Methods and Compositions for Preventing or Delaying Type 1 Diabetes

Abstract

In one aspect, a method of preventing or delaying the onset of clinical type 1 diabetes (T1D) comprising administering a prophylactically effective amount of an anti-CD3 antibody to a non-diabetic subject at risk of T1D, wherein the prophylactically effective amount has a cumulative dose of about 10,500 μg / m 2 to about 14,000 μg / m 2 is provided herein. The method includes administering a prophylactically effective amount of an anti-CD3 antibody having the cumulative dose to a non-diabetic subject at risk of T1D.

Description

Technical Field

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 345,365, filed May 24, 2022; U.S. Provisional Patent Application No. 63 / 367,992, filed Jul. 8, 2022; U.S. Provisional Patent Application No. 63 / 382,382, filed Nov. 4, 2022; U.S. Utility Patent Application No. 18 / 321,964, filed May 23, 2023; and Taiwan Patent Application No. 112119143, filed May 23, 2023, the entire contents of each of which are incorporated herein by reference.

[0002] Sequence Listing This specification includes a sequence listing submitted herewith in the file named 178833-011704.xml, created on May 8, 2023, having the following size: 4,136 bytes, the contents of which are incorporated herein by reference.

[0003] The present disclosure generally relates to compositions and methods for preventing or delaying the onset of clinical type 1 diabetes (T1D) in at-risk subjects, and more specifically, to the use of anti-CD3 antibodies.

Background Art

[0004] Type 1 diabetes (T1D) is caused by the autoimmune destruction of insulin-producing beta cells in the islets of Langerhans and results in dependence on exogenous insulin injections for survival. Approximately 1.6 million Americans have type 1 diabetes, making it the most common disease in childhood after asthma. Despite improvements in treatment, most affected individuals with T1D are unable to consistently achieve their desired blood glucose goals. There are strong concerns regarding increased risks of both morbidity and mortality for individuals with type 1 diabetes. Two recent studies reported that children diagnosed before the age of 10 lost 17.7 years of life, and Scottish men and women diagnosed as adults lost 11 and 13 years of life, respectively.

[0005] In genetically susceptible individuals, T1D progresses through an asymptomatic stage before overt hyperglycemia, initially characterized by the appearance of autoantibodies (stage 1), followed by glucose abnormalities (stage 2). In stage 2, the metabolic response to a glucose load is impaired, but other metabolic markers, such as glycosylated hemoglobin, are normal and insulin treatment is not required. These immunological and metabolic features identify individuals at high risk of developing clinical disease with overt hyperglycemia and the need for insulin treatment (stage 3). When studied in recently diagnosed clinical T1D, several immune interventions have been shown to delay the decline in beta cell function. One promising treatment is the FcR-non-binding anti-CD3 monoclonal antibody teplizumab, which in several studies has been shown to sustainably suppress the loss of beta cell function with short-term treatment and an observable effect over 7 years after diagnosis and treatment. This agent modifies the function of CD8+ T lymphocytes, which are considered important effector cells that cause beta cell death.

SUMMARY OF THE INVENTION

PROBLEMS TO BE SOLVED BY THE INVENTION

[0006] To date, interventions initiated before clinical diagnosis (i.e., stage 1 or 2) have not altered the progression to clinical stage 3 T1D. Therefore, there is a need for treatments that prevent or delay the onset of clinical T1D in high-risk individuals.

MEANS FOR SOLVING THE PROBLEM

[0007] Aspects of the present disclosure relate to a method of preventing or delaying the onset of clinical type 1 diabetes (T1D), the method comprising administering a prophylactically effective amount of an anti-CD3 antibody to a non-diabetic subject at risk of T1D.

[0008] In some embodiments, a method of preventing or delaying the onset of clinical type 1 diabetes (T1D) comprises administering a prophylactically effective amount of an anti-CD3 antibody to a non-diabetic subject at risk of T1D, the prophylactically effective amount being about 10,500 μg / m2 ~about 14,000 μg / m 2 has a cumulative dose of.

[0009] In some embodiments, the non - diabetic subject is an adult subject or a pediatric subject. In some embodiments, the pediatric subject is 8 years of age or older. In some embodiments, the pediatric subject is 7 years of age or older. In some embodiments, the pediatric subject is 6 years of age or older. In some embodiments, the pediatric subject is 5 years of age or older. In some embodiments, the pediatric subject is 4 years of age or older. In some embodiments, the pediatric subject is 3 years of age or older. In some embodiments, the pediatric subject is 2 years of age or older. In some embodiments, the pediatric subject is 1 year of age or older. In some embodiments, the pediatric subject is 1 year of age or younger. In some embodiments, the pediatric subject is an infant.

[0010] In some embodiments, the non - diabetic subject is a blood relative of a patient with T1D.

[0011] In some embodiments, the method further comprises determining that the non - diabetic subject is (1) negative for zinc transporter 8 (ZnT8) antibody, (2) HLA - DR4 +, and / or (3) not HLA - DR3 +.

[0012] In some embodiments, the non - diabetic subject has two or more diabetes - related autoantibodies selected from islet cell antibodies (ICA), insulin autoantibodies (IAA), and antibodies against glutamic acid decarboxylase (GAD), tyrosine phosphatase (IA - 2 / ICA512), or ZnT8.

[0013] In some embodiments, the non - diabetic subject has impaired glucose tolerance in an oral glucose tolerance test (OGTT). In some embodiments, the impaired glucose tolerance in the OGTT is a fasting blood glucose level of 110 - 125 mg / dL, or a 2 - hour plasma of 140 mg / dL or more and less than 200 mg / dL, or an intervening glucose value at 30, 60, or 90 minutes in the OGTT that exceeds 200 mg / dL.

[0014] In some embodiments, non - diabetic subjects have abnormal results in a continuous glucose monitoring system (CGM) that reveal a high sensor average glucose level (110 mg / dL or greater), or high glycemic variability (CV15 or greater), or a short time within range (more than 10% of the time above 140 mg / dL).

[0015] In some embodiments, non - diabetic subjects do not have antibodies against ZnT8.

[0016] In some embodiments, non - diabetic subjects are HLA - DR4 + and not HLA - DR3 +.

[0017] In some embodiments, non - diabetic subjects do not have antibodies against ZnT8, are HLA - DR4 +, and not HLA - DR3 +.

[0018] In some embodiments, non - diabetic subjects are blood relatives of patients with T1D and do not have antibodies against ZnT8. In some embodiments, non - diabetic subjects are blood relatives of patients with T1D, do not have antibodies against ZnT8, are HLA - DR4 +, and not HLA - DR3 +.

[0019] In some embodiments, the anti - CD3 antibody is selected from teplizumab, otelixizumab, or foralumab. In some embodiments, the anti - CD3 antibody is teplizumab.

[0020] In some embodiments, a prophylactically effective amount of the antibody comprises a 10 - to 14 - day treatment course of subcutaneous (SC) injection or intravenous (IV) infusion or oral administration of the anti - CD3 antibody at a cumulative dose exceeding 10,500 micrograms per square meter (μg / m 2 ) In some embodiments, a prophylactically effective amount of the antibody is from about 11,000 μg / m 2 to about 14,000 μg / m 2Includes a 14-day treatment course of subcutaneous (SC) injection, intravenous (IV) infusion, or oral administration of an anti-CD3 antibody at a cumulative dose. In some embodiments, the anti-CD3 antibody is teplizumab or includes teplizumab.

[0021] In some embodiments, a prophylactically effective amount of the antibody is about 10,500 to about 14,000 μg / m 2 about 10,500 to about 13,500 μg / m 2 about 10,500 to about 13,000 μg / m 2 about 10,500 to about 12,500 μg / m 2 about 10,500 to about 12,000 μg / m 2 about 10,500 to about 11,500 μg / m 2 or about 10,500 to about 11,000 μg / m 2 and includes a 10-day to 14-day treatment course of subcutaneous (SC) injection, intravenous (IV) infusion, or oral administration of the anti-CD3 antibody at the indicated dose. In some embodiments, a prophylactically effective amount of the antibody is about 10,500 μg / m 2 11,000 μg / m 2 11,500 μg / m 2 12,000 μg / m 2 12,500 μg / m 2 13,000 μg / m 2 13,500 μg / m 2 or 14,000 μg / m 2 and includes a 10-day to 14-day treatment course of subcutaneous (SC) injection, intravenous (IV) infusion, or oral administration of the anti-CD3 antibody at the indicated dose. In some embodiments, the anti-CD3 antibody is teplizumab or includes teplizumab.

[0022] In some embodiments, the method comprises IV infusion of a 14-day treatment course of an anti-CD3 antibody to non-diabetic subjects at risk of T1D, at about 60 μg / m on each of days 1 to 4 2 about 125 μg / m 2 about 250 μg / m 2 and about 500 μg / m 2 and at about 1,000 μg / m on each of days 5 to 14 2including administering at a dosage of. In some embodiments, the cumulative dosage is about 10,935 μg / m 2 . In some embodiments, the anti-CD3 antibody is selected from teplizumab, otelixizumab, or foralumab. In some embodiments, the anti-CD3 antibody is teplizumab. In some embodiments, the method comprises administering an intravenous infusion of teplizumab over a 14-day treatment course to a non-diabetic subject at risk of T1D at a dosage of about 60 μg / m 2 on each of days 1-4, about 125 μg / m 2 on each of days 1-4, about 250 μg / m 2 on each of days 1-4, and about 500 μg / m 2 on each of days 1-4, and at a dosage of about 1,000 μg / m 2 on each of days 5-14.

[0023] In some embodiments, the method comprises administering an intravenous infusion of an anti-CD3 antibody over a 14-day treatment course to a non-diabetic subject at risk of T1D at a dosage of about 60 μg / m 2 on each of days 1-4, about 125 μg / m 2 on each of days 1-4, about 250 μg / m 2 on each of days 1-4, and about 500 μg / m 2 on each of days 1-4, and at a dosage of about 1,030 μg / m 2 on each of days 5-14. In some embodiments, the cumulative dosage is about 11,235 μg / m 2 . In some embodiments, the anti-CD3 antibody is selected from teplizumab, otelixizumab, or foralumab. In some embodiments, the anti-CD3 antibody is teplizumab. In some embodiments, the method comprises administering an intravenous infusion of teplizumab over a 14-day treatment course to a non-diabetic subject at risk of T1D at a dosage of about 60 μg / m 2 on each of days 1-4, about 125 μg / m 2 on each of days 1-4, about 250 μg / m 2 on each of days 1-4, and about 500 μg / m 2 on each of days 1-4, and at a dosage of about 1,030 μg / m 2 on each of days 5-14.

[0024] In some embodiments, the method comprises administering an intravenous infusion of an anti-CD3 antibody over a 14-day treatment course to a non-diabetic subject at risk of T1D, at about 100 μg / m 2 on each of days 1-4, about 425 μg / m 2 on day 5, about 850 μg / m 2 on day 6, and about 850 μg / m 2 on day 7, and at a dose of about 1,000 μg / m 2 on each of days 5-14. In some embodiments, the cumulative dose is about 12,225 μg / m 2 . In some embodiments, the anti-CD3 antibody is selected from teplizumab, otelixizumab, or fostamab. In some embodiments, the anti-CD3 antibody is teplizumab. In some embodiments, the method comprises administering an intravenous infusion of teplizumab over a 14-day treatment course to a non-diabetic subject at risk of T1D, at about 100 μg / m 2 on each of days 1-4, about 425 μg / m 2 on day 5, about 850 μg / m 2 on day 6, and about 850 μg / m 2 on day 7, and at a dose of about 1,000 μg / m 2 on each of days 5-14.

[0025] In some embodiments, the method comprises administering an intravenous infusion of an anti-CD3 antibody over a 14-day treatment course to a non-diabetic subject at risk of T1D, at about 65 μg / m 2 on each of days 1-4, about 125 μg / m 2 on day 5, about 250 μg / m 2 on day 6, and about 500 μg / m 2 on day 7, and at a dose of about 1,070 μg / m 2 on each of days 5-14. In some embodiments, the cumulative dose is about 11,640 μg / m 2 . In some embodiments, the anti-CD3 antibody is selected from teplizumab, otelixizumab, or fostamab. In some embodiments, the anti-CD3 antibody is teplizumab. In some embodiments, the method comprises administering an intravenous infusion of teplizumab over a 14-day treatment course to a non-diabetic subject at risk of T1D, at about 65 μg / m 2, about 125 μg / m 2 , about 250 μg / m 2 , and about 500 μg / m 2 , and includes administering at a dose of about 1,070 μg / m 2 on each of days 5 - 14.

[0026] In some embodiments, the method comprises administering an intravenous infusion of an anti - CD3 antibody for a 14 - day treatment course to a non - diabetic subject at risk of T1D at about 65 μg / m 2 , about 125 μg / m 2 , about 250 μg / m 2 , and about 500 μg / m 2 on days 1 - 4 respectively, and at a dose of about 1,030 μg / m 2 on each of days 5 - 14. In some embodiments, the cumulative dose is about 11,240 μg / m 2 . In some embodiments, the anti - CD3 antibody is selected from teplizumab, otelixizumab, or foralumab. In some embodiments, the anti - CD3 antibody is teplizumab. In some embodiments, the method comprises administering an intravenous infusion of teplizumab for a 14 - day treatment course to a non - diabetic subject at risk of T1D at about 65 μg / m 2 , about 125 μg / m 2 , about 250 μg / m 2 , and about 500 μg / m 2 on days 1 - 4 respectively, and at a dose of about 1,030 μg / m 2 on each of days 5 - 14.

[0027] In some embodiments, a prophylactically effective amount delays the median time to clinical diagnosis of T1D by at least 50%, at least 80%, or at least 90%. In some embodiments, a prophylactically effective amount delays the median time to clinical diagnosis of T1D by at least 12 months, at least 18 months, at least 24 months, at least 36 months, at least 48 months, or at least 60 months.

[0028] In some embodiments, the method further comprises determining, before or after the administration step, that a non - diabetic subject has more than about 10% TIGIT+KLRG1+CD8+ T cells in total CD3+ T cells, indicating success in preventing or delaying the onset of clinical T1D. In some embodiments, the step of determining TIGIT+KLRG1+CD8+ T cells is by flow cytometry. In some embodiments, the method further comprises determining a decrease in the percentage of CD8+ T cells expressing the proliferation marker Ki67 and / or CD57.

[0029] Some aspects of the present disclosure are methods of preventing or delaying the onset of clinical type 1 diabetes (T1D), comprising administering by IV infusion to a non - diabetic subject 8 years of age or older at risk for T1D, a 14 - day course of teplizumab at a dose of about 65 μg / m 2 on day 1, about 125 μg / m 2 on day 2, about 250 μg / m 2 on day 3, and about 500 μg / m 2 on day 4, and about 1,030 μg / m 2 on each of days 5 - 14.

[0030] Some aspects of the present disclosure are methods of delaying the onset of stage 3 type 1 diabetes (T1D), comprising administering by IV infusion to a subject having a stage 2 T1D diagnosis in need thereof, a 14 - day course of teplizumab at a dose of about 65 μg / m 2 on day 1, about 125 μg / m 2 on day 2, about 250 μg / m 2 on day 3, and about 500 μg / m 2 on day 4, and about 1,030 μg / m 2Relates to a method comprising performing an intravenous infusion of teprilizumab for a 14-day treatment course at a dose of . In some embodiments, the non-diabetic subject is an adult subject or a pediatric subject. In some embodiments, the pediatric subject is 8 years of age or older. In some embodiments, the pediatric subject is 7 years of age or older. In some embodiments, the pediatric subject is 6 years of age or older. In some embodiments, the pediatric subject is 5 years of age or older. In some embodiments, the pediatric subject is 4 years of age or older. In some embodiments, the pediatric subject is 3 years of age or older. In some embodiments, the pediatric subject is 2 years of age or older. In some embodiments, the pediatric subject is 1 year of age or older. In some embodiments, the pediatric subject is less than 1 year of age. In some embodiments, the pediatric subject is an infant.

[0031] In some embodiments, the method comprises recording at least two positive pancreatic islet autoantibodies in a subject having glycemic abnormalities without overt hyperglycemia prior to performing the 14-day treatment course.

[0032] In some embodiments, the subject in need thereof has glycemic abnormalities without overt hyperglycemia and has two or more pancreatic islet autoantibodies.

[0033] In some embodiments, the two or more pancreatic islet autoantibodies include islet cell antibodies (ICA), insulin autoantibodies (IAA), and antibodies against glutamic acid decarboxylase (GAD), tyrosine phosphatase (IA-2 / ICA512) or ZnT8.

[0034] In some embodiments, the method comprises administering an effective amount of a non-steroidal anti-inflammatory drug (NSAID), acetaminophen, an antihistamine, an antiemetic or a combination thereof on each of at least days 1-5, prior to performing the intravenous infusion of the 14-day treatment course. In some embodiments, the method comprises orally administering an NSAID, acetaminophen, an antihistamine, an antiemetic or a combination thereof.

[0035] In some embodiments, the method comprises administering an intravenous infusion in a treatment course of 14 days once a day for at least 30 minutes for 14 consecutive days.

[0036] In some embodiments, the method further comprises, before or after the administration step, determining that a non - diabetic subject has more than about 10% of TIGIT+KLRG1+CD8+ T cells in total CD3+ T cells, which indicates success in preventing or delaying the onset of clinical T1D.

[0037] In some embodiments, the determination of TIGIT+KLRG1+CD8+ T cells is by flow cytometry.

[0038] In some embodiments, the method further comprises determining a decrease in the proportion of CD8+ T cells expressing the proliferation marker Ki67 and / or CD57.

[0039] Another aspect of the disclosure is a method for prognosticating the responsiveness of an anti - CD3 antibody in preventing or delaying the onset of type 1 diabetes (T1D), comprising administering a prophylactically effective amount of an anti - CD3 antibody to a non - diabetic subject at risk of T1D, wherein the prophylactically effective amount has a cumulative dose of about 10,500 μg / m 2 ~ about 14,000 μg / m 2 and determining the C - peptide area under the curve (AUC): glucose AUC ratio, wherein an increase in the ratio indicates responsiveness to the anti - CD3 antibody and / or non - progression to clinical T1D.

[0040] An aspect of the disclosure is an anti - CD3 antibody for use in a method of preventing or delaying the onset of clinical type 1 diabetes (T1D), comprising administering a prophylactically effective amount of the anti - CD3 antibody to a non - diabetic subject at risk of T1D, wherein the prophylactically effective amount is about 10,500 μg / m 2 ~ about 14,000 μg / m 2Relates to an anti-CD3 antibody having a cumulative dosage. In some embodiments, the anti-CD3 antibody is selected from teplizumab, otelixizumab, or faralimab. In some embodiments, the anti-CD3 antibody is teplizumab.

[0041] Aspects of the present disclosure are methods for preventing or delaying the onset of stage 3 type 1 diabetes (T1D), the method comprising performing an intravenous infusion of a 14-day treatment course of teplizumab at a dosage of about 65 μg / m on day 1, about 125 μg / m on day 2, about 250 μg / m on day 3, and about 500 μg / m on day 4, and about 1,030 μg / m on each of days 5 - 14, in a subject having a diagnosis of stage 2 T1D. 2 about 125 μg / m on day 2 2 about 250 μg / m on day 3 2 and about 500 μg / m on day 4 2 and about 1,030 μg / m on each of days 5 - 14 2 in a subject having a diagnosis of stage 2 T1D.

[0042] In some embodiments, the subject in need thereof has two or more pancreatic islet autoantibodies. In some embodiments, the subject in need thereof has glycemic abnormalities without overt hyperglycemia and has two or more pancreatic islet autoantibodies. In some embodiments, the method comprises confirming stage 2 T1D by recording at least two positive pancreatic islet autoantibodies in a subject having glycemic abnormalities without overt hyperglycemia prior to performing the 14-day treatment course. In some embodiments, the pancreatic islet autoantibodies include antibodies against islet cell antibodies (ICA), insulin autoantibodies (IAA), glutamic acid decarboxylase (GAD), tyrosine phosphatase (IA-2 / ICA512), or ZnT8. BRIEF DESCRIPTION OF THE DRAWINGS

[0043]

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Mode for Carrying Out the Invention

[0044] In some embodiments, a method for preventing or delaying the onset of clinical type 1 diabetes (T1D) comprising providing a non-diabetic subject at risk of T1D, administering a prophylactically effective amount of an anti-CD3 antibody to the non-diabetic subject, and determining, before or after the administering step, that the non-diabetic subject has more than about 10% TIGIT+KLRG1+CD8+ T cells in total CD3+ T cells, which indicates success in preventing or delaying the onset of clinical T1D, is provided herein.

[0045] In some embodiments, a method for prognosticating the responsiveness of an anti-CD3 antibody, such as teplizumab, in preventing or delaying the onset of T1D is provided. The method comprises providing a non-diabetic subject at risk of T1D, administering a prophylactically effective amount of an anti-CD3 antibody, such as teplizumab, to the non-diabetic subject, and determining a C-peptide area under the curve (AUC):glucose AUC ratio, an increase in which indicates responsiveness to the anti-CD3 antibody.

[0046] Definitions Certain terms are defined herein below. Further definitions are provided throughout this application.

[0047] As used herein, the articles “a” and “an” refer to one or more of the grammatical objects of the article, e.g., at least one. The use of the terms “a” or “an” when used in combination with the term “comprising” in the specification can mean “one” but is also consistent with the meaning of “one or more,” “at least one,” and “one, or two or more.”

[0048] As used herein, the terms "about" and "approximately" generally mean an acceptable degree of error of the measured quantity, taking into account the nature or precision of the measurement. Exemplary degrees of error are within 30 percent (%), within 25%, within 20%, for example within 10%, or within 5% of a given value's range. The term "substantially" means greater than 50%, greater than 60%, greater than 70%, greater than 80%, and greater than 90% or greater than 95%.

[0049] As used herein, the terms "comprising" or "comprises" are used with respect to compositions, methods, and respective components thereof that are open to including elements that are present in a given embodiment but not specified.

[0050] As used herein, the term "consisting essentially of" refers to the elements necessary for a given embodiment. This term allows for the presence of additional elements that do not substantially affect the basic and novel or functional characteristics of that embodiment of the present disclosure.

[0051] The term "consisting of" refers to the compositions, methods, and respective components thereof described herein that exclude elements not recited in the description of that embodiment.

[0052] The term "antibody" as used herein is used in the broadest sense and includes various antibody structures including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired antigen-binding activity.

[0053] "Antibody fragment" refers to a molecule other than an intact antibody that includes a portion of an intact antibody that binds to an antigen to which the intact antibody binds. Examples of antibody fragments include Fv, Fab, Fab’, Fab’-SH, F(ab’) 2Examples include, but are not limited to, diabodies, linear antibodies, single-chain antibody molecules (e.g., scFv), and multispecific antibodies formed from antibody fragments.

[0054] As used herein, the term "preventive agent" refers to a CD3-binding molecule, such as teprotumumab, that can be used to prevent, treat, manage, or improve one or more symptoms of T1D.

[0055] As used herein, the term "onset" of a disease related to type 1 diabetes refers to a patient who meets the criteria established by the American Diabetes Association for the diagnosis of type 1 diabetes (see Mayfield et al., 2006, Am. Fam. Physician 58:1355-1362).

[0056] As used herein, the terms "prevent", "preventing", and "prevention" refer to the prevention of the onset of one or more symptoms of T1D in a subject, caused by the administration of a preventive or therapeutic agent.

[0057] As used herein, "protocol" includes an administration schedule and dosing plan. The protocols herein are methods of use and include preventive protocols and treatment protocols. A "dosing plan" or "course of treatment" can include administration of a therapeutic or preventive agent in several doses over a period of 1 to 20 days.

[0058] As used herein, the terms "subject" and "patient" are used interchangeably. As used herein, the terms "subject" and "subjects" refer to mammals, more preferably humans, including animals, preferably non-primates (e.g., cows, pigs, horses, cats, dogs, rats, and mice) and primates (e.g., monkeys or humans).

[0059] As used herein, the term "prophylactically effective amount" refers to an amount of teplizumab sufficient to result in a delay or prevention of the onset, recurrence, or development of one or more symptoms of T1D. In some embodiments, the prophylactically effective amount preferably delays the onset of T1D in a subject by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%.

[0060] Various aspects of the present disclosure are described in more detail below. Further definitions are set forth throughout this specification.

[0061] Anti-CD3 Antibodies and Pharmaceutical Compositions The terms "anti-CD3 antibody" and "antibody that binds to CD3" refer to an antibody or antibody fragment that can bind to cluster of differentiation 3 (CD3) with sufficient affinity such that the antibody is useful as a prophylactic, diagnostic, and / or therapeutic agent when targeting CD3. In some embodiments, the degree of binding of the anti-CD3 antibody to an irrelevant non-CD3 protein is less than about 10% of the binding of the antibody to CD3, as measured, for example, by radioimmunoassay (RIA). In some embodiments, the antibody that binds to CD3 has a dissociation constant (Kd) of less than 1 μM, less than 100 nM, less than 10 nM, less than 1 nM, less than 0.1 nM, less than 0.01 nM, or less than 0.001 nM (e.g., 10 -8 M or less, e.g., 10 -8 M to 10 -13 M, e.g., 10 -9 M to 10 -13 M). In some embodiments, the anti-CD3 antibody binds to an epitope of CD3 that is conserved among CD3 from different species.

[0062] In some embodiments, the anti-CD3 antibody may be ChAglyCD3 (otelixizumab). Otelixizumab is a humanized Fc non-binding anti-CD3, which was first evaluated in a Phase 2 trial by the Belgian Diabetes Registry (BDR), then developed by Tolerx, and subsequently conducted a Phase 3 DEFEND new-onset T1D trial in collaboration with GSK (NCT00678886, NCT01123083, NCT00763451). Otelixizumab is administered IV by infusion over 8 days. See, for example, Wiczling et al., J.Clin.Pharmacol.50(5)(May 2010)494-506; Keymeulen et al., N Engl J Med.2005;352:2598-608; Keymeulen et al., Diabetologia.2010;53:614-23; Hagopian et al., Diabetes.2013;62:3901-8; Aronson et al., Diabetes Care.2014;37:2746-54; Ambery et al., Diabet Med.2014;31:399-402; Bolt et al., Eur.J.Immunol.lYY3.23:403-411; Vlasakakis et al., Br J Clin Pharmacol(2019)85 704-714; Guglielmi et al., Expert Opinion on Biological Therapy, 16:6,841-846; Keymeulen et al., N Engl J Med 2005;352:2598-608; Keymeulen et al., BLOOD 2010, VOL115, No.6; Sprangers et al., Immunotherapy(2011)3(11),1303-1316; Daifotis et al., Clinical Immunology(2013)149,268-278, all of which are incorporated herein by reference.

[0063] In some embodiments, the anti-CD3 antibody may be visilizumab (also known as HuM291; Nuvion). Visilizumab is a humanized anti-CD3 monoclonal antibody characterized by a mutated IgG2 isotype, lack of binding to Fcγ receptors, and the ability to selectively induce apoptosis in activated T cells. It has been evaluated in patients with graft-versus-host disease (NCT00720629; NCT00032279) as well as ulcerative colitis (NCT00267306) and Crohn's disease (NCT00267709). See, for example, Sandborn et al., Gut 59(11)(Nov 2010)1485-1492, which is incorporated herein by reference.

[0064] In some embodiments, the anti-CD3 antibody may be faralumab, a fully human anti-CD3 monoclonal antibody developed by Tiziana Life Sciences, PLC with respect to NASH and T2D (NCT03291249). See, for example, Ogura et al., Clin Immunol.2017;183:240-246; Ishikawa et al., Diabetes.2007;56(8):2103-9; Wu et al., J Immunol.2010;185(6):3401-7, all of which are incorporated herein by reference.

[0065] In some embodiments, the anti-CD3 antibody may be teplizumab. Teplizumab, also known as hOKT3yl(Ala-Ala) (containing alanine at positions 234 and 235), is an anti-CD3 antibody engineered to alter the function of T lymphocytes that mediate the destruction of insulin-producing beta cells in the pancreas. Teplizumab binds to an epitope of the CD3ε chain expressed on mature T cells, thereby altering its function. The sequence and composition of teplizumab are disclosed in U.S. Patent Nos. 6,491,916, 8,663,634, and 9,056,906, which are incorporated herein by reference in their entireties. The complete sequences of the light and heavy chains are shown below. The bolded portions are the complementarity-determining regions. Teprilizumab light chain (SEQ ID NO: 1): [Chemical formula] Teprilizumab heavy chain (SEQ ID NO: 2): [Chemical formula]

[0066] In some embodiments, pharmaceutical compositions are provided herein. Such compositions include a prophylactically effective amount of an anti-CD3 antibody and a pharmaceutically acceptable carrier. In some embodiments, the term "pharmaceutically acceptable" means approved by a regulatory agency of the federal or state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeias for use in animals, more specifically in humans. The term "carrier" refers to a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient or vehicle used in the administration of a therapeutic agent. Such pharmaceutical carriers may be sterile liquids such as water and oils, for example of petroleum, animal, vegetable or synthetic origin, for example peanut oil, soybean oil, mineral oil, sesame oil, etc. When administering the pharmaceutical composition intravenously, water is a preferred carrier. Physiological saline as well as aqueous dextrose and glycerol solutions can also be used as liquid carriers, especially as liquid carriers for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skimmed milk powder, glycerol, propylene, glycol, water, ethanol, etc. (see, for example, Handbook of Pharmaceutical Excipients, Arthur H. Kibbe ed., 2000, Am. Pharmaceutical Association, Washington, D.C., which is hereby incorporated by reference in its entirety).

[0067] The composition can also contain, if desired, small amounts of wetting agents or emulsifiers, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained release formulations, etc. Oral formulations can contain standard carriers such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in "Remington’s Pharmaceutical Sciences" by E.W. Martin. Such compositions preferably contain a prophylactically effective amount or therapeutically effective amount of a prophylactic or therapeutic agent, in a purified form, together with a suitable amount of carrier, so as to provide a form for proper administration to a patient. The formulation should be suitable for the mode of administration. In some embodiments, the pharmaceutical composition is sterile and in a form suitable for administration to a subject, preferably an animal subject, more preferably a mammalian subject, most preferably a human subject.

[0068] In some embodiments, it may be desirable to locally administer the pharmaceutical composition to the area in need of treatment, which can be achieved, for example, but not limited to, by local infusion, injection, or an implant, where the implant is a membrane such as a cyalastic membrane, or a porous, non-porous, or gelatinous material containing fibers. Preferably, when administering an anti-CD3 antibody, care must be taken to use a material that does not absorb the anti-CD3 antibody.

[0069] In some embodiments, the composition can be delivered in vesicles, particularly liposomes (Langer, Science 249:1527-1533 (1990); Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally the same book).

[0070] In some embodiments, the composition can be delivered in a controlled release or sustained release system. In some embodiments, a pump can be used to achieve controlled release or sustained release (see, e.g., Langer; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:20; Buchwald et al., 1980, Surgery 88:507; Saudek et al., 1989, N. Engl. J. Med. 321:574). In some embodiments, a polymeric material can be used to achieve controlled release or sustained release of the antibody or fragment thereof of the present invention (see, e.g., Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J., Macromol. Sci. Rev. Macromol. Chem. 23:61; Levy et al., 1985, Science 228:190; During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989, J. Neurosurg. 71:105); U.S. Patent No. 5,679,377; U.S. Patent No. 5,916,597; U.S. Patent No. 5,912,015; U.S. Patent No. 5,989,463; U.S. Patent No. 5,128,326; PCT Publication No. WO 99 / 15154; and PCT Publication No. WO 99 / 20253).Examples of polymers used in sustained release formulations include, but are not limited to, poly(2-hydroxyethyl methacrylate), poly(methyl methacrylate), poly(acrylic acid), poly(ethylene-co-vinyl acetate), poly(methacrylic acid), polyglycolide (PLG), polyanhydrides, poly(N-vinylpyrrolidone), poly(vinyl alcohol), polyacrylamide, poly(ethylene glycol), polylactide (PLA), poly(lactide-co-glycolide) (PLGA), and polyorthoesters. In some embodiments, the polymer used in the sustained release formulation is inert, contains no leachable impurities, is stable upon storage, is sterilized, and is biodegradable. In some embodiments, the controlled release system or sustained release system can be placed near the therapeutic target, i.e., near the lung, and thus only requires a portion of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)).

[0071] Controlled release systems are described in a review by Langer (1990, Science 249:1527-1533). Sustained release formulations containing one or more antibodies or fragments thereof of the invention can be manufactured using any technique known to those of skill in the art. See, for example, U.S. Patent No. 4,526,938; PCT Publication No. WO 91 / 05548 pamphlet; PCT Publication No. WO 96 / 20698 pamphlet; Ning et al., 1996, Radiotherapy & Oncology 39:179-189; Song et al., 1995, PDA Journal of Pharmaceutical Science & Technology 50:372-397; Cleek et al., 1997, Pro. Int’l. Symp. Control. Rel. Bioact. Mater. 24:853-854; and Lam et al., 1997, Proc. Int’l. Symp. Control Rel. Bioact. Mater. 24:759-760, each of which is incorporated herein by reference in its entirety.

[0072] The pharmaceutical composition can be formulated to be compatible with its 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), transmucosal, and rectal administration. In some embodiments, the composition is formulated according to routine procedures as a pharmaceutical composition suitable for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to humans. In some embodiments, the pharmaceutical composition is formulated according to routine procedures for subcutaneous administration to humans. Typically, the composition for intravenous administration is a solution in a sterile isotonic aqueous buffer. Optionally, the composition may also contain solubilizing agents and local anesthetics such as lignocaine to relieve pain at the injection site.

[0073] The composition can be formulated for parenteral administration by injection, such as by bolus injection or continuous infusion. Injectable formulations can be supplied in unit dosage forms, such as ampoules or multi-dose containers, with preservatives added. The composition can take forms such as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulating agents such as suspending agents, stabilizing agents, and / or dispersing agents. Alternatively, the active ingredient may be in powder form, which is constituted with a suitable vehicle, such as sterile pyrogen-free water, before use. In some embodiments, the present disclosure provides dosage forms (e.g., related to pumps or other devices for such delivery) that enable the administration of anti-CD3 antibodies continuously over several hours or days, such as for 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 14 days. In some embodiments, the present invention provides dosage forms that enable the administration of continuously increasing doses, such as increasing from 51 ug / m 2 / day to 826 ug / m 2 / day over 24 hours, 30 hours, 36 hours, 4 days, 5 days, 7 days, 10 days, or 14 days.

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

[0075] Generally, the components of the composition disclosed herein are supplied separately in unit dosage form or mixed together as a dry lyophilized powder or anhydrous concentrate in a sealed container such as an ampoule or sachet indicating the amount of the active agent. When the composition is administered by infusion, the composition can be dispensed in an infusion bottle or bag containing sterile pharmaceutical - grade water or physiological saline. In some embodiments, the composition is in solution. In some embodiments, the composition is packaged in a vial (e.g., a sterile glass vial of 0.9% sodium chloride injection) or an infusion bag (e.g., a polyvinyl chloride (PVC) infusion bag of 0.9% sodium chloride injection). In some embodiments, the vial is for single - dose use. When the composition is administered by injection, an ampoule of sterile water for injection or physiological saline can be provided so that the components can be mixed before administration.

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

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

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

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

[0080] Methods and Uses In some embodiments, the present disclosure provides for administering an anti-human CD3 antibody, such as teplizumab, to an individual at risk of developing type 1 diabetes, or an individual in the preclinical stage of type 1 diabetes but not meeting the diagnostic criteria established by the American Diabetes Association or the Immunology of Diabetes Society, in order to prevent or delay the onset of type 1 diabetes and / or to prevent or delay the need for insulin administration in such patients. In some embodiments, high-risk factors for identifying an at-risk subject include having a first- or second-degree relative diagnosed with type 1 diabetes, impaired fasting glucose (e.g., measuring a glucose level of 100-125 mg / dl at least once after an 8-hour fast), impaired glucose tolerance in response to a 75 g oral glucose tolerance test (OGTT) (e.g., measuring a 2-hour glucose level of 140-199 mg / dl at least once in response to a 75 g OGTT), a white person having an HLA type of DR3, DR4, or DR7, an African person having an HLA type of DR3 or DR4, a Japanese person having an HLA type of DR3, DR4, or DR9, exposure to a virus (e.g., coxsackievirus B, enterovirus, adenovirus, rubella, cytomegalovirus, Epstein-Barr virus), a positive diagnosis according to accepted criteria in the art of at least one other autoimmune disorder (e.g., thyroid disease, celiac disease), and / or detection of autoantibodies in serum or other tissues, particularly ICA and type 1 diabetes-related autoantibodies. In some embodiments, a subject identified as being at risk of developing type 1 diabetes has at least one of the risk factors described herein and / or known in the art. The present disclosure also includes identifying a subject at risk of developing type 1 diabetes, where the subject presents a combination of two or more, three or more, four or more, or more than five of the risk factors disclosed herein or known in the art. In some embodiments, the non-diabetic subject is an adult subject or a pediatric subject. In some embodiments, the pediatric subject is 8 years of age or older. In some embodiments, the pediatric subject is 7 years of age or older. In some embodiments, the pediatric subject is 6 years of age or older.In some embodiments, the pediatric subject is 5 years of age or older. In some embodiments, the pediatric subject is 4 years of age or older. In some embodiments, the pediatric subject is 3 years of age or older. In some embodiments, the pediatric subject is 2 years of age or older. In some embodiments, the pediatric subject is 1 year of age or older. In some embodiments, the pediatric subject is an infant. In some embodiments, the infant is 12 months or younger, 11 months or younger, 10 months or younger, 9 months or younger, 8 months or younger, 7 months or younger, 6 months or younger, 5 months or younger, 4 months or younger, 3 months or younger, 2 months or younger, 1 month or younger.

[0081] Serum autoantibodies associated with type 1 diabetes or associated with factors predisposing to the development of type 1 diabetes are islet cell autoantibodies (e.g., anti-ICA512 autoantibodies), glutamic acid decarboxylase autoantibodies (e.g., anti-GAD65 autoantibodies), IA2 antibodies, ZnT8 antibodies, and / or anti-insulin autoantibodies. Thus, in a specific example according to this embodiment, the present invention encompasses the treatment of an individual having detectable autoantibodies (e.g., anti-IA2, anti-ICA512, anti-GAD, or anti-insulin autoantibodies) associated with factors predisposing to the development of type 1 diabetes or associated with early stage type 1 diabetes, who has not been diagnosed with type 1 diabetes, and / or an individual who is a first-degree or second-degree relative of a type 1 diabetes patient. In some embodiments, the presence of the autoantibody is detected by ELISA, electrochemiluminescence (ECL), radioassay (e.g., Yu et al., 1996, J. Clin. Endocrinol. Metab. 81:4264 - 4267), agglutination PCR (Tsai et al, ACS Central Science 2016 2(3), 139 - 147), or any other method for the immunospecific detection of the antibodies described herein or known to those of skill in the art.

[0082] β-cell function before, during, and after treatment can be evaluated by the methods described herein or by any method known to those of skill in the art. For example, the Diabetes Control and Complications Trial (DCCT) research group established the monitoring of the percentage of glycosylated hemoglobin (HA1 and HA1c) as a standard for the evaluation of glycemic control (DCCT, 1993, N. Engl. J. Med. 329:977-986). Alternatively, the daily insulin requirement, C-peptide level / response, hypoglycemic episodes, and / or characterization of FPIR can be used as markers of β-cell function or to establish a therapeutic index (see Keymeulen et al., 2005, N. Engl. J. Med. 352:2598-2608; Herold et al., 2005, Diabetes 54:1763-1769; U.S. Patent Application Publication No. 2004 / 0038867A1; and Greenbaum et al., 2001, Diabetes 50:470-476, respectively). For example, FPIR is calculated as the sum of insulin values at 1 and 3 minutes after an IGTT, which is performed according to the Islet Cell Antibody Registry User Study Protocol (see, e.g., Bingley et al., 1996, Diabetes 45:1720-1728 and McCulloch et al., 1993, Diabetes Care 16:911-915).

[0083] In some embodiments, the individual at risk of developing T1D may be a non-diabetic subject who is a blood relative of a patient with T1D. In some embodiments, the non-diabetic subject has two or more diabetes-related autoantibodies selected from islet cell antibodies (ICA), insulin autoantibodies (IAA), and antibodies against glutamic acid decarboxylase (GAD), tyrosine phosphatase (IA-2 / ICA512), or ZnT8.

[0084] In some embodiments, the non-diabetic subject has impaired glucose tolerance in an oral glucose tolerance test (OGTT). Impaired glucose tolerance in the OGTT is defined as a fasting blood glucose level of 110-125 mg / dL, or a 2-hour plasma of 140 mg / dL or more and less than 200 mg / dL, or an intervening glucose value at 30, 60, or 90 minutes in the OGTT exceeding 200 mg / dL.

[0085] In some embodiments, the non-diabetic subject has abnormal results that reveal a high sensor average glucose level (110 mg / dL or more), or high glucose variability (CV15 or more), or a short time within the range (more than 10% of the time exceeding 140 mg / dL) in a continuous glucose monitoring system (CGM).

[0086] In some embodiments, non-diabetic subjects responsive to an anti-CD3 antibody such as teplizumab do not have antibodies against ZnT8. In some embodiments, such non-diabetic subjects are HLA-DR4+ and not HLA-DR3+. In some embodiments, such non-diabetic subjects responsive to an anti-CD3 antibody such as teplizumab show an increase in the frequency (or relative amount) of TIGIT+KLRG1+CD8+ T cells (e.g., by flow cytometry) in peripheral blood mononuclear cells after administration (e.g., after 1 month, 2 months, 3 months, or more or less).

[0087] In some embodiments, the methods provided herein include administering an anti-human CD3 antibody, such as teprotumumab, to a subject having stage 2 type 1 diabetes in need thereof. In some embodiments, the subject is an adult. In some embodiments, the subject is a pediatric subject. In some embodiments, the pediatric subject is 8 years of age or older (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 years of age or older). In some embodiments, administration of an anti-human CD3 antibody, such as teprotumumab, delays the onset of stage 3 type 1 diabetes. In some embodiments, the subject has stage 2 type 1 diabetes. In some embodiments, a subject having glycemic abnormalities without overt hyperglycemia has at least two positive pancreatic islet autoantibodies. The ADA and ISPAD guidelines that define the classification and diagnosis of stage 2 T1D are American Diabetes Association Professional Practice Committee-Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022 Jan 1;45(Suppl 1):S17-S38); and Besser REJ, Bell KJ, Couper JJ, Ziegler AG, Wherrett DK, Knip M, Speake C, Casteels K, Driscoll KA, Jacobsen L, Craig ME, Haller MJ. ISPAD clinical practice consensus guidelines 2022: Stages of type 1 diabetes in children and adolescents. Pediatr Diabetes. 2022 Sep 30). In some embodiments, the subject has impaired glucose tolerance on an oral glucose tolerance test (OGTT). In some embodiments, the subject in need thereof meets the criteria for the diagnosis of stage 2 type 1 diabetes and does not have type 2 diabetes.In some embodiments, the methods provided herein include confirming that a subject having glucose dysregulation without overt hyperglycemia has stage 2 type 1 diabetes by demonstrating at least two positive pancreatic islet autoantibodies. In some embodiments, the methods provided herein further include confirming that the subject does not have type 2 diabetes. In some embodiments, a subject having stage 2 type 1 diabetes has both of the following. 1. Two or more of the following pancreatic islet autoantibodies: Glutamic acid decarboxylase 65 (GAD) autoantibody Insulin autoantibody (IAA) Insulinoma-associated antigen 2 autoantibody (IA-2A) Zinc transporter 8 autoantibody (ZnT8A) Islet cell autoantibody (ICA) 2. Glucose dysregulation (e.g., oral glucose tolerance test).

[0088] In some embodiments, stage 2 type 1 diabetes can be diagnosed by other methods known to those of skill in the art.

[0089] Aspects of the disclosure relate to methods of preventing or delaying the onset of stage 3 type 1 diabetes (T1D). In some embodiments, the subject is an adult. In some embodiments, the subject is a pediatric subject who is 1 year old, 2 years old, 3 years old or older, 4 years old or older, 5 years old or older, 6 years old or older, 7 years old or older, 8 years old or older, 9 years old or older, 10 years old or older, 11 years old or older, 12 years old or older, 13 years old or older, 14 years old or older, 15 years old or older, 16 years old or older, 17 years old or older, 18 years old or older. In some embodiments, the subject is an infant (12 months or younger, 11 months or younger, 10 months or younger, 9 months or younger, 8 months or younger, 7 months or younger, 6 months or younger, 5 months or younger, 4 months or younger, 3 months or younger, 2 months or younger, 1 month or younger (e.g., within a few weeks after birth)).

[0090] In some embodiments, a prophylactically effective amount of the antibody is 10,000 micrograms per square meter (μg / m 2It includes a treatment process of 10 to 14 days of subcutaneous (SC) injection, intravenous (IV) infusion, or oral administration of an anti-CD3 antibody at a cumulative dose exceeding 2 about 9,500 to about 14,000 μg / m 2 about 9,500 to about 13,500 μg / m 2 about 9,500 to about 13,000 μg / m 2 about 9,500 to about 12,500 μg / m 2 about 9,500 to about 12,000 μg / m 2 about 9,500 to about 11,500 μg / m 2 about 9,500 to about 11,000 μg / m 2 about 9,500 to about 10,500 μg / m 2 about 9,500 to about 10,000 μg / m 2 about 10,000 to about 14,000 μg / m 2 about 10,000 to about 13,500 μg / m 2 about 10,000 to about 13,000 μg / m 2 about 10,000 to about 12,500 μg / m 2 about 10,000 to about 12,000 μg / m 2 about 10,000 to about 11,500 μg / m 2 about 10,000 to about 11,000 μg / m 2 about 10,000 to about 10,500 μg / m 2 about 10,500 to about 14,000 μg / m 2 about 10,500 to about 13,500 μg / m 2 about 10,500 to about 13,000 μg / m 2 about 10,500 to 12,000 μg / m 2 about 10,500 to about 11,500 μg / m 2 about 10,500 to about 11,000 μg / m2 It includes a treatment process of subcutaneous (SC) injection, intravenous (IV) infusion or oral administration of an anti-CD3 antibody for 10 to 14 days. In some embodiments, the prophylactically effective amount of the antibody is about 11,000 to about 14,000 μg / m 2 about 11,000 to about 13,500 μg / m 2 about 11,000 to about 13,000 μg / m 2 about 11,000 to about 12,500 μg / m 2 about 11,000 to about 12,000 μg / m 2 about 11,000 to about 11,500 μg / m 2 It includes a treatment process of subcutaneous (SC) injection, intravenous (IV) infusion or oral administration of an anti-CD3 antibody for 10 to 14 days. In some embodiments, the prophylactically effective amount of the antibody is about 11,000 to about 14,000 μg / m 2 about 11,000 to about 13,500 μg / m 2 about 11,000 to about 13,000 μg / m 2 about 11,000 to about 12,500 μg / m 2 about 11,000 to about 12,000 μg / m 2 about 11,000 to about 11,500 μg / m 2 It includes a treatment process of subcutaneous (SC) injection, intravenous (IV) infusion or oral administration of an anti-CD3 antibody for 10 to 14 days. In some embodiments, the prophylactically effective amount of the antibody is about 11,500 to about 14,000 μg / m 2 about 11,500 to about 13,500 μg / m 2 about 11,500 to about 13,000 μg / m 2 about 11,500 to about 12,500 μg / m 2 about 11,500 to about 12,000 μg / m 2 It includes a treatment process of subcutaneous (SC) injection, intravenous (IV) infusion or oral administration of an anti-CD3 antibody for 10 to 14 days. In some embodiments, the prophylactically effective amount of the antibody is about 12,000 to about 14,000 μg / m 2 about 12,000 to about 13,500 μg / m 2 about 12,000 to about 13,000 μg / m 2 about 12,000 to about 12,500 μg / m 2It includes a treatment process of subcutaneous (SC) injection, intravenous (IV) infusion, or oral administration of an anti-CD3 antibody for 10 to 14 days. In some embodiments, a prophylactically effective amount of the antibody is about 12,500 to about 14,000 μg / m 2 about 12,500 to about 13,500 μg / m 2 about 12,500 to about 13,000 μg / m 2 It includes a treatment process of subcutaneous (SC) injection, intravenous (IV) infusion, or oral administration of an anti-CD3 antibody for 10 to 14 days. In some embodiments, a prophylactically effective amount of the antibody is about 13,000 to about 14,000 μg / m 2 about 13,000 to about 13,500 μg / m 2 It includes a treatment process of subcutaneous (SC) injection, intravenous (IV) infusion, or oral administration of an anti-CD3 antibody for 10 to 14 days. In some embodiments, a prophylactically effective amount of the antibody is about 13,500 μg / m 2 to about 14,000 μg / m 2 It includes a treatment process of subcutaneous (SC) injection, intravenous (IV) infusion, or oral administration of an anti-CD3 antibody for 10 to 14 days. In some embodiments, a prophylactically effective amount of the antibody is about 10,000 μg / m 2 10,500 μg / m 2 11,000 μg / m 2 11,500 μg / m 2 12,000 μg / m 2 12,500 μg / m 2 13,000 μg / m 2 13,500 μg / m 2 or 14,000 μg / m 2 It includes a treatment process of subcutaneous (SC) injection, intravenous (IV) infusion, or oral administration of an anti-CD3 antibody for 10 to 14 days. In some embodiments, the anti-CD3 antibody is teplizumab or includes teplizumab.

[0091] In some embodiments, a prophylactically effective amount of the antibody is about 10,000 to about 14,000 μg / m 2 about 10,000 to about 13,500 μg / m 2 about 10,000 to about 13,000 μg / m 2, about 10,000 to about 12,500 μg / m 2 , about 10,000 to about 12,000 μg / m 2 , about 10,000 to about 11,500 μg / m 2 , about 10,000 to about 11,000 μg / m 2 , about 10,000 to about 10,500 μg / m 2 includes a 10 - to 14 - day treatment course of intravenous (IV) infusion of teprotumumab at. In some embodiments, a prophylactically effective amount of the antibody is about 10,500 to about 14,000 μg / m 2 , about 10,500 to about 13,500 μg / m 2 , about 10,500 to about 13,000 μg / m 2 , about 10,500 to about 12,500 μg / m 2 , about 10,500 to about 12,000 μg / m 2 , about 10,500 to about 11,500 μg / m 2 , about 10,500 to about 11,000 μg / m 2 includes a 10 - to 14 - day treatment course of intravenous (IV) infusion of teprotumumab at. In some embodiments, a prophylactically effective amount of the antibody is about 11,000 to about 14,000 μg / m 2 , about 11,000 to about 13,500 μg / m 2 , about 11,000 to about 13,000 μg / m 2 , about 11,000 to about 12,500 μg / m 2 , about 11,000 to about 12,000 μg / m 2 , about 11,000 to about 11,500 μg / m 2 includes a 10 - to 14 - day treatment course of intravenous (IV) infusion of teprotumumab at. In some embodiments, a prophylactically effective amount of the antibody is about 11,000 to about 14,000 μg / m 2 , about 11,000 to about 13,500 μg / m 2 , about 11,000 to about 13,000 μg / m 2 , about 11,000 to about 12,500 μg / m 2 , about 11,000 to about 12,000 μg / m 2 , about 11,000 to about 11,500 μg / m 2Includes a 10- to 14-day treatment course of intravenous (IV) infusion of teprotumumab. In some embodiments, a prophylactically effective amount of the antibody is from about 11,500 to about 14,000 μg / m 2 、from about 11,500 to about 13,500 μg / m 2 、from about 11,500 to about 13,000 μg / m 2 、from about 11,500 to about 12,500 μg / m 2 、from about 11,500 to about 12,000 μg / m 2 Includes a 10- to 14-day treatment course of intravenous (IV) infusion of teprotumumab. In some embodiments, a prophylactically effective amount of the antibody is from about 12,000 to about 14,000 μg / m 2 、from about 12,000 to about 13,500 μg / m 2 、from about 12,000 to about 13,000 μg / m 2 、from about 12,000 to about 12,500 μg / m 2 Includes a 10- to 14-day treatment course of intravenous (IV) infusion of teprotumumab. In some embodiments, a prophylactically effective amount of the antibody is from about 12,500 to about 14,000 μg / m 2 、from about 12,500 to about 13,500 μg / m 2 、from about 12,500 to about 13,000 μg / m 2 Includes a 10- to 14-day treatment course of intravenous (IV) infusion of teprotumumab. In some embodiments, a prophylactically effective amount of the antibody is from about 13,000 to about 14,000 μg / m 2 、from about 13,000 to about 13,500 μg / m 2 Includes a 10- to 14-day treatment course of intravenous (IV) infusion of teprotumumab. In some embodiments, a prophylactically effective amount of the antibody is from about 13,500 μg / m 2 to about 14,000 μg / m 2 Includes a 10- to 14-day treatment course of intravenous (IV) infusion of teprotumumab. In some embodiments, a prophylactically effective amount of the antibody is from about 10,000 μg / m 2 、10,500 μg / m 2 、11,000 μg / m 2 、11,500 μg / m 2 、12,000 μg / m 2 、12,500 μg / m2 、13,000 μg / m 2 、13,500 μg / m 2 or 14,000 μg / m 2 and includes a 10 - to 14 - day treatment course of intravenous (IV) infusion of teprotumumab at these levels. In some embodiments, the anti - CD3 antibody is teprotumumab or includes teprotumumab.

[0092] In some embodiments, the method subjects non - diabetic subjects at risk of T1D to an IV infusion treatment course of 14 days at doses of approximately 60 μg / m on days 1 - 4 respectively, 2 approximately 125 μg / m 2 approximately 250 μg / m 2 and approximately 500 μg / m 2 and on each of days 5 - 14 at a dose of approximately 1,000 μg / m. 2 In some embodiments, the cumulative dose is approximately 10,935 μg / m. 2

[0093] In some embodiments, the method subjects non - diabetic subjects at risk of T1D to an IV infusion treatment course of 14 days at doses of approximately 60 μg / m on days 1 - 4 respectively, 2 approximately 125 μg / m 2 approximately 250 μg / m 2 and approximately 500 μg / m 2 and on each of days 5 - 14 at a dose of approximately 1,030 μg / m. 2 In some embodiments, the cumulative dose is approximately 11,235 μg / m. 2

[0094] In some embodiments, the method subjects non - diabetic subjects at risk of T1D to an IV infusion treatment course of 14 days at doses of approximately 100 μg / m on days 1 - 4 respectively, 2 approximately 425 μg / m 2 approximately 850 μg / m 2 and approximately 850 μg / m 2 and on each of days 5 - 14 at a dose of approximately 1,000 μg / m. 2 In some embodiments, the cumulative dose is approximately 12,225 μg / m.​​2 is as follows.

[0095] In some embodiments, the method comprises administering an intravenous infusion over a 14-day treatment course to non-diabetic subjects at risk for T1D, at a dose of about 65 μg / m on each of days 1-4 2 , about 125 μg / m 2 , about 250 μg / m 2 , and about 500 μg / m 2 , and at a dose of about 1,070 μg / m on each of days 5-14. In some embodiments, the cumulative dose is about 11,640 μg / m 2 is as follows. 2 is as follows.

[0096] In some embodiments, the method comprises administering an intravenous infusion over a 14-day treatment course to a subject in need thereof, wherein the daily dose is about 65 μg / m on each of days 1-4 2 , about 125 μg / m 2 , about 250 μg / m 2 , and about 500 μg / m 2 and about 1,030 μg / m on each of days 5-14. In some embodiments, the cumulative dose is about 11,240 μg / m 2 is as follows. 2 is as follows.

[0097] In some embodiments, the method comprises administering an intravenous infusion over a 14-day treatment course to a subject in need thereof, wherein the daily dose is about 60 μg / m on each of days 1-4 2 , about 125 μg / m 2 , about 250 μg / m 2 , and about 500 μg / m 2 and about 1,000 μg / m on each of days 5-14. In some embodiments, the cumulative dose is about 10,935 μg / m 2 is as follows. 2 is as follows.

[0098] In some embodiments, the method comprises administering an intravenous infusion over a 14-day treatment course to a subject in need thereof, wherein the daily dose is about 60 μg / m on each of days 1-4 2 , about 125 μg / m2 , about 250 μg / m 2 , and about 500 μg / m 2 , and on each of the 5th to 14th days, about 1,030 μg / m 2 . In some embodiments, the cumulative dose is about 11,235 μg / m 2 .

[0099] In some embodiments, the method includes performing an intravenous infusion for a 14-day treatment course on a subject in need thereof, and the daily dose is about 100 μg / m on each of the 1st to 4th days 2 , about 425 μg / m 2 , about 850 μg / m 2 , and about 850 μg / m 2 , and on each of the 5th to 14th days, about 1,000 μg / m 2 . In some embodiments, the cumulative dose is about 12,225 μg / m 2 .

[0100] In some embodiments, the method includes performing an intravenous infusion for a 14-day treatment course on a subject in need thereof, and the daily dose is about 65 μg / m on each of the 1st to 4th days 2 , about 125 μg / m 2 , about 250 μg / m 2 , and about 500 μg / m 2 , and on each of the 5th to 14th days, it is a dose of about 1,070 μg / m 2 . In some embodiments, the cumulative dose is about 11,640 μg / m 2 .

[0101] In some embodiments, the method includes performing an intravenous infusion for a 14-day treatment course on a subject in need thereof, and the daily dose is about 65 μg / m on each of the 1st to 4th days 2 , about 125 μg / m 2 , about 250 μg / m 2 , and about 500 μg / m 2 , and on each of the 5th to 14th days, about 1,030 μg / m 2 . In some embodiments, the cumulative dose is about 11,240 μg / m 2 .

[0102] In some embodiments, the daily administration of the anti-CD3 antibody is postponed and resumed by administering all remaining doses on consecutive days to complete a 14-day treatment course.

[0103] In some embodiments, the prophylactically effective amount delays the median time to clinical diagnosis of T1D by at least 50%, at least 80%, or at least 90%, or by at least 12 months, at least 18 months, at least 24 months, at least 36 months, at least 48 months, or at least 60 months, or more.

[0104] In some embodiments, the dosing regimen with an anti-CD3 antibody, such as teplizumab, can be repeated at intervals of 2 months, 4 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 effectiveness of treatment with an anti-CD3 antibody, such as teplizumab, is determined 2 months, 4 months, 6 months, 9 months, 12 months, 15 months, 18 months, 24 months, 30 months, or 36 months after the previous treatment, as described herein or as known in the art.

[0105] In some embodiments, the subject is administered one or more unit doses of an anti-CD3 antibody, such as teplizumab, of about 0.5 to 50 μg / kg, about 0.5 to 40 μg / kg, about 0.5 to 30 μg / kg, about 0.5 to 20 μg / kg, about 0.5 to 15 μg / kg, about 0.5 to 10 μg / kg, about 0.5 to 5 μg / kg, about 1 to 5 μg / kg, about 1 to 10 μg / kg, about 20 to 40 μg / kg, about 20 to 30 μg / kg, about 22 to 28 μg / kg or about 25 to 26 μg / kg to prevent, treat, ameliorate, alleviate, reduce, mitigate, delay, arrest, or end one or more symptoms of T1D. In some embodiments, the subject is administered one or more unit doses of an anti-CD3 antibody, such as teplizumab, of about 200 μg / kg, 178 μg / kg, 180 μg / kg, 128 μg / kg, 100 μg / kg, 95 μg / kg, 90 μg / kg, 85 μg / kg, 80 μg / kg, 75 μg / kg, 70 μg / kg, 65 μg / kg, 60 μg / kg, 55 μg / kg, 50 μg / kg, 45 μg / kg, 40 μg / kg, 35 μg / kg, 30 μg / kg, 26 μg / kg, 25 μg / kg, 20 μg / kg, 15 μg / kg, 13 μg / kg, 10 μg / kg, 6.5 μg / kg, 5 μg / kg, 3.2 μg / kg, 3 μg / kg, 2.5 μg / kg, 2 μg / kg, 1.6 μg / kg, 1.5 μg / kg, 1 μg / kg, 0.5 μg / kg, 0.25 μg / kg, 0.1 μg / kg, or 0.05 μg / kg to prevent, treat, ameliorate, alleviate, reduce, mitigate, delay, arrest, or end one or more symptoms of T1D.

[0106] In some embodiments, the subject is administered one or more doses of an anti-CD3 antibody, such as teplizumab, of about 5 to 1200 μg / m 2 , such as about 60 to 1070 μg / m 2 . In some embodiments, the subject is administered one or more doses of an anti-CD3 antibody, such as teplizumab, to prevent, treat, delay the progression of T1D, delay the onset, ameliorate, alleviate, reduce, mitigate, delay, arrest, or end one or more symptoms of T1D, of 1200 μg / m 2 , 1150 μg / m 2 , 1100 μg / m 2 , 1050 μg / m 2 , 1000 μg / m2 、 950 μg / m 2 、 900 μg / m 2 、 850 μg / m 2 、 800 μg / m 2 、 750 μg / m 2 、 700 μg / m 2 、 650 μg / m 2 、 600 ug / m 2 、 550 μg / m 2 、 500 μg / m 2 、 450 μg / m 2 、 400 μg / m 2 、 350 μg / m 2 、 300 μg / m 2 、 250 μg / m 2 、 200 μg / m 2 、 150 μg / m 2 、 100 μg / m 2 、 50 μg / m 2 、 40 μg / m 2 、 30 μg / m 2 、 20 μg / m 2 、 15 μg / m 2 、 10 μg / m 2 or 5 μg / m 2 Administer one or more unit doses of an anti-CD3 antibody such as teplizumab.

[0107] In some embodiments, a treatment regimen comprising one or more doses of a prophylactically effective amount of an anti-CD3 antibody, such as teplizumab, is administered to a subject, and the treatment course is carried out over 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days or 14 days. In some embodiments, a treatment regimen comprising one or more doses of a prophylactically effective amount of an anti-CD3 antibody, such as teplizumab, is administered to a subject, and the treatment course is carried out over 14 days. In some embodiments, the treatment regimen comprises administering a prophylactically effective amount of the dose daily, every 2 days, every 3 days or every 4 days. In some embodiments, the treatment regimen comprises administering a prophylactically effective amount of the dose on Monday, Tuesday, Wednesday, Thursday of a given week and not administering a prophylactically effective amount of the dose on Friday, Saturday and Sunday of the same week until 14 doses, 13 doses, 12 doses, 11 doses, 10 doses, 9 doses or 8 doses are administered. In some embodiments, the dose administered is the same on each day of the dosing schedule.

[0108] In some embodiments, a treatment regimen comprising one or more doses of a prophylactically effective amount of an anti-CD3 antibody, such as teplizumab, is administered to a subject, wherein the prophylactically effective amount is about 200 μg / kg / day, 175 μg / kg / day, 150 μg / kg / day, 125 μg / kg / day, 100 μg / kg / day, 95 μg / kg / day, 90 μg / kg / day, 85 μg / kg / day, 80 μg / kg / day, 75 μg / kg / day, 70 μg / kg / day, 65 μg / kg / day, 60 μg / kg / day, 55 μg / kg / day, 50 μg / kg / day, 45 μg / kg / day, 40 μg / kg / day, 35 μg / kg / day, 30 μg / kg / day, 26 μg / kg / day, 25 μg / kg / day, 20 μg / kg / day, 15 μg / kg / day, 13 μg / kg / day, 10 μg / kg / day, 6.5 μg / kg / day, 5 μg / kg / day, 3.2 μg / kg / day, 3 μg / kg / day, 2.5 μg / kg / day, 2 μg / kg / day, 1.6 μg / kg / day, 1.5 μg / kg / day, 1 μg / kg / day, 0.5 μg / kg / day, 0.25 μg / kg / day, 0.1 μg / kg / day, or 0.05 μg / kg / day, and / or the prophylactically effective amount is about 1200 μg / m 2 / day, 1150 μg / m2 / day, 1100 μg / m 2 / day, 1050 μg / m 2 / day, 1000 μg / m 2 / day, 950 μg / m 2 / day, 900 μg / 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 / day, 200 μg / m 2 / day, 150 μg / m 2 / day, 100 μg / m 2 / day, 50 μg / m 2 / day, 40 μg / m 2 / day, 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 / day.

[0109] In some embodiments, about 1200 μg / m 2 Hereinafter, 1150 μg / m 2 Hereinafter, 1100 μg / m 2 Hereinafter, 1050 μg / m 2 Hereinafter, 1000 μg / m 2 Hereinafter, 950 μg / m 2 Hereinafter, 900 μg / m 2 Hereinafter, 850 μg / m 2 Hereinafter, 800 μg / m 2 Hereinafter, 750 μg / m 2 Hereinafter, 700 μg / m 2 Hereinafter, 650 μg / m 2 Hereinafter, 600 μg / m2 Less than or equal to 550 μg / m 2 Less than or equal to 500 μg / m 2 Less than or equal to 450 μg / m 2 Less than or equal to 400 μg / m 2 Less than or equal to 350 μg / m 2 Less than or equal to 300 μg / m 2 Less than or equal to 250 μg / m 2 Less than or equal to 200 μg / m 2 Less than or equal to 150 μg / m 2 Less than or equal to 100 μg / m 2 Less than or equal to 50 μg / m 2 Less than or equal to 40 μg / m 2 Less than or equal to 30 μg / m 2 Less than or equal to 20 μg / m 2 Less than or equal to 15 μg / m 2 Less than or equal to 10 μg / m 2 Less than or equal to or 5 μg / m 2 Intravenous administration of an anti-CD3 antibody such as teplizumab is administered for about 24 hours, about 22 hours, about 20 hours, about 18 hours, about 16 hours, about 14 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1.5 hours, about 1 hour, about 50 minutes, about 40 minutes, about 30 minutes, about 20 minutes, about 10 minutes, about 5 minutes, about 2 minutes, about 1 minute, about 30 seconds or about 10 seconds to prevent, treat, improve, alleviate, reduce, mitigate, delay, stop, or end one or more symptoms of type 1 diabetes. The total dose administered over the course of the dosing schedule may be about 9,500, 10,000, 10,500, 11,000, 11,500, 12,000, 12,500, 13,000 or 13,500 ug / m 2 sup. The total dose administered over the course of the dosing schedule is, in some embodiments, about 9,500 to about 14,000 μg / m 2 about 9,500 to about 13,500 μg / m 2 about 9,500 to about 13,000 μg / m 2 about 9,500 to about 12,500 μg / m 2 about 9,500 to about 12,000 μg / m 2 about 9,500 to about 11,500 μg / m 2 about 9,500 to about 11,000 μg / m 2 about 9,500 to about 10,500 μg / m 2, about 9,500 to about 10,000 μg / m 2 is. The total dose over the course of the dosing schedule is, in some embodiments, about 10,500 to about 14,000 μg / m 2 , about 10,500 to about 13,500 μg / m 2 , about 10,500 to about 13,000 μg / m 2 , about 10,500 to about 12,500 μg / m 2 , about 10,500 to about 12,000 μg / m 2 , about 10,500 to about 11,500 μg / m 2 , about 10,500 to about 11,000 μg / m 2 is. For example, the total dose over the course of the dosing schedule is about 10,935 μg / m 2 , about 11,235 μg / m 2 , about 11,240 μg / m 2 , about 11,640 μg / m 2 , or about 12,225 μg / m 2 is.

[0110] In some embodiments, the dose is increased over the first quarter, first half, or first two-thirds of the treatment schedule (e.g., over the first 2, 3, 4, 5, or 6 days of a 10, 12, 14, 16, 18, or 20-day once-daily dosing schedule) until the prophylactically effective daily dose of an anti-CD3 antibody such as teprotumumab is achieved. For example, the dose can be increased over 3 or 4 days of a 14-day dosing schedule. In some embodiments, a treatment schedule is implemented for the subject that includes one or more doses of a prophylactically effective amount of an anti-CD3 antibody such as teprotumumab, where the prophylactically effective amount increases, for example, daily by about 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, 75 μg / kg, 80 μg / kg, 85 μg / kg, 90 μg / kg, 95 μg / kg, 100 μg / kg, or 125 μg / kg, or, for example, daily as the treatment progresses, 1 μg / m 2 , 5 μg / m 2 , 10 μg / m 2 , 15 μg / m 2 , 20 μg / m 2 , 30 μg / m 2 , 40 μg / m 2 , 50 μg / m 2 , 60 μg / m 2 , 70 μg / m 2 , 80 μg / m 2 , 90 μg / m 2 , 100 μg / m 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 / m2 、 500 μg / m 2 、 550 μg / m 2 、 600 μg / m 2 、 or 650 μg / m 2 only increases. In some embodiments, a treatment regimen comprising one or more doses of an anti-CD3 antibody, such as teplizumab, in a prophylactically effective amount is administered to a subject, where the prophylactically effective amount increases 1.25-fold, 1.5-fold, 2-fold, 2.25-fold, 2.5-fold, or 5-fold until the daily prophylactically effective amount of the anti-CD3 antibody, such as teplizumab, is achieved.

[0111] In some embodiments, a subject is administered an anti-CD3 antibody, such as teplizumab, otrexup, or foralumab, intramuscularly in one or more doses of about 200 μg / kg or less, preferably about 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 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 to prevent, treat, ameliorate, relieve, reduce, mitigate, delay, arrest, or terminate one or more symptoms of T1D.

[0112] In some embodiments, the anti-CD3 antibody such as teplizumab, otelixizumab or foralumab is administered subcutaneously to the subject at one or more doses of about 200 μg / kg or less, preferably about 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 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 to prevent, treat, ameliorate, relieve, reduce, mitigate, delay, arrest, or end one or more symptoms of T1D.

[0113] In some embodiments, for the purpose of preventing, treating, ameliorating, alleviating, reducing, lessening, delaying, halting, or ending one or more symptoms of T1D, an anti-CD3 antibody such as teplizumab, otelixizumab, or foralumab is administered intravenously at one or more doses of about 100 ug / kg or less, preferably about 95 ug / kg or less, 90 ug / kg or less, 85 ug / kg or less, 80 ug / kg or less, 75 ug / kg or less, 70 ug / kg or less, 65 ug / kg or less, 60 ug / kg or less, 55 ug / kg or less, 50 ug / kg or less, 45 ug / kg or less, 40 ug / kg or less, 35 ug / kg or less, 30 ug / kg or less, 25 ug / kg or less, 20 ug / kg or less, 15 ug / kg or less, 10 ug / kg or less, 5 ug / kg or less, 2.5 ug / kg or less, 2 ug / kg or less, 1.5 ug / kg or less, 1 ug / kg or less, 0.5 ug / kg or less, or 0.2 ug / kg or less. In some embodiments, for the purpose of preventing, treating, ameliorating, alleviating, reducing, lessening, delaying, halting, or ending one or more symptoms of T1D, the intravenous administration of an anti-CD3 antibody such as teplizumab, otelixizumab, or foralumab at about 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 or less is carried out over about 6 hours, about 4 hours, about 2 hours, about 1.5 hours, about 1 hour, about 50 minutes, about 40 minutes, about 30 minutes, about 20 minutes, about 10 minutes, about 5 minutes, about 2 minutes, about 1 minute, about 30 seconds, or about 10 seconds.

[0114] In some embodiments, for the purpose of preventing, treating, ameliorating, alleviating, reducing, mitigating, delaying, halting, or ending one or more symptoms of T1D, an anti-CD3 antibody such as teplizumab, otelixizumab, or foralumab is orally administered to the subject at one or more doses of about 100 μg / kg or less, preferably about 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. In some embodiments, for the purpose of preventing, treating, ameliorating, alleviating, reducing, mitigating, delaying, halting, or ending one or more symptoms of T1D, the oral administration of an anti-CD3 antibody such as teplizumab, otelixizumab, or foralumab at about 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 or less is carried out over about 6 hours, about 4 hours, about 2 hours, about 1.5 hours, about 1 hour, about 50 minutes, about 40 minutes, about 30 minutes, about 20 minutes, about 10 minutes, about 5 minutes, about 2 minutes, about 1 minute, about 30 seconds, or about 10 seconds.

[0115] In some embodiments where the escalating dose is administered on the first day of the dosing schedule, the dose on day 1 of the dosing schedule is about 5 - 150 μg / m 2 / day, preferably about 55 - 150 μg / m 2 / day, for example about 60 - 100 μg / m2 per day, and by the 3rd, 4th, 5th, 6th, or 7th day, it increases to the daily dose as listed immediately above. In some embodiments, to the subject, on the first day, about 60 μg / m 2 / day, on the second day, about 125 μg / m 2 / day, on the third day, about 250 μg / m 2 / day, on the fourth day, about 500 μg / m 2 / day and on the subsequent days of the dosing schedule (e.g., days 5 - 14), a dose of 1,000 μg / m 2 / day is administered. In some embodiments, to the subject, on the first day, about 60 μg / m 2 / day, on the second day, about 125 μg / m 2 / day, on the third day, about 250 μg / m 2 / day, on the fourth day, about 500 μg / m 2 / day and on the subsequent days of the dosing schedule (e.g., days 5 - 14), a dose of 1,030 μg / m 2 / day is administered. In some embodiments, to the subject, on the first day, about 100 μg / m 2 / day, on the second day, about 425 μg / m 2 / day, on the third day, about 850 μg / m 2 / day, on the fourth day, about 850 μg / m 2 / day and on the subsequent days of the dosing schedule (e.g., days 5 - 14), a dose of 1,000 μg / m 2 / day is administered. In some embodiments, to the subject, on the first day, about 60 μg / m 2 / day, on the second day, about 125 μg / m 2 / day, on the third day, about 250 μg / m 2 / day, on the fourth day, about 500 μg / m 2 / day and on the subsequent days of the dosing schedule (e.g., days 5 - 14), a dose of 1,070 μg / m 2 / day is administered.

[0116] In some embodiments, the initial dose is 1 / 4, 1 / 2, or equal to the daily dose at the end of the dosing schedule, but is administered in divided doses at 6, 8, 10, or 12 hour intervals. For example, a dose of 13 μg / kg / day is administered in four doses of 3 - 4 μg / kg at 6 hour intervals to reduce the level of cytokine release caused by administration of the antibody. In some embodiments, to reduce the potential for cytokine release and other adverse effects, the first 1, 2, 3, or 4 doses or all doses in the dosing schedule are administered more slowly by intravenous administration. For example, a dose of 51 μg / m 2 / day can be administered over about 5 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, and about 22 hours. In some embodiments, the dose is administered by slow infusion over a period of, for example, 20 - 24 hours. In some embodiments the dose is infused by a pump, preferably increasing the concentration of the antibody being administered as the infusion proceeds.

[0117] In some embodiments, for example, the above 60 μg m 2 / day to 1000 μg / m 2 / day or 65 μg m 2 / day to 1030 μg / m 2 / day, a certain percentage of the doses in the dosing schedule are administered as escalating doses. In some embodiments, the percentage is 1 / 10, 1 / 4, 1 / 3, 1 / 2, 2 / 3, or 3 / 4 of the daily dose of the above dosing schedule.

[0118] In some embodiments, anti-CD3 antibodies such as teprotumumab, otelixizumab, or foralumab are not administered daily over several days, but rather are administered by infusion in a continuous manner over at least 30 minutes, for example, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, 24 hours, 30 hours, or 36 hours. The infusion may be constant or may start at a low dose, for example, for the first 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, or 8 hours of the infusion, and then increase to a high dose. Over the course of the infusion, the patient is administered a dose equal to the amount administered in the 5 - 20 day dosing schedule (e.g., the 14 day dosing schedule) described above. For example, about 9500 μg / m 2 2, 10000 μg / m 2 2, 10500 μg / m 2 2, 11000 μg / m 2 2, 11500 μg / m 2 2, 12000 μg / m 2 2, 12500 μg / m 2 2, 13000 μg / m 2 2, 13500 μg / m 2 2, or a cumulative dose of 14000 μg / m 2 2 or more is administered by infusion to a subject in need thereof. For example, a cumulative dose of teprotumumab of about 11,240 μg / m 2 2 or more is administered by infusion to a subject in need thereof over at least 30 minutes. In particular, the rate and duration of the infusion are designed to minimize the level of free anti-CD3 antibody such as teprotumumab, otelixizumab, or foralumab in the subject after administration. In some embodiments, the level of free anti-CD3 antibody such as teprotumumab does not exceed 200 ng / ml of free antibody. Further, the infusion is designed to achieve a combination of at least 50%, 60%, 70%, 80%, 90%, 95%, or 100% T cell receptor coating and modulation.

[0119] In some embodiments, the subject in need thereof is administered an effective amount of an analgesic (e.g., non-steroidal anti-inflammatory drug (NSAID), acetaminophen, etc.), antihistamine, antiemetic, or a combination thereof, prior to performing the IV infusion of the treatment course on each of the 1st to 5th days (e.g., the IV infusion of the 14-day treatment course). In some embodiments, the analgesic (e.g., non-steroidal anti-inflammatory drug (NSAID), acetaminophen, etc.), antihistamine, antiemetic, or a combination thereof can be administered on each of the 1st to 5th days, 1st to 6th days, 1st to 7th days, 1st to 8th days, 1st to 9th days, 1st to 10th days, 1st to 11th days, 1st to 12th days, 1st to 13th days, 1st to 14th days, or during the period of treatment with the anti-CD3 antibody. In some embodiments, the NSAID, acetaminophen, antihistamine, antiemetic, or a combination thereof is administered orally. In some embodiments, the NSAID, acetaminophen, antihistamine, antiemetic, or a combination thereof is administered intravenously. In some embodiments, an antipyretic, antihistamine, and / or antiemetic is administered to the subject in need thereof to reduce cytokine release syndrome. In some embodiments, liver enzymes are monitored, and treatment with the anti-CD3 antibody is discontinued or paused in subjects in whom an elevation of ALT or AST exceeding 5 times the upper limit of the normal value is manifested.

[0120] In some embodiments, anti-CD3 antibodies such as teplizumab, otelixizumab, or faralimab are chronically administered to treat, prevent, or blunt or delay the onset or progression of one or more symptoms of type 1 diabetes, or to improve, alleviate, reduce, mitigate, delay, halt, or end one or more symptoms of type 1 diabetes. For example, in some embodiments, anti-CD3 antibodies such as low-dose teplizumab are administered once a month, twice a month, three times a month, once a week, or even more frequently, as an alternative to the above-described 6- to 14-day dosing schedule, or after the implementation of such a dosing schedule to enhance or maintain its effect. Such low doses are from about 1 μg / m 2 to about 100 μg / m 2 any of, for example, about 5 μg / m 2 、10 μg / m 2 、15 μg / m2 , 20 μg / m 2 , 25 μg / m 2 , 30 μg / m 2 , 35 μg / m 2 , 40 μg / m 2 , 45 μg / m 2 , 50 μg / m 2 , 55 μg / m 2 , 60 μg / m 2 , 65 μg / m 2 , 70 μg / m 2 , 75 μg / m 2 , 80 μg / m 2 , 85 μg / m 2 , 90 μg / m 2 , 95 μg / m 2 or 100 μg / m 2 may also be.

[0121] In some embodiments, anti-CD3 antibodies such as teplizumab, otelixizumab or foralumab are administered by infusion at a medical facility, an infusion center for outpatient patients. In yet other embodiments, anti-CD3 antibodies such as teplizumab, otelixizumab or foralumab are administered by infusion at home. Home infusion therapy involves administering a therapeutic agent, such as an anti-CD3 antibody, using an intravenous or subcutaneous route at the patient's home rather than at a clinic or hospital. Infusion therapy at home can be administered by a home healthcare provider or the patient themselves. In some embodiments, a healthcare provider who has received some training in the operation of the infusion device and the administration of the anti-CD3 antibody can provide the patient with training in self-administration as well as all the necessary equipment and / or supplies required for administration.

[0122] In some embodiments, the subject may be re-administered at a certain point in time after the implementation of the dosing schedule of an anti-CD3 antibody, such as teplizumab, otrexup, or foralumab, for example, based on one or more physiological parameters, or may be performed as a matter of course. Such re-administration may be performed 2 months, 4 months, 6 months, 8 months, 9 months, 1 year, 15 months, 18 months, 2 years, 30 months, or 3 years after the implementation of the dosing schedule, and / or the need for such re-administration can be evaluated, and the treatment course can be performed indefinitely every 6 months, 9 months, 1 year, 15 months, 18 months, 2 years, 30 months, or 3 years.

[0123] Some embodiments are anti-CD3 antibodies for use in a method of preventing or delaying the onset of clinical type 1 diabetes (T1D), comprising administering a prophylactically effective amount of an anti-CD3 antibody to a non-diabetic subject at risk of T1D, 2 ~ about 14,000 μg / m 2 wherein the prophylactically effective amount has a cumulative dose of about 10,500 μg / m to about 14,000 μg / m, and determining that, before and after the administration step, the non-diabetic subject has more than about 10% TIGIT+KLRG1+CD8+ T cells in total CD3+ T cells, indicating success in preventing or delaying the onset of clinical T1D.

[0124] Aspects of the present disclosure are methods of preventing or delaying the onset of clinical type 1 diabetes (T1D), comprising administering a prophylactically effective amount of an anti-CD3 antibody to a non-diabetic subject at risk of T1D, 2 ~ about 14,000 μg / m 2 wherein the prophylactically effective amount has a cumulative dose of about 10,500 μg / m to about 14,000 μg / m.

[0125] In some embodiments, the subject is 8 years of age or older. In some embodiments, the subject is 5 years of age or older. In some embodiments, the subject is 3 years of age or older. In some embodiments, the subject is 1 year of age or older. In some embodiments, the subject is less than 1 year of age.

[0126] In some embodiments, the non - diabetic subject is a blood relative of a patient with T1D.

[0127] In some embodiments, the method further comprises determining that the non - diabetic subject is (1) negative for zinc transporter 8 (ZnT8) antibodies, (2) HLA - DR4 +, and / or (3) not HLA - DR3 +. In some embodiments, the non - diabetic subject has no antibodies against ZnT8. In some embodiments, the non - diabetic subject is HLA - DR4 + and not HLA - DR3 +.

[0128] In some embodiments, the non - diabetic subject has two or more diabetes - related autoantibodies selected from islet cell antibodies (ICA), insulin autoantibodies (IAA), and antibodies against glutamic acid decarboxylase (GAD), tyrosine phosphatase (IA - 2 / ICA512) or ZnT8.

[0129] In some embodiments, the non - diabetic subject has impaired glucose tolerance in an oral glucose tolerance test (OGTT). In some embodiments, the impaired glucose tolerance in the OGTT is a fasting blood glucose level of 110 - 125 mg / dL, or a 2 - hour plasma of 140 mg / dL or more and less than 200 mg / dL, or an intervening glucose value at 30, 60 or 90 minutes in the OGTT exceeding 200 mg / dL.

[0130] In some embodiments, the anti - CD3 antibody is selected from teplizumab, otrexup or foralumab. In some embodiments, the anti - CD3 antibody is teplizumab.

[0131] In some embodiments, the prophylactically effective amount is about 11,000 μg / m 2 ~ about 14,000 μg / m 2 and includes a 14 - day treatment course of subcutaneous (SC) injection or intravenous (IV) infusion or oral administration of the anti - CD3 antibody at a cumulative dose.

[0132] In some embodiments, the method is about 60 μg / m on day 1 2, about 125 μg / m on the second day 2 , about 250 μg / m on the third day 2 , and about 500 μg / m on the fourth day 2 , and about 1,000 μg / m on each of the 5th to 14th days 2 including performing an intravenous infusion for a 14-day treatment course at a dose of

[0133] In some embodiments, the method is about 60 μg / m on the first day 2 , about 125 μg / m on the second day 2 , about 250 μg / m on the third day 2 , and about 500 μg / m on the fourth day 2 , and about 1,030 μg / m on each of the 5th to 14th days 2 including performing an intravenous infusion for a 14-day treatment course at a dose of

[0134] In some embodiments, the method is about 100 μg / m on the first day 2 , about 425 μg / m on the second day 2 , about 850 μg / m on the third day 2 , about 850 μg / m on the fourth day 2 , and about 1,000 μg / m on each of the 5th to 14th days 2 including performing an intravenous infusion for a 14-day treatment course at a dose of

[0135] In some embodiments, the method is about 65 μg / m on the first day 2 , about 125 μg / m on the second day 2 , about 250 μg / m on the third day 2 , and about 500 μg / m on the fourth day 2 , and about 1,070 μg / m on each of the 5th to 14th days 2 including performing an intravenous infusion for a 14-day treatment course at a dose of

[0136] In some embodiments, the method is about 65 μg / m on the first day 2 , about 125 μg / m on the second day 2 , about 250 μg / m on the third day 2 , and about 500 μg / m on the fourth day 2, and performing an intravenous infusion for a 14-day treatment course at a dose of approximately 1,030 μg / m on each of days 5 to 14. 2 This includes.

[0137] In some embodiments, the prophylactically effective amount delays the median time to clinical diagnosis of T1D by at least 50%, at least 80%, or at least 90%. In some embodiments, the prophylactically effective amount delays the median time to clinical diagnosis of T1D by at least 12 months, at least 18 months, at least 24 months, at least 36 months, at least 48 months, or at least 60 months.

[0138] In some embodiments, the method further includes determining, before or after the administration step, that a non-diabetic subject has more than about 10% TIGIT+KLRG1+CD8+ T cells in total CD3+ T cells, which indicates success in preventing or delaying the onset of clinical T1D. In some embodiments, the determination of TIGIT+KLRG1+CD8+ T cells is by flow cytometry. In some embodiments, the method further includes determining a decrease in the percentage of CD8+ T cells expressing the proliferation marker Ki67 and / or CD57.

[0139] Aspects of the present disclosure are methods of preventing or delaying the onset of clinical type 1 diabetes (T1D), the method including administering to a non-diabetic subject 8 years of age or older at risk of T1D, on day 1, approximately 65 μg / m 2 , on day 2, approximately 125 μg / m 2 , on day 3, approximately 250 μg / m 2 , and on day 4, approximately 500 μg / m 2 , and performing an intravenous infusion for a 14-day treatment course of teplizumab at a dose of approximately 1,030 μg / m on each of days 5 to 14. 2 This relates to a method.

[0140] Aspects of the present disclosure are methods of delaying the onset of stage 3 type 1 diabetes (T1D), the method including administering to a subject having a stage 2 T1D diagnosis in need thereof, on day 1, approximately 65 μg / m 2 , on day 2, approximately 125 μg / m 2, about 250 μg / m on the third day 2 , and about 500 μg / m on the fourth day 2 , and for each of days 5 - 14, about 1,030 μg / m 2 relates to a method comprising performing an intravenous infusion of teprilizumab for a 14 - day treatment course at a dose of

[0141] In some embodiments, the subject in need thereof is an adult. In some embodiments, the subject in need thereof is a pediatric subject 8 years of age or older. In some embodiments, the subject in need thereof is a pediatric subject 5 years of age or older. In some embodiments, the subject in need thereof is a pediatric subject 3 years of age or older. In some embodiments, the subject in need thereof is a pediatric subject 1 year of age or older. In some embodiments, the subject in need thereof is a pediatric subject less than 1 year of age.

[0142] In some embodiments, the method comprises recording at least two positive pancreatic islet autoantibodies in a subject having glycemic abnormalities without overt hyperglycemia prior to performing a 14 - day treatment course. In some embodiments, the subject in need thereof has glycemic abnormalities without overt hyperglycemia and has two or more pancreatic islet autoantibodies. In some embodiments, the two or more pancreatic islet autoantibodies include islet cell antibodies (ICA), insulin autoantibodies (IAA), and antibodies against glutamic acid decarboxylase (GAD), tyrosine phosphatase (IA - 2 / ICA512) or ZnT8. In some embodiments, the method comprises administering, for each of at least days 1 - 5, prior to performing the intravenous infusion of the 14 - day treatment course, an effective amount of a non - steroidal anti - inflammatory drug (NSAID), acetaminophen, an anti - histamine, an anti - emetic or a combination thereof. In some embodiments, the method comprises orally administering an NSAID, acetaminophen, an anti - histamine, an anti - emetic or a combination thereof. In some embodiments, the method comprises performing the intravenous infusion of the 14 - day treatment course once a day for 14 consecutive days over at least 30 minutes.

[0143] Aspects of the present disclosure are methods for prognosticating responsiveness to anti-CD3 antibodies in preventing or delaying the onset of type 1 diabetes (T1D), which comprise administering a prophylactically effective amount of an anti-CD3 antibody to a non-diabetic subject at risk of T1D, wherein the prophylactically effective amount has a cumulative dose of about 10,500 μg / m 2 to about 14,000 μg / m 2 administering a prophylactically effective amount of an anti-CD3 antibody having a cumulative dose of about 10,500 μg / m to about 14,000 μg / m to a non-diabetic subject at risk of T1D, and determining the C-peptide area under the curve (AUC):glucose AUC ratio, wherein an increase in the ratio indicates responsiveness to the anti-CD3 antibody and / or non-progression to clinical T1D.

[0144] Aspects of the present disclosure are anti-CD3 antibodies for use in a method of preventing or delaying the onset of clinical type 1 diabetes (T1D), which comprise administering a prophylactically effective amount of an anti-CD3 antibody to a non-diabetic subject at risk of T1D, wherein the prophylactically effective amount has a cumulative dose of about 10,500 μg / m 2 to about 14,000 μg / m 2 administering a prophylactically effective amount of an anti-CD3 antibody having a cumulative dose of about 10,500 μg / m to about 14,000 μg / m to a non-diabetic subject at risk of T1D.

[0145] Aspects of the present disclosure are teplizumab compositions for use in a method of delaying the onset of stage 3 type 1 diabetes (T1D), which comprise performing an intravenous infusion over a 14-day treatment course at a dose of about 65 μg / m on day 1, about 125 μg / m on day 2, about 250 μg / m on day 3, and about 500 μg / m on day 4, and about 1,030 μg / m on each of days 5 to 14 to a subject having a diagnosis of stage 2 T1D in need thereof. 2 about 125 μg / m on day 2 2 about 250 μg / m on day 3 2 and about 500 μg / m on day 4 2 and about 1,030 μg / m on each of days 5 to 14 2 A teplizumab composition is provided that comprises performing an intravenous infusion over a 14-day treatment course at a dose of about 65 μg / m on day 1, about 125 μg / m on day 2, about 250 μg / m on day 3, and about 500 μg / m on day 4, and about 1,030 μg / m on each of days 5 to 14 to a subject having a diagnosis of stage 2 T1D in need thereof.

Example

[0146] Example 1: Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell-mediated destruction of insulin-producing beta cells within the islets of Langerhans. Long-term observational studies spanning over 30 years have described the progression of the autoimmune disease from the first appearance of autoantibodies until significant impairment of beta cell function and often clinical diagnosis with ketoacidosis (1-5). T1D is associated with the lifelong need for exogenous insulin administration for survival, increased morbidity and mortality due to immediate (e.g., hypoglycemia) and long-term complications (e.g., vascular, kidney, and eye diseases), as well as shortened lifespan, disability, and substantial healthcare-related costs (6-9). Therefore, approaches to prevent progression to clinical T1D before irreversible beta cell destruction and insulin deficiency are of utmost importance.

[0147] Changes in beta cell function precede clinical diagnosis of T1D and have been studied in natural history cohorts of individuals identified as being at risk of disease based on the presence of islet autoantibodies (10-12). Several studies have suggested a continuous and intermittent progressive decline in beta cell function that begins years before clinical diagnosis, during a period when glucose tolerance is normal. During this period, there are signs of ongoing autoimmunity. Based on natural history findings, individuals with two or more islet autoantibodies are classified as stages of T1D and further classified according to the level of metabolic dysfunction: stage 1 before glucose abnormalities, stage 2 with glucose abnormalities during an oral glucose tolerance test (OGTT), and stage 3 at clinical presentation with hyperglycemia (2, 13, 14). However, the relationship between changes in beta cell function and clinical disease remains poorly defined. For example, glucose tolerance, defined by the response to an oral glucose tolerance test (OGTT), is known to vary between abnormal and normal values within at-risk individuals (15, 16). Furthermore, the OGTT glucose tolerance classification used to assign clinical diagnosis and beta cell function measured by C-peptide response to a metabolic challenge may not be closely related, and in diagnoses using the OGTT, many individuals have a clinically meaningful C-peptide response (15-18).

[0148] The following is the AUC of the reference dosing schedule (Herold's 14-day dosing schedule used in the Protege and TN-10 trials, Herold et al NEJM 2019). inf , C max and C trough13 (Trough concentration before dosing on day 14) It is a dosing schedule that matches the exposure parameters.

[0149] Individual (conditional) PK simulations were performed using the individual model parameters from the corresponding arms of the PROTECT Phase 3 trial of teprotumumab in newly diagnosed T1D patients for Provention Bio Model 363 (dosing schedules A, B, and C), Model 372 (dosing schedule D).

[0150] Standard (mean) simulations for comparison of exposure values were also performed.

[0151] More than 30 dosing schedules based on Herold's 14-day dosing schedule or the PROTECT dosing schedule were simulated and compared with the reference dosing schedule. Alternative dosing schedules are shown in Table 1.

[0152]

Table 1

[0153] Each of these dosing schedules includes a 4-day ramp-up dosing and subsequent 10-day continuous maintenance dosing, and the infusion period is 30 minutes. Similar to previous T1D dosing schedules, the ramp-up is important to avoid the occurrence of acute events such as those related to cytokine release. · Dosing schedule A: Incorporates the 4-day ramp-up dose and maintenance dose framework of TN-10 (Herold's 14 days) and adjusts approximately 18 - 20% upward for each daily dose. This dosing schedule is C trough13The biological equivalence criteria for the three PK parameters under both conditional and standard (mean) simulations are met, except that the average (standard) simulation ratio is slightly below 0.80 (0.779). (Table 2). The cumulative dose of this dosing schedule is 10,935 μg / m 2 which is about 21% higher compared to Herold's 14-day dosing schedule. ○ Day 1: 60 μg / m 2 ○ Day 2: 125 μg / m 2 ○ Day 3: 250 μg / m 2 ○ Day 4: 500 μg / m 2 ○ Days 5 - 14: 1000 μg / m 2 · Dosing Schedule B: Incorporates the framework of the TN-10 (Herold's 14-day) dosing schedule, with each daily dose adjusted upward by approximately 18 - 25%. This has a 4-day ramp-up similar to Dosing Schedule A, but the maintenance dose is 1030 μg / m 2 which is. This dosing schedule meets all biological equivalence criteria for AUC inf , C max and C trough13 under both conditional and standard (mean) simulations. (Table 2). The cumulative dose of this dosing schedule is 11,235 μg / m 2 which is about 24% higher compared to Herold's 14-day dosing schedule. ○ Day 1: 60 μg / m 2 ○ Day 2: 125 μg / m 2 ○ Day 3: 250 μg / m 2 ○ Day 4: 500 μg / m 2 ○ Days 5 - 14: 1030 μg / m 2 · Dosing Schedule D: Incorporates the framework of the TN-10 (Herold's 14-day) dosing schedule, with each daily dose adjusted upward by approximately 18 - 25%. This has a 4-day ramp-up similar to Dosing Schedule A, but the dose on Day 1 is 65 μg / m 2and the maintenance dose is 1030 μg / m 2 This dosing schedule meets all the biological equivalence criteria for AUC inf , C max and C trough13 under both conditional and standard (mean) simulations (Table 2). The cumulative dose of this dosing schedule is 11,240 μg / m 2 (about 24% higher compared to Herold's 14-day dosing schedule). ○ Day 1: 65 μg / m 2 ○ Day 2: 125 μg / m 2 ○ Day 3: 250 μg / m 2 ○ Day 4: 500 μg / m 2 ○ Days 5 - 14: 1030 μg / m 2 · Dosing schedule C: To simplify the calculation and preparation of the dose, a 2-day ramp-up was incorporated into the backbone of PROTECT's 12-day dosing schedule, and the dose on Day 1 was fine-tuned to 106 μg / m 2 ~100 μg / m 2 The two doses of 850 μg / m 2 on Days 3 and 4 reproduce the PROTECT dosing schedule before administering the maintenance dose of 1000 μg / m 2 This dosing schedule meets the biological equivalence criteria of 80 - 125% for AUC inf , C max and C trough13 under both conditional and standard (mean) simulations (Table 2). The cumulative dose of this dosing schedule is 12,225 μg / m 2 (about 35% higher compared to Herold's 14-day dosing schedule). ○ Day 1: 100 μg / m 2 ○ Day 2: 425 μg / m 2 ○ Day 3: 850 μg / m 2 ○ Day 4: 850 μg / m 2 ○ Days 5 - 14: 1000 μg / m 2

[0154]

Table 2

[0155] Exposure distributions (AUC inf , C max and C trough13 ) of anti-CD3 antibody exposure predicted for the reference dosing schedule (14 days of Herold) and alternative dosing schedules are shown in FIGS. 1 and 5. Exposure distributions (AUC inf , C max and C trough13 ) of anti-CD3 antibody exposure predicted for the Protege and TN-10 dosing schedules (14 days of Herold) and alternative dosing schedules are shown in FIGS. 2 and 6.

[0156] Safety Considerations These dosing schedules are predicted not to result in further safety findings. Predicted Cmax and Ctrough on each day of the 14-day treatment course of the alternative dosing schedules are shown in FIGS. 3 (dosing schedules A and B), 4 (dosing schedule C), and 7 (dosing schedule D) together with values from past clinical trials. The Cmax and Ctrough values for dosing schedules A and B do not exceed the values observed with Protege or TN10 using the 14-day dosing schedule of Herold. The Cmax and Ctrough values for dosing schedule C do not exceed the values observed with the 12-day dosing schedule of PROTECT.

[0157] Furthermore, the inventors evaluated the safety profiles of patients with an AUC inf above 6000 ng*day / mL and patients with an AUC of 6000 ng*day / mL or less in the Protege and TN-10 trials. This value approximately represents the geometric mean exposure of the proposed alternative dosing schedules (Table 3). As shown in Table 4, the safety profiles based on AEs reported in at least 5% of patients appear to be equivalent between the subset of patients with AUC > 6000 ng*day / mL and the subset of patients with ≦ 6000 ng*day / mL.

[0158]

Table 3

[0159]

Table 4

[0160]

Table 5

[0161]

Table 6

[0162]

Table 7

[0163] Safety information on the teprilizumab precursor product hOKT3γ1(Ala-Ala) is available for non-T1D patients including renal transplant patients (Woodle 1999), islet transplant patients (Hering 2004), and psoriatic arthritis patients (Utset 2002). The total cumulative doses evaluated over a 10-day continuous treatment period included 76 mg, 46 mg, and 40 mg for renal transplant patients, islet transplant patients, and psoriatic arthritis patients, respectively. Safety events were similar to those observed in T1D patients who received an average total cumulative dose of approximately 18 - 20 mg over a treatment period of 12 - 14 days.

[0164] Example 2: Additional dosing schedule An alternative dosing schedule is shown in Table 5 below.

[0165]

Table 8

[0166] Example 3: Additional dosing schedule Alternative dosing schedule G is shown in Table 6 below.

[0167]

Table 9

[0168] Example 4: Dosage and Administration The teprotumumab compositions and methods provided herein are shown to delay the onset of stage 3 type 1 diabetes in adults and pediatric patients 8 years of age and older with stage 2 type 1 diabetes.

[0169] Teprotumumab-mzwv (also referred to herein as teprotumumab) is a CD3-directed monoclonal antibody (humanized IgG1 kappa) with a molecular weight of approximately 150 kilodaltons (kDa) and is expressed from a recombinant Chinese hamster ovary (CHO) cell line.

[0170] Teprotumumab injection is supplied as a sterile, preservative-free, clear and colorless solution in a single-dose vial of 2 mg / 2 mL (1 mg / mL) for intravenous use. It contains 1 mg of teprotumumab-mzwv, disodium phosphate (0.26 mg), monosodium phosphate (0.98 mg), polysorbate 80 (0.05 mg), sodium chloride (8.78 mg) and water for injection in 1 mL. The pH is 6.1.

[0171] Clinical Pharmacology Mechanism of Action Teprotumumab-mzwv binds to CD3 (a cell surface antigen present on T lymphocytes) and delays the onset of stage 3 type 1 diabetes in adults and pediatric patients 8 years of age and older with stage 2 type 1 diabetes. This mechanism may involve partial agonist signaling and inactivation of pancreatic beta cell autoreactive T lymphocytes. Teprotumumab-mzwv increases the proportion of regulatory T cells and exhausted CD8+ T cells in peripheral blood.

[0172] Pharmacodynamics Clinical trials have shown that teprotumumab-mzwv binds to CD3 molecules on the surface of both CD4+ and CD8+ T cells during treatment, and the teprotumumab-mzwv / CD3 complex internalizes from the surface of T cells. Pharmacodynamic effects include lymphopenia without T cell depletion reaching a nadir on day 5 of dosing over a 14-day treatment course of teprotumumab-mzwv. The teprotumumab-mzwv exposure-response relationship and time course of pharmacodynamic responses for the safety and efficacy of teprotumumab-mzwv have not been fully characterized.

[0173] Pharmacokinetics The steady-state concentration of teprotumumab-mzwv is not expected to be achieved during the 14-day treatment course of teprotumumab.

[0174] Distribution The central volume of distribution (Vd) of teprotumumab-mzwv was 2.27 L in subjects weighing 60 kg.

[0175] Elimination Teprotumumab-mzwv demonstrated saturable binding and elimination. The mean (SD) terminal elimination half-life and clearance of teprotumumab-mzwv were 4.5 (0.2) days and 2.7 (0.8) L / day, respectively, in subjects weighing 60 kg.

[0176] Metabolism Teprotumumab-mzwv is expected to be metabolized to small peptides via catabolic pathways.

[0177] Special Populations No clinically significant differences in the pharmacokinetics of teprotumumab-mzwv were observed based on age (8 to 35 years), biological sex, or racial group (White, Asian).

[0178] Body Weight Dosing based on BSA normalizes exposure to teprotumumab-mzwv by body weight.

[0179] Immunogenicity The observed incidence of anti-drug antibodies depends greatly on the sensitivity and specificity of the assay. Comparing the incidence of anti-drug antibodies in the tests described below with the incidence of anti-drug antibodies in other tests involving teplizumab-mzwv or other teplizumab formulations is hampered by differences in assay methods and does not allow for a meaningful comparison.

[0180] In a placebo-controlled trial (Study TN-10) in patients 8 years of age and older with stage 2 type 1 diabetes, approximately 59% of teplizumab-treated patients developed anti-teplizumab-mzwv antibodies, and 46% of them developed neutralizing antibodies. There is insufficient information to characterize the effect of ADA on the pharmacokinetics, pharmacodynamics, or efficacy of teplizumab-mzwv. Among teplizumab-treated patients who developed anti-teplizumab-mzwv antibodies, the incidence of rash was higher compared to patients who did not develop anti-teplizumab-mzwv antibodies.

[0181] Patient Selection Adult and pediatric patients 8 years of age and older diagnosed with stage 2 type 1 diabetes are selected for TZIELD treatment.

[0182] In patients with abnormal blood glucose without overt hyperglycemia, stage 2 type 1 diabetes is confirmed by demonstrating that at least two islet cell autoantibodies are positive (FDA-approved tests for islet cell autoantibodies are recommended). In patients who meet the diagnostic criteria for stage 2 type 1 diabetes, it is confirmed from the patient's clinical history that type 2 diabetes is not suspected.

[0183] Administration Instructions and Recommended Dosage Dilute before use. · Each vial is intended for single use only. Preparation a: Sterile glass vial containing 18 mL of 0.9% sodium chloride injection or polyvinyl chloride (PVC) infusion bag containing 18 mL of 0.9% sodium chloride injection. · Withdraw 2 mL of teprotumumab from the vial and slowly add it to 18 mL of 0.9% sodium chloride injection. Mix gently by slowly inverting the vial or rocking the infusion bag. The resulting 20 mL dilution solution contains 100 mcg / mL of teprotumumab-mzwv. · Using a syringe of appropriate size (e.g., 5 mL), withdraw from the 100 mcg / mL solution the calculated dose and the amount of dilution solution needed for that day. · Slowly add the contents of the syringe containing the teprotumumab dose to a 25 mL PVC infusion bag for 0.9% sodium chloride injection. Gently rock the infusion bag to ensure thorough mixing of the solution. Do not shake. · Discard any unused portion of the diluted teprotumumab solution remaining in the sterile glass vial or PVC infusion bag. · Initiate the infusion of teprotumumab within 2 hours of preparation. If not used immediately, store the dilution solution at room temperature [15°C to 30°C (59°F to 86°F)] and complete the infusion within 4 hours of the start of preparation. If not administered within 4 hours of preparation, discard the dilution solution.

[0184] Premedicate with the following oral medications containing (1) non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen, (2) antihistamines, and / or (3) antiemetics for the first 5 days before infusion. Administer additional doses of premedication as needed.

[0185] Administer once daily for 14 consecutive days by intravenous infusion (minimum 30 minutes).

[0186] The recommended dosage for pediatric and adult patients 8 years of age and older based on body surface area (BSA) is shown in the following table.

[0187] Do not administer 2 doses on the same day.

[0188]

Table 10

[0189] Recommendations regarding administration failure If the planned injection fails, resume administration by administering all remaining doses on consecutive days to complete the 14-day treatment course.

[0190] Laboratory evaluation and pre-treatment vaccination Before initiation, perform a complete blood count and liver enzyme tests.

[0191] Use in the following patients is not recommended. Lymphocyte count less than 1,000 lymphocytes / mcL Hemoglobin less than 10 g / dL Platelet count less than 150,000 cells / mcL Absolute neutrophil count less than 1500 cells / mcL ALT or AST elevation more than twice the upper limit of normal (ULN), or bilirubin more than 1.5 times the ULN Laboratory or clinical findings of acute infection due to Epstein-Barr virus (EBV) or cytomegalovirus (CMV) Severe active or chronic active infections other than localized skin infections Perform age-appropriate vaccinations for all ages before starting treatment Administer live attenuated (live) vaccines at least 8 weeks before treatment. Administer inactivated (killed) or mRNA vaccines at least 2 weeks before treatment.

[0192] Dosage form and strength Injection: A clear, colorless solution of 2 mg / 2 mL (1 mg / mL) in a single-dose vial.

[0193] Contraindications None

[0194] Modifications and variations of the described methods and compositions of the present disclosure will be apparent to those skilled in the art without departing from the scope and spirit of the present disclosure. Although the present disclosure has been described in connection with specific embodiments, it should be understood that the claimed present disclosure should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the present disclosure will be intended and understood by those skilled in the art in the relevant fields in which the present disclosure exists and are within the scope of the present disclosure as represented by the following claims.

[0195] Incorporation by reference All patents and publications referred to herein are incorporated herein by reference to the same extent as if each individual patent and publication was specifically and individually indicated to be incorporated by reference.

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Claims

[Claim 1] A method for preventing or delaying the onset of clinical type 1 diabetes (T1D), Administering a prophylactic dose of anti-CD3 antibody to non-diabetic individuals at risk of T1D. Includes, The aforementioned effective preventive dose is approximately 10,500 μg / m². 2 ~Approx. 14,000μg / m 2 A method having a cumulative dose of [a certain value].

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