073] Figure 36 : Chart showing key clinical outcome assessment areas at week 78. DTSQ, Diabetes Treatment Satisfaction Questionnaire; MMRM, Repeated Measures Mixed-Effects Model; HFS, Hypoglycemia Fear Survey; PedsQL, Pediatric Quality of Life Scale. Estimates and p-values ​​are based on the MMRM model with fixed effects of treatment group, visit, randomized age group, screening peak C-peptide category, baseline score, and visit-treatment interaction. Least squares mean difference = telizumab - placebo. PedsQL scores range from 0 to 100, with higher scores indicating better outcomes. The minimum clinically important difference score for PedsQL was 5.27 for children / adolescents and 4.54 for parents. HFS scores range from 0 to 4, with lower scores indicating better outcomes. Symbols have been adjusted for graphical representation. DTSQ scores range from 0 to 48, with higher scores indicating better outcomes.

[0074] Figure 37 Plotting an Emax model: Predicting C-peptide changes and AUC in year 2. The Protégé study was conducted in newly diagnosed (stage 3) T1D patients and tested three telixirmab dosing regimens (full 14 days [approximately 9,030 μg / m²]). 2[Cumulative dose], one-third of the 14-day regimen [1 / 3] and the reduced 6 days [the first 6 days of the full 14-day regimen]). Detailed Implementation

[0075] T1D typically occurs in childhood and adolescence; however, it can also occur in the fifth and sixth decades of adulthood, albeit at a much lower frequency (Atkinson 2014, Bluestone 2010, Streisand 2014). In addition to a higher likelihood of developing some short- and long-term complications, the clinical course and response to immunotherapy differ between children / young adults and older adults. Children and adolescents often experience severe diabetes symptoms (including polydipsia, polyuria, and weight loss) in the days or weeks prior to initial diagnosis, which can lead to clinical presentations of DKA and shock requiring hospitalization (Atkinson 2014, Bluestone 2010, Streisand 2014, Mittermayer 2017). Children and young adults with newly diagnosed T1D often require exogenous insulin.

[0076] This contrasts sharply with the experience of adults who develop T1D, who often have nonspecific symptoms for months or years or are asymptomatic during routine blood glucose screenings. These individuals can usually be managed long-term (months or years) with diet or oral hypoglycemic agents before a clear need for insulin is realized. More definitive research indicates that the rate of β-cell decline varies with age (Greenbaum 2012; Ludvigsson 2013). After decades of research, the Diabetes TrialNet network concluded that "age is the most significant factor influencing the rate of C-peptide decline after diagnosis," as children and adolescents experience a significantly faster decline compared to young adults and older adults with newly diagnosed disease. This faster decline appears to be due to a more toxic and aggressive autoimmune process in children compared to adults, superficially supporting important differences in the immunological etiology of T1D between young adults and older adults (Greenbaum 2012, Campbell-Thompson 2016). Given 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 very effective for children but completely ineffective for adults, and vice versa (Rigby 2014).

[0077] Children and adolescents have the highest risk of developing T1D, with the highest short-term and long-term morbidity and mortality rates, making this group the most likely to benefit from disease-modifying therapies (Wherrett 2015). This was recently confirmed by a large study showing that individuals diagnosed with T1D in childhood and adolescence have a 4-6 times higher lifetime mortality risk compared to their age-independent peers, including a 7-fold higher risk of death from cardiovascular disease. This mortality risk contrasts sharply with individuals diagnosed with T1D in adulthood, who have approximately a 3-fold higher risk of all-cause and cardiovascular disease-related mortality compared to their healthy peers (Rawshani 2017, Rawshani 2018). Recent reports indicate that individuals with T1D have a life expectancy approximately 11-13 years shorter than other healthy, age-matched individuals (Lind 2014, Huo 2016). While the goal of T1D research is to reduce morbidity and mortality in all individuals with T1D, it is clear that the most pressing need is for those who develop T1D in childhood and adolescence.

[0078] Therefore, a therapy needs to be developed for the children who are most likely to benefit from it.

[0079] This disclosure relates to methods for treating type 1 disease (T1D) in subjects in need. This document provides methods for preserving β-cell function and improving the clinical management of T1D in children compared to the natural course of the disease and current standards of care, including exogenous insulin therapy. Preservation of β-cell function is expected to translate into clinical and / or metabolic benefits, consistent with improved ability to maintain glycemic control and short- and / or long-term outcomes. In some embodiments, the method includes administering a first course of daily doses of telixirumab for 12 days to a patient diagnosed with T1D aged 8 to 17 years within 6 weeks of diagnosis, and a second course of daily doses of telixirumab for 12 days, with a 6-month interval between the first and second courses. In some embodiments, the method further includes assessing the AUC of C-peptide at 78 weeks (18 months or 1.5 years) after the MMTT, and / or assessing clinical endpoints such as insulin use, HbA1c levels, and episodes of hypoglycemia.

[0080] This article provides a method for treating clinical type 1 diabetes (T1D) involving administering a total dose greater than approximately 9000 μg / m² to subjects in need. 2A 12-day course of telizumab is administered, wherein the subject has a peak C-peptide level of at least 0.2 pmol / mL during the MMTT prior to administration of the 12-day course of telizumab. Such a C-peptide level indicates that the subject is still producing insulin. In some embodiments, administration of the 12-day course of telizumab can substantially protect β cells, prevent β cell death over time, and / or significantly reduce the degree of β cell death over time. In some embodiments, administration of the 12-day course of telizumab can mitigate or prevent a decrease in pancreatic insulin production capacity. In some embodiments, administration of the 12-day course of telizumab can reduce or eliminate the need for insulin use. In some embodiments, the method comprises administering two 12-day courses spaced 6 or 12 months apart.

[0081] In some embodiments, the subject has been diagnosed with T1D within 6 weeks prior to the administration step. In some embodiments, the subject is approximately 8 to 17 years old.

[0082] In some embodiments, each dose is administered parenterally. In some embodiments, each dose is administered via intravenous infusion.

[0083] In some embodiments, the administration procedure reduces insulin use by at least 10% compared to subjects treated with placebo.

[0084] In some embodiments, administration of telizumab can reduce the amount of insulin required by the subject to maintain or reduce HbA1c. I. definition

[0085] Some terms are defined as follows. Other definitions are provided throughout the application.

[0086] As used herein, the articles “a” and “an” refer to one or more species (e.g., at least one species) as the grammatical object of the article. When used with the term “including” in this text, the use of the words “a” and “an” may mean “one species”, but it is also consistent with the meanings of “one or more species”, “at least one species”, and “more than one species”.

[0087] As used herein, “about” and “approximately” generally refer to the acceptable degree of error of a measured quantity given the nature or precision of the measurement. Exemplary error levels are within 20% (%) of a given range, typically within 10%, and more typically within 5%. The term “substantially” means more than 50%, preferably more than 80%, and most preferably more than 90% or 95%.

[0088] As used herein, the term "comprising" refers to compositions, methods, and their respective components that are present in a given embodiment but may contain unspecified elements.

[0089] As used herein, the term "consistently of" refers to those elements required for a given embodiment. This term allows for the presence of additional elements that do not materially affect the basic and novel or functional features of the embodiment disclosed herein.

[0090] The term “composed of” refers to the compositions, methods and their respective components described herein, excluding any elements not listed in the description of this embodiment.

[0091] The term “antibody” is used in the broadest sense in this article and covers a variety of antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, as long as they exhibit the desired antigen-binding activity.

[0092] "Antibody fragment" refers to a molecule other than a complete antibody that contains a portion of the complete antibody that binds to an antigen. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; biantibodies; linear antibodies; single-chain antibody molecules (e.g., scFv); and multispecific antibodies formed from antibody fragments.

[0093] As used in this article, the term “onset” for T1D refers to patients who meet the criteria for diagnosis of T1D established by the American Diabetes Association (see Mayfield et al., Am Fam Physician [American Family Physician] (2006) 58:1355-62).

[0094] As used herein, “regimen” includes a dosing schedule and a dosing regimen. A regimen in this document is a method of use and includes a treatment regimen. A “dosing regimen,” “dosing regimen,” or “course of treatment” may include the administration of multiple doses of a therapeutic agent over 1 to 20 days.

[0095] As used herein, the terms “subject” and “patient” are used interchangeably. As used herein, the term “subject” refers to an animal, preferably a mammal, including nonprimates (e.g., cattle, 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 receives treatment within 6 weeks of T1D diagnosis. In some embodiments, the patient population includes children who are positive for at least one T1D-related autoantibody at screening and have a peak stimulating C-peptide of ≥ 0.2 pmol / mL.

[0096] As used in this article, the term “child” (and its variations) includes children aged 8 to 17 years.

[0097] As used herein, the term “effective amount” refers to an amount of telizumab sufficient to delay or prevent the development, recurrence, or onset of one or more symptoms of T1D.

[0098] As used herein, the terms "treat," "treatment," and "treating" refer to the improvement of one or more symptoms associated with T1D resulting from the administration of one or more CD3-binding molecules. In some embodiments, such a term refers to reducing the average number of hypoglycemic episodes in humans. In other embodiments, such a term refers to maintaining reference levels of C-peptide in peripheral blood.

[0099] In some embodiments, the effective amount reduces one or more T1D symptoms 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%, or at least 95%.

[0100] The various aspects of this disclosure are described in further detail below. Additional definitions are listed throughout the specification. II. Anti-CD3 antibody and drug composition

[0101] The terms "anti-CD3 antibody" and "CD3-binding antibody" refer to antibodies or antibody fragments capable of binding to differentiation cluster 3 (CD3) with sufficient affinity, making the antibody usable as a CD3-targeting prophylactic, diagnostic, and / or therapeutic agent. In some embodiments, the anti-CD3 antibody binds to less than about 10% of unrelated non-CD3 proteins, for example, as measured by radioimmunoassay (RIA). In some embodiments, the dissociation constant (Kd) of the CD3-binding antibody is <1 μM, <100 nM, <10 nM, <1 nM, <0.1 nM, <0.01 nM, or <0.001 nM (e.g., 10 μM, <100 nM, <100 nM, <100 nM, <100 nM, <100 nM, <0.1 nM, <0.01 nM, or <0.001 nM). -8 M or smaller, for example, 10 -8 M to 10 -13 M, for example, 10 -9 M to 10 -13 M). In some embodiments, the anti-CD3 antibody binds to an epitope of CD3 that is conserved in CD3 from different species.

[0102] In some embodiments, the anti-CD3 antibody may be ChAglyCD3 (oxizumab). Oxizumab is a humanized Fc-nonbinding anti-CD3 antibody that was initially evaluated by the Belgian Diabetes Registry (BDR) in a phase 2 study, then developed by Tolerx, and subsequently conducted in collaboration with GSK in the phase 3 DEFEND new-onset T1D trials (NCT00678886, NCT01123083, NCT00763451). Oxizumab is administered via intravenous infusion over 8 days. See, for example, Wiczling et al., J Clin Pharmacol. [Journal of Clinical Pharmacology] (2010) 50(5):494-506; Keymeulen et al., N EnglJ Med. [New England Journal of Medicine] (2005) 352:2598-608; Keymeulen et al., Diabetologia. [Diabetology] (2010) 53:614-23; Hagopian et al., Diabetes [Diabetes] (2013) 62:3901-8; Aronson et al., Diabetes Care [Diabetes Care] (2014) 37:2746-54; Ambery et al., Diabetes Med. [Diabetes Medicine] (2014) 31:399-402; Bolt et al., Eur J Immunol. [European Journal of Immunology] (1993) 23(2):403-11; Vlasakakis et al., Br J Clin Pharmacol. [British Journal of Clinical Pharmacology] (2019) 85:704-714; Guglielmi et al., Expert Opinion on Biological Therapy [Biological Therapy Expert Opinion] (2016) 16(6):841-6; Keymeulen et al., N Engl J Med. [New England Journal of Medicine] (2005) 352(25):2598-608; Keymeulen et al., Blood [Blood] (2010) 115(6):1145-55; Sprangers et al., Immunotherapy [Immunotherapy] (2011) 3(11):1303-16; Daifotis et al., Clinical Immunology [Clinical Immunology] (2013) 149:268-78; All of the above references are incorporated herein by reference.

[0103] In some embodiments, the anti-CD3 antibody may be vesizumab (also known as HuM291; Nuvion). Vesizumab is a humanized anti-CD3 monoclonal antibody characterized by a mutated IgG2 isotype lacking binding to the Fcγ receptor and capable of selectively inducing apoptosis in activated T cells. It has been evaluated in patients with graft-versus-host disease (NCT00720629; NCT00032279) and ulcerative colitis (NCT00267306) and Crohn's disease (NCT00267709). See, for example, Sandborn et al., Gut [Gut] (2010) 59(11):1485-92, which is incorporated herein by reference. III. telizumab

[0104] In some embodiments, the anti-CD3 antibody may be telizumab. Telizumab, 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 β cells in the pancreatic islets. Telizumab binds to epitopes on the CD3ε chain expressed on mature T cells, thereby altering their function. Following telizumab treatment, circulating T cells (and other lymphocytes) are temporarily reduced, potentially including marginalization and exhaustion (Long 2017, Sherry 2011). In addition to reducing T cell effector function, telizumab appears to increase the number and function of regulatory T cells (Tregs) (Ablamunits 2010, Bisikirska 2005, Long 2017, Waldron-Lynch 2012). Recent studies have shown that telimumab induces immune “exhaustion” in effector CD8+ T cell subsets, potentially making them more susceptible to regulation or loss (Long 2016, Long 2017). In summary, these mechanistic data suggest that telimumab not only “inhibits” the β-cell immune destruction process but also acts as an immune “modulator,” facilitating the rebalancing of effectors and regulatory arms associated with T1D autoimmunity, and supporting the idea that telimumab may have the ability to reintroduce β-cell self-tolerance (Lebastchi 2013).

[0105] The sequence and composition of telizumab 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 telizumab is approximately 150 KD. The complete sequences of the light and heavy chains are shown below. The bolded portions are complementarity-determining regions (CDRs). Tselituzumab light chain (SEQ ID NO: 1): Tselituzumab heavy chain (SEQ ID NO: 2):

[0106] In some embodiments, this document provides pharmaceutical compositions. Such compositions comprise an effective amount of an anti-CD3 antibody and a pharmaceutically acceptable carrier. In some embodiments, the term "pharmaceuticalally acceptable" means approved by a U.S. federal or state regulatory agency or listed in the U.S. Pharmacopeia or other recognized pharmacopoeia for use in animals, and more particularly humans. The term "carrier" refers to a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient, or medium administered with the therapeutic agent. Such drug carriers can be sterile liquids, such as water and oils, including liquids of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous solutions of glucose and glycerol 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, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerin, propylene, ethylene glycol, water, ethanol, etc. (see, for example, Handbook of Pharmaceutical Excipients, Arthur H. Kibbe (ed., 2000, incorporated in whole by reference), Am. Pharmaceutical Association, Washington, DC).

[0107] If desired, the composition may also contain small amounts of wetting agents or emulsifiers, or pH buffers. These compositions may be in the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations, etc. Oral formulations may include standard carriers such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. EWMartin describes examples of suitable drug carriers in Remington's Pharmaceutical Sciences. Such compositions contain a therapeutically effective amount of a preferred purified form of the therapeutic agent, and an appropriate amount of carrier to provide a suitable form of administration to the patient. The formulation should be suitable for the mode of administration. In some embodiments, the pharmaceutical composition is sterile and administered to a subject, preferably an animal subject, more preferably a mammalian subject, and most preferably a human subject, in a suitable form.

[0108] In some embodiments, it may be desirable to apply the pharmaceutical composition topically to the area requiring treatment; this can be achieved, for example, but not limited to, local infusion, injection, or via an implant, which is a porous, non-porous, or gel-like material, including membranes such as salivary membranes or fibers. Preferably, when administering anti-CD3 antibodies, care must be taken to use materials that are not absorbed by the anti-CD3 antibodies.

[0109] In some embodiments, the composition may be delivered in vesicles, particularly liposomes (see Langer, Science (1990) 249:1527-33; Treat et al., 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; generally see ibid.).

[0110] In some embodiments, the composition may be delivered in a controlled-release or sustained-release system. In some embodiments, a pump may be used to achieve controlled-release or sustained-release (see Langer, ibid.; Sefton, 1987, CRC Crit. Ref. Biomed.Eng. [Biomedical Engineering Qualification Review] 14:20; Buchwald et al., 1980, Surgery [Surgery] 88:507; Saudek et al., N Engl J Med. [New England Journal of Medicine] (1989) 321:574). In some embodiments, polymeric materials may be used to achieve controlled or sustained release of the antibodies or fragments thereof disclosed herein (see, for example, Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Press, Pocaraton, Florida (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, J Macromol Sci Rev Macromol Chem. (1983) 23:61; see also Levy et al., Science (1985) 228:190; During et al., Ann Neurol. (1989) 25:351; Howard et al., J Neurosurg. (1989) 71:105; US Patent No. 5,679,377; US Patent No. 5,916,597; US Patent No. 5,912,015; US Patent No. 5,989,463; US Patent No. 5,128,326; PCT Publication No. WO 99 / 15154; and PCT Publication No. WO 99 / 20253). Examples of polymers for use 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), polyglycolic acid (PLG), polyanhydride, poly(N-vinylpyrrolidone), poly(vinyl alcohol), polyacrylamide, poly(ethylene glycol), polylactide (PLA), poly(lactide-co-glycolic acid) (PLGA), and polyorthoesters.In some embodiments, the polymer used in the sustained-release formulation is inert, free of leaching impurities, stable during storage, sterile, and biodegradable. In some embodiments, the controlled-release or sustained-release system can be placed near the therapeutic target (i.e., the lungs), so that only a portion of the systemic dose is required (see, for example, Goodson, in Medical Applications of Controlled Release, ibid., Vol. 2, pp. 115-138 (1984)).

[0111] Langer (1990, Science 249:1527-1533) discussed controlled-release systems in a review. Any technique known to those skilled in the art can be used to prepare sustained-release formulations comprising one or more antibodies or fragments thereof disclosed herein. See, for example, U.S. Patent No. 4,526,938; PCT Publication No. WO 91 / 05548; PCT Publication No. WO 96 / 20698; Ning et al., Radiotherapy & Oncology (1996) 39:179-189; Song et al., PDA Journal of Pharmaceutical Science & Technology (1995) 50:372-97; Cleek et al., Proceedings of the International Symp Control Rel Bioact Mater. (1997) 24:853-4; and Lam et al., Proceedings of the International Symp Control Rel Bioact Mater. (1997) 24:759-60, each of which is incorporated herein by reference in its entirety.

[0112] Pharmaceutical compositions can be formulated to be compatible with their intended route of administration. Examples of routes of administration include, but are not limited to, parenteral, such as intravenous, intradermal, subcutaneous, oral, intranasal (e.g., inhalation), transdermal (topical), mucosal, and rectal administration. In some embodiments, the composition is formulated according to conventional procedures to be suitable for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to humans. In some embodiments, the pharmaceutical composition is formulated according to conventional procedures for subcutaneous administration to humans. Typically, compositions for intravenous administration are solutions in sterile isotonic buffer solutions. If necessary, the composition may also include a solubilizer and a local anesthetic, such as lidocaine, to reduce pain at the injection site.

[0113] The composition can be formulated for parenteral administration by injection, such as by bolus or continuous infusion. Injectable formulations can be provided in unit dosage forms, such as in ampoules or multi-dose containers, with added preservatives. The composition can be in the form of a suspension, solution, or emulsion, for example, in an oily or aqueous medium, and may contain pharmaceutical formulations such as suspending agents, stabilizers, and / or dispersants. Alternatively, the active ingredient can be in powder form for reconstitution with a suitable medium (e.g., sterile, pyrogen-free water) prior to use.

[0114] In some embodiments, this disclosure provides dosage forms that allow for continuous administration of anti-CD3 antibodies over hours or days (e.g., associated with a pump or other device for such delivery), for example, over 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. In some embodiments, this disclosure provides dosage forms that allow for administration of continuously increasing doses, for example, from 106 µg / m² over 24 hours, 30 hours, 36 hours, 4 days, 5 days, 7 days, 10 days, or 12 days. 2 / day increased to 850 µg / m 2 / day or from 211 µg / m 2 / day increased to 840 µg / m 2 / sky.

[0115] The composition can be formulated into neutral or salt form. Pharmaceutically acceptable salts include those that form with anions, such as those derived from hydrochloric acid, phosphoric acid, acetic acid, oxalic acid, tartaric acid, etc., and those that form with cations, such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxide, isopropylamine, triethylamine, 2-ethylaminoethanol, histidine, procaine, etc.

[0116] Typically, the components of the compositions disclosed herein are provided individually or in combination in unit dosage forms, for example, as lyophilized powders or anhydrous concentrates in sealed containers such as ampoules or sachets indicating the amount of active agent. When the composition is administered by infusion, it can be dispensed using an infusion bottle containing sterile pharmaceutical-grade water or saline. When the composition is administered by injection, ampoules of sterile water or saline for injection can be provided so that the components can be mixed prior to administration.

[0117] Specifically, this disclosure provides that anti-CD3 antibodies or pharmaceutical compositions thereof can be packaged in sealed containers, such as ampoules or pouches, indicating the amount of the drug. In some embodiments, anti-CD3 antibodies or pharmaceutical compositions thereof are provided in sealed containers as dry sterile lyophilized powder or anhydrous concentrate and can be reconstituted, for example, with water or saline to an appropriate concentration for administration to a subject. Preferably, anti-CD3 antibodies or pharmaceutical compositions thereof are provided in sealed containers as dry sterile lyophilized powder at a unit dose 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 agents or pharmaceutical compositions of this disclosure should be stored in their original containers at 2°C to 8°C, and the therapeutic agents or pharmaceutical compositions of this disclosure should be administered within 1 week after reconstitution, preferably within 5 days, 72 hours, 48 ​​hours, 24 hours, 12 hours, 6 hours, 5 hours, 3 hours, or 1 hour. In some embodiments, the pharmaceutical composition is supplied in liquid form in sealed containers indicating the amount and concentration of the drug. Preferably, the liquid form of the administration composition is supplied in a sealed container at a concentration of 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 2°C to 8°C.

[0118] In some embodiments, this disclosure provides that the compositions of this disclosure are packaged in sealed containers such as ampoules or pouches indicating the amount of anti-CD3 antibody.

[0119] If desired, the composition may be provided in a packaging or dispenser device, which may contain one or more unit dosage forms containing the active ingredient. The packaging may include, for example, metal or plastic foil, such as blister packs.

[0120] The amount of the composition of this disclosure that is effective in treating one or more symptoms associated with T1D can be determined using standard clinical techniques. The precise dosage used in the formulation may also depend on the route of administration and the severity of the condition, and should be determined based on the physician's judgment and the individual patient's situation. The effective dosage can be inferred from dose-response curves derived from in vitro or animal model testing systems. IV. Methods and uses

[0121] In some embodiments, this disclosure includes administering an anti-human CD3 antibody (e.g., telizumab) to a patient aged 8 to 17 years who has a peak C-peptide level of ≥ 0.2 pmol / mL during a T1D diagnosis 6 weeks prior. In some embodiments, the peak C-peptide level at screening is in the range of 0.2 pmol / mL (inclusive) to 0.7 pmol / mL (inclusive).

[0122] In some embodiments, T1D diagnosis is made according to the American Diabetes Association (ADA) criteria. According to the ADA's definition of a clinical diagnosis of diabetes, an individual must meet one of the following four criteria: • Fasting plasma glucose (FPG) ≥ 126 mg / dL (7.0 mmol / L). Fasting is defined as abstaining from calorie intake for at least 8 hours. • During the oral glucose tolerance test (OGTT), 2-hour postprandial blood glucose (PG) ≥ 200 mg / dL (11.1 mmol / L). The test should be performed as described by the World Health Organization (WHO) using a glucose load containing the equivalent of 75 g of anhydrous glucose dissolved in water. • Hemoglobin A1C (HbA1c) ≥ 6.5% (48 mmol / mol). This test should be performed in a laboratory using a method certified and standardized by the National Glycohemoglobin Standardization Program (NGSP) for the Diabetes Control and Complications Trial (DCCT). • In patients with typical symptoms of hyperglycemia or hyperglycemic crisis, randomized PG ≥ 200 mg / dL (11.1 mmol / L).

[0123] For the clinical diagnosis of T1D, the ADA recommends that plasma glucose, rather than HbA1c, should be used to diagnose acute T1D episodes in individuals with symptoms of hyperglycemia.

[0124] According to the ADA, for patients with typical symptoms, a blood glucose test is sufficient to diagnose clinical diabetes (hyperglycemic symptoms or a hyperglycemic crisis plus a random blood glucose level ≥ 200 mg / dL [11.1 mmol / L]). In these cases, knowing the blood glucose level is crucial because it not only confirms that the symptoms are caused by diabetes but also informs management decisions. Some providers may also want to know HbA1c to determine when the patient has had hyperglycemia. Furthermore, T1D, formerly known as "insulin-dependent diabetes mellitus" or "juvenile-onset diabetes," accounts for 5%–10% of diabetes cases 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 as the presence of one or more of these autoimmune markers.

[0125] In some embodiments, the diagnosis of T1D is performed using a continuous glucose monitoring system (CGM) that reveals a high average blood glucose level (>= 110 mg / dL), or high variability in blood glucose (CV >= 15), or a short period of time within the range (>= 10% of the time above 140 mg / dL).

[0126] In some embodiments, patients diagnosed with clinical T1D are positive for at least one of the following T1D-related autoantibodies: glutamate decarboxylase 65 (GAD65) autoantibody, islet antigen 2 (IA-2) autoantibody, zinc transporter 8 (ZnT8) autoantibody, islet cell cytoplasmic autoantibody (ICA), or insulin autoantibody (if tested within the first 14 days of insulin therapy). In some embodiments, the presence of autoantibodies is detected by ELISA, electrochemiluminescence (ECL), radiometric analysis (see, for example, Yu et al., J Clin Endocrinol Metab. [Journal of Clinical Endocrinology and Metabolism] (1996) 81:4264-7), agglutination PCR (Tsai et al., ACS Central Science [Journal of Central Science] (2016) 2(3):139-47), or by any other method described herein or known to those skilled in the art for antibody immunospecific detection.

[0127] It has been recognized that β-cells continue to be lost after a T1D diagnosis. To maximize the effect of β-cell preservation on patients with recoverable endogenous insulin production levels, patients awaiting treatment must have peak C-peptide levels ≥ 0.2 pmol / mL within 6 weeks of T1D diagnosis and during the MMTT.

[0128] In some embodiments, the methods provided herein prevent or delay the need to administer insulin to a patient.

[0129] β-cell function before, during, and after treatment can be assessed by the methods described herein or any method known to a person skilled in the art. For example, the Diabetes Control and Complications Trial (DCCT) study group has established monitoring of glycated hemoglobin percentages (HbA1 and HbA1c) as a standard for assessing glycemic control (DCCT, N Engl J Med. [New England Journal of Medicine] (1993) 329:977-86). Alternatively, characterization of daily insulin requirements, C-peptide levels / response, hypoglycemic episodes, and / or FPIR can be used as markers of β-cell function or to establish therapeutic indices (see Keymeulen et al., N Engl J Med. [New England Journal of Medicine] (2005) 352:2598-2608; Herold et al., Diabetes [Diabetes] (2005) 54:1763-9; U.S. Patent Application Publication No. 2004 / 0038867 A1; and Greenbaum et al., Diabetes [Diabetes] (2001) 50:470-476). For example, FPIR is calculated as the sum of insulin values ​​at 1 minute and 3 minutes after IGTT, based on the Pancreatic Islet Cell Antibody Registry User Study Protocol (see, for example, Bingley et al., Diabetes (1996) 45:1720-8 and McCulloch et al., Diabetes Care (1993) 16:911-5).

[0130] In some embodiments, the effective amount includes 106-850 micrograms per square meter (μg / m²). 2 A 12-day course of subcutaneous intravenous (IV) infusion of an anti-CD3 antibody, such as teglitzumab. In some embodiments, the total dose over the duration of the regimen is approximately 14,000 μg / m². 2 13500 μg / m 2 13000 μg / m 2 12500 μg / m 2 12000 μg / m 2 11500 μg / m 2 11000 μg / m 2 10500 μg / m 2 10000 μg / m 2 9500 μg / m 2 9000 μg / m 2 8000 μg / m2 7000 μg / m 2 6000 μg / m 2 And it can be less than 5000 μg / m 2 4000 μg / m 2 3000 μg / m 2 2000 μg / m 2 Or 1000 μg / m 2 In some embodiments, the total dose over the duration of the regimen is approximately 9030 μg / m². 2 Approximately 14000 μg / m 2 Approximately 9030 μg / m 2 Approximately 13500 μg / m 2 Approximately 9000 μg / m 2 Approximately 13000 μg / m 2 Approximately 9000 μg / m 2 Approximately 12500 μg / m 2 Approximately 9000 μg / m 2 Approximately 12000 μg / m 2 Approximately 9000 μg / m 2 Approximately 11500 μg / m 2 Approximately 9000 μg / m 2 Approximately 11000 μg / m 2 Approximately 9000 μg / m 2 Approximately 10500 μg / m 2 Approximately 9000 μg / m 2 Approximately 10000 μg / m 2 Approximately 9000 μg / m 2 Approximately 9500 μg / m 2 In some embodiments, the total dose over the duration of the regimen is approximately 9030 μg / m². 2 Approximately 14000 μg / m 2 Approximately 9030 μg / m 2 Approximately 13500 μg / m 2 Approximately 9030 μg / m 2 Approximately 13000 μg / m 2 Approximately 9030 μg / m 2 Approximately 12500 μg / m 2 Approximately 9030 μg / m 2 Approximately 12000 μg / m 2 Approximately 9030 μg / m 2 Approximately 11500 μg / m 2Approximately 9030 μg / m 2 Approximately 11000 μg / m 2 Approximately 9030 μg / m 2 Approximately 10500 μg / m 2 Approximately 9030 μg / m 2 Approximately 10000 μg / m 2 Approximately 9030 μg / m 2 Approximately 9500 μg / m 2 .

[0131] Unbound by theory, exceeding approximately 9,000 μg / m 2 The cumulative dose of telizumab is expected to have a C-peptide retention of approximately 9,000 μg / m 2 The efficacy was comparable. This is because the exposure / response curve surprisingly reached a plateau, beyond which increasing the dose did not improve efficacy. C-peptide retention was assessed using data from the Protégé study. The model-predicted changes in tegizumab AUC and C-peptide relative to baseline were plotted, and Emax analysis was performed. These data indicate that the Emax model describes the relationship between 2-year tegizumab exposure and C-peptide changes. Figure 37 As shown, telizumab AUC levels are greater than approximately 1500 ng*hr / mL (lower than approximately 9,000 µg / mL for other targets). 2 At the dose-predicted lowest AUC (1789 ng*hr / mL), no further improvement in C-peptide was observed with increasing teglizumab exposure. Therefore, these data suggest that above approximately 9000 μg / mL... 2 The telizumab dose has a similar effect on C-peptide retention as approximately 9000 μg / m 2 The therapeutic effect is comparable to that shown.

[0132] In some embodiments, the effective dose comprises a 12-day course of intravenous infusion of telizumab, with a first dose of 106 μg / m² on day 1. 2 Teglituzumab, second dose on day 2, 425 μg / m² 2 Teglituzumab, and one dose of 850 μg / mcg daily from day 3 to 12. 2 In some embodiments, the effective dose comprises a 12-day course of intravenous infusion of telizumab, with a first dose of 211 μg / m² on day 1. 2 Teglituzumab, second dose on day 2, 423 μg / m 2 Teglituzumab, and one dose of 840 μg / m² daily from days 3 to 12. 2 In some embodiments, the effective dose comprises a 12-day course of intravenous infusion of telizumab, with the first dose on day 1 being approximately 100 μg / m². 2Teglituzumab, second dose on day 2, approximately 400 μg / m². 2 Teglitumab, third dose on day 3, approximately 850 μg / m² 2 and approximately 1,200 μg / m² per day from day 4 to 12. 2 In some embodiments, the effective dose comprises a 12-day course of intravenous infusion of telizumab, with the first dose on day 1 being approximately 100 μg / m². 2 Teglituzumab, second dose on day 2, approximately 400 μg / m². 2 Teglitumab, third dose on day 3, approximately 850 μg / m² 2 and approximately 1,300 μg / m² per day from day 4 to 12. 2 In some embodiments, the effective dose comprises a 12-day course of intravenous infusion of telizumab, with the first dose on day 1 being approximately 100 μg / m². 2 Teglituzumab, second dose on day 2, approximately 400 μg / m². 2 Teglitumab, third dose on day 3, approximately 850 μg / m² 2 and approximately 1,400 μg / m² per day from day 4 to 12. 2 In some embodiments, the effective dose comprises a 12-day course of intravenous infusion of telizumab, with the first dose on day 1 being approximately 200 μg / m². 2 Teglituzumab, second dose on day 2, approximately 400 μg / m². 2 Teglitumab, third dose on day 3, approximately 850 μg / m² 2 and approximately 1,200 μg / m² per day from day 4 to 12. 2 In some embodiments, the effective dose comprises a 12-day course of intravenous infusion of telizumab, with the first dose on day 1 being approximately 200 μg / m². 2 Teglituzumab, second dose on day 2, approximately 400 μg / m². 2 Teglitumab, third dose on day 3, approximately 850 μg / m² 2 and approximately 1,300 μg / m² per day from day 4 to 12. 2 In some embodiments, the effective dose comprises a 12-day course of intravenous infusion of telizumab, with the first dose on day 1 being approximately 200 μg / m². 2 Teglituzumab, second dose on day 2, approximately 400 μg / m². 2 Teglitumab, third dose on day 3, approximately 850 μg / m² 2 and approximately 1,400 μg / m² per day from day 4 to 12. 2 .

[0133] The dosing regimens described herein include two or more cycles of anti-CD3 antibody, such as telizumab, comprising a first cycle administered at week 1 and a second cycle administered at week 26. In some embodiments, telizumab is administered via IV infusion in two cycles, with the first cycle beginning on day 1 (week 1) and the second cycle beginning at approximately day 182 (week 26). Each cycle consists of daily infusions for 12 days, with a cumulative telizumab dose of 9000 µg / m² per cycle. 2 In some embodiments, telizumab is administered via intravenous infusion in two cycles. The first cycle begins on day 1 (week 1), and the second cycle begins at approximately day 182 (week 26). Each cycle consists of daily infusions for 12 days, with a cumulative telizumab dose of 9500 µg / m² per cycle. 2 In some embodiments, telizumab is administered via intravenous infusion in two cycles. The first cycle begins on day 1 (week 1), and the second cycle begins at approximately day 182 (week 26). Each cycle consists of daily infusions for 12 days, with a cumulative telizumab dose of 10,000 µg / m² per cycle. 2 In some embodiments, telizumab is administered via intravenous infusion in two cycles. The first cycle begins on day 1 (week 1), and the second cycle begins at approximately day 182 (week 26). Each cycle consists of daily infusions for 12 days, with a cumulative telizumab dose of 10,500 µg / m² per cycle. 2 In some embodiments, telizumab is administered via intravenous infusion in two cycles. The first cycle begins on day 1 (week 1), and the second cycle begins at approximately day 182 (week 26). Each cycle consists of daily infusions for 12 days, with a cumulative telizumab dose of 11,000 µg / m² per cycle. 2 In some embodiments, telizumab is administered via intravenous infusion in two cycles. The first cycle begins on day 1 (week 1), and the second cycle begins at approximately day 182 (week 26). Each cycle consists of daily infusions for 12 days, with a cumulative telizumab dose of 11,500 µg / m² per cycle. 2 In some embodiments, telizumab is administered via intravenous infusion in two cycles. The first cycle begins on day 1 (week 1), and the second cycle begins at approximately day 182 (week 26). Each cycle consists of daily infusions for 12 days, with a cumulative telizumab dose of 12,000 µg / m² per cycle. 2In some embodiments, telizumab is administered via intravenous infusion in two cycles. The first cycle begins on day 1 (week 1), and the second cycle begins at approximately day 182 (week 26). Each cycle consists of daily infusions for 12 days, with a cumulative telizumab dose of 12,500 µg / m² per cycle. 2 In some embodiments, telizumab is administered via intravenous infusion in two cycles. The first cycle begins on day 1 (week 1), and the second cycle begins at approximately day 182 (week 26). Each cycle consists of daily infusions for 12 days, with a cumulative telizumab dose of 13,000 µg / m² per cycle. 2 In some embodiments, telizumab is administered via intravenous infusion in two cycles. The first cycle begins on day 1 (week 1), and the second cycle begins at approximately day 182 (week 26). Each cycle consists of daily infusions for 12 days, with a cumulative telizumab dose of 13,500 µg / m² per cycle. 2 In some embodiments, telizumab is administered via intravenous infusion in two cycles. The first cycle begins on day 1 (week 1), and the second cycle begins at approximately day 182 (week 26). Each cycle consists of daily infusions for 12 days, with a cumulative telizumab dose of 14,000 µg / m² per cycle. 2 In some embodiments, the 12-day treatment course has a 2-day escalation phase and a fixed 10-day maximum dosing period. In some embodiments, 106 μg / m² is administered on day 1. 2 Tegliotumab, administered on day 2 at 425 μg / m². 2 Tegliotumab, administered at 850 μg / m² daily from days 3 to 12. 2 Tilizumab.

[0134] In other embodiments, the treatment course may 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 such as telizumab is determined as described herein, or as is known in the art, at 2 months, 4 months, 5 months, 6 months, 9 months, 12 months, 15 months, 18 months, 24 months, 30 months, or 36 months after prior treatment.

[0135] In some embodiments, at approximately 5-1200 μg / m 2 Preferred concentration: 106-850 μg / m 2Administer one or more doses, preferably 12 daily doses, of an anti-CD3 antibody such as telizumab to a subject to treat one or more symptoms of T1D, or to slow the progression of T1D or improve one or more symptoms of T1D.

[0136] In some embodiments, a treatment regimen comprising two cycles of daily effective doses of an anti-CD3 antibody, such as telizumab, is administered to the subject, wherein the cycles are 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 dose daily, every 2 days, every 3 days, or every 4 days.

[0137] In some embodiments, a treatment regimen comprising one or more doses of a preventatively effective amount of an anti-CD3 antibody, such as tegizumab, is administered to the subject, wherein the preventatively 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 preventive effective dose is 1200 μg / m 2 / day, 1150 μg / m 2 / day, 1100 μg / m 2 / day, 1050 μg / m 2 / day, 1000 μg / m 2 / day, 950 μg / m 2 / day, 900μg / m 2 / day, 850 μg / m 2 / day, 800 μg / m 2 / day, 750 μg / m 2 / day, 700 μg / m 2 / day, 650 μg / m 2 / day, 600 μg / m 2 / day, 550 μg / m 2 / day, 500 μg / m 2 / day, 450 μg / m 2 / day, 400 μg / m 2 / day, 350 μg / m 2 / day, 300 μg / m 2 / day, 250 μg / m 2 200 μg / m 2 / day, 150 μg / m 2 / day, 100 μg / m 2 / day, 50 μg / m 2 / day, 40 μg / m 2 30 μg / m 2 / day, 20 μg / m 2 / day, 15 μg / m 2 / day, 10 μg / m 2 / day or 5 μg / m 2 / sky.

[0138] In some embodiments, the intravenous dose is 1200 μg / m 2 or less, 1150 μg / m 2 or less, 1100 μg / m 2 or less, 1050 μg / m 2 or less, 1000 μg / m 2 or less, 950 μg / m 2 or less, 900 μg / m 2 or less, 850 μg / m 2 or less, 800 μg / m 2 or less, 750 μg / m 2 or less, 700 μg / m 2 or less, 650 μg / m 2 or less, 600 μg / m 2 or less, 550 μg / m 2 or less, 500 μg / m 2 or less, 450 μg / m 2 or less, 400 μg / m 2 or less, 350 μg / m 2 or less, 300 μg / m 2 or less, 250 μg / m2 or less, 200 μg / m 2 or less, 150 μg / m 2 or less, 100 μg / m 2 or less, 50 μg / m 2 or less, 40 μg / m 2 or less, 30 μg / m 2 or less, 20 μg / m 2 or less, 15 μg / m 2 or less, 10 μg / m 2 or less, or 5 μg / m 2 Or fewer anti-CD3 antibodies, such as telixirumab, may be administered over approximately 24 hours, approximately 22 hours, approximately 20 hours, approximately 18 hours, approximately 16 hours, approximately 14 hours, approximately 12 hours, approximately 10 hours, approximately 8 hours, approximately 6 hours, approximately 4 hours, approximately 2 hours, approximately 1.5 hours, approximately 1 hour, approximately 50 minutes, approximately 40 minutes, approximately 30 minutes, approximately 20 minutes, approximately 10 minutes, approximately 5 minutes, approximately 2 minutes, approximately 1 minute, approximately 30 seconds, or approximately 10 seconds to prevent, treat, or improve one or more symptoms of type 1 diabetes. The total dose over the duration of the regimen is preferably less than approximately 14,000 μg / m². 2 13500 μg / m 2 13000μg / m 2 12500 μg / m 2 12000 μg / m 2 11500 μg / m 2 11000 μg / m 2 10500 μg / m 2 10000 μg / m 2 9500 μg / m 2 9000 μg / m 2 8000 μg / m 2 7000 μg / m 2 6000 μg / m 2 And it can be less than 5000 μg / m 2 4000 μg / m 2 3000 μg / m 2 2000 μg / m 2 Or 1000 μg / m 2 In some embodiments, the daily dose administered in the regimen is approximately 100 μg / m². 2 Approximately 200 μg / m 2 Approximately 100 μg / m 2 Approximately 500 μg / m2 Approximately 100 μg / m 2 Approximately 1000 μg / m 2 or approximately 500 μg / m 2 Approximately 1000 μg / m 2 .

[0139] In some embodiments, the dose is increased in the first three, first quarter doses of the treatment regimen (e.g., the first three days of a 12-day regimen with one dose per day) until the effective daily dose of an anti-CD3 antibody such as telizumab is reached. In some embodiments, a treatment regimen comprising one or more effective doses of an anti-CD3 antibody, such as telizumab, is administered to the subject, wherein the effective dose is increased daily, for example, by 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, 4 μg / kg, 5 μg / kg, 10 μg / kg, 15 μg / kg, 20 μg / kg, 25 μg / kg, 30 μg / kg, 35 μg / kg, 40 μg / kg, 45 μg / kg, 50 μg / kg, 55 μg / kg, 60 μg / kg, 65 μg / kg, 70 μg / kg, etc. μg / kg, 75 μg / kg, 80 μg / kg, 85 μg / kg, 90 μg / kg, 95 μg / kg, 100 μg / kg or 125 μg / kg; or increase daily as treatment progresses, for example by 100 μg / kg. 2 150 μg / m 2 200 μg / m 2 250 μg / m 2 300 μg / m 2 350 μg / m 2 400 μg / m 2 450 μg / m 2 500 μg / m 2 550 μg / m 2 600 μg / m 2 Or 650 μg / m 2 In some embodiments, a treatment regimen comprising one or more doses of an effective amount of an anti-CD3 antibody, such as telizumab, is administered to the subject, wherein 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, such as telizumab, is reached.

[0140] In some embodiments, one or more doses of 200 μg / kg or less are administered intramuscularly to the subject, 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, 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, 15 μg / kg or less, 10 μg / kg or less, 5 μg / kg or less, 2.5 μg / kg or less, 2 Anti-CD3 antibodies such as telizumab, at doses of 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, are used to treat or improve one or more symptoms of T1D.

[0141] In some embodiments, one or more doses of 200 μg / kg or less are administered subcutaneously to the subject, 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, 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, 15 μg / kg or less, 10 μg / kg or less, 5 μg / kg or less, 2.5 μg / kg or less, 2 Anti-CD3 antibodies such as telizumab, at doses of 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, are used to treat or improve one or more symptoms of T1D.

[0142] In some embodiments, one or more doses of 100 μg / kg or less are administered intravenously to the subject, 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, 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. μg / kg or less of anti-CD3 antibodies such as telizumab are used to treat or improve one or more symptoms of T1D. In some embodiments, the intravenous dose is 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, 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. An anti-CD3 antibody such as teliximab at µg / kg or less may be administered over approximately 6 hours, approximately 4 hours, approximately 2 hours, approximately 1.5 hours, approximately 1 hour, approximately 50 minutes, approximately 40 minutes, approximately 30 minutes, approximately 20 minutes, approximately 10 minutes, approximately 5 minutes, approximately 2 minutes, approximately 1 minute, approximately 30 seconds, or approximately 10 seconds to treat or improve one or more symptoms of T1D.

[0143] In some embodiments, one or more doses of 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, 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, are administered orally to the subject. µg / kg or less of anti-CD3 antibodies such as telizumab are used to treat or improve one or more symptoms of T1D. In some embodiments, the oral dose is 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, 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. An anti-CD3 antibody such as teliximab at µg / kg or less may be administered over approximately 6 hours, approximately 4 hours, approximately 2 hours, approximately 1.5 hours, approximately 1 hour, approximately 50 minutes, approximately 40 minutes, approximately 30 minutes, approximately 20 minutes, approximately 10 minutes, approximately 5 minutes, approximately 2 minutes, approximately 1 minute, approximately 30 seconds, or approximately 10 seconds to treat or improve one or more symptoms of T1D.

[0144] In some embodiments, escalating doses are administered during the first few days of the dosing regimen, with a dose of 100-250 µg / m² on day 1. 2 / day, preferably 106 µg / m 2 / day, increasing to the daily dose just described above on days 2 and 3. For example, on day 1, the subject is given approximately 106 µg / m 2The daily dose was approximately 425 µg / m² on day 2. 2 / day, and 850 µg / m² for the following days of the regimen (e.g., days 3–12). 2 / day. In some embodiments, on day 1, the subject is administered approximately 211 µg / m 2 The daily dose was approximately 423 µg / m² on day 2. 2 / day, approximately 840 µg / m² on day 3 and the following days of the regimen (e.g., days 3–12). 2 / sky.

[0145] In some embodiments, to reduce the likelihood of cytokine release and other adverse reactions, the initial 1, 2, or 3 doses, or all doses, of the regimen are administered more slowly via intravenous administration. For example, 106 µg / m 2 The daily dose can be administered over approximately 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, and 22 hours. In some embodiments, the dose is administered by slow infusion over a period of, for example, 20 to 24 hours. In some embodiments, the dose is infused in a pump, preferably with the concentration of the antibody being administered increasing as the infusion proceeds.

[0146] In some embodiments, an effective amount of analgesic (e.g., nonsteroidal anti-inflammatory drug (NSAID), acetaminophen), antihistamine, antiemetic, or a combination thereof is administered to the subject in need at least on days 1-5 of a course of IV infusion (e.g., a 12-day course of IV infusion). In some embodiments, the analgesic (e.g., nonsteroidal anti-inflammatory drug (NSAID), acetaminophen), antihistamine, antiemetic, or a combination thereof may be administered on days 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-11, 1-12, or during the duration of antiCD3 antibody treatment. In some embodiments, the analgesic (e.g., nonsteroidal anti-inflammatory drug (NSAID), acetaminophen), antihistamine, antiemetic, or a combination thereof is administered approximately 30 minutes prior to the IV infusion daily. In some embodiments, the NSAID, acetaminophen, antihistamine, antiemetic, or a combination thereof is administered orally. In some embodiments, NSAIDs, acetaminophen, antihistamines, antiemetics, or combinations thereof are administered intravenously. In some embodiments, antipyretics, antihistamines, and / or antiemetics are administered to subjects in need to alleviate cytokine release syndrome. In some embodiments, liver enzymes are monitored, and treatment with anti-CD3 antibodies is stopped or suspended in subjects whose ALT or AST levels are elevated more than 5 times the upper limit of normal.

[0147] In some embodiments, the aforementioned 106 μg / m 2 / day up to 850 μg / m 2 The set dose portion of the / day regimen is administered in incremental doses.

[0148] In some embodiments, anti-CD3 antibodies, such as telizumab, are not administered at daily doses over several days, but rather via infusion in an uninterrupted manner over 4, 6, 8, 10, 12, 15, 18, 20, 24, 30, or 36-hour intervals. The infusion may be constant, or it may begin with a lower dose, for example, at the initial 1, 2, 3, 5, 6, or 8 hours of infusion, and then increase to a higher dose. During the infusion, the patient receives a dose equal to the amount administered in the 5- to 20-day regimen described above. For example, approximately 150 µg / m² may be administered. 2 200 µg / m 2 250 µg / m 2 500 µg / m 2 750 µg / m 2 1000 µg / m 2 1500 µg / m 2 2000 µg / m 2 3000 µg / m 2 4000 µg / m 2 5000 µg / m 2 6000 µg / m 2 7000 µg / m 2 8000 µg / m 2 9000 µg / m 2 9500 µg / m 2 10000 µg / m 2 10500 µg / m 2 11000 µg / m 2 11500 µg / m 2 12000 µg / m 2 12500 µg / m 2 13000 µg / m 2 13500 µg / m 2 Or 14000 µg / m 2The dosage. Specifically, the infusion rate and duration are designed to minimize the level of free anti-CD3 antibodies, such as telizumab, in the subject after administration. In some embodiments, the level of free anti-CD3 antibodies, such as telizumab, should not exceed 200 ng / ml of free antibody. Furthermore, the infusion is designed to achieve at least 50%, 60%, 70%, 80%, 90%, 95%, or 100% combined T-cell receptor coating and modulation.

[0149] In some embodiments, long-term administration of anti-CD3 antibodies such as tegizumab is used to treat one or more symptoms of T1D, or to slow the progression of T1D or improve one or more symptoms of T1D. For example, in some embodiments, low doses of anti-CD3 antibodies such as tegizumab are administered once a month, twice a month, three times a month, once a week, or even more frequently, as an alternative to the aforementioned 6 to 14-day dosing regimens or after administration of such regimens to enhance or maintain their effects. This low dose may be 1 μg / m 2 Up to 100 μg / m 2 Within a range, for example, approximately 5 µg / m 2 10 µg / m 2 15 µg / m 2 20 µg / m 2 25µg / m 2 30 µg / m 2 35 µg / m 2 40 µg / m 2 45 µg / m 2 or 50 µg / m 2 .

[0150] In some embodiments, a subject may be re-dosed at some point after two cycles of an anti-CD3 antibody, such as telizumab, administration, for example, based on one or more physiological or biomarker parameters, or as can be taken for granted. Such re-dosing and / or assessment of the need for such re-dosing may be performed at 2, 4, 6, 8, 9, 1, 15, 18, 2, 30, or 3 years after administration of the dosing regimen, and may include indefinite administration of a cycle every 6 months, 9 months, 1 year, 15 months, 18 months, 2 years, 30 months, or 3 years.

[0151] In some embodiments, before and / or after administration of a 12-day course of tegizumab (e.g., at intervals of 1-6 months, 2-5 months, or approximately 3 months), the levels (or relative amounts) of phenotypically exhausted T cells, such as TIGIT+KLRG1+CD8+ T cells or PD-1+CD8+ T cells, relative to all CD3+ T cells are determined, for example, by flow cytometry. In some embodiments, the levels of TIGIT+KLRG1+CD8+CD3+ T cells may be monitored, for example, by flow cytometry. In some embodiments, when the levels of TIGIT+KLRG1+CD8+CD3+ T cells and / or PD-1+CD8+CD3+ T cells correspond to (e.g., return to) baseline levels, an additional 12-day course of an anti-CD3 antibody, such as tegizumab, is administered. In some embodiments, the baseline levels of TIGIT+KLRG1+CD8+CD3+ T cells and / or PD-1+CD8+CD3+ T cells are less than 5% of all CD3+ T cells. In some embodiments, the determination of TIGIT+, KLRG1+, or PD-1+ phenotype-exhausted CD8+ T cells is performed approximately 3 months (or approximately 1–6 months) after administration of the second 12-day treatment cycle. In some embodiments, if the subject has more than approximately 10% TIGIT+KLRG1+CD8+ T cells and / or PD-1+CD8+ T cells in all CD3+ T cells, monitoring may be performed annually. In some embodiments, if the subject has less than approximately 10% TIGIT+KLRG1+CD8+ T cells and / or PD-1+CD8+ T cells in all CD3+ T cells, monitoring may be performed every approximately 3–6 months.

[0152] In some embodiments, re-dosing includes administering additional (e.g., a second, third, or more) 12-day courses of telizumab, each with a total dose exceeding approximately 9000 μg / m². 2 As described herein. In some embodiments, an additional 12-day course of telixirmab includes a first dose of 106 μg / m² on day 1. 2 Teglituzumab, second dose on day 2, 425 μg / m² 2 Teglituzumab, and one dose of 850 μg / mcg daily from day 3 to 12. 2 The total dose was approximately 9031 μg / m³. 2 In other embodiments, an additional 12-day course of telixirmab includes a first dose of 211 μg / m² on day 1. 2 Teglituzumab, second dose on day 2, 423 μg / m 2 Teglituzumab, and one dose of 840 μg / m² daily from days 3 to 12. 2The total dose was approximately 9034 μg / m³. 2 .

[0153] In some embodiments, additional (e.g., a second, third, or more) 12-day courses of anti-CD3 antibodies such as telizumab may be administered approximately 12 to approximately 24 months after the previous 12-day course, for example, 12, 13, 14, 15, 16, 17, 19, 20, 21, 22, 23, or 24 months.

[0154] In some embodiments, an anti-CD3 antibody, such as telizumab, is administered to achieve or maintain glycated hemoglobin (HbA1 or HbA1c) levels below 8%, below 7.5%, below 7%, below 6.5%, below 6%, below 5.5%, or 5% or lower. At the start of treatment, the patient's HbA1 or HbA1c level is below 8%, below 7.5%, below 7%, below 6.5%, below 6%, or more preferably between 4% and 6% (preferably measured in the absence of other diabetes treatments, such as the administration of exogenous insulin). Such patients preferably retain at least 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, or 20% of β-cell function before the start of treatment. In some embodiments, the administration of the anti-CD3 antibody prevents damage, thereby slowing disease progression and reducing the need for insulin administration. In some embodiments, the treatment methods provided herein result in HbA1 or HbA1c levels being 7% or less, 6.5% or less, 6% or less, 5.5% or less, or 5% or less at 6, 9, 12, 15, 18, or 24 months after prior treatment. In some embodiments, administration of anti-CD3 antibodies according to the methods provided herein at 6, 9, 12, 15, 18, or 24 months after prior treatment results in a reduction of the average HbA1 or HbA1c level in patients by approximately 5%, approximately 10%, approximately 15%, approximately 20%, approximately 25%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, or approximately 70% compared to pre-treatment levels. In some embodiments, administration of anti-CD3 antibodies according to the methods provided herein at 6, 9, 12, 15, 18, or 24 months after prior treatment resulted in an average increase of only 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% in patients compared to pre-treatment levels.

[0155] In some embodiments, administration of an anti-CD3 antibody, such as telizumab, according to the methods provided herein in children and adolescents aged 8–17 years diagnosed with T1D within the past 6 weeks has slowed β-cell loss and / or preserved β-cell function over a period of 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 2, 24 months, or longer (as demonstrated by, for example, higher C-peptide levels, fewer episodes of hypoglycemia or hyperglycemia, increased duration of (glucose) range, reduced insulin use, or other assessment methods known in the art). In some embodiments, administration of an anti-CD3 antibody, such as telizumab, according to the methods provided herein in children and adolescents aged 8–17 years diagnosed with T1D within 6 weeks prior to administration of the first dose of the anti-CD3 antibody has slowed β-cell loss and / or preserved β-cell function over a period of 18 months (78 weeks). In some embodiments, administration of anti-CD3 antibodies, such as telizumab, according to the methods provided herein has slowed β-cell loss and / or preserved β-cell function, as measured by C-peptide levels, within 18 months (78 weeks) in children and adolescents aged 8–17 years diagnosed with T1D within 6 weeks prior to administration of the first dose of anti-CD3 antibody.

[0156] In some embodiments, administration of an anti-CD3 antibody, such as telizumab, resulted in a reduction of insulin use by 0.1 U / kg / day or more in subjects diagnosed with T1D within 6 weeks prior to the administration of their first dose of an anti-CD3 antibody, compared to subjects receiving placebo, while achieving similar target glycemic control (HbA1c) in subjects treated with an anti-CD3 antibody. In some embodiments, administration of an anti-CD3 antibody, such as telizumab, improved TIR and reduced insulin use by 0.1 U / kg / day or more in subjects diagnosed with T1D within 6 weeks prior to the administration of their first dose of an anti-CD3 antibody, compared to subjects receiving placebo. In some embodiments, administration of an anti-CD3 antibody, such as telizumab, resulted in a reduction of baseline HbA1c by 0.1 to 1 point or more, compared to subjects receiving placebo. In some embodiments, administration of an anti-CD3 antibody, such as telizumab, reduces insulin use by 10% to 15%, 15% to 20%, 20% to 25%, 25% to 30%, 10% to 20%, 20% to 30%, 10% to 30%, or more than 30% compared to subjects receiving placebo.

[0157] In some embodiments, administering an anti-CD3 antibody, such as telizumab, to a subject in need reduces the insulin dose by at least 0.1 U / kg / day or maintains the insulin dose.

[0158] In some embodiments, in subjects aged 8–17 years diagnosed with T1D within 6 weeks prior to administration of the first dose of an anti-CD3 antibody, administration of an anti-CD3 antibody such as telizumab resulted in a mean C-peptide level 40% to 80% or more higher at 78 weeks compared to subjects receiving placebo. In some embodiments, administration of an anti-CD3 antibody such as telizumab resulted in a mean C-peptide level 40% to 45%, 45% to 50%, 50% to 55%, 55% to 60%, 60% to 65%, 65% to 70%, 70% to 75%, 75% to 80%, or more higher at 78 weeks compared to subjects receiving placebo. For example, administration of an anti-CD3 antibody such as telizumab resulted in a mean C-peptide level 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or more higher at 78 weeks compared to subjects receiving placebo.

[0159] In some embodiments, administration of an anti-CD3 antibody, such as telizumab, to subjects aged 8–17 years diagnosed with T1D within 6 weeks prior to administration of the first dose of the anti-CD3 antibody resulted in an increase of 3% to 10% or more in the time within the glycemic range as assessed by a glucose monitoring system. For example, administration of the first dose of the anti-CD3 antibody resulted in an increase of 3% to 6%, 6% to 10%, 3% to 4%, 4% to 5%, 5% to 6%, 6% to 7%, 7% to 8%, 8% to 9%, 9% to 10%, or more in the time within the glycemic range as assessed by a glucose monitoring system.

[0160] Some embodiments relate to telizumab for use in a method of treating clinical type 1 diabetes (T1D), the method comprising administering a total dose greater than about 9000 μg / m² to a subject in need. 2 A 12-day course of telizumab.

[0161] In some embodiments, the total dose is approximately 9000 μg / m². 2 Approximately 9500 μg / m 2 Between [specific values]. In some embodiments, the total dose is approximately 9000 μg / m³. 2 Approximately 14000 μg / m 2 between.

[0162] In some embodiments, the 12-day treatment course includes a first dose of 106 μg / m² on day 1. 2 Teglituzumab, second dose on day 2, 425 μg / m² 2 Teglituzumab, and one dose of 850 μg / mcg daily from day 3 to 12. 2 And the total dose was approximately 9031 μg / m 2 .

[0163] In some embodiments, the 12-day treatment course includes a first dose of 211 μg / m² on day 1. 2 Teglituzumab, second dose on day 2, 423 μg / m 2 Teglituzumab, and one dose of 840 μg / m² daily from days 3 to 12. 2 And the total dose was approximately 9034 μg / m 2 .

[0164] In some embodiments, the method may include administering telizumab in first and second 12-day courses of treatment. In some embodiments, the first and second 12-day courses of treatment are administered at intervals of about 1-6 months, about 2-5 months, or about 3 months.

[0165] In some embodiments, the method may include administering a third or more 12-day cycles of telizumab to subjects in need, with a total dose of more than about 9000 μg / m² per cycle. 2 .

[0166] In some embodiments, the third or more 12-day cycles of telizumab include a first dose of 106 μg / m² on day 1. 2 Teglituzumab, second dose on day 2, 425 μg / m² 2 Teglituzumab, and one dose of 850 μg / mcg daily from day 3 to 12. 2 And the total dose for each course of treatment is approximately 9031 μg / m². 2 .

[0167] In some embodiments, the third or more 12-day cycles of telixirmab include a first dose of 211 μg / m² on day 1. 2 Teglituzumab, second dose on day 2, 423 μg / m 2 Teglituzumab, and one dose of 840 μg / m² daily from days 3 to 12. 2 And the total dose for each course of treatment is approximately 9034 μg / m². 2 .

[0168] In some embodiments, a third or more 12-day cycles of telizumab are administered at intervals of approximately 12 months to approximately 24 months.

[0169] In some embodiments, the method may further include measuring the baseline levels of TIGIT+KLRG1+CD8+ T cells or PD-1+CD8+ T cells relative to all CD3+ T cells after each 12-day treatment cycle, monitoring the levels of TIGIT+KLRG1+CD8+CD3+ T cells, and administering an additional 12-day cycle of telizumab when the levels of TIGIT+KLRG1+CD8+CD3+ T cells or PD-1+CD8+CD3+ T cells return to baseline levels. In some embodiments, TIGIT+KLRG1+CD8+CD3+ T cells or PD-1+CD8+CD3+ T cells are measured by flow cytometry. In some embodiments, TIGIT+KLRG1+CD8+CD3+ T cells or PD-1+CD8+CD3+ T cells are monitored by flow cytometry. In some embodiments, TIGIT+KLRG1+CD8+CD3+ T cells or PD-1+CD8+CD3+ T cells are measured approximately 1–6 months, approximately 2–5 months, or approximately 3 months after each 12-day treatment cycle. In some embodiments, if the subject has more than approximately 10% TIGIT+KLRG1+CD8+ T cells or PD-1+CD8+ T cells in all CD3+ T cells, follow-up monitoring is performed annually. In some embodiments, if the subject has less than approximately 10% TIGIT+KLRG1+CD8+ T cells in all CD3+ T cells, follow-up monitoring is performed approximately every 3–6 months. In some embodiments, if the subject has less than approximately 10% PD-1+CD8+ T cells in all CD3+ T cells, follow-up monitoring is performed approximately every 3–6 months.

[0170] In some embodiments, the subject in need has been diagnosed with T1D within 6 weeks prior to the administration step.

[0171] In some embodiments, the administration step reduces insulin use, HbA1c levels, hypoglycemic episodes, or combinations thereof by at least 10% compared to pre-treatment levels.

[0172] In some embodiments, each dose is administered parenterally.

[0173] In some embodiments, each dose is administered via intravenous infusion.

[0174] In some embodiments, the subjects were approximately 8 to 17 years old.

[0175] In some embodiments, subjects have a peak C-peptide level of ≥ 0.2 pmol / mL during the MMTT. In some embodiments, subjects with the need have a peak C-peptide level of 0.2 pmol / mL to 0.7 pmol / mL during the MMTT.

[0176] In some embodiments, subjects receiving telizumab had higher mean C-peptide values ​​compared to controls receiving placebo.

[0177] In some embodiments, the method further includes assessing the AUC of C-peptide at 78 weeks following the MMTT. In some embodiments, administration of telizumab maintains higher C-peptide levels compared to administration of placebo to patients.

[0178] In some embodiments, the subject has at least 20% β-cell function prior to administration of the first dose of telizumab for the first 12-day course.

[0179] In some embodiments, the reduction in insulin use, HbA1c levels, hypoglycemic episodes, or a combination thereof lasts for 12 months or longer.

[0180] Some aspects involve methods for treating clinical T1D, which include administering a total dose greater than approximately 9000 μg / m² to subjects in need. 2 A 12-day course of telizumab. Some aspects involve the use of telizumab in a method of treating clinical T1D, which involves administering a total dose greater than about 9000 μg / m² to the subject in need. 2 A 12-day course of telizumab.

[0181] In some embodiments, a method for treating clinical type 1 diabetes (T1D) is provided, the method comprising administering a total dose of approximately 9000 μg / m² to a subject in need. 2 Approximately 9500 μg / m 2 A 12-day course of telizumab. In some embodiments, a method of treating clinical T1D is provided, comprising administering a total dose of approximately 9000 μg / m² to a subject in need. 2 Approximately 14000 μg / m 2 A 12-day course of telizumab.

[0182] In some embodiments, anti-CD3 antibodies such as telizumab, oxizumab, or francirumab are administered via infusion at a medical facility or outpatient infusion center. However, in other embodiments, anti-CD3 antibodies such as telizumab, oxizumab, or francirumab are administered via infusion in a home setting. Home infusion therapy involves administering therapeutic agents, such as anti-CD3 antibodies, via intravenous or subcutaneous routes at the patient's home rather than in a doctor's office or hospital. Home infusion therapy can be administered by a family healthcare professional or the patient themselves. In some embodiments, a healthcare professional with some training in the operation of infusion devices and the administration of anti-CD3 antibodies can provide the patient with self-administration training and all necessary equipment and / or supplies required for administration. V. Exemplary embodiments

[0183] The following describes non-limiting exemplary embodiments of this disclosure. 1. A method for treating type 1 diabetes (T1D), the method comprising: The total dose administered to subjects in need was approximately 9000 μg / m². 2 Approximately 9500 μg / m 2 The first 12-day course of telizumab, wherein the subject in need had a peak C-peptide level of at least 0.2 pmol / mL during a mixed dietary tolerance test (MMTT) prior to administration of the first 12-day course of telizumab; and The total dose administered to the subjects in need was approximately 9000 μg / m². 2 Approximately 9500 μg / m 2 The second 12-day course of teliximab, in which the first and second 12-day courses of teliximab are administered at intervals of approximately 6 months to approximately 12 months. 2. A method for treating type 1 diabetes (T1D), the method comprising: The total dose administered to subjects in need was approximately 9000 μg / m². 2 Approximately 14000 μg / m 2 The first 12-day course of telizumab, wherein the subject in need had a peak C-peptide level of at least 0.2 pmol / mL during a mixed dietary tolerance test (MMTT) prior to administration of the 12-day course of telizumab; and The total dose administered to the subjects in need was approximately 9000 μg / m². 2 Approximately 14000 μg / m 2 The second 12-day course of teliximab, in which the first and second 12-day courses of teliximab are administered at intervals of approximately 6 months to approximately 12 months. 3. The method as described in Example 1, wherein the 12-day treatment course includes a first dose of 106 μg / m² on day 1. 2 Teglituzumab, second dose on day 2, 425 μg / m² 2 Teglituzumab, and one dose of 850 μg / mcg daily from day 3 to 12. 2 And the total dose was approximately 9031 μg / m³. 2 . 4. The method as described in any one of Examples 1-3, wherein the subject in need is approximately 8-17 years old. 5. The method as described in any one of Examples 1-4, wherein the subject in need has been diagnosed with T1D within 6 weeks prior to administration of the first 12-day course of telizumab. 6. The method as described in Example 1 or 2, further comprising administering a third or more 12-day cycles of telizumab to a subject in need, each cycle containing a total dose greater than about 9000 μg / m². 2 . 7. The method as described in Example 6, wherein the third or more 12-day cycles of telizumab comprise a first dose of 106 μg / m² on day 1. 2 Teglituzumab, second dose on day 2, 425 μg / m² 2 Teglituzumab, and one dose of 850 μg / mcg daily from day 3 to 12. 2 The total dose for each treatment course is approximately 9031 μg / m². 2 . 8. The method as described in Example 7, wherein the third or more 12-day cycles of telizumab are administered at intervals of about 6 months to about 24 months. 9. The method as described in any one of Examples 1-8, the method comprising: After each 12-day treatment course, the baseline levels of TIGIT+KLRG1+CD8+ T cells relative to all CD3+ T cells and / or the baseline levels of PD-1+CD8+ T cells relative to all CD3+ T cells were measured. Monitor the levels of TIGIT+KLRG1+CD8+CD3+ T cells and / or PD-1+CD8+CD3+ T cells; and When the levels of TIGIT+KLRG1+CD8+CD3+ T cells and / or PD-1+CD8+CD3+ T cells return to baseline levels, administer an additional 12-day course of telizumab. 10. The method as described in Example 9, wherein the baseline levels of TIGIT+KLRG1+CD8+ T cells and / or PD-1+CD8+ T cells are less than approximately 5% of all CD3+ T cells. 11. The method as described in Example 9, wherein TIGIT+KLRG1+CD8+CD3+ T cells and / or PD-1+CD8+CD3+ T cells are determined by flow cytometry. 12. The method as described in Example 9, wherein TIGIT+KLRG1+CD8+CD3+ T cells and / or PD-1+CD8+CD3+ T cells are monitored by flow cytometry. 13. The method as described in Example 9, wherein TIGIT+KLRG1+CD8+CD3+ T cells and / or PD-1+CD8+CD3+ T cells are measured approximately 1-6 months, approximately 2-5 months, or approximately 3 months after each 12-day treatment course. 14. The method as described in Example 9, wherein if the subject has more than about 10% TIGIT+KLRG1+CD8+ T cells and / or more than about 10% PD-1+CD8+ T cells in all CD3+ T cells, then follow-up monitoring is performed annually. 15. As described in Example 9, if the subject has less than about 10% TIGIT+KLRG1+CD8+ T cells and / or less than about 10% PD-1+CD8+ T cells in all CD3+ T cells, follow-up monitoring shall be performed every about 3-6 months. 16. The method as described in any one of Examples 1-15, wherein each dose of telizumab is administered parenterally. 17. The method as described in any one of Examples 1-16, wherein each dose of telizumab is administered by intravenous infusion. 18. The method as described in any one of Examples 1-17, wherein during the Mixed Diet Tolerance Trial (MMTT), the subject in need has a peak C-peptide level between 0.2 pmol / mL and 0.7 pmol / mL. 19. The method as described in any one of Examples 1-18, wherein the subject in need has a peak C-peptide level of at least 0.7 pmol / mL during the Mixed Diet Tolerance Trial (MMTT). 20. The method of any one of Examples 1-19, wherein the method comprises assessing the area under the time-concentration curve (AUC) of C-peptide at 78 weeks following a mixed dietary tolerance test (MMTT). 21. The method as described in any one of Examples 1-20, wherein the subjects in need who received telizumab had a higher mean C-peptide value compared to the control group that received placebo. 22. The method as described in any one of Examples 1-21, wherein administration of telizumab to the subject in need resulted in a mean C-peptide value that was 40% to 80% or more higher over 78 weeks compared to a subject receiving a placebo. 23. The method as described in any one of Examples 1-22, wherein, compared with subjects administered placebo, subjects in need administered telizumab maintain or reduce baseline HbA1c levels and / or maintain or increase the time within the range while using less insulin. 24. The method as described in any one of Examples 1-23, wherein the subject in need has at least 20% β-cell function prior to administration of the first dose. 25. The method of any one of Examples 1-24, wherein administration of telizumab to the subject in need results in a 10% to 30% or more reduction in insulin dose compared to a subject receiving a placebo. 26. The method of any one of Examples 1-25, wherein administration of telizumab to the subject in need reduces the insulin dose by at least 0.1 U / kg / day or maintains the insulin dose. 27. The method as described in any one of Examples 1-26, wherein administration of telizumab to the subject in need results in a reduction of HbA1c baseline of 0.1 to 1 point or more compared to a subject receiving placebo. 28. The method of any one of Examples 1-27, wherein administration of tilimizumab to the subject in need increases the time (%) within the blood glucose range assessed using a glucose monitoring system by 3% to 10% or more. 29. A method for increasing the mean C-peptide level in subjects with type 1 diabetes, the method comprising: The total dose administered to the subjects was approximately 9000 μg / m². 2 Approximately 9500 μg / m 2 The first 12-day course of telizumab, wherein the subject had a peak C-peptide level of at least 0.2 pmol / mL during a mixed dietary tolerance test (MMTT) prior to administration of the first 12-day course of telizumab; and The total dose administered to the subjects was approximately 9000 μg / m². 2 Approximately 9500 μg / m 2 The second 12-day course of telixirmab, in which the first and second 12-day courses of telixirmab were administered at intervals of approximately 6 months to approximately 12 months, and Compared with those who received placebo, administration of teliximab increased the average C-peptide value by 40% to 80% or more. 30. A method for increasing the mean C-peptide level in subjects with type 1 diabetes, the method comprising: The total dose administered to the subjects was approximately 9000 μg / m². 2 Approximately 14000 μg / m 2The first 12-day course of telizumab, wherein the subject had a peak C-peptide level of at least 0.2 pmol / mL during a mixed dietary tolerance test (MMTT) prior to administration of the first 12-day course of telizumab; and The total dose administered to the subjects was approximately 9000 μg / m². 2 Approximately 14000 μg / m 2 The second 12-day course of telixirmab, in which the first and second 12-day courses of telixirmab were administered at intervals of approximately 6 months to approximately 12 months, and Compared with those who received placebo, administration of teliximab increased the average C-peptide value by 40% to 80% or more. 31. Tiglizamab for use in a method of treating type 1 diabetes (T1D), the method comprising: The total dose administered to subjects in need was approximately 9000 μg / m². 2 Approximately 9500 μg / m 2 The first 12-day course of telizumab, wherein the subject in need had a peak C-peptide level of at least 0.2 pmol / mL during a mixed dietary tolerance test (MMTT) prior to administration of the first 12-day course of telizumab; and The total dose administered to the subjects in need was approximately 9000 μg / m². 2 Approximately 9500 μg / m 2 The second 12-day course of teliximab, in which the first and second 12-day courses of teliximab are administered at intervals of approximately 6 months to approximately 12 months. 32. Tiglizamab for use in a method of treating type 1 diabetes (T1D), the method comprising: The total dose administered to subjects in need was approximately 9000 μg / m². 2 Approximately 14000 μg / m 2 The first 12-day course of telizumab, wherein the subject in need had a peak C-peptide level of at least 0.2 pmol / mL during a mixed dietary tolerance test (MMTT) prior to administration of the first 12-day course of telizumab; and The total dose administered to the subjects in need was approximately 9000 μg / m². 2 Approximately 14000 μg / m 2 The second 12-day course of teliximab, in which the first and second 12-day courses of teliximab are administered at intervals of approximately 6 months to approximately 12 months. 33. Tiglizamab used in a method for increasing the mean C-peptide value in subjects with type 1 diabetes, the method comprising: The total dose administered to the subjects was approximately 9000 μg / m². 2 Approximately 9500 μg / m 2 The first 12-day course of telizumab, wherein the subject had a peak C-peptide level of at least 0.2 pmol / mL during a mixed dietary tolerance test (MMTT) prior to administration of the first 12-day course of telizumab; and The total dose administered to the subjects was approximately 9000 μg / m². 2 Approximately 9500 μg / m 2 The second 12-day course of telixirmab, in which the first and second 12-day courses of telixirmab were administered at intervals of approximately 6 months to approximately 12 months, and Compared with those who received placebo, administration of teliximab increased the average C-peptide value by 40% to 80% or more. 34. Tiglizamab for use in a method for increasing the mean C-peptide value in subjects with type 1 diabetes, the method comprising: The total dose administered to the subjects was approximately 9000 μg / m². 2 Approximately 14000 μg / m 2 The first 12-day course of telizumab, wherein the subject had a peak C-peptide level of at least 0.2 pmol / mL during a mixed dietary tolerance test (MMTT) prior to administration of the first 12-day course of telizumab; and The total dose administered to the subjects was approximately 9000 μg / m². 2 Approximately 14000 μg / m 2 The second 12-day course of telixirmab, in which the first and second 12-day courses of telixirmab were administered at intervals of approximately 6 months to approximately 12 months, and Compared with those who received placebo, administration of teliximab increased the average C-peptide value by 40% to 80% or more. Example Example 1. Population pharmacokinetic simulation of telithrumab introduction

[0184] Tiglizamab is a 150 kDa monoclonal antibody that binds to the CD3-ε epitope of the T-cell receptor (TCR) complex. The antibody's primary mechanism of action involves binding to a CD3 antigen target on T cells. A population pharmacokinetic (PK) model was developed to describe tiglizamab concentrations following IV administration. The tiglizamab PK is described as a quasi-steady-state (QSS) approximation of a target-mediated drug disposition (TMDD) model. The aim of this study was to use this model to simulate and compare the concentration-time profiles of tiglizamab after several dosing regimens of interest. Target

[0185] The goal of the analysis is: • The following three dosing regimens were simulated using a previously developed population PK model: - "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 ; -Option 1: Day 1: 211 µg / m 2 Day 2: 423 µg / m 2 Days 3-12: 840 µg / m 2 ; -Option 2: Day 1: 106 µg / m 2 Day 2: 425 µg / m 2 Days 3-12: 850 µg / m 2 . • Describe and compare the concentration-time profile of telizumab under the three dosing regimens described above. Subjects and methods Dosing regimen

[0186] The Herold regimen is a 14-day course of telizumab, consisting of the following: 51 μg / m² administered daily via intravenous (IV) infusion (over at least 30 minutes) on days 1–4 of the study. 2 103 μg / m 2 207 μg / m 2 and 413 μg / m 2 And during the study, 826 μg / m² was infused daily from day 5 to day 14. 2 The total dose for a 14-day treatment course is approximately 9034 μg / m². 2 For a body surface area (BSA) of 1.92 m² 2In the subjects, this dosing schedule delivers approximately 17 mg of telizumab. The maximum amount of drug delivered at steady state is designed to coat 50% to 80% of the available CD3 on T cells without significant excess of free, unbound drug (expected at steady state < 200 ng / mL).

[0187] New regimen 1 is a 12-day course of telizumab, consisting of the following: 211 μg / m² administered via intravenous infusion (over at least 30 minutes) daily on days 1 and 2 of the study. 2 and 423 μg / m 2 And during the study, 840 μg / m² was infused daily from day 3 to day 12. 2 The total dose for a 12-day treatment course is approximately 9034 μg / m². 2 .

[0188] New regimen 2 is a 12-day course of telizumab, consisting of the following: 106 μg / m² intravenously (over 30 minutes) daily on days 1 and 2 of the study. 2 and 425 μg / m 2 And during the study, 850 μg / m² was infused daily from day 3 to day 12. 2 The total dose for a 12-day treatment course is approximately 9031 μg / m². 2 .

[0189] It is clear that all three regimens will deliver the same total dose, but in regimens 1 and 2, the delivery takes place within the original Herold regimen over 12 days instead of 14 days. simulation

[0190] The final model from the previous analysis was used for simulation. The concentration-time process was simulated over 40 days (day 0 to day 40), with 10 time points per day. The model included the study effects because patients from the Protégé Encore study were found to have higher clearance and central volume than patients from the Protégé study. Therefore, these two studies were simulated separately. Simulations were performed using covariate values ​​from four typical patients, specifically: • Adult patients with undetectable anti-drug antibodies [ADA]: 18-year-old, 60 kg male, BSA 1.67 m 2 ; • Adult patients with high ADA levels: 18-year-old, 60 kg male, BSA 1.67 m 2 ; • Pediatric patient with no detectable ADA: 13-year-old male, 45 kg, BSA 1.33 m 2 ; • Pediatric patients with high ADA levels: 13-year-old male, 45 kg, BSA 1.33 m 2 .

[0191] For each of these patients, population-predicted concentrations over time for each of the three dosing regimens were calculated and then compared graphically. Then, parameters for 1000 similar patients were simulated using model-estimated inter-individual variability, and individual concentration-time processes were calculated using this model. The median and 90% prediction interval of the simulated concentrations at each time point for each regimen were calculated and compared graphically. Furthermore, the mean and standard deviation of the simulated values ​​one day after the last dose were calculated and compared. software

[0192] The simulation was conducted using NONMEM software version 7.4.1 (ICON Development Solutions). Computer resources included Intel... ® Processor, Windows 7 Professional or later operating system, and Intel ® The Visual Fortran Professional compiler (version 11.0) was used on a personal computer. Graphs and all other statistical analyses (including the evaluation of the NONMEM output) were performed using R version 3.4.4 on Windows (R project, r-project.org). result

[0193] Simulation results of a typical adult patient with no detected ADA, such as Figure 1 As shown. Concentrations predicted in all dosing regimens of the Protégé study were higher than those in the Encore study. Concentrations in dosing regimens 1 and 2 were almost indistinguishable, except for slight differences in the first two 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 after the last dose (Herold regimen on day 14, regimens 1 and 2 on day 12), concentrations were almost identical. Simulations including inter-individual variability ( Figure 2-4 Table 1 confirms these observations. Table 1 shows the mean and standard deviation of the predicted concentrations (ng / mL) for 1000 simulated subjects in the Protégé study. Table 1. Predicted concentrations of telizumab: C1 day after the last dose 谷

[0194] Simulation results of a typical adult patient with high levels of ADA, as shown in the figure. Figure 5-8As shown. As expected, overall telizumab levels were much lower in subjects with very high immunogenic responses, but the conclusions regarding the differences between the three study dosing regimens still hold.

[0195] Simulation results of typical pediatric patients, such as Figure 9-16 As shown, they are very similar to those in adult patients, indicating that proportional BSA administration provides similar exposure for pediatric and adult populations.

[0196] Figure 17-24 The concentration curves comparing the Herold protocol and Protocol 2 over a longer period are shown, and Tables 2 and 3 summarize the C values ​​from 0 to 42 days in the simulation. max And AUC. The graph shows that by day 42, the concentration was very low, therefore the AUC... 0-42 The value of AUC 无穷 They are essentially the same. Table 2 shows the mean and standard deviation of the predicted maximum concentration (ng / mL) for 1000 simulated subjects obtained using the Protégé model 205. Table 3 shows the mean and standard deviation of the predicted AUC (ng / mL*day) for 1000 simulated subjects from 0 to 42 days obtained using the Protégé model 205. Table 2. Predicted concentrations of telizumab: C max Table 3. Predicted concentrations of telithrumab: AUC 0-42 in conclusion

[0197] Simulations show that: • Except for the first day of dosing, the predicted concentrations of telizumab were almost identical for the two recommended dosing regimens (Rule 1 and Rule 2); • Compared to the Herold regimen, the predicted concentration of telizumab increased more rapidly during dosing in regimens 1 and 2, but all regimens were almost identical on the last day of dosing; • The predicted concentrations of telizumab were almost identical for all three regimens one day after the last dose; • BSA proportional dosing provides a uniform level of exposure for adult and pediatric subjects with different body size measurements. Example 2. A phase 3 randomized, double-blind, multinational, placebo-controlled study was conducted to evaluate the efficacy and safety of the humanized, FCR-unbound, anti-CD3 monoclonal antibody tilimuzumab (PRV-031) in newly diagnosed children and adolescents with type 1 diabetes (T1D).

[0198] Tiglizumab (also known as PRV-031, hOKT3γ1[Ala-Ala], and MGA031) is a humanized 150 kDalton monoclonal antibody (mAb) that binds to the CD3-ε epitope of the T-cell receptor. Tiglizumab was developed in preclinical studies that demonstrated its ability to alter the immunopathogenesis of diabetes by targeting T cells (cells that help initiate and coordinate the autoimmune processes leading to type 1 diabetes [T1D]) through this mechanism and to prevent and reverse the disease in relevant animal models. The aim of this study was to evaluate tiglizumab in children and adolescents recently diagnosed with T1D. Tiglizumab holds promise as a first-in-class disease-modifying therapy to improve healthcare management and overall prospects for patients suffering from the most devastating short- and long-term consequences of this disease. Assumption

[0199] The hypothesis of this study is that tesilizumab is safe, well-tolerated, and effective in slowing β-cell loss and maintaining clinically relevant levels of β-cell function in newly diagnosed children and adolescents with T1D, while improving key aspects of T1D clinical management within 18 months. Target

[0200] The main objective is: • Determine whether two courses of telizumab slowed β-cell loss and preserved β-cell function within 18 months (78 weeks) in children and adolescents aged 8–17 years who were diagnosed with T1D within the past 6 weeks.

[0201] The secondary objective is: • Assess participants’ improvements in key clinical parameters of diabetes management, including insulin use, glycemic control (including hemoglobin A1c [HbA1c] and time within target range [TIR]), and clinically significant hypoglycemic episodes. • Determine the safety and tolerability of two cycles of intravenous (IV) administration of telixirmab. • Evaluate the pharmacokinetics (PK) and immunogenicity of two cycles of IV telizumab.

[0202] The exploratory goal is: • Assess β-cell function and T1D-focused clinical parameters • Assess immune, endocrine, molecular, and genetic markers end

[0203] The primary endpoint is: • The area under the time-concentration curve (AUC) of C-peptide after the 4-hour (4h) mixed diet tolerance test (MMTT) at week 78, a measure of endogenous insulin production and β-cell function.

[0204] The secondary endpoints are as follows: A. Key clinical endpoints: • Exogenous insulin use: defined as the daily average at week 78, in units of kilograms per day (U / kg / day). • HbA1c level: expressed as % and mmol / mol at week 78. •TIR: Represented as the percentage of the average daily time within a 24-hour period during which a participant's blood glucose (BG) is >70 but ≤180 mg / dL (>3.9 to ≤10.0 mmol / L), assessed using continuous glucose monitoring (CGM) at week 78. • Clinically significant hypoglycemic episodes: defined as the total number of episodes with a blood glucose (BG) reading < 54 mg / dL (3.0 mmol / L) and / or episodes of severe cognitive impairment requiring external assistance to recover from randomization to week 78. B. Safety endpoint: • Incidence of treatment-associated adverse events (TEAEs), adverse events of particular concern (AESIs), and serious adverse events (SAEs) • The incidence of infections occurring during treatment of particular concern, including but not limited to tuberculosis, infections requiring IV antibiotic therapy or hospitalization, Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections, or severe viremia (i.e., DNA-based polymerase chain reaction viral load > 10,000 copies / mL or 10 6 (cells) and shingles • Investigate the incidence and severity of drug infusion-related reactions, either immediately or with delay, such as hypersensitivity reactions, pain requiring interruption or cessation of infusion, cytokine release syndrome, and serum sickness. C. PK and immunogenicity endpoints: • Serum concentration of teliximab • Incidence and titer of anti-telizumab antibodies after treatment course 3. The exploratory endpoints are as follows: A. Assessment of β-cell function and health status throughout the study: •4h MMTT C-peptide AUC • Participants with a recognized clinically significant peak C-peptide level ≥ 0.2 pmol / mL during the 4-hour and 2-hour (2-hour) MMTT. • The ratio of proinsulin to C-peptide, a measure of endoplasmic reticulum stress and dysfunction in β-cells. B. Clinical endpoints focusing on T1D during the study period, unless otherwise stated: • Exogenous insulin use (U / kg / day) •HbA1c levels • Participants with poor glycemic control were defined as having HbA1c ≥ 9%. • The number of participants who do not require exogenous insulin, as they are able to achieve local, regional, or national age-based HbA1c and / or routine blood glucose management goals. • Assess blood glucose control based on BG values ​​obtained from intermittent (i.e., spot checks, finger-prick) blood glucose meter readings. • Assess glycemic control based on BG values ​​obtained from CGM readings, including but not limited to TIR; time of hyperglycemia and hypoglycemia ranges; daily, daytime, and nighttime average BG levels and estimated HbA1c; and glycemic variability. • Clinically significant hypoglycemic episodes from randomization to week 39 and from week 39 to week 78 • The incidence of “typical” hypoglycemia is defined as a blood glucose level ≥ 54 mg / dL (3.0 mmol / L) but < 70 mg / dL (3.9 mmol / L) and / or a non-severe clinical episode. • The incidence of diabetic ketoacidosis (DKA) requiring medical care is defined as elevated serum or urinary ketones above the upper limit of normal (ULN) and serum bicarbonate < 15 mmol / L or blood pH < 7.3, or both, leading to a hyperglycemic episode during outpatient or emergency room visits or hospitalization. • Patient-reported outcomes measured through tools such as the Quality of Life Inventory™ (PedsQL) Diabetes Module, the Hypoglycemia Fear Scale (HFS), and the Diabetes Treatment Satisfaction Questionnaire (DTSQ). • The impact on family life is measured using the PedsQL Family Impact questionnaire reported by parents. C. Comprehensive clinical endpoint: • Participants with HbA1c within the American Diabetes Association (ADA) target range (i.e., < 7.5%) and exogenous insulin doses within specific ranges (< 0.25, 0.25 to < 0.50, 0.50 to < 0.75, 0.75 to < 1.0, 1.0 to < 1.25, and ≥ 1.25 U / k / d). • Participants with HbA1c < 6.5% and < 7.0% and exogenous insulin dose < 0.5 U / kg / day or 0.25 U / kg / day D. Immunological and endocrinological endpoints during the study: • Phenotypic and functional characteristics of the WBC population, including T cells, B cells, and natural killer (NK) cells. • Serum pro-inflammatory and modulatory cytokine profiles and other immune mediators • The quantity, type, and titer of T1D autoantibodies • Antibody subclass level • Evidence of recent CVB infection • Levels of circulating hormones (e.g., glucagon, incretin, adiponectin) and other factors (e.g., lipid factors, cholesterol, triglycerides) associated with the pathophysiological process of T1D E. Molecular and genetic endpoints during the study: • Circulating methylated and unmethylated insulin DNA levels as an assessment of β-cell stress and damage • Gene expression and transcriptome analysis • Association between human leukocyte antigen (HLA) type and clinical, metabolic, and immune assessments Research Design Overview

[0205] This is a phase 3, randomized, double-blind, placebo-controlled, multinational, multicenter study. Approximately 300 participants were recruited and randomly assigned in a 2:1 ratio to either the telixizumab group (N = 200) or the placebo group (N = 100). Figure 25 The study design diagram is provided.

[0206] To minimize bias and potential confounding factors in treatment allocation and to improve the validity of statistical analysis, participants were randomly assigned to groups at a 2:1 ratio using randomized blocks and stratification based on the following criteria: • Peak C-peptide levels at screening: Within the range of 0.2 (inclusion criterion) to 0.7 pmol / mL (inclusive), compared to >0.7 pmol / mL • Age for randomization: 8 to 12 years (inclusive), compared to >12 to 17 years.

[0207] Modified dosing schedule for participants affected by COVID-19 pandemic restrictions:

[0208] To address force majeure issues caused by COVID-19, participants who were unable to receive a second course of treatment approximately 6 months after randomization (scheduled for a visit on day 182 [week 26]) due to COVID-19-related restrictions were instead scheduled to begin their second course at a visit on day 364 (week 52) (approximately 12 months) after randomization.

[0209] Revised dosing schedule as follows Figure 26 As shown. These participants underwent study procedures and assessments according to the modified event dosing schedule.

[0210] The reference to starting the second course of treatment on day 364 (or week 52) as mentioned in the entire protocol applies only to this group of participants.

[0211] Telizumab or a matched placebo is administered via intravenous infusion in two cycles. The first cycle begins on day 1 (week 1), and the second cycle begins on day 182 (week 26), approximately 6 or 12 months later. Each cycle consists of a daily infusion for 12 days.

[0212] The total study duration for each participant was up to 84 weeks. This included a 6-week screening period and a 78-week post-randomization period. Treatment consisted of two 12-day cycles spaced 6 or 12 months apart, followed by a post-treatment observation period of approximately 52 or 26 weeks. The final visit occurred at week 78.

[0213] For participants who adhered to the revised dosing schedule, treatments were spaced approximately 12 months apart, with a post-treatment observation period of approximately 26 weeks. The final visit also occurred at week 78. research group

[0214] This study recruited male and female participants aged 8 to 17 years with newly diagnosed type 1 diabetes mellitus (T1D) who were able to be randomized and begin study treatment within 6 weeks of diagnosis. To be eligible for randomization, participants must have been positive for at least one T1D-related autoantibody and have a peak stimulating C-peptide level ≥ 0.2 pmol / mL at screening. They must also meet all specific inclusion criteria and not meet any exclusion criteria. Dosage and administration

[0215] On the day of randomization (Day 1), each participant received the first dose of the study drug during the first 12-day cycle, as shown in the table below. On approximately Day 182, each participant received the first dose of the second 12-day cycle. The study drug (telizumab or placebo) was administered by the study approver via IV infusion at the study site or other qualified facility. The dose of the study drug was calculated based on the participant's body surface area (BSA) measured on Day 1 of each cycle. Dosage adjustments were not permitted. Revised dosing schedule

[0216] Participants who were unable to receive a second 12-day course due to COVID-19 pandemic restrictions received the second course at approximately day 364 (week 52 visit).

[0217] The study drug infusion for each treatment day should be administered within 20 to 28 hours after the previous dose. For example, if the dose for day 1 is administered at noon, the dose for day 2 should be administered between 8 a.m. and 4 p.m.

[0218] Dosing of the study drug (telizumab or placebo) was based on BSA, using height and weight obtained during this visit and the Mosteller formula (BSA = square root [height (cm) x weight (kg) / 3600]). Intervention measures description Table 4 Key Assessment

[0219] MMTT: To quantify endogenous β-cell function, participants underwent a standardized metabolic stimulation test for C-peptide (a 1:1 byproduct of insulin production). Participants consumed a fixed amount of a beverage containing known amounts of carbohydrates, fats, and proteins. Following consumption, BG, insulin, and C-peptide levels were measured over time. A 2-hour MMTT was performed at screening, and a 4-hour MMTT was performed at randomization and at weeks 26, 52, and 78 for assessment of key endpoints.

[0220] HbA1c: This is the percentage of red blood cells (measured as hemoglobin) that become non-enzymatically glycated in proportion to blood glucose levels. On average, this indicates the average blood glucose level over approximately 3 months. It is a key clinical target for T1D management.

[0221] Insulin use: 7-day average data collected prior to each designated visit to quantify exogenous insulin injections.

[0222] Hypoglycemia: Clinically significant and potentially life-threatening hypoglycemia is a consequence of insulin therapy and is more likely to occur in patients attempting to achieve glycemic control goals. This study asked participants to record information regarding blood glucose levels < 70 mg / dL (3.9 mmol / L) and / or events consistent with hypoglycemia. Particular attention was paid to clinically significant hypoglycemic events defined as reliable blood glucose readings < 54 mg / dL (3.0 mmol / L) and / or severe cognitive impairment and / or physical conditions requiring external assistance to recover.

[0223] Glucose monitoring: Participants or caregivers will perform intermittent glucose monitoring (e.g., spot checks or finger-pricks) multiple times daily as an essential part of blood glucose management to measure insulin dosage and assist with diet and activity. All participants should bring a blood glucose meter for testing at all visits. In addition to data on blood glucose control, participants will report their pre-meal and bedtime BG readings at specific times during the study period, and glucose levels will be assessed every 2 weeks using a CGM.

[0224] Quality of life questionnaires: Surveys were used to assess participants’ overall health and well-being, as well as the effects of tellizumab, such as the PedsQL Diabetes Module, HFS, DTSQ, and the Parent-Reported PedsQL Family Impact Module.

[0225] Pharmacokinetic and immunogenicity assessment: Tilizumab concentrations were analyzed in blood samples collected at specific time points throughout the study. Anti-tilizumab antibodies, including neutralizing antibodies (NAb), were measured. Security assessment

[0226] Adverse events, serious adverse events, and adverse events of particular concern. Assess relevance and severity. Severity will be graded according to the Common Terminology Standard for Adverse Events (CTCAE) version 5.0.

[0227] Infusion-related reactions

[0228] Severe infection

[0229] Clinical laboratory testing

[0230] Vital signs and physical examination Statistical methods General considerations

[0231] All statistical inferences were based on two-tailed tests at an alpha level of 0.05. All data were summarized by study drug group. Categorical variables were summarized by the number and percentage of individuals falling into each category. Continuous variables were summarized by mean, median, standard deviation, minimum, and maximum. Unless otherwise stated, baseline values ​​were defined as the most recent values ​​collected prior to the first dose of the study drug.

[0232] For the efficacy endpoint, the analysis population consists of all randomized participants who received any amount of the study drug, referred to as the intention-to-treat (ITT) population. In this population, participants are analyzed in the treatment group corresponding to the treatment they were randomly assigned to, regardless of the actual treatment they received.

[0233] For the safety endpoint, the analysis cohort consists of all randomly assigned study participants who received at least one dose of the study drug; this cohort is referred to as the safety cohort. For this cohort, participants are analyzed in the treatment group corresponding to the treatment they actually received, regardless of which treatment they were randomly assigned to.

[0234] For PK and immunogenicity, the analysis population is all participants in the safety population who provided at least one evaluable sample. Sample size determination

[0235] The study sample size was calculated based on the expected clinically relevant effects and results from placebo-treated participants in previous teglizumab studies. Since C-peptide AUC is right-skewed, ln(AUC+1) was used to transform the data for analysis. Limited 18-month C-peptide data were available from previous pediatric and adolescent studies where the stimulating C-peptide AUC at study participation was >0.2 pmol / mL. Estimates ranged from approximately 0.22 nmol / L to 0.32 nmol / L, with standard deviations between 0.18 and 0.22. Using an estimate of 0.25 nmol / L, the geometric mean for the placebo group was converted to exp(0.25)-1 = 0.28. This study aimed to demonstrate a difference of at least 40% in C-peptide response between teglizumab and placebo. In the geometric mean, this translates to a value of (1.4 * 0.28) = 0.392. Therefore, the plan is to recruit approximately 300 participants, assuming a two-sided α = 0.05, a power of 90%, randomization in a 2:1 ratio, and a dropout rate of 10%. Efficacy Analysis

[0236] The primary endpoint was the difference in C-peptide ln (AUC+1) between treatment groups at week 78 using the ITT population. C-peptide was measured in a 4-hour MMTT. Treatment differences in C-peptide at week 78 were assessed using analysis of covariance (ANCOVA). Missing data for patients who dropped out before the end of the study were estimated based on patients in the same treatment group who discontinued treatment in a similar manner but were measured at their scheduled visits. The model included treatment (telizumab or placebo), age, and peak C-peptide at baseline as covariates.

[0237] Sensitivity analysis was performed using the critical point method. The same estimations and models as in the primary analysis were used, but a critical point was identified that altered the C-peptide conclusions at 18 months. Repeated measures analysis could also be used to assess sensitivity.

[0238] If the primary endpoint is p < 0.05, the Hochberg step-up method is used to assess secondary clinical endpoints to address diversity issues.

[0239] As with the primary endpoint, ANCOVA was used to assess the percentage of time at week 78 that participants’ insulin use, HbA1c, and BG levels were within the target range of >70 to ≤180 mg / dL (>3.9 to ≤10.0 mmol / L).

[0240] During the first 7 days of the study visit and at randomization, participants self-recorded their average total exogenous insulin use (U / kg / day) in an electronic diary. Data from at least 5 of these 7 days were used for analysis. The model included age, baseline insulin use, peak C-peptide at baseline, and treatment group as covariates.

[0241] The model used to assess HbA1c will include age, baseline HbA1c, treatment group, and baseline peak C-peptide as covariates.

[0242] Time within the range of blood glucose was defined as the average percentage of time within the range 10 to 14 days after each study visit. The model included baseline time within the range, treatment group, age, and baseline peak C-peptide.

[0243] The incidence (number of events / exposure time) of clinically significant hypoglycemic episodes at week 78 was compared between groups. Data were obtained from intermittent blood glucose monitoring, continuous blood glucose monitoring, participant electronic diaries, and CRFs. A clinically significant episode was defined as a reliable BG value < 54 mg / dL (3.0 mmol / L) and / or a hypoglycemic event requiring external assistance (e.g., seizures, syncope, severe confusion with or without a verified low BG reading). A negative binomial model was used to assess the incidence of clinically significant hypoglycemic episodes in each study participant to account for the possibility of over-dispersion in hypoglycemic episode-related events within participant groups. The model used to assess clinically significant hypoglycemia included age, treatment group, and baseline peak C-peptide as covariates. Other analyses

[0244] Other analyses, including those on safety, pharmacokinetic and immunogenicity, and exploratory endpoints, were performed using established and recognized statistical methods.

[0245] Additional safety and efficacy analyses were conducted on a subgroup of participants who started a second course of treatment at their week 52 visit due to COVID-19 pandemic restrictions.

[0246] This study focused on individuals with significant β-cell function. It has been recognized that β-cells continue to be lost after a T1D diagnosis. To maximize the effect of β-cell preservation on patients with recoverable endogenous insulin production levels, this study recruited participants who had peak C-peptide levels ≥ 0.2 pmol / mL within 6 weeks of T1D diagnosis and during a mixed diet tolerance test (MMTT). The value of 0.2 pmol / mL was chosen because it is a critical and acceptable threshold for C-peptide, associated with a lower incidence of clinically important short- and long-term T1D-related complications (Lachin 2014, Palmer 2001, Palmer 2009). Random grouping and stratification

[0247] To minimize bias and potential confounding factors in treatment allocation and to improve the validity of statistical analysis, participants were randomly assigned to groups at a 2:1 ratio using randomized blocks and stratification based on the following criteria: Peak C-peptide levels at screening: in the range of 0.2 (inclusion criterion) to 0.7 pmol / mL (inclusive), compared with >0.7 pmol / mL

[0248] Age for randomization: 8 to 12 years (inclusive) vs. > 12 to 17 years.

[0249] Study Duration: The total study duration for each participant was up to 84 weeks. This includes a 6-week screening period and a 78-week post-randomization period. The post-randomization period consisted of two 12-day treatment cycles spaced 6 months apart, and a post-treatment observation period of approximately 52 weeks. The last visit occurred at week 78.

[0250] For participants who adhered to the revised dosing schedule, treatments were spaced approximately 12 months apart, with a post-treatment observation period of approximately 26 weeks. The last visit also occurred at week 78.

[0251] The overall study length and key assessment time points were chosen because of the natural process of residual β-cell loss after T1D diagnosis and the study objective of demonstrating the durability of the effect and confirming the safety of telizumab after treatment. At diagnosis, a significant number of β-cells may remain, typically estimated at 10%–20% of the normal β-cell mass, but in some cases exceeding 40% (Matveyenko 2008, Campbell-Thompson 2016). At T1D diagnosis, much of this remaining β-cell appears to be functionally impaired due to metabolic or immune (i.e., cytokine-induced) stress. Some β-cell function may recover within days, weeks, or months through exogenous insulin therapy and correction of pH, electrolyte, and fluid disturbances (i.e., DKA) that often occur at diagnosis. This observation is often referred to as the “honeymoon period,” during which insulin requirements can be significantly reduced, sometimes independently of exogenous insulin. These effects are transient, and over time, typically within one year of diagnosis, complete insulin replacement becomes inevitable due to the autoimmune elimination of these remaining β-cells. Due to the known individual variability in the natural history of β-cell loss, the effects of disease-modifying therapies aimed at preserving β-cell function are difficult to distinguish from the honeymoon period effects during the first 12 months after a T1D diagnosis.

[0252] The 18-month time point for the primary and key secondary clinical endpoints provides crucial data needed to integrate tilimuzumab as a disease-modifying therapy for T1D into routine medical practice and is consistent with existing endpoint guidelines recommended by the EMA and FDA. Data from natural history studies and intervention trials of T1D suggest that β-cell loss in T1D patients can vary considerably, particularly in the weeks to months following diagnosis. Because this study recruited younger participants close to T1D diagnosis (i.e., within 6 weeks), the possibility of honeymoon phenomena (or spontaneous, transient partial remissions) could add complexity, potentially persisting for up to approximately one year in the study population (Abdul-Rasoul 2006). The 18-month time point for the primary and key secondary clinical endpoints allows for minimization of the large inherent natural metabolic variability resulting from different trajectories of β-cell loss and / or transient enhancement of β-cell function due to honeymoon phenomena, thus allowing the true effects of tilimuzumab on β-cell function and clinical parameters to be distinguished from chance.

[0253] Other key assessments were conducted at randomization, week 26 (6 months), and week 52 (12 months) to better understand the natural history of β-cell decline and the role of telizumab in this particular study population.

[0254] Furthermore, primary and key clinical endpoints were assessed approximately one year after the last dose of study drug (except for participants receiving the modified dosing schedule). Duration of action is considered an important characteristic of modified therapy for intermittent T1D. At this point, a 12-month treatment-off period can be considered a reasonable timeframe to validate assertions of metabolic and clinically relevant durable benefits while maintaining positive metabolism and clinical efficacy.

[0255] Throughout this study, participants were assessed regularly through face-to-face interviews, physical examinations, self-reports, and laboratory tests. Assessments were performed daily during the two 12-day treatment cycles and periodically between cycles and during post-treatment follow-up. The treatment onset and discontinuation observation periods in this study were entirely within, if not significantly exceeded, the timeframes traditionally used to assess the safety and side effects of immunotherapies approved for other autoimmune diseases, including pediatric indications. At similar doses and regimens as used in this study, telizumab was generally well-tolerated with minimal side effects and no clear short- or long-term adverse event signals. It is anticipated that, based on further confirmatory data from this study, the side effects of telizumab will continue to be considered acceptable for inclusion in care programs for children and adolescents newly diagnosed with T1D.

[0256] Placebo control is used to establish the frequency and magnitude of changes in clinical, safety, metabolic, and exploratory endpoints that may occur in the absence of active treatment. Stratified randomization is used to minimize bias in assigning participants to treatment groups, increase the likelihood of equalization of known and unknown participant attributes (e.g., demographics and baseline characteristics) across treatment groups, and improve the validity of statistical comparisons between treatment groups. Blinding of treatment is used to reduce potential bias during data collection and the assessment of all study endpoints. research group Selection criteria

[0257] Each potential participant must meet all of the following criteria to participate in the study: • Participants can be male or female. • Participants were 8 to 17 years old (inclusive) at the time of randomization / start of study drug administration. • The participant had been diagnosed with T1D according to ADA criteria. • Participants were able to be randomized and begin treatment with the study drug within 6 weeks (42 days) after being formally diagnosed with T1D according to ADA criteria. • At screening, participants must have a peak stimulating C-peptide level ≥ 0.2 pmol / mL in the 2-hour mixed dietary tolerance test (2h MMTT). (Note: This screening 2h MMTT must only be performed 6 days after diagnosis to reduce metabolic instability.) • Prior to randomization, participants tested positive for at least one of the following T1D-related autoantibodies: o-glutamate decarboxylase 65 (GAD65) autoantibody oIslet antigen 2 (IA-2) autoantibodies zinc transporter 8 (ZnT8) autoantibody o Pancreatic islet cell cytoplasmic autoantibodies (ICA) or o Insulin autoantibodies (if tested within the first 14 days of insulin therapy) • Female participants with fertility potential must have a negative result for highly sensitive serum (β-human chorionic gonadotropin [β-HCG]) during screening. • Participants who have reached puberty must agree to comply with the following contraceptive requirements. (Note: In countries with legislation regarding the age of sexual activity, participants must comply with local age restrictions for the use of contraception.) From 30 days before the first dose of the study drug until the end of the study, women of reproductive potential (defined as premenopausal women who are capable of getting pregnant, i.e., those who have reached menarche or, even without menarche, have reached Tanner stage 3 breast development) or women who acquire reproductive potential during the study must maintain abstinence or use two methods of contraception (including oral, transdermal, injectable or implantable contraceptives, intrauterine devices, female condoms, diaphragms with spermicide, cervical caps, sexual partners using condoms, or sexual partners being infertile). Men who have entered puberty (i.e., the spermatogenesis stage) and whose partners are of fertility potential must use barrier contraception in addition to having their partners use another method of contraception during each course of treatment, from one week before each dose of the study drug to 120 days after the last dose (a complete spermatogenesis cycle). • Before receiving the investigational drug, participants must follow and / or consent to age-appropriate routine immunizations and adhere to current local, regional, and / or national guidelines for immunosuppressed individuals and patients with chronic diseases (diabetes). • Participants agreed not to receive other forms of experimental treatment during the study, especially agents that may have immunomodulatory properties and / or stimulate pancreatic β-cell regeneration or insulin secretion. • Participants and / or their appropriate legal guardians must sign an informed consent form (ICF) and / or indicate their consent in accordance with local, regional, and / or country-specific research participation guidelines. Exclusion criteria

[0258] Any potential participant who meets any of the following criteria is excluded from study participation: the participant has a known allergy, severe reaction, intolerance, hypersensitivity or anaphylactic reaction to human, humanized or mouse monoclonal antibodies, telizumab or any of its components or excipients. • Participants had actively participated in a clinical trial of a therapeutic drug, invasive medical device, or vaccine within 12 weeks prior to the first dose of the investigational drug, or had received an experimental treatment that might alter T1D disease. • Participants have serious kidney, heart, blood vessel, lung, gastrointestinal, nerve, blood, rheumatism, tumor, mental illness or immune deficiency. • Participants had any autoimmune disease other than T1D (e.g., rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, systemic lupus erythematosus), except for clinically stable thyroid or celiac disease. • Participants who had an active infection (including a positive SARS-CoV-2 test) and / or a fever ≥ 38.5°C (101.3°F) within 48 hours prior to randomization, were susceptible to infection, or had a chronic, relapsing, or opportunistic infectious disease, including but not limited to kidney, respiratory, or skin infections, Pneumocystis carinii, aspergillosis, latent or active granulomatous infection, histoplasmosis, or coccidioidomycosis. • Participants must have a history or serological evidence of current or past infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) at the time of screening. • Participants have any of the following conditions related to tuberculosis (TB): o History of latent or active TB Signs and / or symptoms of oTB o Recent close contact with a known or suspected patient with active TB, unless appropriate isoniazid is administered for tuberculosis prophylaxis. o A history of chest X-ray consistent with active TB or old inactive TB, A history of a positive skin test result for a purified protein derivative (>10 mm induration); or o Screening results showed a positive or repeatedly indeterminate interferon gamma release assay (IGRA; e.g., QuantiFERON-TB assay). o If local, regional, or national regulations require, a recent (within 3 months) chest X-ray, or an X-ray performed during screening and read by a qualified radiologist, must be consistent with current active TB or old inactive TB. • At the time of screening, participants had clinically active EBV infection, including but not limited to infectious mononucleosis, or a level of EBV per milliliter or per 100 milliliters at the time of study screening. 6 The EBV viral load per lymphocyte is ≥ 10,000 copies (Rosenzweig 2010). • At the time of screening, participants had clinically active CMV infection or a CMV viral load of 10 / mL or 10 / mL. 6 10,000 copies of lymphocytes (Verkrise 2006). • Participants were diagnosed with severe liver disease based on results from the central laboratory, or had alanine aminotransferase (ALT) and / or aspartate aminotransferase (AST) > 2X or total bilirubin (TBili) > 1.5X at the time of screening relative to the age- and sex-specific upper limit of normal (ULN). (Note: Participants with Gilbert's syndrome may be admitted with the approval of a medical monitor.) • Within 10 days prior to randomization / first dose of study drug, individuals were confirmed to have any of the following hematological parameters through repeated testing: o Lymphocyte count: < 1000 / µL Neutrophil count: < 1000 / µL Platelet count: < 100,000 platelets / µL o-hemoglobin: < 10 g / dL It should be noted that for individuals with one or more blood cell counts below or above the normal range, specific hematological, oncological, or other systemic diseases that may lead to exclusion and / or have not been identified to date should be considered. • Current or prior (within 30 days prior to screening) treatments known to cause significant and lasting changes in the course of T1D or immune status, including high-dose inhaled, extensive local, or systemic corticosteroids. (Note: Short-term (i.e., approximately 2 weeks or less) administration of corticosteroids for the treatment of transient disease is permitted.) • Currently or previously (within 30 days prior to screening) treated for hyperglycemia with medications other than insulin (e.g., metformin, sulfonylureas, meglitinides, thiazolidinediones, exenatide, liraglutide, dipeptidyl peptidase-4 [DPP-IV] inhibitors, or amylin). • Current or previous (within 30 days prior to screening) use of any medication known to significantly affect glucose tolerance (e.g., atypical antipsychotics, phenylhydantoin, niacin). • Currently or planned to use a highly restrictive dietary regimen for T1D management, such as a very low or ultra-low carbohydrate diet. • The following vaccines were recently administered or are planned for administration: o Live vaccines (e.g., varicella, measles, mumps, rubella, cold and flu attenuated intranasal influenza vaccine and smallpox): within 8 weeks prior to randomization and the start of administration of the study drug or planned / required administration, up to week 52 or 78 of the study (if the modified dosing schedule is followed). o Non-infectious (e.g., recombinant, inactivated, or other "non-live") vaccines: within 2 weeks before each course of treatment until 6 weeks after each course of treatment. • Pregnant women who test positive for β-HCG in their blood at screening or in their urine before starting the study drug, who wish to become pregnant, plan to donate eggs (ovules, oocytes), and / or are breastfeeding to provide their own breast milk for the baby throughout the study period. • Men who plan to have children or donate sperm during each course of treatment, from one week before each dose of the study drug to 120 days after the last dose (a complete spermatogenesis cycle). • Individuals with a history of alcohol, drug, or chemical abuse within the 12 months prior to the study screening. • Individuals with medical, psychological, or social conditions that the principal investigators believe could interfere with the safety and proper conduct of the trial. • Individuals who are directly involved in the proposed research or other research under the guidance of the researcher or research institution as employees of the researcher or research institution, as well as family members of these employees or researchers. While there are no specific weight-based exclusions, weight-based participation criteria may exist due to differences in national, regional, and / or local blood volume restrictions for research study participants, depending on the participant's location. Researchers will confirm that potential participants meet any specific weight-based criteria due to any limitations imposed by these location-specific blood volume restrictions. Treatment allocation

[0259] Random grouping and stratification procedures

[0260] Participants were randomly assigned to one of two treatment groups, with a participant ratio of 2:1 for the telizumab group and the placebo group. Randomization was balanced using randomized blocks and stratified according to peak C-peptide levels at screening (0.2 to 0.7 pmol / mL (inclusive) vs. > 0.7 pmol / mL) and age at randomization (8 to 12 years (inclusive) vs. > 12 to 17 years).

[0261] This was a double-blind study. All participants remained blinded throughout the study.

[0262] In some embodiments, T1D diagnosis is performed according to ADA criteria. In some embodiments, a patient diagnosed with T1D is positive for at least one of the following T1D-related autoantibodies: glutamate decarboxylase 65 (GAD65) autoantibody, islet antigen 2 (IA-2) autoantibody, zinc transporter 8 (ZnT8) autoantibody, islet cell cytoplasmic autoantibody (ICA), or insulin autoantibody (if tested within the first 14 days of insulin therapy).

[0263] Study drug preparation: At the start of each 12-day course of study drug administration, the participant’s current BSA was calculated using the Mosteller formula, BSA = square root [height (cm) x weight (kg) / 3600], using the height and weight obtained on that day.

[0264] Telizumab and placebo were prepared according to the Pharmacy Manual provided to the field.

[0265] Two (2) mL of the study drug should be drawn from the study drug vial and slowly diluted by gentle mixing in 18 mL of 0.9% sodium chloride injection. The resulting 20 mL 1:10 dilution is used as the initial study drug solution, containing either placebo or telizumab at a concentration of 100 μg / mL. This initial drug solution should then be added to 25 mL of 0.9% sodium chloride solution. Finally, the resulting formulation should be gently mixed before administration to the participants.

[0266] Vascular access: This study required intravenous infusions and blood draws over two 12-day cycles. It should be recognized that intravenous access (for infusions and blood draws for laboratory sampling) can be challenging for the pediatric population, the focus of this study. Children's veins are smaller than adults', making catheter insertion potentially more challenging, and they may exhibit significant resistance to catheter placement and / or venipuncture.

[0267] Recognizing the above, this study also allows for the use of temporary and intermediate-term vascular access methods in addition to the use of "traditional" intravenous peripheral catheters. In particular, "midline" or peripherally inserted central catheter (PICC) lines can be used to study drug infusion and blood draw (where applicable, depending on the characteristics of the access line and local, regional, or national guidelines). Pre-dosing and investigational drug infusion:

[0268] Based on local availability and practice standards, study participants receive an oral pre-dose consisting of an NSAID (tablet or liquid) and a locally approved antihistamine (tablet or liquid) for at least the first 5 days of each study drug course. If the investigator determines that the participant is suitable for tolerating the infusion, the participant may receive one or both of these pre-dose administrations for the remaining study drug dose. The pre-dose should be administered at least 30 minutes before the start of the study drug infusion. If NSAID use is contraindicated, oral acetaminophen (tablet or liquid) may be administered.

[0269] The investigational drug (telizumab or placebo) is prepared and supplied by designated personnel or equivalent pharmacists in accordance with a pharmacy manual.

[0270] The pharmacy manual should be followed to ensure that the IV drug delivery device used is made of materials compatible with the investigational drug.

[0271] Tiglizumab for intravenous administration can be prepared using only 0.9% sodium chloride. When administering tiglizumab, no solutions other than 0.9% sodium chloride should be used through the same intravenous tubing. If it is necessary to use the same intravenous tubing to infuse other drugs or solutions, the tubing should be flushed with 0.9% sodium chloride solution before and after the tiglizumab infusion.

[0272] According to standard practice, the study drug is administered intravenously within at least 30 minutes.

[0273] Once the infusion solution has been completely administered, infuse an additional volume of saline solution equal to the volume contained in the infusion tubing at the same constant rate to ensure that all study drugs have been cleared from the infusion tubing. The start and end times of the infusion must be recorded.

[0274] During and for an additional 60 minutes after infusion, assess participants' vital signs (i.e., blood pressure, respiratory rate, and heart rate) every 15 minutes and monitor for signs or symptoms of infusion reaction. These symptoms include, but are not limited to, fever, chills, headache, nausea, vomiting, infusion site pain, allergic reactions, wheezing, dyspnea, urticaria, and hypotension. If a participant develops signs or symptoms of infusion reaction during the 60-minute observation period after infusion, observe the participant for another 60 minutes or until the reaction subsides, whichever is longer. Diabetes management and insulin use:

[0275] All enrolled participants, with the assistance of their healthcare provider, should receive intensive diabetes management for their type 1 diabetes (T1D) using approved therapies, in accordance with the recommendations of the American Diabetes Association (ADA) or local, regional, or national guidelines, to achieve glucose levels that appear to reduce some of the short- and long-term sequelae of T1D. Currently, the ADA's glycemic targets focus on management strategies to achieve HbA1c levels < 7.5% (58 mmol / mol) in individuals 17 years of age and younger, and < 7.0% (53 mmol / mol) in individuals 18 years of age and older, while minimizing severe or frequent hypoglycemic events.

[0276] Blood glucose targets should be attempted through appropriate blood glucose monitoring, administration of exogenous insulin, and monitoring of activity levels and diet. Exogenous insulin may include intermittent administration or rapid-acting, intermediate-acting, and / or long-acting insulin administered via a personal insulin pump. Blood glucose levels should be measured at least four times daily, including before meals and at bedtime.

[0277] Insulin use, including product type, dosage, and dosing schedule, is expected to change during the study. As part of routine clinical care for T1D, participants' insulin doses may be increased, decreased, or even discontinued if the attending physician determines it is clinically appropriate.

[0278] If a participant fails to reach their blood glucose target, the research team should contact the participant's primary clinical care team to explore possible adjustments to the insulin regimen, referral to a registered dietitian, or other methods that may improve glucose control. Insulin discontinuation

[0279] If a participant achieves an HbA1c level ≤ 6.5% while using ≤ 0.25 U / kg / day of insulin, insulin therapy may be discontinued. Participants should continue to monitor their blood glucose and HbA1c levels as per the protocol, and urine ketones should be monitored daily. During routine blood glucose monitoring, if a participant's blood glucose level exceeds 200 mg / dL (11.1 mmol / L) and / or urine ketones are moderate or higher, the participant should consult their attending physician and / or clinical field staff for further evaluation. If fasting blood glucose exceeds 126 mg / dL (7 mmol / L) or HbA1c exceeds 6.5%, as demonstrated by repeated testing, resumption of insulin therapy should be considered. Randomization, treatment and monitoring Week 1 of the research visit

[0280] Patients should receive pre-selection medications for an NSAID (e.g., ibuprofen) (or acetaminophen if an NSAID is contraindicated) and an antihistamine (e.g., diphenhydramine) for at least the first 5 days of treatment, unless contraindicated due to drug allergy or sensitivity. The study drug infusion may begin at least 30 minutes after the pre-administration. Administration of the study drug should be performed according to the pharmacy manual. According to standard practice, the study drug should be administered intravenously over 30 minutes, but the rate may be slowed if signs or symptoms of intolerance are present. Once the infusion solution has been completely administered, infuse an additional volume of saline at the same constant rate as the volume contained in the infusion tubing to ensure that all study drug has been cleared from the tubing. The start and end times of the infusion should be recorded. Days 2-12: Continue the first course of infusion.

[0281] If there are no clinical or laboratory problems, the patient may receive the next infusion as described above at least 30 minutes after administration of a prophylactic NSAID (acetaminophen if an NSAID is contraindicated) and an antihistamine. Any signs or symptoms of intolerance or infusion reaction should be closely monitored during and for 60 minutes after the infusion. Days 2-11

[0282] Between days 2 and 11, patients were subsequently able to leave the facility and return the following day for the next study drug infusion. Day 12

[0283] On day 12 after the completion of the last infusion of this course of treatment, and after observation for at least 30 minutes, a continuous glucose monitoring (CGM) sensor was applied, and participants were provided with instructions on CGM monitoring care and use. Study visits in weeks 4, 8, 12, and 20

[0284] The visit window for these study visits was ± 4 days from the target visit date. During these visits, participants returned to the site for the scheduled visit and underwent clinical and / or laboratory evaluations. Notably, at week 12, a CGM sensor was applied, and participants were provided with instructions on CGM monitoring care and use.

[0285] At the week 20 visit, participants were given instructions for the week 26 4h MMTT, including overnight fasting and insulin administration before the MMTT. Study visit week 26: 4h MMTT and second course of treatment (or week 52, if the modified dosing schedule is followed)

[0286] The visit window for these studies was ± 3 days from the target visit date. Days 182-193

[0287] Clinical and laboratory assessments (including a 4-hour MMTT) and administration of the investigational drug to initiate the second course of treatment on day 182.

[0288] Of particular note is that height and weight should be obtained at this visit and used for BSA-based dosing calculations for the second course of treatment. Following the guidelines for the first course of the study drug, patients should be pre-administered an oral NSAID (acetaminophen if an NSAID is contraindicated) and an antihistamine at least 30 minutes before the start of the initial five study drug infusions (and subsequent infusions as needed). Administration of the study drug should be in accordance with the pharmacy manual, 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 response during and for an additional 60 minutes after the infusion.

[0289] On certain dates, blood samples were drawn within 30 minutes prior to the administration of the study drug to measure serum telizumab levels. Days 183-192 (days 2-11 of the second course of treatment)

[0290] Patients can leave the facility between days 183 and 192 and return the following day for the next study drug infusion. Day 193 (Day 12 of the second course of treatment)

[0291] After the last infusion of this treatment course is completed and the patient is observed for at least 30 minutes, the CGM sensor is applied, and the patient is provided with instructions on CGM monitoring care and use. The study was conducted during weeks 30, 34, 39, 52, and 65.

[0292] The visit window for weeks 30, 34, 39, and 52 was ± 4 days from the target visit date. The visit window for week 65 was ± 7 days. A 4-hour MMTT was conducted during the week 52 visit.

[0293] At the end of the 39th, 52nd, and 65th week visits, apply the CGM sensor and provide additional training and instructions updates on CGM care and use as needed. Study visits in weeks 39 and 65

[0294] Patients were given instructions for the 4-hour MMTT at weeks 52 and 78, including overnight fasting and pre-MMTT insulin administration. At the week 65 visit, patients were assigned a CGM device for home use to begin around week 76. Week 78 of the research visit

[0295] The visit window for this study was ± 7 days from the target visit date. During this visit, a 4-hour MMTT was performed. efficacy assessment Mixed Diet Tolerance Test

[0296] A 2-hour MMTT is performed at screening to determine study eligibility (based on peak C-peptide levels). 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. The 4-hour MMTT is used at and after randomization because it has been shown to be more accurate and reliable than the 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 entry into the study. C-peptide, serum glucose, and insulin are assessed from samples from these assessments. Samples are stored for potential future assessments, including but not limited to proinsulin levels. C-peptide and glucose are measured in serum samples. The MMTT is performed after an overnight fast, between approximately 7:00 am and 10:00 am, strictly following insulin administration guidelines. A 2-hour MMTT takes approximately 130 minutes to perform, and a 4-hour MMTT takes approximately 250 minutes. Hemoglobin A1c

[0297] HbA1c was assessed as a blood test during selected study visits. Insulin use

[0298] Participants recorded their daily insulin use in an electronic diary at selected times 7 days prior to randomization and at visits approximately at weeks 12, 26, 39, 52, 65, and 78. Patients recorded all short-acting, intermediate-acting, and long-acting insulin administered as intermittent injections or used with an insulin pump during this period. No insulin use data were recorded the day before or on the day of the study visit. If a patient forgot to record insulin use the day before or several days before the visit, insulin use should be continued for up to 72 hours after administration to obtain data for up to 7 days. Every effort should be made to collect a total of 7 days of insulin use data for all of the above visits except for week 78 (the final visit), as patients return to their electronic diaries at the final visit. hypoglycemia

[0299] Throughout the study, participants recorded clinically significant and other non-severe and non-major hypoglycemic episodes by assessing glucometer readings. Glucose monitoring (1) Intermittent glucose monitoring (finger-tip)

[0300] Blood glucose levels other than MMTT and CGM were recorded and analyzed as endpoints at different time points. As part of routine care, blood glucose levels were typically measured at least four times daily with a finger-prick glucometer, including before each meal and at bedtime. At screening, participants were provided with a study-provided glucometer and glucometer strips, but they could use their own if they wished. Each participant was instructed to bring their glucometer to each visit (if they used multiple glucometers, such as at home and school) for testing. Additionally, approximately seven times throughout the study, participants recorded their blood glucose levels before breakfast, lunch, and dinner, and at bedtime in their study electronic log for seven consecutive days prior to the randomization visit and visits at weeks 12, 26, 39, 52, 65, and 78. Similar to the recording of insulin use data, blood glucose data were not recorded the day before and on the day of the study visit. If a participant forgot to record their finger-prick glucose measurement before the visit, it should be recorded immediately after the visit for 72 hours. Every effort should be made to collect BG data for a total of 7 days for all of the above visits except for week 78 (the last visit), as participants returned electronic diaries at the time of the last visit. (2) Continuous glucose monitoring

[0301] “Continuous” glucose monitors record interstitial glucose levels (which are very close to blood glucose values) at fixed time intervals, for example, every 5–15 minutes, depending on the device. A growing body of clinical research supports this measurement and its assessment, providing valuable and unique insights into glycemic control in diabetes. In this study, CGM assessment was performed to provide key secondary clinical and exploratory endpoint data to address whether and how telixirumab affects glycemic control, such as glucose shift, time spent within a specific glucose range, and daily average glucose values ​​(Steck 2014, Helminen 2016, Danne 2017). Recent international consensus statements on CGM monitoring support the use of measurements of time percentages within the range (target, hypoglycemia, and hyperglycemia) and glycemic variability in clinical trials as key indicators of diabetes control (Danne 2017).

[0302] Throughout the study, glycemic control was assessed using CGM approximately seven times: after randomization and completion of the treatment at week 26; after visits at weeks 12, 39, 52, and 65; and before the visit at week 78. The CGM sensor was placed by qualified researchers who provided education and training on CGM use and maintenance. The sensor may remain in place for up to two weeks. If the sensor dislodges within these two weeks, it can be replaced by the participant, a knowledgeable family member / guardian, or a qualified medical professional.

[0303] To minimize any confounding factors in glucose measurement during study drug infusion, CGM sensors were placed on participants after completion of the first and second cycles of study drug administration and after further clinical and laboratory assessments on the dates specified in the event timeline. Sensors were also placed on participants at week 12, 39, 52, and 65 visits, after all clinical and laboratory assessments and the MMTT were completed.

[0304] Study CGM readings are not intended for the medical management of participants' diabetes, but may be conducted under the supervision of the participants' healthcare team. It is worth noting that routine use of personal CGMs is permitted under the guidance of the participants' regular healthcare provider.

[0305] Sampling and CGM blood glucose assessment are expected to include, but are not limited to, mean BG, blood glucose variability (BG standard deviation [SD]), maximum and minimum BG values ​​over time, and BG > 70 but ≤ 180 mg / dL (> 3.9 but ≤ 10.0 mmol / L, Grade 1 (> 180 but ≤ 250 mg / dL) (> 10 but ≤ 13.9 mmol / L)) and Grade 2 hyperglycemia (> 250 mg / dL (> 13.9 mmol / L)) and Grade 1 (≤ 70 but ≥ 54 mg / dL (≤ 3.9 but ≥ 3.0 mmol / L)) and Grade 2 (< 54 mg / dL (< 3.0 mmol / L)) incidence and / or percentage time of hypoglycemia (Seaquist 2013, International Hypoglycemia Study Group (IHSG) 2017, Agiostratidou (2017). Pharmacokinetics and Immunogenicity Evaluate:

[0306] Venous blood samples should be collected according to the event schedule to measure serum concentrations of telizumab, anti-telizumab antibodies, and neutralizing antibodies (NAb). Additionally, samples should be collected at the early termination visit for subjects who discontinue study treatment early or who experience suspected immunogenicity-related adverse events (e.g., infusion reactions, injection site reactions, or hypersensitivity reactions).

[0307] Collect venous blood samples. Samples collected for the analysis of telixirmab serum concentrations and telixirmab antibody levels can also be used to assess safety or efficacy, address issues that arise during or after the study period, further characterize immunogenicity, or evaluate relevant biomarkers. Analysis program

[0308] Serum samples were analyzed using validated, specific, and sensitive immunoassay methods. Pharmacokinetic parameters

[0309] Serum concentration-time data for teglizumab were analyzed using nonlinear mixed-effects modeling (using NONMEM software) to obtain the primary PK parameters, clearance (CL), and volume of distribution. PK curves, along with other available data, were used to develop a population PK model, incorporating the effects of primary covariates (e.g., sex, race, ethnicity, antibody) on CL and volume of distribution. The initial model was one previously developed for teglizumab. All PK parameters are presented in tabular and descriptive summary statistics, including arithmetic mean, geometric mean (AUC, C10), and other statistical methods. max(and its derived parameters), median, range, standard deviation, and coefficient of variation. Data from this study may be combined with data from other studies. Exploratory and other assessments Immunological and serological assessment

[0310] Immune assessment may include, but is not limited to, monitoring T-cell and B-cell profiles via flow cytometry. In addition, serum levels of circulating pro-inflammatory and anti-inflammatory cytokines, as well as other soluble factors that may influence T1D progression, can be assessed.

[0311] To investigate whether and how tilimuzumab induces changes in lymphocyte subsets and the expression of markers indicating functional states (i.e., activation and depletion), flow cytometry is planned as part of the exploratory endpoint. Quantitative subset analysis will be performed on fresh samples, including assessment of CD4+ T cells, CD8+ T cells, B cells, and NK cells (i.e., quantitative lymphocyte subset composite assay (Panel) or TBNK composite assay). Additionally, samples for PBMC assessment will be collected at specified time points, processed, and stored for future “in-depth” phenotypic analysis, antigen-specific analysis (i.e., tetramers), and functional responses to antigen-specific and non-specific stimuli. Some of these analyses may be performed using conventional flow cytometry, CyTOF, or other techniques.

[0312] To determine whether and how teglizumab affects cytokine levels through cytokine release or lymphocyte regulation, blood samples were collected at selected time points before and after study drug administration. Samples were processed and stored. Analysis was expected to be performed only within selected time intervals, which could include after a critical number of participants had completed their week 52 visit or other key time points. Examples of measurable cytokines include interleukin (IL)2 (IL-2), IL-4, IL-5, IL-6, IL-8, IL-10, interferon-γ, and tumor necrosis factor-α. In addition, other serum assessments could be performed, including evaluation for hormones or other metabolically active substances that may affect metabolic control (e.g., glucagon, incretin, lipid factors, adiponectin, or cholesterol). Assessment methods could include antibody-based multiplex assays, modified aptamer binding techniques, or other platforms.

[0313] Key markers indicating the presence of autoimmune processes targeting the islets include assessing the presence and titers of anti-GAD65, anti-insulin, anti-IA-2, anti-ZnT8, and anti-ICA ​​autoantibodies. Several natural history studies have demonstrated that detecting these combinations of autoantibodies is an accurate predictor of T1D. Therapies affecting T1D progression can alter the presence or titers of autoantibodies. Furthermore, telizumab may have an impact on general antibody subclasses. Therefore, assessing the effect of telizumab on the presence and titers of T1D autoantibodies in the context of evaluating total antibody subclasses is crucial. Qualitative and quantitative assessment of antibody subclasses (e.g., IgG, IgA, and IgM) can indicate changes in the type of helper T cell response to T1D-related autoantigens.

[0314] Recent data suggest that CVB infection may be a trigger for breaking self-tolerance in individuals susceptible to T1D, and a precursor to β-cell destruction that ultimately leads to T1D. A better understanding of the relationship between CVB infection and newly diagnosed T1D patients could contribute to the development of novel therapies for the treatment and / or prevention of T1D. Blood samples obtained for exploratory analysis can be used for serological, molecular, and other assessments of CVB infection. β-cell stress assessment

[0315] It has been proposed that disease progression is associated with alterations in “β-cell stress,” particularly due to attempts to enhance endogenous insulin production from residual β-cells, which may disrupt intracellular processes and directly or indirectly cause harmful inflammatory mediators. It has been suggested that measuring specific β-cell products may be a marker of this process, and that β-cell recovery due to immune intervention may lead to a reduction in these markers. In this study, two such markers will be exploratoryly evaluated: the proinsulin-to-C-peptide ratio and serum levels of circulating methylated insulin DNA. Samples suitable for these analyses were collected, processed, and stored. pharmacodynamic sub-studies

[0316] To evaluate the pharmacodynamic (PD) effects of tesilizumab, namely its CD3 receptor occupancy and regulation, a sub-study was conducted. Pharmacogenomics (DNA) assessment

[0317] The HLA system is a group of genes that encode proteins of the human major histocompatibility complex (MHC). An individual's MHC haplotype helps understand the interactions of different types of lymphocytes that may contribute to T1D and may help identify individuals at risk for T1D (Roark 2014). Participants' MHC haplotypes were determined. The results of genotyping analysis can be used to correlate with disease progression, treatment response, and to identify subgroups that preferentially respond to telizumab.

[0318] Pharmacogenomic studies of DNA, RNA, or other genetic material can also help understand the mechanisms by which telizumab affects T1D, the immune system, or individuals who preferentially respond to telizumab. One example is the anticipated assessment of methylated insulin-DNA, but studies could also include transcript / transcriptome, microarray, or whole-genome assessments. Samples suitable for these analyses were collected, processed, and / or stored. Quality of life assessment

[0319] People with type 1 disease (T1D) may appear healthy, but managing their condition is a lifelong daily task, requiring multiple daily assessments and treatments, along with close monitoring of their diet, health status, and exercise. Therefore, T1D patients and their families bear a tremendous burden every day (Monaghan 2015, Mittermayer 2017). Furthermore, even the most actively managed T1D patients are at risk of severe short- and long-term morbidity and mortality. Thus, it is recognized that T1D patients not only suffer from medical sequelae but also bear a significant emotional, personal, familial, and psychological burden (Monaghan 2015). Understanding whether and how treatment can affect these other measures of "quality of life" is a growingly recognized aspect of the potentially beneficial effects of treatments that can alter the course of T1D. This study had participants complete questionnaires such as the PedsQL Diabetes Module, HFS, DTSQ, and PedsQL Family Impact Module at specified times in the event timeline (Driscoll 2016, Trancone 2016, Bradley 2009, Gonder-Frederick 2011, Varni 2018). Management of cytokine release syndrome

[0320] In a previous phase 3 study of telixirza, approximately 6% of participants with type 1 diabetes (T1D) experienced cytokine release syndrome after receiving telixirza. Symptoms of cytokine release syndrome include, but are not limited to, rash, headache, nausea, vomiting, chills, and fever. Most symptoms occur in the first few days of treatment and are mild to moderate in severity. Cytokine release syndrome is time-limited and appears to resolve regardless of whether telixirza administration is interrupted.

[0321] Despite pre-administration, participants in this study may still experience cytokine release syndrome, which may require supplemental therapy and / or modification of the study drug administration. Management recommendations for these symptoms are as follows. Complementary Therapy

[0322] Complementary therapy is intended for symptom management. The same pre-administration can be used as follows: • Locally approved NSAIDs, such as ibuprofen (tablets or liquid), diclofenac, naproxen, meloxicam, or tenoxicam, should be administered in accordance with appropriate age restrictions and practice standards. • If NSAIDs cannot be used, acetaminophen can be added or used as a substitute. If necessary, continued NSAID administration should be considered. • Antihistamines can continue to be used. For more severe or prolonged symptoms, the following medications may be administered according to local practice standards: • Antihistamines, such as IV diphenhydramine • Acetaminophen can be used in combination with antihistamines and can be repeated every 4 to 6 hours; hydroxyzine can be used during the day to avoid sedation. • More potent NSAIDs, such as ketorolac. • Acetaminophen in combination with codeine or pethidine is used to treat myalgia, chills and shivering. Ondansetron is used to manage GI symptoms such as nausea and vomiting. • Saline pills help support hemodynamics. Modify the administration of research drugs

[0323] If cytokine release syndrome is associated with an allergic reaction or angioedema, the investigational drug should be permanently discontinued, regardless of whether hemodynamic support (i.e., adrenaline and / or blood pressure medication) or mechanical ventilation is required.

[0324] Symptoms alone are usually not sufficient to warrant modification of investigational drugs. However, if cytokine release syndrome is associated with the following laboratory abnormalities, the drug should be discontinued: The investigational drug should be permanently discontinued if: ALT and / or AST > 5X ULN, total bilirubin > 3X ULN; ALT and / or AST > 3X ULN, and total bilirubin > 2X ULN (Haydner's rule); platelet count < 50,000 / µL, neutrophil count < 500 cells / µL, and hemoglobin < 8.5 g / dL (laboratory tests should confirm these results over two consecutive days of administration). Study drug administration may be temporarily interrupted if: ALT and / or AST > 3X ULN but ≤ 5X ULN, total bilirubin > 2X ULN but ≤ 3X ULN, platelet count > 50,000 but ≤ 100,000, or hemoglobin > 8.5 g / dL but ≤ 10 g / dL (laboratory tests can be repeated on the same day). If the repeated test is normal, the dose for that day can be administered. If the value remains within the above range or worsens, or if the test cannot be repeated on the same day, the dose for that day should be discontinued. If the above issues are resolved within 2 days, the administration of the research drug can be resumed as originally planned. ▪ If the above-mentioned issues remain unresolved after two consecutive days of interruption, you must consult a medical monitor regarding the continued administration of the investigational drug.

[0325] Glucocorticoids (e.g., prednisone 1–1.5 mg / kg / day, twice daily) should be reserved for the treatment of refractory symptoms or grade 3 or higher events that cannot be relieved by the aforementioned medications. There is evidence that glucocorticoids may interfere with the mechanism of action of tilimab, and therefore should be administered for the shortest possible duration. If an investigator deems it necessary to use glucocorticoids to relieve refractory signs or symptoms, they should follow applicable standard care recommendations and treatment guidelines and promptly notify the medical monitor. Blood glucose levels should be carefully monitored during glucocorticoid administration. Laboratory testing Hematological combination test •WBC Classification • Hemoglobin • Hematocrit • Platelet count Serum chemical combination test and liver function test •sodium Potassium •chloride • Bicarbonate • Blood urea nitrogen (BUN) • Creatinine •glucose •calcium • Phosphate •albumin • Total protein Liver function tests • Total bilirubin (TBili) • Direct bilirubin (DBili) • Aspartate aminotransferase (AST) • Alanine aminotransferase (ALT) • Alkaline phosphatase (ALP) Quantitative TBNK subset assay •CD4 + T cells •CD8 + T cells •B cells •NK cells Quantitative immunoglobulin combination detection •IgA •IgG •IgM Combined blood lipid test (fasting) • Total cholesterol High-density lipoprotein (HDL) • Low-density lipoprotein (LDL) • Triglycerides Coagulation assay (for screening only) • Prothrombin time (PT) Partial thromboplastin time (PTT) • International Normalized Ratio (INR) Urine analysis •pH •proportion •protein •glucose • Ketones • Bilirubin • Nitrite • Leukocyte esterase • Blood cells / hemoglobin Other tests • Serum pregnancy testing (only when screening women of fertility potential) • HIV antibody serology (only during screening) • HBV antibody serological / antigen combination test (only for screening) • HCV antibody serology (only during screening) •VZV antibody serology •CMV serology •EBV serology •CMV DNA PCR •EBV DNA PCR • MHC haplotype (only in week 1, i.e., when randomized) • Interferon-gamma release assay (IGRA) for tuberculosis detection •HbA1c Diabetes-related laboratory tests: • Type 1 diabetes antibodies (anti-insulin, anti-GAD-65, ICA, anti-ZnT8, anti-IA2) • Connecting peptide (C-peptide) •insulin • Proinsulin result

[0326] The patients’ demographic and baseline characteristics are shown in Table 5 below. Table 5. Demographic and clinical characteristics of PROTECT patients at baseline.

[0327] The results showed that the study met its primary endpoint: at week 78, telimumab treatment resulted in a significant difference in the mean change in C-peptide AUC levels from baseline compared to placebo. After telimumab administration, the mean C-peptide AUC remained stable until week 26, then decreased at weeks 52 and 78. Figure 31A In contrast, in patients receiving placebo, the mean C-peptide AUC decreased at all time points. A pre-specified exploratory analysis showed that, compared to placebo, a higher proportion of patients receiving telizumab at week 78 had clinically significant peak C-peptide levels ≥ 0.2 pmol / mL (94.9% [95% CI 89.5, 97.6] vs. 79.2% [95% CI 67.7, 87.4]). Figure 32 and Figure 33 Data showed that tesilizumab preserved β-cell function as measured by C-peptide levels. In comparison, patients receiving tesilizumab had a mean C-peptide level at week 78 that was 59.3% higher than those receiving placebo. Table 6A

[0328] The retention of C-peptide was accompanied by a positive numerical trend in insulin use and time-in-range (TIR), which was favorable for telizumab, while the secondary endpoints were not statistically significant.

[0329] Secondary endpoints were assessed to understand the impact of telizumab treatment on clinical parameters. Consistent with treatment-target glycemic management, mean HbA1c was rapidly controlled and there were no differences between groups at week 78 (Table 6B). Figures 34A-34B The TIR difference between the telithrumab group and the placebo group was 4.71% (95% CI -1.72, 11.15) (Table 6B); the proportion of patients achieving a TIR ≥70% is shown in... Figure 31B middle. Table 6B *A separate prespecified analysis of insulin use throughout the study showed a difference of 0.141 U / kg / day at week 78 (95% CI, -0.230, -0.051) (MMRM, based on observed data). #Estimated incidence ratio = telizumab / placebo

[0330] At week 78, the mean daily insulin dose for patients treated with telizumab and placebo was 0.45 units / kg / day and 0.6 units / kg / day, respectively (difference = 0.13 (95% CI -0.28, 0.02; P = 0.085, ANCOVA)) (Table 6B), and the insulin dose was lower at all time points after week 12 when assessed using a pre-specified repeated measures mixed model (MMRM) analysis. Figure 31C ).

[0331] In the exploratory analysis, at each post-baseline time point, a higher proportion of patients receiving telizumab met the pre-specified definition of clinical response compared to placebo. Figure 31D The results were also consistent with the previously used definition of remission based solely on insulin dose (≤0.25 U / kg / d). Figure 35 The incidence of clinically significant hypoglycemic events was similar across the groups. When differentiated by severity, the incidence of grade 3 events was lower in the telizumab group (incidence ratio 0.29 [95% CI 0.13, 0.62], Table 7). Table 7: Sensitivity analysis of PROTECT efficacy for clinically significant hypoglycemic events—electronic diary and eCRF * To illustrate the potential underreporting of clinically significant hypoglycemic events in electronic diaries, a post-hoc sensitivity analysis was performed, including grade 2 and above hypoglycemic adverse events reported in the adverse event eCRF.

[0332] A similar trend was observed in the analysis of pre-defined compliance schemes (Table 8). Table 8: Supportive Assessment of PROTECT Efficacy—Compliant Groups

[0333] Baseline was defined as the most recent value collected prior to administration of the first dose of telizumab or placebo. Both groups achieved target HbA1c, and the proportion of patients with glucose TIR was not statistically significantly different between the groups (Table 6B); a greater proportion of patients receiving telizumab achieved the glucose TIR target of ≥70% at all study visits, but this difference was not statistically significant compared to placebo. Figure 31BThroughout the study, there was no difference in TBR < 4% between the two groups (at week 78, 2.48% for telizumab and 2.8% for placebo). The mean time above the range was similar between the groups (14%–29% for telizumab and 16%–33% for placebo; Table 8), with telizumab ≤ 25% until week 52, while placebo was ≤ 25% until week 26.

[0334] Analysis of COA measurements ( Figure 36 The results showed that adolescents in the tesilizumab group had less perceived decline in diabetes control at week 78 (mean LS difference 1.1 [95% CI 0.0, 2.1]), which was supported by parents who reported high satisfaction with their adolescents’ treatment at week 78 (DTSQ-parent version; mean LS difference 2.4 [95% CI 0.3, 4.5]).

[0335] The retention of C-peptide is supported by the following: • Insulin use was numerically lower in patients treated with telizumab (unit: U / kg / day), while both treatment groups (telizumab group and placebo group) achieved similar target glycemic control (HbA1c). • Patients treated with teglizumab had a numerically longer time within the target glucose range (i.e., the target glucose range).

[0336] At week 78, the mean insulin use (U / kg / day) of patients treated with tilimuzumab was the same as the mean insulin use (baseline) of patients before tilimuzumab administration. In contrast, the mean insulin use of patients receiving placebo increased from baseline to week 78.

[0337] It should be noted that two patients in the telizumab group were able to discontinue insulin at week 78. No patients in the placebo group were able to discontinue insulin at week 78.

[0338] The HbA1c levels were similar in both treatment groups, confirming that the patients had achieved their treatment goals. Patients receiving placebo required more insulin to maintain or lower HbA1c levels compared to those treated with tilimizumab.

[0339] Patients treated with telizumab showed improvement in time-to-surface efficacy compared to those receiving placebo.

[0340] Figure 27 It is a chart showing insulin usage at different time points (baseline, week 12, week 26, week 39, week 52, week 65, and week 78). Figure 27The results showed that patients treated with telithrumab had numerically lower insulin usage.

[0341] Table 9 below shows that more patients using telizumab discontinued insulin. Table 9

[0342] Figure 28 It is a graph showing the percentage of subjects who met the requirements of Hb1Ac ≤ 6.5% and daily insulin dose ≤ 0.25 units / kg / day at different time points (baseline, week 12, week 26, week 39, week 52, week 65, and week 78). Figure 28 The results showed that more patients receiving telizumab met the insulin discontinuation criteria: Hb1Ac ≤ 6.5% and daily insulin dose ≤ 0.25 units / kg / day.

[0343] Figure 29 It is a graph showing HbA1c levels at different time points (baseline, week 12, week 26, week 39, week 52, week 65, and week 78). Figure 29 The results showed that both treatment groups achieved the target HbA1c level.

[0344] Figure 30 It is a chart showing the percentage of time within a range at different time points (baseline, week 12, week 26, week 39, week 52, week 65, and week 78). Figure 30 The study showed that patients treated with telizumab had a longer time-in-range (TIR).

[0345] The use of assistive technologies (e.g., continuous glucose monitoring, insulin pumps) may have resulted in a similar incidence of clinically important hypoglycemic events in both the telizumab and placebo groups.

[0346] The security analysis did not reveal any new security signals. Table 10

[0347] Compared with placebo (n = 111), patients treated with telizumab (n = 217) had significantly higher stimulating C-peptide levels at week 78 (difference of least squares mean = 0.13 [95% CI 0.09, 0.17; P < 0.001]), with 95% (95% CI 89.5, 97.6) maintaining clinically significant peak C-peptide levels ≥ 0.2 pmol / mL, compared to 79% (95% CI 67.7, 87.4) with placebo (P < 0.001). Patients receiving telizumab used lower insulin doses to meet glycemic targets, had longer periods within the glucose range, fewer grade 3 hypoglycemias, and a higher predefined frequency of clinical remissions. Adverse events were limited to the period of administration, transient, self-limiting, and consistent with existing experience.

[0348] In summary, compared with patients receiving placebo (who had numerically better time range and less insulin use), tesilizumab treatment in newly diagnosed stage 3 T1D patients (8 to 17 years old) resulted in statistically significant improvements in β-cell retention, as demonstrated by maintaining higher C-peptide levels at 78 weeks.

[0349] Modifications and variations of the methods and compositions described in this disclosure will be apparent to those skilled in the art without departing from the scope and spirit of this disclosure. Although this disclosure has been described in conjunction with specific embodiments, it should be understood that the claimed content of this disclosure should not be unduly limited to such specific embodiments. In fact, various modifications to the modes of implementation of this disclosure are intended and understood by those skilled in the art to be within the scope of this disclosure as expressed by the following claims. Incorporate by reference

[0350] All patents and publications mentioned in this specification are incorporated herein by reference to the same extent that each individual patent and publication expressly and individually indicates its inclusion by reference. References 1. Abdul-Rasoul M, Habib H, Al-Khouly M. “The honeymoon phase” in children with type 1 diabetes mellitus: frequency, duration, and influential factors. Pediatr Diabetes. 2006;7(2):101-107. 2.Ablamunits V, Bisikirska B, Herold KC. Acquisition of regulatoryfunction by human CD8+ T cells treated with anti-CD3 antibody requires TNF.Eur J Immunol. 2010;40(10):2891-2901. 3.Agiostratidou G, Anhalt H, Ball D, et al. Standardizing clinicallymeaningful outcome measures beyond HbA1c for type 1 diabetes: a consensusreport of the American Association of Clinical Endocrinologists, the AmericanAssociation of Diabetes Educators, the American Diabetes Association, theEndocrine Society, JDRF International, The Leona M. and Harry B. HelmsleyCharitable Trust, the Pediatric Endocrine Society, and the T1D Exchange.Diabetes Care. 2017;40(12):1622-1630. 4.Akirav EM, Kushner JA, Herold KC. β cell mass and type 1 diabetes:Going, going, gone? Diabetes. 2008;57:2883-2888. 5.American Diabetes Association. 12. Children and Adolescents:Standards of medical Care in Diabetes-2018. Diabetes Care. 2018;41(Suppl. 1):S126-S136. 6.Atkinson MA. Type 1 diabetes. Lancet. 2014;383(9911):69-82 7.Battelino T, Alexander CM, Amiel SA, et al. Continuous glucosemonitoring and metrics for clinical trials: an international consensusstatement. The lancet Diabetes & endocrinology 2023;11:42-57. 8.Bisikirska B, Colgan J, Luban J, Bluestone, JA, Herold KC. TCRstimulation with modified anti-CD3 mAb expands CD8+ T cell population andinduces CD8+CD25+ Tregs. J Clin Invest. 2005;115(10):2904-2913. 9.Bluestone JA, Herold K, and Eisenbarth G. Genetics, pathogenesisand clinical interventions in type 1 diabetes. Nature. 2010;464(7293):1293-1300. 10.Boyle KD, Keyes-Elstein L, Ehlers MR, et al. Two- and four-hourtests differ in capture of C-peptide responses to a mixed meal in type 1diabetes. Diabetes Care. 2016;39:e76-78. 11.Bradley C, Loewenthal K, Woodcock A, et al. Development of thediabetes treatment satisfaction questionnaire (DTSQ) for teenagers andparents: the DTSQ-Teen and the DTSQ-Parent. Diabetologia. 2009;52: (Suppl 1)S397, Abstract 1013. 12.Campbell-Thompson M, Fu A, Kaddis JS, et al. Insulitis and β-cellmass in the natural history of type 1 diabetes. Diabetes. 2016;65:719-731. 13.Danne T, Nimri R, Battelino T, et al. International consensus onuse of continuous glucose monitoring. Diabetes Care 2017;40:1631-1640. 14.Diabetes Control and Complications Trial Research Group.Hypoglycemia in the Diabetes Control and Complications Trial. Diabetes. 1997;46(2): 271-286. 15.Diabetes Prevention Trial-Type 1 Diabetes Study Group. Effects ofinsulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med2002;346:1685-91. 16.DiMeglio LA, Acerini CL, Codner E, et al. ISPAD Clinical PracticeConsensus Guidelines 2018: Glycemic control targets and glucose monitoringfor children, adolescents, and young adults with diabetes. Pediatr Diabetes.2018 Oct;19 Suppl 27:105-114. 17.Driscoll KA, Raymond J, Naranjo D, et al. Fear of hypoglycemia inchildren and adolescents and their parents with type 1 diabetes. Curr DiabRep. 2016;16(8):77. 18.European Medicines Agency. Ethical Considerations for ClinicalTrials on Medicinal Products Conducted with the Paediatric Population. 2008.https: / / ec.europa.eu / health / sites / health / files / files / eudralex / vol-10 / ethical_considerations_en.pdf. Accessed September 27, 2018. 19.Feutren G, Papoz L, Assan R, et al. Cyclosporin increases the rateand length of remissions in insulin-dependent diabetes of recent onset.Results of a multicentre double-blind trial. Lancet (London, England) 1986;2:119-24. 20.Fonolleda M, Murillo M, Vázquez F, et al. Remission phase inpaediatric type 1 diabetes: new understanding and emerging biomarkers. HormRes Paediatr. 2017;88(5):307-315. 21.Gitelman SE, Gottlieb PA, Rigby MR, et al. Antithymocyte globulintreatment for patients with recent-onset type 1 diabetes: 12-month results ofa randomised, placebo-controlled, phase 2 trial. Lancet Diabetes Endocrinol.2013;1(4):306-16. 22.Gonder-Frederick L, Nyer M, Shepard JA. Assessing fear ofhypoglycemia in children with Type 1 diabetes and their parents. DiabetesManag (Lond). 2011;1(6): 627-639. 23.Greenbaum CJ, Beam CA, Boulware D et al. Fall in C peptide duringfirst 2 years from diagnosis: evidence of at least two distinct phases fromcomposite type 1 diabetes TrialNet data. Diabetes. 2012;61:2066-2073. 24.Hagopian W, Ferry RJ Jr, Sherry N et al, Protégé TrialInvestigators. Teplizumab preserves C-peptide in recent-onset type 1diabetes: two-year results from the randomized, placebo-controlled Protégétrial. Diabetes. 2013;62(11):3901-8. doi: 10.2337 / db13-0236. Epub 2013 Jun25. 25.Helminen O, Pokka T, Tossavainen P, et al. Continuous glucosemonitoring and HbA1c in the evaluation of glucose metabolism in children athigh risk for type 1 diabetes mellitus. Diabetes Res Clin Pract. 2016;120:89-96. 26.Herold KC, Hagopian W, Auger JA, Poumian-Ruiz E, Taylor L,Donaldson D, Gitelman SE, Harlan DM, Xu D, Zivin RA, Bluestone JA. Anti-CD3monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med. 2002May 30;346(22):1692-1698. 27.Herold KC, Gitelman SE, Umest M et al. A single course of anti-CD3monoclonal antibody hOKT3γ1(Ala-Ala) results in improvement in C-peptideresponses and clinical parameters for at least 2 years after onset of type 1diabetes. Diabetes. 2005;54:1-7. 28.Herold KC, Gitelman SE, Ehlers MR, et al. Teplizumab (anti-CD3mAb) treatment preserves C-peptide responses in patients with new-onset type1 diabetes in a randomized controlled trial: metabolic and immunologicfeatures at baseline identify a subgroup of responders. Diabetes. 2013(a);62(11):3766-3774. 29.Herold KC, Gitelman SE, Willi SM, et al. Teplizumab treatment mayimprove C-peptide responses in participants with type 1 diabetes after thenew-onset period: a randomised controlled trial. Diabetologia. 2013(b);56(2):391-400. 30.Herold KC, Bundy BN, Long SA, et al. An Anti-CD3 Antibody,Teplizumab, in Relatives at Risk for Type 1 Diabetes. N Engl J Med. 2019 Jun9. doi: 10.1056 / NEJMoa1902226. [Epub ahead of print] 31.Hilliard ME, Lawrence JM, Modi AC, et al. Identification ofminimal clinically important difference scores of the PedsQL in children,adolescents, and young adults with type 1 and type 2 diabetes. Diabetes care2013;36:1891-7. 32.Huo L, Harding JL, Peeters A, et al. Life expectancy of type 1diabetic patients during 1997-2010: a national Australian registry-basedcohort study. Diabetologia. 2016;59(6):1177-85. 33.International Hypoglycaemia Study Group. Glucose Concentrations ofLess Than 3.0 mmol / L (54 mg / dL) Should Be Reported in Clinical Trials: AJoint Position Statement of the American Diabetes Association and theEuropean Association for the Study of Diabetes. Diabetes Care. 2016;dc162215. 34.Joint Commission. High Alert Medications and Patient Safety.Sentinel Event Alert. Issue 11. November 19,1999. https: / / www.jointcommission.org / assets / 1 / 18 / SEA_11.pdf. Accessed August 21, 2018. 35.Karvonen M, Viik-Kajander M, Moltchanova E, et al. Incidence ofchildhood type 1 diabetes worldwide. Diabetes Mondiale (DiaMond) ProjectGroup. Diabetes Care. 2000;23(10):1516-1526. 36.Kuhtreiber WM, Washer SL, Hsu E, et al. Low levels of C-peptidehave clinical significance for established Type 1 diabetes. Diabet Med. 2015Oct;32(10):1346-53. 37.Lachin JM, McGee P, Palmer JP; DCCT / EDIC Research Group. Impact ofC-peptide preservation on metabolic and clinical outcomes in the DiabetesControl and Complications Trial. Diabetes. 2014;63(2):739-748. 38.Laitinen OH, Honkanen H, Pakkanen O, et al. Coxsackievirus B1 isassociated with induction of β-cell autoimmunity that portends type 1diabetes. Diabetes. 2014;63(2):446-455. 39.Lebastchi J, Deng S, Lebastchi AH, et al. Immune therapy and β-cell death in type 1 diabetes. Diabetes. 2013;62(5):1676-1680. 40.Lin A, Northam EA, Werther GA, Cameron FJ. Risk factors fordecline in IQ in youth with type 1 diabetes over the 12 years from diagnosis / illness onset. Diabetes Care. 2015;38:236-242. 41.Lind M, Svensson AM, Kosiborod M, et al. Glycemic control andexcess mortality in type 1 diabetes. N Engl J Med. 2014;371:1972-1982. 42.Long SA, Thorpe J, DeBerg HA, et al. Partial exhaustion of CD8 Tcells and clinical response to teplizumab in new-onset type 1 diabetes. Sci.Immunol. 2016;1(5):1-23. 43.Long SA, Thorpe J, Herold KC, et al. Remodeling T cellcompartments during anti-CD3 immunotherapy of type 1 diabetes. Cell Immunol.2017 Sep;319:3-9. 44.Ludvigsson J, Carlsson A, Deli A, et al. Decline of C-peptideduring the first year after diagnosis of Type 1 diabetes in children andadolescents. Diabetes Res Clin Pract. 2013;100(2):203-209. 45.Masharani UB, Becker J. Teplizumab therapy for type 1 diabetes.Expert Opin Biol Ther. 2010;10(3): 459-465. 46.Matveyneko AV and Butler PC. Relationship between β cell mass anddiabetes onset. Diabetes Obes Metab. 2008;10:23-31. 47.Mittermayer F, Caveney E, De Oliveira C, et al. Addressing UnmetMedical Needs in Type 1 Diabetes: A Review of Drugs Under Development. CurrDiabetes Rev. 2017;13(3):300-314. 48.Monaghan M, Helgeson V, Wiebe D. Type 1 diabetes in youngadulthood. Curr Diabetes Rev. 2015;11(4):239-250. 49.Mortensen HB, Hougaard P, Swift P, et al. New definition for thepartial remission period in children and adolescents with type 1 diabetes.Diabetes Care. 2009;32:1384-1390. 50.National Cancer Institute. Common Terminology Criteria for AdverseEvents (CTCAE). https: / / ctep.cancer.gov / protocolDevelopment / electronic_applications / ctc.htm. Updated March 1, 2018. Accessed September 27, 2018. 51.Orban T, Bundy B, Becker DJ, et al. Co-stimulation modulation withabatacept in patients with recent-onset type 1 diabetes: a randomised,double-blind, placebo-controlled trial. Lancet 2011;378(9789):412-419. 52.Palmer JP, Fleming GA, Greenbaum CJ, et al. C-peptide is theappropriate outcome measure for type 1 diabetes clinical trials to preservebeta-cell function: report of an ADA workshop, 21-22 October 2001. Diabetes.2004;53(1):250-264. 53.Palmer JP. C-peptide in the natural history of type 1 diabetes.Diabetes Metab Res Rev. 2009;25(4):325-328. 54.Rawshani A, Rawshani A, Franzén S, et al. Mortality andCardiovascular Disease in Type 1 and Type 2 Diabetes. N Engl J Med. 2017;376(15):1407-1418. 55.Rawshani A, Sattar N, Franzén S, et al. Excess mortality andcardiovascular disease in young adults with type 1 diabetes in relation toage at onset: a nationwide, register-based cohort study. Lancet. 2018;392(10146):477-486. 56.Rigby MR, DiMeglio LA, Rendell MS, et al. Targeting of memory Tcells with alefacept in new-onset type 1diabetes (T1DAL study): 12-monthresults of a randomised, double-blind, placebo-controlled phase 2 trial.Lancet Diabetes Endocrinol. 2013;1(4):284-294. 57.Rigby MR, Ehlers MR. Targeted Immune Interventions for Type 1Diabetes: Not as Easy as it Looks! Curr Opin Endocrinol Diabetes Obes. 2014;21(4): 271-278. 58.Rigby MR, Harris KM, Pinckney A, et al. Alefacept providessustained clinical and immunological effects in new-onset type 1 diabetespatients. J Clin Invest. 2015;125(8):3285-3296. 59.Roark CL, Anderson KM, Simon LJ, et al. Multiple HLA epitopescontribute to type 1 diabetes susceptibility. Diabetes. 2014;63(1):323-331. 60.Rosenzweig M, Rosenthal CA, Torres VM, Vaickus L. Development of aquantitative assay to measure EBV viral load in patients with autoimmune type1 diabetes and healthy subjects. J Virol Methods. 2010;164(1-2):111-115. 61.Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia anddiabetes: a report of a workgroup of the American Diabetes Association andthe Endocrine Society. Diabetes Care. 2013;36(5):1384-1395. 62.Secrest AM, Becker DJ, Kelsey SF, LaPorte RE, and Orchard TJ.Characterising sudden death and dead-in-bed syndrome in Type 1 diabetes:analysis from 2 childhood-onset Type 1 diabetes registries. Diabet Med. 2011;28(3): 293-300. 63.Sherry N, Hagopian W, Ludvigsson J, et al., Protégé TrialInvestigators. Teplizumab for treatment of type 1 diabetes (Protégé study):1-year results from a randomised, placebo-controlled trial. Lancet. 2011;378(9790):487-97. 64.Sorensen JS, Johannesen J, Pociot F, et al. Residual β-cellfunction 3-6 years after onset of type 1 diabetes reduces risk of severehypoglycemia in children and adolescents. Diabetes Care. 2013;36:3454-3459. 65.Sosenko JM, Skyler JS, Herold KC, et al. The metabolic progressionto type 1 diabetes as indicated by serial oral glucose tolerance testing inthe Diabetes Prevention Trial-type 1. Diabetes. 2012;61(6):1331-7. 66.Steck AK, Dong F, Taki I, et al. Early hyperglycemia detected bycontinuous glucose monitoring in children at risk for type 1 diabetes.Diabetes Care. 2014;37:2031-2033. 67.Steffes MW, Sibley S, Jackson M, Thomas W. Beta-cell function andthe development of diabetes-related complications in diabetes control andcomplications trial. Diabetes Care. 2003;26:832-836. 68.Streisand R. Young children with type 1 diabetes: challenges,research, and future directions. Curr Diab Rep. 2014;14(9):520. pp1-16. 69.Trancone A, Bonfanti R, Iafusco D, et al. Evaluating theexperience of children with type 1 diabetes and their parents taking part inan artificial pancreas clinical trial over multiple days in a diabetes campsetting. Diabetes Care. 2016;39:2158-2164. 70.Varni JW, Delamater AM, Hood KK, et al. PedsQL 3.2 Diabetes Modulefor children, adolescents, and young adults: reliability and validity in type1 diabetes. Diabetes Care. 2018; dc172707. 71.Verkruyse LA, Storch GA, Devine SM, et al. Once daily gancicloviras initial pre-emptive therapy delayed until threshold CMV load > or = 10000copies / ml: a safe and effective strategy for allogeneic stem cell transplantpatients. Bone Marrow Transplant. 2006;37(1):51-6. 72.Waldron-Lynch F, Henegariu O, Deng S, et al. Teplizumab induceshuman gut-tropic regulatory cells in humanized mice and patients. Sci TranslMed. 2012;4(118):118ra12. 73.Wherrett DK, Chiang JL, Delamater AM, et al. Defining pathways fordevelopment of disease-modifying therapies in children with type 1 diabetes:a consensus report. Diabetes Care. 2015;38(10):1975-85. 74.Ziegler AG and Nepom GT. Prediction and pathogenesis in type 1diabetes. Immunity. 2010;32:468-478.

Claims

1. A method for treating type 1 diabetes (T1D), comprising administering two 12-day cycles of telizumab to a subject in need at intervals of at least about 3 months, or about 6 months, about 26 weeks, about 12 months, or about 52 weeks, each cycle containing about 9000 μg / m². 2 Approximately 14000 μg / m 2 The total dose of telizumab, wherein the subject had a peak C-peptide level of at least 0.2 pmol / mL during the mixed diet tolerance test (MMTT) and optionally during the two-hour MMTT prior to administration of the first 12-day course of telizumab.

2. The method of claim 1, wherein the total telixirzab dose in each 12-day treatment cycle is approximately 9000 μg / m². 2 Approximately 9500 μg / m 2 .

3. The method of claim 2, wherein each 12-day treatment course includes a first dose of 106 μg / m² on day 1. 2 Teglituzumab, second dose on day 2, 425 μg / m² 2 Teglituzumab, and one dose of 850 μg / mcg daily from day 3 to 12. 2 Tegizumab, with a total dose of approximately 9031 μg / m² per cycle. 2 .

4. The method of any one of claims 1-3, wherein the subject is approximately 8 to 17 years old.

5. The method of any one of claims 1-4, wherein the subject has been diagnosed with T1D within 6 weeks prior to administration of the first 12-day course of telizumab.

6. The method of any one of claims 1-5, wherein the subject has at least 20% β-cell function prior to administration of the first treatment.

7. The method of any one of claims 1-6, further comprising administering one or more additional 12-day courses of telizumab to the subject in need, each additional course containing a total dose exceeding approximately 9000 μg / m². 2 .

8. The method of claim 7, wherein each additional 12-day cycle of telixirzab comprises a first dose of 106 μg / m² on day 1. 2 Teglituzumab, second dose on day 2, 425 μg / m² 2 Teglituzumab, and one dose of 850 μg / mcg daily from day 3 to 12. 2 The total dose of telizumab in each additional cycle is approximately 9031 μg / m². 2 .

9. The method of claim 8, wherein each additional 12-day course of telixirumab is administered approximately 6 months or approximately 26 weeks after the previous course of treatment, or approximately 24 months or approximately 104 weeks after the previous course of treatment.

10. The method of any one of claims 1-9, further comprising: TIGIT was measured after each 12-day treatment course. + KLRG1 + CD8 + T cells relative to all CD3 + Baseline T cell levels and / or PD-1 + CD8 + T cells relative to all CD3 + Baseline levels of T cells; Monitoring TIGIT + KLRG1 + CD8 + CD3 + T cell levels and / or PD-1 + CD8 + CD3 + The level of T cells; and In these TIGIT + KLRG1 + CD8 + CD3 + T cells and / or PD-1 + CD8 + CD3 + Once T-cell levels return to baseline, administer an additional 12-day course of telizumab.

11. The method of claim 10, wherein these TIGITs + KLRG1 + CD8 + Baseline levels of T cells and / or these PD-1 + CD8 + Baseline T cell levels were lower than all CD3 levels. + T cells account for approximately 5%.

12. The method of claim 10 or 11, wherein the assay is performed by flow cytometry.

13. The method of any one of claims 10-12, wherein TIGIT is applied approximately 1-6 months, approximately 2-5 months, or approximately 3 months after each 12-day treatment course. + KLRG1 + CD8 + CD3 + T cells and / or PD-1 + CD8 + CD3 + This assay of T cells.

14. The method of any one of claims 10-13, wherein if the subject has all CD3 + T cells contain more than 10% TIGIT + KLRG1 + CD8 + T cells and / or more than about 10% PD-1 + CD8 + T cells are then monitored annually.

15. The method of any one of claims 10-13, wherein if the subject has all CD3 + T cells have less than about 10% TIGIT + KLRG1 + CD8 + T cells and / or less than approximately 10% PD-1 + CD8 + T cells are then monitored approximately every 3-6 months.

16. The method of any one of claims 1-15, wherein each dose of telizumab is administered parenterally.

17. The method of any one of claims 1-16, wherein each dose of telizumab is administered by intravenous infusion, optionally wherein the subject is pre-administered with (1) a nonsteroidal anti-inflammatory drug or acetaminophen, (2) an antihistamine and / or (3) an antiemetic within three, four, five, six or seven days prior to each dose in each treatment cycle.

18. The method of any one of claims 1-17, wherein, prior to administration of the first 12-day course of telizumab, during the MMTT, optionally during the two-hour MMTT, the subject in need has a peak C-peptide level in the range of 0.2 pmol / mL to 0.7 pmol / mL, or at least 0.7 pmol / mL.

19. The method of any one of claims 1-18, wherein the subject in need of telizumab is administered telizumab. After the first course of treatment, maintain a peak C-peptide level of at least 0.2 pmol / mL for approximately 78 weeks; Approximately 78 weeks after the first course of treatment, patients had higher C-peptide levels, or 40% to 80% or more higher C-peptide levels, compared to control subjects who did not receive telizumab. Following the first treatment course, maintain or exceed the pre-treatment level of the area under the C-peptide time-concentration curve (AUC) during the MMTT, optionally during the four-hour MMTT, for approximately 26 weeks; and / or Approximately 78 weeks after the first course of treatment, the subjects had a higher C-peptide AUC compared to control subjects who did not receive telizumab.

20. The method of any one of claims 1-19, wherein the subject receiving telizumab maintains the pre-treatment HbA1c level; or has a reduced HbA1c level relative to the pre-treatment level or relative to a control subject not receiving telizumab, optionally wherein the HbA1c level is reduced by 0.1 to 1 point or more than 1 point, further optionally wherein the HbA1c level is reduced to 6.5% or lower.

21. The method of any one of claims 1-20, wherein the subject in need of receiving telizumab has an increased time-in-range (TIR) ​​relative to a control subject who has not received telizumab, optionally wherein the TIR is increased by 3% to 10%, or by more than 10%.

22. The method of any one of claims 1-21, wherein the subject who requires telizumab maintains the pre-treatment insulin dose; or requires a reduced insulin dose relative to the pre-treatment dose or relative to a control subject who has not received telizumab, optionally wherein the insulin use is reduced by 10%-30% or more than 30%, further optionally wherein the insulin dose is reduced by at least 0.1 units / kg / day or to no more than 0.25 units / kg / day.

23. The method of any one of claims 1-22, wherein the subject in need of administering telizumab has an HbA1c level of ≤ 6.5% and requires an insulin dose of ≤ 0.25 units / kg / day; and / or experiences fewer grade 3 hypoglycemic episodes compared to control subjects who have not received telizumab.

24. A method for slowing the loss of β-cell function in a subject with type 1 diabetes (T1D) for at least about six months or at least about 26 weeks, comprising administering two 12-day cycles of telizumab to the subject in need at intervals of at least about three months, or about six months, or about 12 months, each cycle containing about 9000 μg / m². 2 Approximately 9500 μg / m 2 The total dose, wherein the subject is aged approximately 8 to 17 years and (i) has been diagnosed with T1D within 6 weeks prior to administration of the first course of treatment and / or (ii) has a peak C-peptide level of at least 0.2 pmol / mL during a mixed diet tolerance test (MMTT) prior to administration of the first course of treatment, optionally during a two-hour MMTT.

25. The method of claim 24, wherein each 12-day treatment course includes a first dose of 106 μg / m² on day 1. 2 Teglituzumab, second dose on day 2, 425 μg / m² 2 Teglituzumab, and one dose of 850 μg / mcg daily from day 3 to 12. 2 Tegizumab, and the total dose for each cycle is approximately 9031 μg / m². 2 .

26. The method of claim 24 or 25, wherein each dose of telizumab is administered by intravenous infusion, optionally wherein the subject is pre-administered with (1) a nonsteroidal anti-inflammatory drug or acetaminophen, (2) an antihistamine and / or (3) an antiemetic within three, four, five, six or seven days prior to each dose in each treatment cycle.

27. The method of any one of claims 24-26, wherein the administration of telizumab slows the loss of β-cell function for at least about 18 months or 78 weeks.

28. The method of any one of claims 24-27, wherein the administration of telizumab produces the following effects: Maintaining pre-treatment C-peptide levels or having higher C-peptide levels compared to control subjects who did not receive tilimizumab, optionally by 40% to 80% or more; The required insulin dose was lower compared to control subjects who did not receive telizumab; The duration of time was longer in the range compared to control subjects who did not receive tilimizumab; and / or Compared with control subjects who did not receive tilimuzumab, there were fewer grade 3 hypoglycemic episodes.

29. A tilizumab for use in the method of any one of claims 1-28.

30. Use of telizumab in the manufacture of a pharmaceutical agent for use in any one of claims 1-28.

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