Methods to reduce the use of exogenous insulin

Abstract

Methods for reducing the use of exogenous insulin are provided herein. In some embodiments, such methods involve administering approximately 9000 μg / m³ of exogenous insulin to the subject requiring it. 2 ~Approx. 14000μg / m 2 This may include administering a total dose of teplizumab over a course of 12 to 14 days.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 493,113, filed on 30 March 2023, the disclosure of which is incorporated herein by reference in whole.

[0002] Sequence List This application includes a sequence listing, which is submitted electronically in .XML format and is incorporated herein by reference in its entirety. The .XML copy was created on 22 March 2024, named "122548.WO060.xml", and has a size of 3,387 bytes. [Background technology]

[0003] Type 1 diabetes (T1D) is caused by the autoimmune destruction of insulin-producing beta cells in the islets of Langerhans, leading to dependence on exogenous insulin injections for survival. Approximately 1.6 million Americans have T1D, and it remains one of the most common childhood illnesses, second only to asthma. Despite improvements in treatment, most individuals with T1D are unable to consistently achieve their desired blood glucose targets. There remains strong concern about the increased risk of both morbidity and mortality for individuals with T1D. [Overview of the Initiative] [Means for solving the problem]

[0004] Some aspects of this disclosure relate to methods for reducing the use of exogenous insulin in subjects requiring it, the method relating to approximately 9000 μg / m² 2 ~Approx. 14000μg / m 2 This includes administering a total dose of teplizumab for a 12- to 14-day course, with teplizumab administration resulting in a reduction of at least 0.08 U / kg / day in exogenous insulin use.

[0005] In some embodiments, administration of teplizumab reduces the use of exogenous insulin by at least 0.08 U / kg / day in the first year. In some embodiments, administration of teplizumab reduces the use of exogenous insulin by at least 0.10 U / kg / day in the second year.

[0006] In some embodiments, the method involves administering a 12-day course of teplizumab to a subject. In further embodiments, the 12-day course of teplizumab includes a first dose of approximately 106 μg / m2 of teplizumab on day 1, a second dose of approximately 425 μg / m2 of teplizumab on day 2, and a single dose of approximately 850 μg / m2 of teplizumab on each of days 3 through 12.

[0007] In other embodiments, the method includes administering a 14-day course of teplizumab to a subject. In further embodiments, the 14-day course of teplizumab includes a first dose of approximately 100 μg / m2 of teplizumab on day 1, a second dose of approximately 425 μg / m2 of teplizumab on day 2, a third dose of approximately 850 μg / m2 of teplizumab on day 3, a fourth dose of approximately 850 μg / m2 of teplizumab on day 4, and a single dose of approximately 1000 μg / m2 of teplizumab on each of days 5 through 14.

[0008] In some embodiments, the method involves administering a first and second 12- to 14-day course of teprizumab. In some embodiments, the first and second 12- to 14-day courses are administered approximately 6 months apart.

[0009] In some embodiments, the method involves administering a first and second 12-day course of teplizumab. In some embodiments, the first and second 12-day courses are administered approximately 6 months apart.

[0010] In some embodiments, the target population requiring it is approximately 7.5 years of age or older.

[0011] In some embodiments, the method includes administering teplizumab by intravenous infusion.

[0012] In some embodiments, the reduction in exogenous insulin use is carried out over a period of more than one year.

[0013] Some aspects of this disclosure relate to teplizumab used in a method for reducing the use of exogenous insulin in subjects where it is needed, the method being approximately 9000 μg / m² 2 ~Approx. 14000μg / m 2 This includes administering a total dose of teplizumab for a 12- to 14-day course, with teplizumab administration resulting in a reduction of at least 0.08 U / kg / day of exogenous insulin use.

[0014] This disclosure also provides the use of teplizumab for the manufacture of a pharmaceutical product for reducing the use of exogenous insulin in a subject that requires it, in a manner relating to the present invention. [Brief explanation of the drawing]

[0015] [Figure 1] Forest plot of least squares mean difference between the teplizumab group and the control group in change from baseline in C peptide AUC. Panel A: This analysis includes five clinical trials with 1-year data. The analysis uses both imputed and unimputed data. Panel B: This analysis includes three clinical trials for which 1-year and 2-year data were available. The analysis uses both imputed and unimputed data. [Figure 2]Mean (SE) values ​​of C-peptide and insulin use observed in clinical trials. Panel A: C-peptide AUC values ​​at 1 year from five trials using 1-year data. The p-value at 1 year was determined from the ANCOVA model on 1-year integrated observational data. Panel B: C-peptide AUC values ​​at 2 years from three trials using 2-year data. The p-value at 2 years was determined from ANCOVA on 2-year integrated observational data. Panel C: Average insulin use over 1 year. The p-value at 1 year was determined from ANCOVA on 1-year integrated observational data. Panel D: Average insulin use over 2 years. The p-value at 2 years was determined from ANCOVA on 2-year integrated observational data. [Figure 3] Forest plot of least squares mean difference in insulin use from baseline between the teplizumab group and the control group. Panel A: This analysis includes five clinical trials with 1-year data. The analysis uses both imputed and unimputed data. Panel B: This analysis includes three clinical trials for which 1-year and 2-year data were available. The analysis uses both imputed and unimputed data. [Modes for carrying out the invention]

[0016] I. Definition Certain terms are defined below in this specification. Further definitions are provided throughout this application.

[0017] As used herein, the articles “a” and “an” refer to one or more than one of the grammatical objects of the article, for example, at least one. In the specification, the use of the terms “a” or “an” in combination with the term “comprising” may mean “one,” but also coincides with the meanings of “one or more,” “at least one,” and “one or more.”

[0018] As used herein, “about” and “approximately” generally mean an acceptable degree of error in a measured quantity, taking into account the nature or precision of the measurement. An exemplary degree of error is within 20%, typically within 10%, and more typically within 5% of a given range of values. The term “substantially” means more than 50%, preferably more than 80%, most preferably more than 90%, or more than 95%.

[0019] As used herein, the terms “comprising” or “comprises” are used with respect to compositions, methods, and their respective components that are open to including elements present in a given embodiment but not specified.

[0020] As used herein, the term “essentially derived from” refers to 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 disclosure.

[0021] The term "consisting of" refers to the compositions, methods, and their respective components described herein, excluding elements not described in the description of the embodiments.

[0022] The term "antibody" as used herein is used in its broadest sense and encompasses a variety of antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, as long as they exhibit the desired antigen-binding activity.

[0023] An "antibody fragment" refers to a molecule other than an intact antibody that contains a portion of the intact antibody that binds to the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2, diabodies, linear antibodies, single-chain antibody molecules (e.g., scFv), and multispecific antibodies formed from antibody fragments.

[0024] As used herein, the term “onset” of the disease in relation 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).

[0025] As used herein, “protocol” includes an administration schedule and administration plan. A protocol as used herein is a method of use and includes a treatment protocol. An “administration regimen,” “dosage regimen,” or “course of treatment” includes several administrations of the therapeutic agent over a period of 1 to 20 days.

[0026] As used herein, the terms “subject” and “patient” are interchangeable. As used herein, the terms “subject” and “multiple subjects” refer to mammals, preferably animals, including non-primates (e.g., cattle, pigs, horses, cats, dogs, rats, and mice) and primates (e.g., monkeys or humans), more preferably humans. In some embodiments, the patient population includes children. In some embodiments, the patient population includes children newly diagnosed with T1D. In some embodiments, the patient population is treated within six weeks after T1D diagnosis. In some embodiments, the patient population includes children who are positive for at least one T1D-related autoantibody and have a peak stimulated C peptide of 0.2 pmol / mL or higher at screening.

[0027] As used herein, the term “child” (and its variations) includes children between approximately 8 and 17 years of age.

[0028] As used herein, the term “effective dose” means an amount of teplizumab sufficient to delay or prevent the onset, recurrence, or onset of one or more symptoms of T1D.

[0029] As used herein, the terms "treat", "treatment" and "treating" refer to the amelioration of one or more symptoms associated with T1D resulting from the administration of one or more CD3-binding molecules. In some embodiments, such terms refer to a decrease in the average number of hypoglycemic episodes in a human. In other embodiments, such terms refer to the maintenance of a reference level of C-peptide in peripheral blood.

[0030] In some embodiments, the effective amount reduces one or more T1D symptoms by at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%.

[0031] Various aspects of the present disclosure are described in more detail below. Further definitions are set forth throughout this specification.

[0032] II. Anti-CD3 Antibodies and Pharmaceutical Compositions The terms "anti-CD3 antibody" and "antibody that binds CD3" refer to an antibody or antibody fragment that can bind to differentiation antigen cluster 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 CD3 has a dissociation constant 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 -13It has a dissociation constant (Kd) of M). In some embodiments, the anti-CD3 antibody binds to CD3 epitopes that are conserved among CD3s from different species.

[0033] In some embodiments, the anti-CD3 antibody may be ChAglyCD3 (otelixizumab). Oterixizumab is a humanized Fc-unbound anti-CD3 antibody that was first evaluated in a Phase 2 trial by the Belgian Diabetes Registry (BDR), then developed by Tolerx, and subsequently used in a Phase 3 DEFEND new-onset T1D trial in collaboration with GSK (NCT00678886, NCT01123083, NCT00763451). Oterixizumab is administered intravenously by infusion over an 8-day period. For example, Wiczling et al., J. Clin. Pharmacol. (2010) 50(5):494-506; Keymeulen et al., N Engl J Med. (2005) 352:2598-608; Keymeulen et al., Diabetologia. (2010) 53:614-23; Hagopian et al. 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.(1993)23:403-11;Vlasakakis et al. al.,Br J Clin See Pharmacol (2019) 85:704-14; Guglielmi et al, Expert Opin Biol Ther. (2016) 16(6):841-6; Keymeulen et al., N Engl J Med. (2005) 352:2598-608; Keymeulen et al., Blood (2010) 115(6):1145-55; Sprangers et al., Immunotherapy (2011) 3(11):1303-6; and Daifotis et al., Clinical Immunology (2013) 149:268-78.

[0034] In some embodiments, the anti-CD3 antibody may be bicilizumab (also known as HuM291; Nuvion). Bicilizumab is a humanized anti-CD3 monoclonal antibody characterized by a mutated IgG2 isotype, lack of binding to the Fcγ receptor, and the ability to selectively induce apoptosis in activated T cells. It was evaluated in patients with graft-versus-host disease (NCT00720629; NCT00032279), ulcerative colitis (NCT00267306), and Crohn's disease (NCT00267709). See, for example, Sandborn et al., (2010) Gut 59(11):1485-92.

[0035] III. Teprizumab In some embodiments, the anti-CD3 antibody may be teprizumab. Teprizumab, 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, mediating the destruction of insulin-producing beta cells in pancreatic islets. Teprizumab binds to the epitope of the CD3ε chain expressed on mature T cells, thereby altering its function. Circulating T cells (and other lymphocytes) are transiently reduced after teprizumab treatment, a process that may involve periphery trend and depletion (Long 2017, Sherry 2011). In addition to the reduction of T cell effector function, teprizumab appears to increase both the number and function of regulatory T cells (Tregs) (Ablamunits 2010, Bisikirska 2005, Long 2017, Waldron-Lynch 2012). More recent studies have shown that teprizumab induces immunological "exhaustion" in a subset of effector CD8+ T cells, possibly making them more sensitive to modulation or deletion (Long 2016, Long 2017). Taken together, these mechanistic data suggest that teprizumab is an immune "modulator" that not only "suppresses" the process of β-cell immune destruction, but rather promotes the reequalization of the effector and regulatory arms involved in T1D autoimmunity, and that teprizumab may have the ability to contribute to the reintroduction of β-cell self-tolerance (Lebastchi 2013).

[0036] The sequence and composition of teprizumab are disclosed in U.S. Patent Nos. 6,491,916; 8,663,634; and 9,056,906. The molecular weight of teprizumab is approximately 150 kD. The complete sequences of the light and heavy chains are shown below. The bolded portion is the complementarity-determining region. Teprizumab light chain (SEQ ID NO: 1): [ka] Teprizumab heavy chain (SEQ ID NO: 2): [ka]

[0037] In some embodiments, pharmaceutical compositions are provided herein. Such compositions comprise an effective amount of anti-CD3 antibody and a pharmaceutically acceptable carrier. In some embodiments, the term “pharmaceutically acceptable” means approved by a federal or state regulatory agency for use in animals, more specifically in humans, or listed in the United States Pharmacopeia (US Pharmacopeia) or other generally recognized pharmacopoeias. The term “carrier” refers to a diluent, adjuvant (e.g., Freund’s adjuvant (complete and incomplete)), excipient, or vehicle used for administering a therapeutic agent. Such pharmaceutical carriers may be sterile liquids such as water and oil, e.g., of petroleum, animal, plant, or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solution and aqueous dextrose and aqueous glycerol solutions can also be used as liquid carriers, particularly as liquid carriers for injection. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, and ethanol (see, for example, Handbook of Pharmaceutical Excipients, Arthur H. Kibbe (ed.), 2000, Am. Pharmaceutical Association, Washington, DC, which is incorporated herein by reference in its entirety).

[0038] The compositions may also contain small amounts of wetting agents or emulsifiers, or pH buffers, if desired. These compositions may take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations, etc. Oral formulations may contain standard carriers such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin. Such compositions contain a therapeutically effective amount of the therapeutic agent, preferably in a purified form, together with an appropriate amount of carrier, to provide a form for appropriate 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, and most preferably a human subject.

[0039] In some embodiments, it may be desirable to administer the pharmaceutical composition topically to the area requiring treatment, which can be achieved, for example, by topical injection, injection, or implantation, the implantation being a membrane such as a Sialastic 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 in which the anti-CD3 antibody is not absorbed.

[0040] In some embodiments, the composition can be delivered into vesicles, particularly liposomes (Langer, Science (1990) 249:1527-33; 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 ibid. for general information).

[0041] In some embodiments, the composition can be delivered by a controlled-release system or a continuous-release system. In some embodiments, a pump can be used to achieve controlled-release or continuous-release (see 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, polymer materials can be used to achieve controlled or sustained release of the antibody or fragment thereof of this disclosure (see, for example, 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, J Macromol. Sci. Rev. Macromol. Chem. (1983) 23:61; also Levy et al., (1985) Science 228:190; During et al., (1989) Ann Neurol. 25:351; Howard et al., (1989) J See 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; International Publication No. 99 / 15154; and International Publication No. 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), polyanhydride, poly(N-vinylpyrrolidone), poly(vinyl alcohol), polyacrylamide, poly(ethylene glycol), polylactide (PLA), poly(lactide-co-glycolide) (PLGA), and polyorthoesters. In some embodiments, the polymers used in sustained-release formulations are inert, free of leachyparticles, stable at storage, sterilizable, and biodegradable. In some embodiments, controlled-release or sustained-release systems can be positioned near the therapeutic target, i.e., the lungs, and therefore require only a portion of the systemic dose (see, for example, Goodson, Medical Applications of Controlled Release, supra, vol.2, pp.115-138 (1984)).

[0042] The controlled-release system is described in a review by Langer (1990, Science 249:1527-1533). A sustained-release formulation comprising one or more antibodies or fragments thereof of this disclosure can be manufactured using any technique known to those skilled in the art. For example, see publications No. 4,526,938; International Publication No. 91 / 05548; International Publication No. 96 / 20698; Ning et al., (1996) Radiotherapy & Oncology 39:179-89; 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. 24:853-4; and Lam et al., (1997) Proc Int'l Symp Control Rel Bioact Mater. 24:759-760.

[0043] Pharmaceutical compositions can be formulated to suit their intended route of administration. Examples of routes of administration include, but are not limited to, parenteral, 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, a composition for intravenous administration is a solution in a sterile isotonic aqueous buffer. If necessary, the composition may also contain a solubilizer and a local anesthetic such as lignocaine to relieve pain at the injection site.

[0044] The composition may be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. The injectable formulation may be supplied in unit dosage forms with preservatives, such as ampoules or multi-dose containers. The composition may take the form of a suspension, solution or emulsion in an oily or aqueous vehicle and may contain formulation agents such as suspending agents, stabilizers and / or dispersing agents. Alternatively, the active ingredient may be in powder form consisting of a suitable vehicle, such as sterile pyrogen-free water, before use.

[0045] In some embodiments, the Disclosure provides a dosage form (e.g., related to a pump or other device for such delivery) that enables the administration of an anti-CD3 antibody continuously over several hours or days, for example, over 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 20 hours, 24 hours, 30 hours, 36 hours, 4 days, 5 days, 7 days, 10 days, or 12 days. In some embodiments, the Disclosure provides a continuously increasing dose, for example, over 24 hours, 30 hours, 36 hours, 4 days, 5 days, 7 days, 10 days, or 12 days, such as 106 μg / m². 2 850 μg / m² per day 2 / day or 211 μg / m² 2 840 μg / m² per day 2Provides a dosage form that allows for the administration of increasing doses up to 1 day.

[0046] The composition can be formulated in neutral or salt form. Examples of pharmaceutically acceptable salts include those formed from anions derived from hydrochloric acid, phosphoric acid, acetic acid, oxalic acid, tartaric acid, etc., and those formed from cations derived from sodium, potassium, ammonium, calcium, ferric hydroxide, isopropylamine, triethylamine, 2-ethylaminoethanol, histidine, procaine, etc.

[0047] Generally, the components of the compositions disclosed herein are supplied separately in unit dosage forms, for example, as dry lyophilized powders or anhydrous concentrates in sealed containers such as ampoules or pouches indicating the amount of activator, or they are mixed together. When the compositions are administered by infusion, they can be dispensed in infusion bottles containing sterile pharmaceutical-grade water or saline. When the compositions are administered by injection, ampoules of sterile water or saline for injection can be provided so that the components can be mixed before administration.

[0048] In particular, this disclosure provides that anti-CD3 antibodies or their pharmaceutical compositions can be packaged in sealed containers such as ampoules or pouches indicating the amount of drug. In some embodiments, the anti-CD3 antibody or its pharmaceutical composition is supplied as a dry, sterile, 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 saline. Preferably, the anti-CD3 antibody or its pharmaceutical composition is supplied as a dry, sterile, lyophilized powder in a sealed container in a unit dose of at least 5 mg, more preferably at least 10 mg, at least 15 mg, at least 25 mg, at least 35 mg, at least 45 mg, at least 50 mg, at least 75 mg, or at least 100 mg. The lyophilized pharmaceutical compositions herein should be stored in their original containers at 2°C to 8°C, and the therapeutic agents or pharmaceutical compositions herein should be administered within one week, preferably within 5 days, 72 hours, 48 ​​hours, 24 hours, 12 hours, 6 hours, 5 hours, 3 hours, or 1 hour after reconstitution. In some embodiments, the pharmaceutical composition is supplied in 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 supplied in a sealed container with a concentration of at least 0.25 mg / ml, more preferably at least 0.5 mg / ml, at least 1 mg / ml, at least 2.5 mg / ml, at least 5 mg / ml, at least 8 mg / ml, at least 10 mg / ml, at least 15 mg / ml, at least 25 mg / ml, at least 50 mg / ml, at least 75 mg / ml, or at least 100 mg / ml. The liquid form should be stored in its original container at 2°C to 8°C.

[0049] In some embodiments, the Disclosure provides that the composition of the Disclosure is packaged in a sealed container, such as an ampoule or pouch, indicating the amount of anti-CD3 antibody.

[0050] The composition may, if desired, be provided in a pack or dispenser device that can contain one or more unit dosage forms containing the active ingredient. The pack may include metal or plastic foil, such as a blister pack.

[0051] The amount of the composition of this disclosure effective for treating one or more symptoms associated with T1D can be determined by standard clinical techniques. The exact dose used in the formulation may also depend on the route of administration and the severity of the condition, and may be determined according to the practitioner's judgment and the circumstances of each patient. The effective dose can be extrapolated from dose-response curves obtained from in vitro or animal model test systems.

[0052] IV. Method and Use Methods for reducing the use of exogenous insulin in subjects requiring the use of exogenous insulin are provided herein. In some embodiments, the method reduces the amount of exogenous insulin to about 9000 μg / m². 2 ~Approx. 14000μg / m 2 This includes administering the total dose of teplizumab for a 12- to 14-day course, with teplizumab administration resulting in a reduction of at least 0.08 U / kg / day of exogenous insulin use.

[0053] In some embodiments, administration of teplizumab reduces the use of exogenous insulin by at least 0.08 U / kg / day in the first year. In some embodiments, administration of teplizumab reduces the use of exogenous insulin by at least 0.10 U / kg / day in the second year.

[0054] In some embodiments, C-peptide levels are maintained by teplizumab administration, as reflected by increased endogenous insulin production and decreased exogenous insulin requirements.

[0055] In some embodiments, the method includes administering a 12-day course of teplizumab to a subject. In other embodiments, the method includes administering a 14-day course of teplizumab to a subject.

[0056] In some embodiments, the method involves administering a first and second 12- to 14-day course of teprizumab. In some embodiments, the first and second 12- to 14-day courses are administered approximately 6 months apart.

[0057] In some embodiments, the method involves administering a first and second 12-day course of teplizumab. In some embodiments, the first and second 12-day courses are administered approximately 6 months apart.

[0058] In some embodiments, the subjects requiring it have stage 3 type 1 diabetes. In some embodiments, the subjects requiring it have been diagnosed with stage 3 type 1 diabetes 5 to 31 weeks prior to the administration step. In some embodiments, the subjects requiring it are approximately 7.5 years of age or older.

[0059] In some embodiments, the method includes administering teplizumab by intravenous infusion.

[0060] In some embodiments, the reduction in exogenous insulin use lasts for a period of one year, two years, or longer.

[0061] In some embodiments, the methods provided herein result in a reduction in insulin requirements or independence from exogenous insulin.

[0062] Type 1 diabetes typically develops in childhood and adolescence, but can also occur, albeit much less frequently, in adulthood in one's 50s and 60s (Atkinson 2014, Bluestone 2010, Streisand 2014).

[0063] In some embodiments, an anti-human CD3 antibody, such as teplizumab, is administered to patients aged 8–17 years who have been diagnosed with T1D six weeks prior, characterized by a peak C-peptide level of 0.2 pmol / mL or higher during a mixed-food tolerance test (MMTT). In some embodiments, the peak C-peptide level at screening is in the range of 0.2 pmol / mL (inclusive) to 0.7 pmol / mL (inclusive).

[0064] In some embodiments, the T1D diagnosis follows the criteria of the American Diabetes Association (ADA). The clinical diagnosis of diabetes as defined by the ADA must meet one of the following four criteria:

[0065] Fasting blood glucose (FPG) is 126 mg / dL (7.0 mmol / L) or higher. Fasting is defined as having no calorie intake for at least 8 hours.

[0066] A 2-hour plasma glucose (PG) level of 200 mg / dL (11.1 mmol / L) or higher during an oral glucose tolerance test (OGTT) is required. This test must be performed using a glucose load containing the equivalent of 75 g of anhydrous glucose dissolved in water, as described by the World Health Organization (WHO).

[0067] A hemoglobin A1c (HbA1c) level of 6.5% or higher (48 mmol / mol) is required. The test must be performed in a laboratory certified by the National Glycohemoglobin Standardization Program (NGSP) and using a standardized method for measuring complications of diabetes control (DCCT).

[0068] In patients with typical hyperglycemia or hyperglycemic crisis symptoms, random prostaglandins (PGs) levels should be 200 mg / dL (11.1 mmol / L) or higher.

[0069] Regarding the clinical diagnosis of type 1 diabetes (T1D), the ADA suggests that plasma glucose levels, rather than HbA1c, should be used to diagnose the acute onset of T1D in individuals exhibiting symptoms of hyperglycemia.

[0070] According to the ADA, measuring plasma glucose is sufficient to diagnose clinical diabetes (random plasma glucose ≥ 200 mg / dL [11.1 mmol / L], in addition to symptoms of hyperglycemia or hyperglycemic crisis) in patients with typical symptoms. In such cases, knowing the plasma glucose level is crucial as it not only confirms that the symptoms are due to diabetes but also provides information for determining the management strategy. Some healthcare professionals may also want to know the HbA1c to determine when the patient has been experiencing hyperglycemia. Furthermore, T1D, formerly called "insulin-dependent diabetes" or "juvenile-onset diabetes," accounts for 5–10% of diabetes cases and is caused by cell-mediated autoimmune destruction of pancreatic β-cells. Autoimmune markers include islet cell autoantibodies as well as autoantibodies against GAD (GAD65), insulin, tyrosine phosphatases IA-2 and IA-2β, and ZnT8. T1D is defined by the presence of one or more of these autoimmune markers.

[0071] In some embodiments, T1D is diagnosed by using a continuous glucose monitoring system (CGM) that reveals high sensor mean glucose levels (≥110 mg / dL), high blood glucose variability (CV ≥15), or a low percentage of time within a certain range (≥10% of time above 140 mg / dL).

[0072] In some embodiments, patients diagnosed with clinical T1D are positive for testing for at least one of the following T1D-related autoantibodies: glutamate decarboxylase 65 (GAD65) autoantibody, islet antigen 2 (IA-2) autoantibody, zinc transporter 8 (ZnT8) autoantibody, islet cytoplasmic autoantibody (ICA), or insulin autoantibody (if tested within 14 days of initiating insulin therapy). In some embodiments, the presence of autoantibodies 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 immunospecific detection of antibodies described herein or antibodies known to those skilled in the art.

[0073] It has been observed that β-cell loss continues even after a T1D diagnosis. To maximize the effect of β-cell maintenance in patients with recoverable levels of endogenous insulin production, patients treated with several embodiments of iontotherapy are those who have been diagnosed with T1D within the last six weeks and whose peak C-peptide level during a mixed diet tolerance test (MMTT) is 0.2 pmol / mL or higher.

[0074] In some embodiments, the methods provided herein reduce, prevent, or delay the need for the administration of exogenous insulin to a patient.

[0075] Beta-cell function before, during, and after treatment can be evaluated by the methods described herein or by any method known to those skilled in the art. For example, the DCCT (Diabetes Control and Complications Trial) study group established monitoring of glycosylated hemoglobin (HA1 and HA1c) percentages as a standard for evaluating blood glucose control (DCCT, 1993, N.Engl.J.Med. 329:977-986). Alternatively, the characterization of daily insulin requirements, C-peptide levels / responses, hypoglycemic episodes, and / or FPIRs may be used as markers of β-cell function or to establish therapeutic indices (see Keymeulen et al., (2005) N Engl J Med. 352:2598-608; Herold et al., (2005) Diabetes 54:1763-9; U.S. Patent Application Publication No. 2004 / 0038867A1; and Greenbaum et al., 2001, Diabetes 50:470-6, respectively). For example, FPIR is calculated as the sum of insulin levels at 1 minute and 3 minutes after IGTT, as performed according to the Islet Cell Antibody Registry User Study Protocol (see, for example, Bingley et al., (1996) Diabetes 45:1720-8 and McCulloch et al., (1993) Diabetes Care 16:911-5).

[0076] In some embodiments, the effective dose of an anti-CD3 antibody such as teprizumab is 10,000 micrograms / square meter (μg / m²). 2 This includes a 10-14 day course of subcutaneous (SC) injection, intravenous (IV) infusion, or oral administration of anti-CD3 antibodies in cumulative doses exceeding 100%.

[0077] In some embodiments, the effective dose of an anti-CD3 antibody, such as teprizumab, is approximately 9,500 to 14,000 μg / m² of the anti-CD3 antibody. 2 , about 9,500 to about 13,500μg / m 2 , about 9,500 to about 13,000μg / m 2, about 9,500 to about 12,500 μg / m 2 , about 9,500 to about 12,000μg / m 2 , about 9,500 to about 11,500 μg / m 2 , about 9,500 to about 11,000μg / m 2 , about 9,500 to about 10,500 μg / m 2 , about 9,500 to about 10,000μg / m 2 This includes a 10-14 day course of subcutaneous (SC) injection, intravenous (IV) infusion, or oral administration. In some embodiments, the effective dose of an anti-CD3 antibody, such as teprizumab, is approximately 10,000 μg / m². 2 , 10,500 μg / m 2 , 11,000 μg / m 2 , 11,500 μg / m² 2 , 12,000 μg / m 2 , 12,500 μg / m 2 , 13,000 μg / m 2 , 13,500 μg / m² 2 , or 14,000 μg / m² 2 This includes a 10-14 day course of subcutaneous (SC) injection, intravenous (IV) infusion, or oral administration of an anti-CD3 antibody. In some embodiments, the anti-CD3 antibody is teprizumab or comprises teprizumab.

[0078] In some embodiments, the effective amount is 10⁶ to 850 micrograms / square meter (μg / m²). 2 This regimen includes a 12- to 14-day course of subcutaneous intravenous (IV) infusion of an anti-CD3 antibody such as teprizumab. In some embodiments, the total dose over the duration of the regimen is approximately 14,000 μg / m². 2 , 13500 μg / m² 2 , 13000 μg / m² 2 , 12500 μg / m² 2 , 12000 μg / m 2 , 11500 μg / m² 2 , 11000 μg / m² 2 , 10500 μg / m² 2 , 10000 μg / m 2 9500 μg / m² 2 9000 μg / m² 2, 8000 μg / m 2 7000 μg / m² 2 , 6000 μg / m 2 Therefore, 5000 μg / m 2 , 4000 μg / m 2 , 3000 μg / m 2 , 2000 μg / m 2 , or 1000 μg / m² 2 It may be less than 9030 μg / m². In some embodiments, the total dose over the duration of the regimen is approximately 9030 μg / m². 2 ~Approx. 14000μg / m 2 , about 9030μg / m 2 ~Approx. 13500μg / m 2 , about 9000μg / m 2 ~Approx. 13000μg / m 2 , about 9000μg / m 2 ~Approx. 12500μg / m 2 , about 9000μg / m 2 ~Approx. 12000μg / m 2 , about 9000μg / m 2 ~Approx. 11500μg / m 2 , about 9000μg / m 2 ~Approx. 11000μg / m 2 , about 9000μg / m 2 ~Approx. 10500μg / m 2 , about 9000μg / m 2 ~about 10000μg / m 2 , about 9000μg / m 2 ~Approx. 9500μg / m 2 In some embodiments, the total dose over the duration of the regimen is approximately 9030 μg / m². 2 ~Approx. 14000μg / m 2 , about 9030μg / m 2 ~Approx. 13500μg / m 2 , about 9030μg / m 2 ~Approx. 13000μg / m 2 , about 9030μg / m 2 ~Approx. 12500μg / m 2 , about 9030μg / m 2 ~Approx. 12000μg / m 2 , about 9030μg / m 2 ~Approx. 11500μg / m 2, about 9030 μg / m 2 ~ about 11000 μg / m 2 , about 9030 μg / m 2 ~ about 10500 μg / m 2 , about 9030 μg / m 2 ~ about 10000 μg / m 2 , about 9030 μg / m 2 ~ about 9500 μg / m 2 .

[0079] Although not bound by theory, when the cumulative dose of teprotumumab exceeds about 9,000 μg / m 2 , efficacy equivalent to that shown at about 9,000 mg can be expected in terms of C-peptide maintenance. This is because the exposure-response curve surprisingly reaches a plateau and efficacy does not increase with further increases in dose. The evaluation of C-peptide maintenance was performed using data from the Protege trial. The predicted AUC of teprotumumab and the change in C-peptide from baseline were plotted and an Emax analysis was performed. These data indicate that the Emax model explains the relationship between the exposure of teprotumumab and the change in C-peptide after 2 years. Even when the AUC value of teprotumumab exceeds about 1500 ng*hr / mL (below the lowest predicted AUC value of 1,789 ng*hr / mL at a dose of about 9,000 μg / m 2 ), no further improvement in C-peptide was observed with increasing teprotumumab exposure. Therefore, these data suggest that even at doses of teprotumumab above about 9,000 mg, there is efficacy equivalent to that at about 9,000 mg in terms of C-peptide maintenance.

[0080] In some embodiments, the effective amount comprises a first dose of 106 μg / m 2 of teprotumumab on day 1, a second dose of 425 μg / m 2 of teprotumumab on day 2, and a 12-day course of IV infusion of teprotumumab at a single dose of 850 μg / m 2 on each of days 3 - 12.

[0081] In some embodiments, the effective dose is 211 μg / m² on day 1. 2 The first dose of teplizumab, 423 μg / m² on day 2. 2 The second dose of teprizumab, and 840 μg / m² on each of days 3 through 12. 2 This includes a 12-day course of IV infusions of teplizumab in a single dose.

[0082] In some embodiments, the effective dose is approximately 100 μg / m² on day 1. 2 The first dose of teplizumab was approximately 400 μg / m² on day 2. 2 The second dose of teplizumab was approximately 850 μg / m² on day 3. 2 The third dose, and approximately 1,200 μg / m² each on days 4 through 12. 2 This includes a 12-day course of IV infusions of teplizumab.

[0083] In some embodiments, the effective dose is approximately 100 μg / m² on day 1. 2 The first dose of teplizumab was approximately 400 μg / m² on day 2. 2 The second dose of teplizumab was approximately 850 μg / m² on day 3. 2 The third dose, and approximately 1,300 μg / m² each on days 4 through 12. 2 This includes a 12-day course of IV infusions of teplizumab.

[0084] In some embodiments, the effective dose is approximately 100 μg / m² on day 1. 2 The first dose of teplizumab was approximately 400 μg / m² on day 2. 2 The second dose of teplizumab was approximately 850 μg / m² on day 3. 2 The third dose, and approximately 1,400 μg / m² each on days 4 through 12. 2 This includes a 12-day course of IV infusions of teplizumab.

[0085] In some embodiments, the effective dose is approximately 200 μg / m² on day 1. 2 The first dose of teplizumab was approximately 400 μg / m² on day 2. 2 The second dose of teplizumab was approximately 850 μg / m² on day 3.2 The third dose, and approximately 1,200 μg / m² each on days 4 through 12. 2 This includes a 12-day course of IV infusions of teplizumab.

[0086] In some embodiments, the effective dose is approximately 200 μg / m² on day 1. 2 The first dose of teplizumab was approximately 400 μg / m² on day 2. 2 The second dose of teplizumab was approximately 850 μg / m² on day 3. 2 The third dose, and approximately 1,300 μg / m² each on days 4 through 12. 2 This includes a 12-day course of IV infusions of teplizumab.

[0087] In some embodiments, the effective dose is approximately 200 μg / m² on day 1. 2 The first dose of teplizumab was approximately 400 μg / m² on day 2. 2 The second dose of teplizumab was approximately 850 μg / m² on day 3. 2 The third dose, and approximately 1,400 μg / m² each on days 4 through 12. 2 This includes a 12-day course of IV infusions of teplizumab.

[0088] In some embodiments, this method provides approximately 60 μg / m² on days 1 to 4, respectively. 2 , about 125μg / m 2 , about 250μg / m 2 , and approximately 500 μg / m² 2 A 14-day course of intravenous infusion, and approximately 1,000 μg / m³ each on days 5 through 14. 2 This includes administering a dose of the drug. In some embodiments, the cumulative dose is approximately 10,935 μg / m². 2 That is the case.

[0089] In some embodiments, this method provides approximately 60 μg / m² on days 1 to 4, respectively. 2 , about 125μg / m 2 , about 250μg / m 2 , and approximately 500 μg / m² 2 This involves an IV infusion course over 14 days, and approximately 1,030 μg / m³ each on days 5 through 14.2 This includes administering a dose of the drug. In some embodiments, the cumulative dose is approximately 11,235 μg / m². 2 That is the case.

[0090] In some embodiments, this method involves applying approximately 100 μg / m² on days 1 to 4, respectively. 2 , about 425 μg / m 2 , about 850 μg / m 2 , and approximately 850 μg / m² 2 A 14-day course of intravenous infusion, and approximately 1,000 μg / m³ each on days 5 through 14. 2 This includes administering a dose of the drug. In some embodiments, the cumulative dose is approximately 12,225 μg / m². 2 That is the case.

[0091] In some embodiments, this method provides approximately 65 μg / m² on days 1 to 4, respectively. 2 , about 125μg / m 2 , about 250μg / m 2 , and approximately 500 μg / m² 2 This involves an IV infusion course over 14 days, and approximately 1,070 μg / m³ administered on each of days 5 through 14. 2 This includes administering a dose of the drug. In some embodiments, the cumulative dose is approximately 11,640 μg / m². 2 That is the case.

[0092] In some embodiments, this method provides approximately 65 μg / m² on days 1 to 4, respectively. 2 , about 125μg / m 2 , about 250μg / m 2 , and approximately 500 μg / m² 2 This involves an IV infusion course over 14 days, and approximately 1,030 μg / m³ each on days 5 through 14. 2 This includes administering a dose of the drug. In some embodiments, the cumulative dose is approximately 11,240 μg / m². 2 That is the case.

[0093] This specification provides a treatment regimen consisting of two or more courses of administration with an anti-CD3 antibody such as teprizumab, including a first course administered in week 1 and a second course administered in week 26. In some embodiments, teprizumab is administered by intravenous infusion in two courses, with the first course starting on day 1 (week 1) and the second course starting around day 182 (week 26), each course of treatment consisting of daily infusions for 10 to 14 days, for example, 12 or 14 days, and the cumulative teprizumab dose for each course of treatment being 9000 μg / m² 2 In some embodiments, teplizumab is administered by intravenous infusion in two courses, with the first course starting on day 1 (week 1) and the second course starting around day 182 (week 26). Each course of treatment consists of daily infusions for 10 to 14 days, for example, 12 or 14 days, and the cumulative dose of teplizumab for each course of treatment is 9500 μg / m². 2 In some embodiments, teplizumab is administered by intravenous infusion in two courses, with the first course starting on day 1 (week 1) and the second course starting around day 182 (week 26). Each course of treatment consists of daily infusions for 10 to 14 days, for example, 12 or 14 days, and the cumulative dose of teplizumab for each course of treatment is 10,000 μg / m². 2 In some embodiments, teplizumab is administered by intravenous infusion in two courses, with the first course starting on day 1 (week 1) and the second course starting around day 182 (week 26). Each course of treatment consists of daily infusions for 10 to 14 days, for example, 12 or 14 days, and the cumulative dose of teplizumab for each course of treatment is 10,500 μg / m². 2 In some embodiments, teplizumab is administered by IV infusion in two courses, with the first course starting on day 1 (week 1) and the second course starting around day 182 (week 26), each treatment course consisting of 10 to 14 days, for example, 12 or 14 days of daily infusions, and the cumulative dose of teplizumab for each course is 11,000 μg / m². 2In some embodiments, teplizumab is administered by IV infusion in two courses, with the first course starting on day 1 (week 1) and the second course starting around day 182 (week 26), each treatment course consisting of 10 to 14 days, for example, 12 or 14 days of daily infusions, and the cumulative dose of teplizumab for each course is 11500 μg / m². 2 In some embodiments, teplizumab is administered by intravenous infusion in two courses, with the first course starting on day 1 (week 1) and the second course starting around day 182 (week 26). Each course of treatment consists of daily infusions for 10 to 14 days, for example, 12 or 14 days, and the cumulative dose of teplizumab for each course of treatment is 12,000 μg / m². 2 In some embodiments, teplizumab is administered by intravenous infusion in two courses, with the first course starting on day 1 (week 1) and the second course starting around day 182 (week 26). Each course of treatment consists of daily infusions for 10 to 14 days, for example, 12 or 14 days, and the cumulative dose of teplizumab for each course of treatment is 12,500 μg / m². 2 In some embodiments, teplizumab is administered by intravenous infusion in two courses, with the first course starting on day 1 (week 1) and the second course starting around day 182 (week 26). Each course of treatment consists of daily infusions for 10 to 14 days, for example, 12 or 14 days, and the cumulative teplizumab dose for each course of treatment is 13,000 μg / m². 2 In some embodiments, teplizumab is administered by intravenous infusion in two courses, with the first course starting on day 1 (week 1) and the second course starting around day 182 (week 26). Each course of treatment consists of daily infusions for 10 to 14 days, for example, 12 or 14 days, and the cumulative dose of teplizumab for each course of treatment is 13,500 μg / m². 2In some embodiments, teplizumab is administered by intravenous infusion in two courses, with the first course starting on day 1 (week 1) and the second course starting around day 182 (week 26). Each course of treatment consists of daily infusions for 10 to 14 days, for example, 12 or 14 days, and the cumulative teplizumab dose for each course of treatment is 14,000 μg / m². 2 In some embodiments, the 12-day course has a 2-day ramp-up period and a 10-day fixed maximum dose period. In some embodiments, the dose is 106 μg / m². 2 Teplizumab was administered on day 1 at a dose of 425 μg / m². 2 Teplizumab was administered on day 2 at a dose of 850 μg / m². 2 Teplizumab is administered on days 3 through 12.

[0094] In other embodiments, the course of administration can be repeated at intervals of 2, 4, 5, 6, 8, 9, 10, 12, 15, 18, 24, 30, or 36 months. In some embodiments, the efficacy of treatment with an anti-CD3 antibody such as teplizumab is determined 2, 4, 5, 6, 9, 12, 15, 18, 24, 30, or 36 months after the previous treatment, as described herein or as known in the art.

[0095] In some embodiments, the subject is given approximately 5 μg / m² to treat, slow the progression of, or improve one or more symptoms of T1D. 2 ~1200 μg / m 2 For example, 106 μg / m² 2 ~850 μg / m 2 One or more doses of an anti-CD3 antibody, such as teprizumab, are administered, for example, 12 daily doses.

[0096] In some embodiments, subjects are administered a treatment regimen comprising two courses of daily administration of an effective dose of an anti-CD3 antibody, such as teprizumab, which is administered over 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. In some embodiments, the treatment plan includes administering an effective dose daily, every 2 days, every 3 days, or every 4 days.

[0097] In some embodiments, subjects are administered a treatment regimen comprising one or more doses of a prophylactic effective dose of anti-CD3 antibody (e.g., teprizumab), where the prophylactic effective dose is 200 μg / kg / day, 175 μg / kg / day, 150 μg / kg / day, 125 μg / kg / day, 100 μg / kg / day, 95 μg / kg / day, 90 μg / kg / day, 85 μg / kg / day, 80 μg / kg / day, 75 μg / kg / day, 70 μg / kg / day, 65 μg / kg / day, 60 μg / kg / day, 55 μg / kg / day, 50 μg / kg / day, 45 μg / kg / day, 40 μg / kg / The recommended daily dose is 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 preventively effective dose is 1200 μg / kg / day. 2 / day, 1150μg / m 2 / day, 1100μg / m 2 / day, 1050μg / m 2 / day, 1000μg / m 2 / day, 950 μg / m 2 / day, 900μg / m 2 / day, 850 μg / m 2 / day, 800μg / m 2 / day, 750 μg / m 2 / day, 700 μg / m 2 / day, 650 μg / m 2 / day, 600μg / m 2 / day, 550μg / m 2 / day, 500μg / m 2 / day, 450μg / m 2 / day, 400μg / m 2 / day, 350μg / m 2 / day, 300μg / m 2 / day, 250 μg m 2 / day, 200μg / m 2 / day, 150μg / m 2 / day, 100μg / m 2 / day, 50μg / m 2 / day, 40 μg m 2 / day, 30μg / m 2 / day, 20 μg / m 2 / day, 15μg / m 2 / day, 10μg / m 2 / day, or 5 μg / m² 2 / day

[0098] In some embodiments, 1200 μg / m² 2 Below, 1150μg / m 2 Below, 1100μg / m 2 Below, 1050μg / m 2 Below, 1000μg / m 2 Below, 950μg / m 2 Below, 900μg / m 2 Below 850μg / m 2 Below 800μg / m 2 Below, 750μg / m 2 Below, 700μg / m 2 Below, 650μg / m 2 Below, 600μg / m 2 Below, 550μg / m 2 Below, 500μg / m 2 Below, 450μg / m 2 Below 400μg / m 2 Below 350μg / m 2 Below 300μg / m 2 Below 250μg / m 2 Below, 200μg / m 2 Below 150μg / m 2 Below, 100μg / m 2Below, 50μg / m 2 Below, 40μg / m 2 Below, 30μg / m 2 Below, 20μg / m 2 Below, 15μg / m 2 Below, 10μg / m 2 The following, or 5 μg / m² 2 The following intravenous doses of anti-CD3 antibodies, such as teplizumab, are administered over approximately 24 hours, 22 hours, 20 hours, 18 hours, 16 hours, 14 hours, 12 hours, 10 hours, 8 hours, 6 hours, 4 hours, 2 hours, 1.5 hours, 1 hour, 50 minutes, 40 minutes, 30 minutes, 20 minutes, 10 minutes, 5 minutes, 2 minutes, 1 minute, 30 seconds, or 10 seconds to prevent, treat, or improve one or more symptoms of type 1 diabetes. In some embodiments, the total dose over the duration of the regimen is approximately 14,000 μg / m². 2 , 13500 μg / m² 2 , 13000 μg / m² 2 , 12500 μg / m² 2 , 12000 μg / m 2 , 11500 μg / m² 2 , 11000 μg / m² 2 , 10500 μg / m² 2 , 10000 μg / m 2 9500 μg / m² 2 9000 μg / m² 2 , 8000 μg / m 2 7000 μg / m² 2 , 6000 μg / m 2 It is less than 5000 μg / m². 2 , 4000 μg / m 2 , 3000 μg / m 2 , 2000 μg / m 2 , or 1000 μg / m² 2 It may be less than 100 μg / m². In some embodiments, the daily dose administered in the regimen is approximately 100 μg / m². 2 ~about 200μg / m 2 , about 100μg / m 2 ~about 500μg / m 2 , about 100μg / m 2 ~Approx. 1000μg / m 2 , or approximately 500 μg / m²2 ~Approx. 1000μg / m 2 That is the case.

[0099] In some embodiments, the dose is escalated over the first three doses of the treatment regimen (e.g., once daily dose over the first three days of a 12-day regimen) until an effective daily dose of an anti-CD3 antibody such as teprizumab is achieved. In some embodiments, the subject is administered a treatment regimen comprising one or more effective doses of an anti-CD3 antibody such as teprizumab, where the effective dose is, for example, 0.01 μg / kg, 0.02 μg / kg, 0.04 μg / kg, 0.05 μg / kg, 0.06 μg / kg, 0.08 μg / kg, 0.1 μg / kg, 0.2 μg / kg, 0.25 μg / kg, 0.5 μg / kg, 0.75 μg / kg, 1 μg / kg, 1.5 μg / kg, 2 μg / kg, 4μg / kg, 5μg / kg, 10μg / kg, 15μg / kg, 20μg / kg, 25μg / kg, 30μg / kg, 35μg / kg, 40μg / kg, 45μg / kg, 50μg / kg, 55μg / kg, 60μg / k g, 65μg / kg, 70μg / kg, 75μg / kg, 80μg / kg, 85μg / kg, 90μg / kg, 95μg / kg, 100μg / kg or 125μg / kg; 2 , 150 μg / m 2 , 200 μg / m 2 , 250 μg / m 2 300 μg / m² 2 , 350 μg / m 2 , 400 μg / m 2 , 450 μg / m 2 500 μg / m² 2 550 μg / m² 2 600 μg / m² 2 Alternatively, 650 μg / m² 2 The dose increases daily as treatment progresses. In some embodiments, the subject is given a treatment plan comprising one or more doses of an effective dose of an anti-CD3 antibody such as teprizumab, where the effective dose is increased 1.25-fold, 1.5-fold, 2-fold, 2.25-fold, 2.5-fold, or 5-fold until an effective daily dose of the anti-CD3 antibody such as teprizumab is achieved.

[0100] In some embodiments, the target may be 200 μg / kg or less, preferably 175 μg / kg or less, 150 μg / kg or less, 125 μg / kg or less, 100 μg / kg or less, 95 μg / kg or less, 90 μg / kg or less, 85 μg / kg or less, 80 μg / kg or less, 75 μg / kg or less, 70 μg / kg or less, 65 μg / kg or less, 60 μg / kg or less, 55 μg / kg or less, 50 μg / kg or less, in order to treat or alleviate one or more symptoms of T1D. One or more doses of an anti-CD3 antibody, such as teplizumab, are administered intramuscularly at doses of ≤ g / kg, ≤ 45 μg / kg, ≤ 40 μg / kg, ≤ 35 μg / kg, ≤ 30 μg / kg, ≤ 25 μg / kg, ≤ 20 μg / kg, ≤ 15 μg / kg, ≤ 10 μg / kg, ≤ 5 μg / kg, ≤ 2.5 μg / kg, ≤ 2 μg / kg, ≤ 1.5 μg / kg, ≤ 1 μg / kg, ≤ 0.5 μg / kg, or ≤ 0.2 μg / kg.

[0101] In some embodiments, the target may be 200 μg / kg or less, preferably 175 μg / kg or less, 150 μg / kg or less, 125 μg / kg or less, 100 μg / kg or less, 95 μg / kg or less, 90 μg / kg or less, 85 μg / kg or less, 80 μg / kg or less, 75 μg / kg or less, 70 μg / kg or less, 65 μg / kg or less, 60 μg / kg or less, 55 μg / kg or less, 50 μg / kg or less, in order to treat or alleviate one or more symptoms of T1D. One or more doses of an anti-CD3 antibody, such as teplizumab, are administered subcutaneously at doses of ≤μg / kg, ≤45μg / kg, ≤40μg / kg, ≤35μg / kg, ≤30μg / kg, ≤25μg / kg, ≤20μg / kg, ≤15μg / kg, ≤10μg / kg, ≤5μg / kg, ≤2.5μg / kg, ≤2μg / kg, ≤1.5μg / kg, ≤1μg / kg, ≤0.5μg / kg, or ≤0.2μg / kg.

[0102] In some embodiments, the target is given one or more doses of 100 μg / kg or less by intravenous administration, preferably 95 μg / kg or less, 90 μg / kg or less, 85 μg / kg or less, 80 μg / kg or less, 75 μg / kg or less, 70 μg / kg or less, 65 μg / kg or less, 60 μg / kg or less, 55 μg / kg or less, 50 μg / kg or less, 45 μg / kg or less, 40 μg / kg or less, and 35 μg / kg. The following includes administering anti-CD3 antibodies such as teplizumab at concentrations of 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 treat or improve one or more symptoms of T1D. In some embodiments, to treat or improve one or more symptoms of T1D, the dosage is 100 μg / kg or less, 95 μg / kg or less, 90 μg / kg or less, 85 μg / kg or less, 80 μg / kg or less, 75 μg / kg or less, 70 μg / kg or less, 65 μg / kg or less, 60 μg / kg or less, 55 μg / kg or less, 50 μg / kg or less, 45 μg / kg or less, 40 μg / kg or less, 35 μg / kg or less, 30 μg / kg or less, 25 μg / kg or less, 20 μg / Intravenous administration of anti-CD3 antibodies such as teplizumab is performed over approximately 6 hours, 4 hours, 2 hours, 1.5 hours, 1 hour, 50 minutes, 40 minutes, 30 minutes, 20 minutes, 10 minutes, 5 minutes, 2 minutes, 1 minute, 30 seconds, or 10 seconds. The dosage is ≤kg, ≤15μg / kg, ≤10μg / kg, ≤5μg / kg, ≤2μg / kg, ≤1.5μg / kg, ≤1μg / kg, ≤2μg / kg, ≤1.5μg / kg, ≤1μg / kg, ≤0.5μg / kg, or ≤0.2μg / kg.

[0103] In some embodiments, the subjects are given one or more oral doses of 100 μg / kg or less, preferably 95 μg / kg or less, 90 μg / kg or less, 85 μg / kg or less, 80 μg / kg or less, 75 μg / kg or less, 70 μg / kg or less, 65 μg / kg or less, 60 μg / kg or less, 55 μg / kg or less, 50 μg / kg or less, 45 μg / kg or less, 40 μg / kg or less, and 35 μg / kg or less. The following includes administering anti-CD3 antibodies such as teplizumab at concentrations of 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 treat or improve one or more symptoms of T1D. In some embodiments, to treat or improve one or more symptoms of T1D, the dosage is 100 μg / kg or less, 95 μg / kg or less, 90 μg / kg or less, 85 μg / kg or less, 80 μg / kg or less, 75 μg / kg or less, 70 μg / kg or less, 65 μg / kg or less, 60 μg / kg or less, 55 μg / kg or less, 50 μg / kg or less, 45 μg / kg or less, 40 μg / kg or less, 35 μg / kg or less, 30 μg / kg or less, 25 μg / kg or less, 20 μg Oral administration of anti-CD3 antibodies such as teplizumab is performed over approximately 6 hours, 4 hours, 2 hours, 1.5 hours, 1 hour, 50 minutes, 40 minutes, 30 minutes, 20 minutes, 10 minutes, 5 minutes, 2 minutes, 1 minute, 30 seconds, or 10 seconds. The dosage is ≤ / kg, ≤15 μg / kg, ≤10 μg / kg, ≤5 μg / kg, ≤2 μg / kg, ≤1.5 μg / kg, ≤1 μg / kg, ≤2 μg / kg, ≤1.5 μg / kg, ≤1 μg / kg, ≤0.5 μg / kg, or ≤0.2 μg / kg.

[0104] In some embodiments where the escalating dose is administered on the first day of the drug regimen, the dose on day 1 of the regimen is 100-250 μg / m². 2 The dose is / day, and is gradually increased to the daily dose listed above by the second and third days. For example, on the first day, the subject receives approximately 106 μg / m². 2 / day, approximately 425 μg / m² on the second day 2 850 μg / m² per day, and on subsequent regimen days (e.g., days 3-12)2 The daily dose is administered. In some embodiments, subjects receive approximately 211 μg / m² on day 1. 2 / day, approximately 423 μg / m² on the second day 2 Approximately 840 μg / m² per day, on the 3rd day and subsequent days of the regimen (e.g., days 3-12). 2 Administer the daily dose.

[0105] In some embodiments where the escalating dose is administered on the first day of the dosing plan, the dose on day 1 of the dosing plan is approximately 5 to 150 μg / m2 / day, preferably approximately 55 to 150 μg / m2 / day. 2 / day, for example, approximately 60-100 μg / m² 2 The dose is / day and is gradually increased to the daily dose listed above by the 3rd, 4th, 5th, 6th, or 7th day. In some embodiments, the subject receives approximately 60 μg / m² on day 1. 2 / day, approximately 125 μg / m² on the second day 2 / day, approximately 250 μg / m² on the 3rd day 2 / day, approximately 500 μg / m² on the 4th day 2 1,000 μg / m² per day and on subsequent days of the administration plan (e.g., days 5-14) 2 The daily dose is administered. In some embodiments, subjects receive approximately 60 μg / m² on day 1. 2 / day, approximately 125 μg / m² on the second day 2 / day, approximately 250 μg / m² on the 3rd day 2 / day, approximately 500 μg / m² on the 4th day 2 1,030 μg / m² per day and on subsequent days of the administration plan (e.g., days 5-14) 2 The daily dose is administered. In some embodiments, subjects receive approximately 100 μg / m² on day 1. 2 / day, approximately 425 μg / m² on the second day 2 / day, approximately 850 μg / m² on the 3rd day 2 / day, approximately 850 μg / m² on the 4th day 2 1,000 μg / m² per day and on subsequent days of the administration plan (e.g., days 5-14) 2 The daily dose is administered. In some embodiments, subjects were given approximately 60 μg / m² on day 1. 2 / day, approximately 125 μg / m² on the second day 2 / day, approximately 250 μg / m² on the 3rd day2 / day, approximately 500 μg / m² on the 4th day 2 1,070 μg / m² per day and on subsequent days of the administration plan (e.g., days 5-14) 2 Administer the daily dose.

[0106] In some embodiments, the first one, two, or three doses, or all doses, in the dosing regimen are administered more slowly by intravenous administration to reduce the potential for cytokine release and other adverse effects. For example, 106 μg / m² 2 The daily dose may be administered over periods of approximately 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, and 22 hours. In some embodiments, the dose is administered by slow infusion over a period of, for example, 20 to 24 hours. In some embodiments, the dose is infused by a pump, preferably increasing the concentration of the antibody being administered as the infusion progresses.

[0107] In some embodiments, the above 106 μg / m² 2 / day~850μg / m 2 A certain percentage of the daily regimen dose is administered in gradually increasing doses.

[0108] In some embodiments, anti-CD3 antibodies such as teplizumab are administered not in daily doses over several days, but rather in continuous infusions over 4, 6, 8, 10, 12, 15, 18, 20, 24, 30, or 36 hours. Infusions may be constant, or they may begin with a low dose for the first 1, 2, 3, 5, 6, or 8 hours of the infusion, and then be increased to a higher dose. Throughout the course of infusions, the patient receives a dose equivalent to that administered in the 5-20 day regimen described above. For example, approximately 150 μg / m². 2 , 200 μg / m 2 , 250 μg / m 2 500 μg / m² 2 750 μg / m² 2, 1000 μg / m 2 , 1500 μg / m 2 , 2000 μg / m 2 , 3000 μg / m 2 , 4000 μg / m 2 , 5000 μg / m 2 , 6000 μg / m 2 7000 μg / m² 2 , 8000 μg / m 2 9000 μg / m² 2 9500 μg / m² 2 , 10000 μg / m 2 , 10500 μg / m² 2 , 11000 μg / m² 2 , 11500 μg / m² 2 , 12000 μg / m 2 , 12500 μg / m² 2 , 13000 μg / m² 2 , 13500 μg / m² 2 Or 14000 μg / m² 2 The dose may be administered. In particular, the infusion rate and duration are designed to minimize the level of free anti-CD3 antibodies, such as teprizumab, in the subject after administration. In some embodiments, the level of free anti-CD3 antibodies, such as teprizumab, should not exceed 200 ng / ml of free antibody. Furthermore, the infusion is designed to achieve a combination of T cell receptor coating and modulation of at least 50%, 60%, 70%, 80%, 90%, 95%, or 100%.

[0109] In some embodiments, anti-CD3 antibodies such as teprizumab are administered chronically to treat, slow the progression of, or reverse one or more symptoms of type 1 diabetes. For example, in some embodiments, low doses of anti-CD3 antibodies such as teprizumab are administered once a month, twice a month, three times a month, once a week, or more frequently, as an alternative to the 6-14 day dosing regimen described above, or after the implementation of such a regimen to enhance or maintain its effect. Such low doses are 1 μg / m² 2 ~100 μg / m 2 For example, approximately 5 μg / m² 2 , 10 μg / m2 , 15 μg / m 2 , 20 μg / m 2 , 25 μg / m 2 , 30 μg / m 2 , 35 μg / m 2 , 40 μg / m 2 , 45 μg / m 2 , or 50 μg / m² 2 It could be one of the following.

[0110] In some embodiments, subjects may be readministered at some point after administration of two courses of anti-CD3 antibody, such as a teplizumab regimen, based on, for example, one or more physiological or biomarker parameters. Such readministering may be performed at 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 start of the treatment plan, and / or the need for such readministering may be assessed, and the treatment course may be repeated indefinitely every 6 months, 9 months, 1 year, 15 months, 18 months, 2 years, 30 months, or 3 years.

[0111] In some embodiments, the level (or relative amount) of phenotypically exhausted T cells, such as TIGIT+KLRG1+CD8+CD3+ cells, relative to total CD3+ T cells is determined, for example, by flow cytometry, before and / or after a 12-day course of teprizumab (e.g., at intervals of 1–6 months, 2–5 months, or about 3 months). In some embodiments, the level of TIGIT+KLRG1+CD8+CD3+ T cells can be monitored, for example, by flow cytometry. In some embodiments, an additional 12-day course of an anti-CD3 antibody, such as teprizumab, is administered when the level of TIGIT+KLRG1+CD8+CD3+ T cells corresponds to a baseline level (e.g., returns to a baseline level). In some embodiments, the determination of TIGIT+KLRG1+CD8+CD3+ T cells is about 3 months (or about 1–6 months) after the administration of a second 12-day course. In some embodiments, if the subject has more than approximately 10% TIGIT+KLRG1+CD8+ T cells among all CD3+ T cells, monitoring may be performed once a year. In some embodiments, if the subject has less than approximately 10% TIGIT+KLRG1+CD8+ T cells among all CD3+ T cells, monitoring may be performed approximately every 3 to 6 months.

[0112] In some embodiments, the re-administration is approximately 9000 μg / m² as described herein. 2 This includes administering additional (e.g., second, third, or more) courses of teplizumab for 12 to 14 days, each exceeding a total dose of 106 μg / m². In some embodiments, the additional 12-day course of teplizumab is 106 μg / m² on day 1. 2 The first dose of teplizumab was administered on day 2 at 425 μg / m². 2 The second dose of teplizumab, and 850 μg / m² on days 3 through 12. 2 This includes a single dose, with a total dose of approximately 9031 μg / m². 2 In another embodiment, the additional 12-day course of teplizumab is 211 μg / m² on day 1. 2 The first dose of teplizumab was administered on day 2 at 423 μg / m². 2The second dose of teplizumab, and 840 μg / m² on days 3 through 12. 2 It contains one dose, and the total dose is approximately 9034 μg / m². 2 That is the case.

[0113] In some embodiments, an additional (e.g., second, third, or more) 12- to 14-day course of an anti-CD3 antibody such as teplizumab may be administered approximately 12 to 24 months after the administration of the previous 12- to 14-day course, for example, 12, 13, 14, 15, 16, 17, 19, 20, 21, 22, 23, or 24 months after the administration of the previous 12- to 14-day course.

[0114] This specification provides methods and teplizumab administration regimens for reducing exogenous insulin use. In some embodiments, an anti-CD3 antibody such as teplizumab is administered to reduce exogenous insulin use by at least 0.08 U / kg / d (e.g., 0.08 U / kg / d, 0.09 U / kg / d, 0.10 U / kg / d, 0.11 U / kg / d or lower).

[0115] In some embodiments, subjects treated with an anti-CD3 antibody such as teprizumab use less exogenous insulin compared to pre-treatment levels (e.g., at least 0.08 U / kg / d less). In some embodiments, administration of an anti-CD3 antibody such as teprizumab leads to the discontinuation of exogenous insulin use.

[0116] In some embodiments, an anti-CD3 antibody, such as teplizumab, is administered to reduce or maintain glycosylated hemoglobin (HA1 or HA1c) levels to less than 8%, less than 7.5%, less than 7%, less than 6.5%, less than 6%, less than 5.5%, or 5% or less. At the start of treatment, the patient's HA1 or HA1c level is less than 8%, less than 7.5%, less than 7%, less than 6.5%, less than 6%, or more preferably 4% to 6% (preferably measured in the absence of other treatments for diabetes, such as exogenous insulin administration). It is desirable that such patients preferably retain at least 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, or 20% beta-cell function prior to the start of treatment. In some embodiments, administration of an anti-CD3 antibody prevents impairment, thereby slowing disease progression and reducing the need for insulin administration. In some embodiments, the therapeutic methods provided herein result in HA1 or HA1c levels being 7% or less, 6.5% or less, 6% or less, 5.5% or less, or 5% or less after 6 months, 9 months, 12 months, 15 months, 18 months, or 24 months following prior treatment. In some embodiments, administration of anti-CD3 antibodies by the methods provided herein reduces the mean level of HA1 or HA1c in patients by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70% after 6 months, 9 months, 12 months, 15 months, 18 months, or 24 months following prior treatment compared to pre-treatment levels. In some embodiments, administration of anti-CD3 antibodies by the methods provided herein increases the mean level of HA1 or HA1c in patients by only about 0.5%, about 1%, about 2.5%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% compared to the pre-treatment level 6 months, 9 months, 12 months, 15 months, 18 months, or 24 months after prior treatment.

[0117] In some embodiments, administration of an anti-CD3 antibody, particularly teplizumab, according to the methods provided herein slows β-cell loss and / or maintains β-cell function (as demonstrated, for example, by C-peptide levels, episodes of hypoglycemia or hyperglycemia, time within the range of (blood glucose levels), insulin use, or other assessment methods known in the art) over a period of 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 2, 2, 24 months or longer in children and adolescents aged 8–17 years diagnosed with T1D within the past 6 weeks. In some embodiments, administration of an anti-CD3 antibody, particularly teplizumab, according to the methods provided herein slows β-cell loss and / or maintains β-cell function over a period of 18 months (78 weeks) in children and adolescents aged 8–17 years diagnosed with T1D within the past 5–31 weeks.

[0118] In some embodiments, the subjects are adults. In some embodiments, the subjects are children. In some embodiments, the children are 7 years of age or older. In some embodiments, the children are 6 years of age or older. In some embodiments, the children are 5 years of age or older. In some embodiments, the children are 4 years of age or older. In some embodiments, the children are 3 years of age or older. In some embodiments, the children are 1 year of age or older. In some embodiments, the children are infants.

[0119] Some embodiments relate to teplizumab for use in methods of treating clinical type 1 diabetes (T1D), with a dose of approximately 9000 μg / m² to subjects requiring it. 2 This includes administering a total dose of teplizumab exceeding [a certain value] over a 12-day course.

[0120] In some embodiments, the total dose is approximately 9000 to 9500 μg / m². 2 In some embodiments, the total dose is approximately 9000 to 14000 μg / m². 2 That is the case.

[0121] In some embodiments, a 12-day course involves a dose of 106 μg / m² on day 1. 2 The first dose of teplizumab was administered on day 2 at 425 μg / m². 2 The second dose of teplizumab, and 850 μg / m² on days 3 through 12. 2 It contains one dose, and the total dose is approximately 9031 μg / m². 2 That is the case.

[0122] In some embodiments, a 12-day course involves a dose of 211 μg / m² on day 1. 2 The first dose of teplizumab was administered on day 2 at 423 μg / m². 2 The second dose of teplizumab, and 840 μg / m² on days 3 through 12. 2 It contains one dose, and the total dose is approximately 9034 μg / m². 2 That is the case.

[0123] In some embodiments, the method may involve administering a first and second 12-day course of teplizumab. In some embodiments, the first and second 12-day courses are administered at intervals of approximately 1 to 6 months, approximately 2 to 5 months, or approximately 3 months.

[0124] In some embodiments, the method may involve administering a third or more 12-day course of teprizumab to a subject requiring it, with a total dose of approximately 9000 μg / m² per course. 2 That's all.

[0125] In some embodiments, the third or subsequent 12-day course of teplizumab is administered at a dose of 106 μg / m² on day 1. 2 The first dose of teplizumab was administered on day 2 at 425 μg / m². 2 The second dose of teplizumab, and 850 μg / m² on days 3 through 12. 2 The first dose is included, and the total dose for each course is approximately 9031 μg / m². 2 That is the case.

[0126] In some embodiments, the third or subsequent 12-day course of teplizumab is administered at a dose of 211 μg / m² on day 1. 2 The first dose of teplizumab was administered on day 2 at 423 μg / m². 2 The second dose of teplizumab, and 840 μg / m² on days 3 through 12. 2 The first dose is included, and the total dose for each course is approximately 9034 μg / m². 2 That is the case.

[0127] In some embodiments, the third and subsequent 12-day courses of teplizumab are administered at intervals of approximately 12 to 24 months.

[0128] In some embodiments, the method may further include determining a baseline level of TIGIT+KLRG1+CD8+ cells for all CD3+ T cells after each 12-day course of administration, monitoring the level of TIGIT+KLRG1+CD8+CD3+ T cells, and administering an additional 12-day course of teplizumab when the level of TIGIT+KLRG1+CD8+CD3+ T cells returns to baseline levels. In some embodiments, the determination of TIGIT+KLRG1+CD8+CD3+ T cells is performed by flow cytometry. In some embodiments, the monitoring of TIGIT+KLRG1+CD8+CD3+ T cells is performed by flow cytometry. In some embodiments, the determination of TIGIT+KLRG1+CD8+CD3+ T cells is performed approximately 1 to 6 months, approximately 2 to 5 months, or approximately 3 months after each 12-day course of administration. In some embodiments, if the subject has more than approximately 10% TIGIT+KLRG1+CD8+ T cells among all CD3+ T cells, subsequent monitoring is performed annually. In some embodiments, if the subject has less than approximately 10% TIGIT+KLRG1+CD8+ T cells among all CD8+ T cells, subsequent monitoring is performed approximately every 3 to 6 months.

[0129] In some embodiments, the subjects requiring it have been diagnosed with T1D within six weeks prior to the administration step.

[0130] In some embodiments, the administration step results in at least a 10% reduction in insulin use, HbA1c levels, hypoglycemic episodes, or a combination thereof, compared to pre-treatment levels.

[0131] In some embodiments, each dose is administered parenterally.

[0132] In some embodiments, each dose is administered by intravenous infusion.

[0133] In some embodiments, the target group is between 8 and 17 years old.

[0134] In some embodiments, subjects requiring it have a peak C peptide level of ≥0.2 pmol / mL during a mixed diet tolerance test (MMTT).

[0135] In some embodiments, subjects receiving teplizumab had higher mean C-peptide levels compared to controls receiving placebo.

[0136] In some embodiments, the method further includes evaluating the area under the time concentration curve (AUC) of C-peptide after a mixed diet tolerance test (MMTT) over 78 weeks.

[0137] In some embodiments, the subject requiring it has at least 20% beta cell function before the administration of the first dose.

[0138] In some embodiments, the reduction in insulin use, HbA1c levels, hypoglycemic episodes, or a combination thereof is achieved over a period of 12 months or longer.

[0139] Some embodiments describe methods for treating clinical type 1 diabetes (T1D) in which a total dose of approximately 9000 μg / m² is administered to a subject in need. 2The present invention relates to a method comprising administering teplizumab exceeding 12 mg / m² for 12 days. Some embodiments relate to teplizumab for use in a method of treating clinical type 1 diabetes (T1D), to subjects requiring it, at a dose of approximately 9000 μg / m². 2 This includes administering a total dose of teplizumab exceeding [a certain value] over a 12-day course.

[0140] In some embodiments, a method for treating clinical type 1 diabetes (T1D) is provided, in which approximately 9000 to approximately 9500 μg / m³ is administered to a subject in need. 2 A method is provided comprising administering teplizumab in a total dose over a 12-day course. In some embodiments, a method for treating clinical type 1 diabetes (T1D) is provided, in which a subject requiring it is given approximately 9000 to approximately 14000 μg / m². 2 A method is provided which involves administering teplizumab in a 12-day course with a total dose of [amount].

[0141] V. Exemplary Embodiments Non-limiting exemplary embodiments of this disclosure are further listed below. 1. A method for reducing the use of exogenous insulin in a subject requiring it, the method comprising administering to the subject a course of teplizumab for 12 to 14 days at a total dose of about 9000 μg / m2 to about 14000 μg / m2, wherein the administration of teplizumab results in a reduction of at least 0.08 U / kg / day of the use of exogenous insulin. 2. The method according to Embodiment 1, wherein administration of teplizumab reduces the amount of exogenous insulin used by at least 0.08 U / kg / day in the first year. 3. The method according to Embodiment 1, wherein administration of teplizumab reduces the amount of exogenous insulin used by at least 0.10 U / kg / day in the second year. 4. The method according to Embodiment 1, comprising administering a 12-day course of teplizumab to the subject. 5. The method according to Embodiment 1, comprising administering a 14-day course of teplizumab to the subject. 6. The method according to Embodiment 1, comprising administering a first and second 12- to 14-day course of teprizumab. 7. The method according to Embodiment 6, wherein the first and second 12- to 14-day courses are administered at intervals of approximately 6 months. 8. The method according to Embodiment 1, comprising administering a first and second 12-day course of teprizumab. 9. The method according to Embodiment 8, wherein the first and second 12-day courses are administered at intervals of approximately 6 months. 10. The method according to Embodiment 1, wherein the subject requiring it has stage 3 type 1 diabetes. 11. Any one of Embodiments 1 to 10, comprising administering teplizumab by intravenous infusion. 12. The method according to any one of Embodiments 1 to 10, wherein the subject requiring it is approximately 7.5 years of age or older. 13. The method according to any one of Embodiments 1 to 10, wherein the reduction in exogenous insulin use is carried out over a period of more than one year. 14. Teplizumab for use in a method for reducing the use of exogenous insulin in a subject requiring it, the method comprising administering teplizumab to the subject in a course of 12 to 14 days at a total dose of about 9000 μg / m2 to about 14000 μg / m2, wherein the administration of teplizumab results in a reduction of at least 0.08 U / kg / day of the use of exogenous insulin. [Examples]

[0142] In November 2022, teplizumab was approved as the first drug to delay the onset of stage 3 type 1 diabetes in adults and children aged 8 years and older with stage 2 type 1 diabetes, based on data from the primary trial TN-10. To evaluate the effect of teplizumab on maintaining endogenous insulin production, a pooled analysis of C-peptide data from 609 patients (375 teplizumab and 234 controls) from five stage 3 clinical trials was performed. The primary outcome of the pooled analysis, change from baseline in stimulated C-peptide, was significantly improved after one or two courses of teplizumab at year 1 (mean increase of 0.08 pmol / ml, p<0.0001) and year 2 (mean increase of 0.12 pmol / ml, p<0.0001). An analysis of exogenous insulin use also showed an overall decrease of 0.08 U / kg / d (p<0.0001) in year 1 and 0.10 U / kg / d (p=0.0001) in year 2. A pooled safety analysis was conducted on five clinical trials enrolling stage 2 or stage 3 patients, including 1018 patients (approximately 1500 patients treated with teplizumab - followed up). This analysis showed that the most common adverse events included lymphopenia, rash, and headache, the majority of which occurred during and after the first few weeks following teplizumab administration and generally resolved without intervention. These data confirm the consistency in maintenance of beta-cell function as measured by C-peptide and the safety profile characterized by self-limiting adverse events after one or two teplizumab treatments across multiple clinical trials.

[0143] Introduction Teplizumab was the first drug approved to alter the progression of autoimmunity in type 1 diabetes and the first drug approved for delaying any autoimmune disease in pre-clinical patients. This approval followed decades of trials, starting with preclinical studies, and included six clinical trials: five in patients with post-clinical diagnosis (stage 3) and one in patients with pre-clinical diagnosis (stage 2) who had two or more islet autoantibodies and glycemic abnormalities.

[0144] Teplizumab is a humanized IgG1 monoclonal antibody (mAb) that binds with high affinity to the epsilon chain of CD3 (CD3ε). Its complementarity-determining region (CDR) is derived from Ortho Kung T3 (OKT3), the first mAb approved for human use as a treatment for acute solid graft rejection. OKT3 was humanized to minimize immunogenicity. Two Leu-to-Ala substitutions were introduced in the Fc region, minimizing Fc receptor binding. As a result, T cell activation, T cell proliferation, and cytokine release in human peripheral blood mononuclear cell cultures were reduced 100 to 1,000 times compared to OKT3. 1-5 Early studies on the mechanism have shown that partial agonism leads to the action of CD8+ T cells, which are essential for autoimmune-mediated pancreatic beta cell destruction. 6-10 .

[0145] Teplizumab was initially tested as a treatment for acute transplant rejection and psoriatic arthritis. 11-14 At the same time, experiments using spontaneously occurring and chemically induced diabetic model mice showed that continuous administration, which has been necessary for immunotherapies tested to date, was unnecessary, providing evidence for the reversal, prevention, and immune tolerance of autoimmune diabetes. 15-17 .

[0146] The first randomized clinical trial targeting stage 3 type 1 diabetes was a phase 2 clinical trial (Trial 1), which evaluated the safety, tolerability, and efficacy of teplizumab given as a single 12 or 14-day course of treatment in patients with newly diagnosed stage 3 diabetes. 18 Efficacy was evaluated based on the maintenance of beta-cell function by assessing the C-peptide response to a mixed-diet tolerance test (MMTT). Following the success of this trial, a randomized phase 2 trial (AbATE[NCT00129259]) was conducted, administering a second course of teplizumab one year later to extend the duration of response. 18-20Subsequently, two Phase 3 trials (Protege and Encore [NCT00385697 and NCT00920582]) were conducted to test three dosing regimens of teplizumab administered over two courses at 6 - month intervals. In these trials, novel and unvalidated tests were conducted with the composite of exogenous insulin usage and HbA1c as the primary endpoints. In the interim analysis, the Protege trial did not meet the primary endpoint, leading to the end and discontinuation of further clinical development. 21 At the time these two trials ended, another Phase 2 trial (Delay [NCT00378508]) evaluated the effect of teplizumab in patients with clinically significant levels of stimulated C - peptide (e.g., > 0.2 pmol / ml) who were 4 - 12 months after the diagnosis of type 1 diabetes. 22 All five clinical trials showed promising C - peptide maintenance.

[0147] The second - stage trial, TN - 10 (NCT01030861), was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and conducted by the Type 1 Diabetes TrialNet to evaluate whether a single dose of teplizumab delays or prevents the clinical diagnosis of type 1 diabetes in patients with early - stage type 1 diabetes (stage 2). 23 In the trial, relatives of patients with type 1 diabetes aged 8 - 49 years with two or more islet autoantibodies and glycemic abnormalities were enrolled. The results showed that the median time to the onset of clinical type 1 diabetes was statistically significantly delayed compared to placebo patients, indicating that the decline of beta - cells was stabilized, leading to the maintenance of beta - cell function, and in the latest analysis, a delay in progression up to 2.7 years was reported. 23,24 。

[0148] The results of clinical trials support the maintenance of beta - cell function evaluated by C - peptide, a measure of endogenous insulin production. However, individual trials had different protocol designs, including heterogeneous eligibility criteria and the nature of the control groups, which may affect the overall interpretation of the results. 25 。

[0149] Therefore, the primary objective of this integrated analysis was to confirm the consistency of the effect of teprotumumab on beta cell function measured by stimulated C peptide levels across five clinical trials in stage 3 clinical type 1 diabetes patients. A secondary efficacy analysis was conducted for exogenous insulin use. A comprehensive review of the safety experience with teprotumumab in type 1 diabetes patients in both stage 2 and stage 3 was also evaluated.

[0150] Methods 1. Clinical trials The designs of six clinical trials have been published previously (Table 1). 19、20、22、23、26 The dosing regimens evolved over time to accommodate pediatric patients, from a 14-day dosing regimen (Study 1: 4 escalating doses based on body weight, total dose for 10 days) to 12 days (Study 1: 2-day escalation with a total dose for 10 days based on body surface area [BSA]) to 14 days (AbATE, Delay, Protege, Encore: 4-day escalation with a total dose for 10 days based on BSA) based on safety experience. All patients in the trials received standard care management for type 1 diabetes with insulin therapy. The investigators were advised to target glycemic control based on the recommendations of the American Diabetes Association. No specific algorithm for insulin administration was shown.

[0151] Most patients received, for the cumulative dose of 9,034 μg / m 2 on day 1, 51 μg / m 2 on day 2, 103 μg / m 2 on day 3, 206 μg / m 2 on day 4, 413 μg / m 2 and on days 5 to 14, 826 μg / m 2Patients received a complete 14-day regimen via intravenous infusion of teplizumab, including [specific ingredient]. Patients were randomly assigned to receive two courses of treatment in the Protege, Encore (at randomization and 6 months), and AbATE (at randomization and 12 months), one course of treatment in the Trial 1 and Delay, and in the Delay trial, patients could choose a second course of treatment (open-label). The Protege and Encore trials also included a regimen with a lower cumulative dose (6 days [2426 μg / m²]). 2 ] or a 14-day regimen of one-third dose [2985 μg / m²] 2 ]) was also considered. The low-dose regimen of Protege and the second course of Delay were not included in the efficacy analysis, but were included in the safety analysis.

[0152] 2. Efficacy Analysis Analysis of aC peptide response All five trials included in the combined efficacy analysis were conducted in patients with stage 3 type 1 diabetes who received a complete 14-day regimen and were randomized, placebo-controlled, or treated with a fixed timeframe design of standard care (Table 1). Patients in these trials were enrolled within 6, 8, 12, and 12 weeks of type 1 diabetes diagnosis for Trials 1, AbATE, Protege, and Encore, or within 4–12 months of type 1 diabetes diagnosis for the Delay trial. Stimulated C-peptide levels were detectable in all patients. Trials 1 and AbATE were open-label and randomized to either the investigational drug or standard care, while Delay, Protege, and Encore were double-blind, randomized, and placebo-controlled. Trials 1, AbATE, and Delay were conducted by academic researchers at US sites, while Protege and Encore were conducted by MacroGenics at sites in the US, Eastern Europe, and India.

[0153] A one-stage integrated intention-to-treatment (ITT) analysis was performed using individual patient data from all five trials, including one-year follow-up, and three trials (Trial 1, AbATE, and Protege), including two-year follow-up. The ITT population included all patients randomized to the 12- and 14-day teplizuma prednises in Trial 1, as well as the full 14-day teplizuma prednises in AbATE, Protege, Encore, and Delay, and patients randomized to standard care or placebo (e.g., control group) in all five trials (Table 2).

[0154] The primary endpoint was the change from baseline in the area under the C-peptide curve (AUC). Baseline was defined as the C-peptide measurement obtained before the first dose of teplizumab. The AUC in the 4-hour MMTT was converted by dividing it by 240 or the time to the last measurement for the C-peptide (ln(AUC+1)). The C-peptide was measured by radioimmunoassay (Study 1), TOSOH assay (AbATE and Delay), and chemiluminescence assay with Immulite® 2000 (Protege and Encore).

[0155] [Table 1]

[0156] [Table 2]

[0157] [Table 3]

[0158] Under the assumptions of "random missing data" and "non-random missing data," two analyses were performed on both observational and imputed missing data through multiple imputation methods. Changes from baseline C peptide were analyzed using analysis of covariance (ANCOVA). ANCOVA included age as a covariate, baseline C peptide, and treatment as the primary effect due to trials and trial-specific interactions. A trial-specific interaction term was included to assess whether there were differences in effects depending on the characteristics of individual trials and to adjust for these differences. Using the results from ANCOVA, the least squares mean (LSM) of each C peptide change from baseline AUC treatment difference, along with 95% confidence intervals (CI), was estimated. The number of treatment courses and their timing were determined by the trials and were therefore not included as separate covariates in ANCOVA. Parameter estimates and 95% CIs were created for the imputed dataset by averaging the estimates of 100 imputations. All parameter estimates for the treatment LSM and the difference in their respective 95% CIs are shown in a forest plot.

[0159] b. Analysis of exogenous insulin use The second pooled analysis evaluated the daily exogenous insulin use (U / kg / day) in the same trials. This analysis used the mean total daily insulin dose (all insulin). Individual patient data for insulin use were collected from all five trials with one-year follow-up, and from trials 1, AbATE, and Protege where two-year data were available. ANCOVA was used to assess treatment differences in insulin use, using covariates including baseline insulin use, treatment, age, trial, and treatment-specific interactions. Both observed and supplemented data were analyzed.

[0160] 3.Safety analysis All five trials included in the combined safety analysis were conducted in Stage 2 (TN-10) or Stage 3 (AbATE, Protege, Encore, and Delay) clinical trials using BSA-based dosing regimens (Supplementary Tables 1 and 3). Safety data from Trial 1 were not included because it included weight-based dosing. Safety assessments included analyses of adverse events (AEs), mechanism-related adverse events considered to be adverse events of special interest (AESIs), and serious adverse events (SAEs). The safety population consisted of all patients in the three dosing regimens (full 14-day, 6-day, and 1 / 3-dose 14-day regimens) who received at least one dose of teplizumab or were randomized to placebo or standard care (e.g., control). Data are described using descriptive statistics. All analyses were performed using SAS software version 9.4.

[0161] result 1. Efficacy Analysis Analysis of aC peptide response The ITT population for the efficacy analysis included a total of 609 patients from five clinical trials: 375 in the teplizumab group and 234 in the control group. In the teplizumab group, 88% of patients completed their respective trials. In the teplizumab group, 3 patients (0.8%) withdrew early due to adverse events, and 17 patients (4.5%) were lost to follow-up. In the control group, there were no patients who withdrew early due to adverse events, and 6 patients (2.6%) were lost to follow-up.

[0162] Baseline demographics and clinical characteristics were similar across treatment groups, but there were some differences between study cohorts (Table 2). Patients in Protege and Encore were older and had a longer time since diagnosis than those in Study 1 and AbATE. Patients in the Delay study were, by design, 4–12 months since diagnosis.

[0163] The forest plot of the LSM differences and their respective 95% CIs for changes from baseline C-peptide from the integrated analysis of five trials is presented in Panel A of Figure 1. These data show a highly statistically significant (p<0.0001) maintenance of C-peptide with teprilizumab treatment compared to placebo or standard care for both 1-year and 2-year data (observed and imputed). For the observed data, the difference in treatment effect between the teprilizumab and control groups was 0.08 (95% CI: 0.04, 0.12) pmol / mL at year 1 and 0.12 (95% CI: 0.07, 0.17) pmol / mL at year 2. For the imputed data, the difference in treatment effect between the teprilizumab and control groups was 0.09 (95% CI: 0.05, 0.13) pmol / mL at year 1 and 0.10 (95% CI: 0.05, 0.16) pmol / mL at year 2.

[0164] The individual trials and annual analyses are shown in Panel B of Figure 1. There was a significant improvement in C-peptide in each trial, except for Encore, which had a large amount of missing data due to early termination of the trial. In each of the three trials using the available 2-year data, teprilizumab treatment significantly maintained C-peptide levels compared to placebo.

[0165] The C-peptide plots for 1-year and 2-year data are shown in Panels A and B of Figure 2, respectively. The C-peptide AUC values at the 6-month time point increased in the teprilizumab group (mean increases of 5% and 8% for 1-year and 2-year data, respectively) and decreased in the control group. The decrease in C-peptide AUC from baseline at year 1 was 8% and 27% in the teprilizumab and control groups, respectively (p<0.0001). In the trials using 2-year data, the decrease from baseline levels was 34% and 51% in teprilizumab and control, respectively (p<0.0001).

[0166] b. Integrated analysis of exogenous insulin use Because each clinical trial used a therapeutic approach aimed at achieving goals for diabetes management, any effect of teplizumab treatment on endogenous beta-cell function is reflected in changes in exogenous insulin requirements.

[0167] In the forest plot of the pooled analysis of insulin use, the teprizumab treatment group showed a statistically significant reduction in insulin use at 1 year (-0.08 U / kg / d [-0.12, -0.05]; p < 0.0001) and 2 years (-0.10 U / kg / d [-0.15, -0.05]; p = 0.0001) compared to the control group (Figure 3, Panels A and B, respectively). Individually, Trial 1 and AbATE showed statistically significantly lower insulin use in teprizumab-treated patients compared to controls (p < 0.0001 at 1 and 2 years for both trials). However, the point estimates across all trials supported the reduction in insulin use in teprizumab-treated patients.

[0168] The time course of insulin use is graphically shown in panels C and D of Figure 2. Baseline values ​​were similar in both groups. Significantly lower insulin use was observed in three trials (AbATE, Protege, and Encore) with 1-year (0.58 vs. 0.65 U / kg / day; p<0.0001) and 2-year data (0.66 vs. 0.74 U / kg / day; p=0.0001). Insulin discontinuation data is available only for the Protege trial, where patients did not discontinue insulin unless instructed by the principal investigator. Despite treatment being blinded, at year 1, 5.3% (11 / 207) of patients in the full-dose 14-day teplizumab group were not taking insulin, compared to 0% (0 / 98) in the control group (p=0.02). At year 2, three of these 11 patients remained insulin-discontinued, while all control patients continued insulin (p<0.05).

[0169] 2.Safety analysis a. Integrated safety analysis A total of 1,018 patients with stage 2 and stage 3 type 1 diabetes were included in the safety pooled analysis. 773 were randomized to teplizumab treatment, and 245 were randomized to control (Table 3). The follow-up period for patients receiving teplizumab treatment was approximately 1,500 patient-years. Baseline demographic and clinical characteristics in this expanded group were similar across treatment groups.

[0170] [Table 4]

[0171] Table 4 summarizes the adverse events (AEs). Nearly all patients in either treatment group experienced AEs, most of which were of grade 1 or grade 2 severity, typically occurring during or immediately after the administration period. The majority of AEs resolved without intervention. AEs leading to permanent discontinuation of the study drug were reported in 14.3% and 3.7% of the teplizumab and control groups, respectively. The most common reasons for discontinuation in the teplizumab group were laboratory findings (7.7%; mainly elevated liver enzymes meeting the protocol-defined discontinuation threshold) and hematological and lymphatic disorders (3.2%; including neutropenia, thrombocytopenia, lymphopenia, and anemia).

[0172] [Table 5]

[0173] SAEs were reported in 12.4% and 8.2% of patients in the teplizumab and control groups, respectively, but the majority (76.7%) were considered unrelated to treatment. The most common SAEs were related to the underlying pathophysiology of type 1 diabetes, with the most notable being diabetic ketoacidosis (DKA) (n=18, 2.3% teplizumab; n=1, 0.4% control) and ketoacidosis (n=1, 0.1% teplizumab; n=0, control). These events were reported at an average of 10 months after the end of teplizumab treatment, and the mean HbA1c level around the time of the event was 11.9%, suggesting underlying poor glycemic control. SAEs of hypoglycemic events were observed only in stage 3 patients and not in stage 2 patients. The rates of hypoglycemic loss of consciousness and hypoglycemic coma were similar in both groups.

[0174] Table 4 shows the most common adverse events (AEs) reported in 10% or more of patients in either group. AEs reported more frequently in the teplizumab group than in the control group were lymphopenia, leukopenia, neutropenia, decreased blood bicarbonate levels, and rash, all of which occurred during the treatment period and typically resolved within 4 weeks of initiation. Lymphopenia was observed in approximately 80% of teplizumab-treated patients, with the lowest point being day 5 of treatment. It resolved during continued medication and was consistent with peripheral lymphocyte trend, not with cellular depletion.

[0175] Cytokine release syndrome (CRS) was reported in 5.8% (46 / 791) and 1.2% (3 / 245) of teplizumab patients and control patients, respectively. CRS typically occurred during the first 3–5 days of administration and resolved within 2–3 days of onset. Most (88%) events were grade 1 or 2 in severity and were treated with non-prescription medications.

[0176] Infection rates were similar between teplizumab-treated patients (53.0%) and control patients (52.7%), with serious infections occurring in 3.5% and 2% of teplizumab patients and control patients, respectively. New Epstein-Barr virus (EBV) infections were reported in 18 (2.3%) and 10 (4.1%) teplizumab patients and control patients, respectively. EBV reactivation was reported in 40 (5.1%) teplizumab-treated patients and 6 (2.4%) control patients. EBV viremia was detected in 25 (3.2%) and 3 (1.2%) teplizumab patients and control patients, respectively, 2-3 weeks after administration, and was generally asymptomatic and resolved spontaneously without antiviral medication. New cytomegalovirus (CMV) infections were detected in 5 patients (0.6%) treated with teplizumab and 2 patients (0.8%) in the control group. CMV reactivation occurred in 4 patients (0.5%) treated with teplizumab; none of these cases were symptomatic, and all resolved spontaneously without antiviral treatment.

[0177] Hypersensitivity reactions, including anaphylaxis (0.1%), angioedema (0.3%), peripheral edema (1.6%), and urticaria (1.9%), were reported in patients treated with teplizumab. Rashes were observed in 48% of teplizumab patients and 15% of control patients, respectively.

[0178] Consideration TZIELD® (teplizumab-mzwv), a disease-modifying therapy, has been approved as the first treatment to delay the onset of clinically stage 3 type 1 diabetes. Teplizumab is thought to modify disease progression from stage 2 to stage 3 type 1 diabetes by maintaining beta-cell function. Over the past 20 years, five clinical trials of teplizumab in stage 3 type 1 diabetes have demonstrated maintenance of beta-cell function, as measured by C-peptide levels. To assess the consistency of beta-cell maintenance, a pooled analysis of C-peptide data from the five clinical trials was conducted and supported by an analysis of exogenous insulin use. A comprehensive safety experience review was evaluated by integrating data from 791 teplizumab-treated patients representing approximately 1,500 patients-yearly follow-ups. 18ー23 This represents the most comprehensive data to date on single-agent disease modification in type 1 diabetes.

[0179] A pooled efficacy analysis showed that C-peptide levels were maintained to a significantly greater extent in patients treated with teplizumab compared to controls at 1 and 2 years post-treatment. The increase in C-peptide levels, an indicator of endogenous insulin production, was supported by a reduction in exogenous insulin use.

[0180] It is important to note that the patients were heterogeneous in terms of other patient characteristics, such as age (a potential determinant of the rate of C-peptide decline), location (North America, India, Eastern Europe), clinical habits, and adolescent status that may affect insulin sensitivity. 27Furthermore, some patients received treatment immediately after diagnosis, while others received treatment up to one year after diagnosis, suggesting biological differences in the autoimmune processes of the patients. Additionally, different assays were used for C-peptide measurement. However, the same protocol for MMTT was followed in all trials, and the analysis included changes in beta-cell function from baseline. An exploratory analysis of data from the Protege trial indicated that the teplizumab-induced C-peptide responsiveness was greater in patients with a pre-randomization diagnosis of less than six weeks prior, and in US patients, where baseline metabolic parameters were suggested to be less advanced than in patients from other regions. 21 In the Delay trial, which investigated teplizumab in patients diagnosed with stage 3 type 1 diabetes within the past 4 to 12 months, the time since diagnosis did not significantly alter the therapeutic effect on the C-peptide response. 22 However, the magnitude of the therapeutic effect of teplizumab on the C-peptide response between patients and control patients was smaller in that trial than in trials where patients were treated with teplizumab within weeks of diagnosis. Therefore, treatment may be necessary for an optimal response to the drug immediately after or even before the diagnosis of the clinical disease. In Protege and Delay, teplizumab was effective across all age groups, but younger patients treated with teplizumab had a better C-peptide response than older patients. Data from these trials are from the PROTECT trial (NCT03875729), which is evaluating teplizumab in newly diagnosed stage 3 type 1 diabetes patients aged 8–17 years with evidence of residual beta-cell function. 28 It is used in the design. The results of the pooled analysis showed significant differences in C-peptide maintenance across multiple trials, and the trials supporting the consistency of the effect of teplizumab treatment suggest that its biological effect is robust and reproducible and not specific to any particular trial or patient characteristics.

[0181] The safety profile of teplizumab was characterized by mild to moderate adverse events, which were self-limiting. CRS was observed in 5.8% of patients and was likely attributable to the partial agonist effect of teplizumab. 1,29 The incidence of serious infections (3.5% for teplizumab vs. 2% for control) was higher, but the overall incidence of infections was similar between treatment groups. Lymphocytopenia was observed in the majority of teplizumab-treated patients (approximately 80%), but treatment was continued and the condition improved without interruption of treatment. 30,31 Importantly, the onset of transient lymphopenia did not appear to be associated with an overall increased risk of infection. Although not included in the pooled analysis, a 7-year follow-up of patients in the AbATE trial showed no increased risk of infection and no malignancies were observed. 32 Previous preclinical studies and cell analyses from teplizumab-treated patients have suggested that this partial agonist signaling may lead to partial depletion of CD8+ T cells. Indeed, studies of patients in the AbATE and rTN-10 trials showed that CD8+ TIGIT+ KLRG1+ memory T cells in teplizumab-treated patients showed signs of exhaustion, and the production levels of inflammatory cytokines TNFα and IFNγ, which are associated with T cell-mediated β-cell death, were lower. 24 Teplizumab targets activated effector cells and preserves regulatory T cells and memory T cells against previously encountered pathogens, thus maintaining beta cells is achieved without long-term effects on immune capacity. 32 .

[0182] The integrated analysis of C peptide could not address whether the benefit of a second course of teplizumab was greater than that of a single treatment course, and future trials may help address this. The trial design, which targeted blood glucose levels, had limitations in its ability to assess the therapeutic effect on HbA1c levels. Nevertheless, improvements in HbA1c levels were observed at several time points in Trial 1 and AbATE.

[0183] In conclusion, the combined efficacy analysis provided robust evidence for statistically significant maintenance of beta-cell function in patients with stage 3 type 1 diabetes associated with the clinical benefit of reduced exogenous insulin requirements. These data provide a biological basis for disease-modifying therapies for type 1 diabetes and further support teplizumab as a promising treatment for addressing the underlying autoimmune pathology of type 1 diabetes. The recent approval for delaying the onset of stage 3 type 1 diabetes in adult patients and children aged 8 years and older with stage 2 type 1 diabetes, built upon the data presented herein, represents the first step toward achieving the goal of developing disease-modifying therapies.

[0184] Modifications and alterations of the methods and compositions described herein will be apparent to those skilled in the art without departing from the scope and spirit of the disclosure. Although the disclosure has been described in relation to specific embodiments, it should be understood that the claimed disclosure should not be unduly limited to such specific embodiments. In fact, various modifications of the described embodiments for carrying out the disclosure are intended and understood by those skilled in the art in which the disclosure exists and fall within the scope of the disclosure as expressed by the following claims.

[0185] Embedding by reference All patents and publications referenced herein are incorporated herein by reference to the same extent as each individual patent and publication is specifically and individually indicated as being incorporated by reference.

[0186] References 1.Xu D, Alegre ML, Varga SS, et al.In vitro characterization of five humanized OKT3 effector function variant antibodies.Cell Immunol.Feb 25 2000;200(1):16-26.doi:10.1006 / cimm.2000.1617 2.Gaglia J,Kissler S.Anti-CD3 Antibody for the Prevention of Type 1 Diabetes:A Story of Perseverance.Biochemistry.Oct 08 2019;58(40):4107-4111.doi:10.1021 / acs.biochem.9b00707 3.Kuhn C,Weiner HL.Therapeutic anti-CD3 monoclonal antibodies:from bench to bedside.Immunotherapy.Jul 2016;8(8):889-906.doi:10.2217 / imt-2016-0049 4.LP.COBP.Prescribing Information Orthoclone OKT3.worldwideweb.drugs.com / pro / orthoclone-okt3.html 5.Masharani UB,Becker J.Teplizumab therapy for type 1 diabetes.Expert Opin Biol Ther.Mar 2010;10(3):459-65.doi:10.1517 / 14712591003598843 6.Long SA,Thorpe J,DeBerg HA,et al.Partial exhaustion of CD8 T cells and clinical response to teplizumab in new-onset type 1 diabetes.Sci Immunol.Nov 2016;1(5)doi:10.1126 / sciimmunol.aai7793 7.Long SA,Thorpe J,Herold KC,et al.Remodeling T cell compartments during anti-CD3 immunotherapy of type 1 diabetes.Cell Immunol.Sep 2017;319:3-9.doi:10.1016 / j.cellimm.2017.07.007 8.Ablamunits V,Bisikirska B,Herold KC.Acquisition of regulatory function by human CD8(+)T cells treated with anti-CD3 antibody requires TNF.Eur J Immunol.Oct 2010;40(10):2891-901.doi:10.1002 / eji.201040485 9.Bisikirska B,Colgan J,Luban J,Bluestone JA,Herold KC.TCR stimulation with modified anti-CD3 mAb expands CD8+ T cell population and induces CD8+CD25+ Tregs.J Clin Invest.Oct 2005;115(10):2904-13.doi:10.1172 / jci23961 10.Lebastchi J,Deng S,Lebastchi AH,et al.Immune therapy and β-cell death in type 1 diabetes.Diabetes.May 2013;62(5):1676-80.doi:10.2337 / db12-1207 11.Woodle ES,Bluestone JA,Zivin RA,et al.Humanized,nonmitogenic OKT3 antibody,huOKT3 gamma(Ala-Ala):initial clinical experience.Transplant Proc.Jun 1998;30(4):1369-70.doi:10.1016 / s0041-1345(98)00278-4 12.Woodle ES,Xu D,Zivin RA,et al.Phase I trial of a humanized,Fc receptor nonbinding OKT3 antibody,huOKT3gamma1(Ala-Ala)in the treatment of acute renal allograft rejection.Transplantation.Sep 15 1999;68(5):608-16.doi:10.1097 / 00007890-199909150-00003 13.Utset TO,Auger JA,Peace D,et al.Modified anti-CD3 therapy in psoriatic arthritis:a phase I / II clinical trial.J Rheumatol.Sep 2002;29(9):1907-13. 14.Hering BJ,Kandaswamy R,Harmon JV,et al.Transplantation of cultured islets from two-layer preserved pancreases in type 1 diabetes with anti-CD3 antibody.Am J Transplant.Mar 2004;4(3):390-401.doi:10.1046 / j.1600-6143.2003.00351.x 15.Hayward AR,Shreiber M.Neonatal injection of CD3 antibody into nonobese diabetic mice reduces the incidence of insulitis and diabetes.J Immunol.Sep 01 1989;143(5):1555-9. 16.Chatenoud L,Thervet E,Primo J,Bach JF.Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice.Proc Natl Acad Sci USA.Jan 04 1994;91(1):123-7.doi:10.1073 / pnas.91.1.123 17.Chatenoud L,Primo J,Bach JF.CD3 antibody-induced dominant self tolerance in overtly diabetic NOD mice.J Immunol.Mar 15 1997;158(6):2947-54. 18.Herold KC,Hagopian W,Auger JA,et al.Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus.N Engl J Med.May 30 2002;346(22):1692-8.doi:10.1056 / NEJMoa012864 19.Herold KC,Gitelman SE,Masharani U,et al.A single course of anti-CD3 monoclonal antibody hOKT3gamma1(Ala-Ala)results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes.Diabetes.Jun 2005;54(6):1763-9.doi:10.2337 / diabetes.54.6.1763 20.Herold KC,Gitelman SE,Ehlers MR,et al.Teplizumab(anti-CD3 mAb)treatment preserves C-peptide responses in patients with new-onset type 1 diabetes in a randomized controlled trial:metabolic and immunologic features at baseline identify a subgroup of responders.Diabetes.Nov 2013;62(11):3766-74.doi:10.2337 / db13-0345 21.Sherry N,Hagopian W,Ludvigsson J,et al.Teplizumab for treatment of type 1 diabetes(Protege study):1-year results from a randomised,placebo-controlled trial.Lancet.Aug 6 2011;378(9790):487-97.doi:10.1016 / s0140-6736(11)60931-8 22.Herold KC,Bundy BN,Long SA,et al.An Anti-CD3 Antibody,Teplizumab,in Relatives at Risk for Type 1 Diabetes.N Engl J Med.Aug 15 2019;381(7):603-613.doi:10.1056 / NEJMoa1902226 23.Herold KC,Gitelman SE,Willi SM,et al.Teplizumab treatment may improve C-peptide responses in participants with type 1 diabetes after the new-onset period:a randomised controlled trial.Diabetologia.Feb 2013;56(2):391-400.doi:10.1007 / s00125-012-2753-4 24.Sims EK,Bundy BN,Stier K,et al.Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals.Sci Transl Med.Mar 3 2021;13(583)doi:10.1126 / scitranslmed.abc8980 25.Jacobsen LM,Bundy BN,Greco MN,et al.Comparing Beta Cell Preservation Across Clinical Trials in Recent-Onset Type 1 Diabetes.Diabetes Technol Ther.Dec 2020;22(12):948-953.doi:10.1089 / dia.2020.0305 26.Herold KC,Gitelman SE,Ehlers MR,et al.Teplizumab(anti-CD3 mAb)treatment preserves C-peptide responses in patients with new-onset type 1 diabetes in a randomized controlled trial:metabolic and immunologic features at baseline identify a subgroup of responders.Diabetes.Nov 2013;62(11):3766-74.doi:10.2337 / db13-0345 27.Greenbaum CJ,Beam CA,Boulware D,et al.Fall in C-peptide during first 2 years from diagnosis:evidence of at least two distinct phases from composite Type 1 Diabetes TrialNet data.Diabetes.Aug 2012;61(8):2066-73.doi:10.2337 / db11-1538 28.Recent-onset type 1 diabetes trial evaluating efficacy and safety of teplizumab(PROTECT):clinicaltrials.gov / ct2 / show / NCT03875729 29.Alegre ML,Peterson LJ,Xu D,et al.A non-activating “humanized“ anti-CD3 monoclonal antibody retains immunosuppressive properties in vivo.Transplantation.Jun 15 1994;57(11):1537-43. 30.Herold KC,Gitelman S,Greenbaum C,et al.Treatment of patients with new onset Type 1 diabetes with a single course of anti-CD3 mAb Teplizumab preserves insulin production for up to 5 years.Clin Immunol.Aug 2009;132(2):166-73.doi:10.1016 / j.clim.2009.04.007 31.Waldron-Lynch F,Henegariu O,Deng S,et al.Teplizumab induces human gut-tropic regulatory cells in humanized mice and patients.Sci Transl Med.Jan 25 2012;4(118):118ra12.doi:10.1126 / scitranslmed.3003401 32.Perdigoto AL,Preston-Hurlburt P,Clark P,et al.Treatment of type 1 diabetes with teplizumab:clinical and immunological follow-up after 7 years from diagnosis.Diabetologia.Apr 2019;62(4):655-664.doi:10.1007 / s00125-018-4786-9 33.Abdul-Rasoul M,Habib H,Al-Khouly M.“The honeymoon phase” in children with type 1 diabetes mellitus:frequency,duration,and influential factors.Pediatr Diabetes.2006;7(2):101-107. 34.Ablamunits V,Bisikirska B,Herold KC.Acquisition of regulatory function by human CD8+ T cells treated with anti-CD3 antibody requires TNF.Eur J Immunol.2010;40(10):2891-2901. 35.Agiostratidou G,AnhaltH,Ball D,et al.Standardizing clinically meaningful outcome measures beyondHbA1c for type 1 diabetes:a consensus report of the American Association of Clinical Endocrinologists,the American Association of Diabetes Educators,the American Diabetes Association,the Endocrine Society,JDRF International,The Leona M.andHarry B.Helmsley Charitable Trust,the Pediatric Endocrine Society,and the T1D Exchange.Diabetes Care.2017;40(12):1622-1630. 36.Akirav EM,Kushner JA,Herold KC.β cell mass and type 1 diabetes:Going,going,gone? Diabetes.2008;57:2883-2888. 37.American Diabetes Association.12.Children and Adolescents:Standards of medical Care in Diabetes-2018.Diabetes Care.2018;41(Suppl.1):S126-S136. 38.Atkinson MA.Type 1 diabetes.Lancet.2014;383(9911):69-82 39.Bisikirska B,Colgan J,Luban J,Bluestone,JA,Herold KC.TCR stimulation with modified anti-CD3 mAb expands CD8+ T cell population and induces CD8+CD25+ Tregs.J Clin Invest.2005;115(10):2904-2913. 40.Bluestone JA,Herold K,and Eisenbarth G.Genetics,pathogenesis and clinical interventions in type 1 diabetes.Nature.2010;464(7293):1293-1300. 41.Boyle KD,Keyes-Elstein L,Ehlers MR,et al.Two- and four-hour tests differ in capture of C-peptide responses to a mixed meal in type 1 diabetes.Diabetes Care.2016;39:e76-78. 42.Bradley C,Loewenthal K,Woodcock A,et al.Development of the diabetes treatment satisfaction questionnaire(DTSQ)for teenagers and parents:the DTSQ-Teen and the DTSQ-Parent.Diabetologia.2009;52:(Suppl 1)S397,Abstract 1013. 43.Campbell-Thompson M,Fu A,Kaddis JS,et al.Insulitis and β-cell mass in the natural history of type 1 diabetes.Diabetes.2016;65:719-731. 44.Danne T,Nimri R,Battelino T,et al.International consensus on use of continuous glucose monitoring.Diabetes Care 2017;40:1631-1640. 45.Diabetes Control and Complications Trial Research Group.Hypoglycemia in the Diabetes Control and Complications Trial.Diabetes.1997;46(2):271-286. 46.DiMeglio LA,Acerini CL,Codner E,et al.ISPAD Clinical Practice Consensus Guidelines 2018:Glycemic control targets and glucose monitoring for children,adolescents,and young adults with diabetes.Pediatr Diabetes.2018 Oct;19 Suppl 27:105-114. 47.Driscoll KA,Raymond J,Naranjo D,et al.Fear of hypoglycemia in children and adolescents and their parents with type 1 diabetes.Curr Diab Rep.2016;16(8):77. 48.European Medicines Agency.Ethical Considerations for Clinical Trials on Medicinal Products Conducted with the Paediatric Population.2008.https: / / ec.europa.eu / health / sites / health / files / files / eudralex / vol-10 / ethical_considerations_en.pdf.Accessed September 27,2018. 49.Fonolleda M,Murillo M,Vazquez F,et al.Remission phase in paediatric type 1 diabetes:new understanding and emerging biomarkers.Horm Res Paediatr.2017;88(5):307-315. 50.Gitelman SE,Gottlieb PA,Rigby MR,et al.Antithymocyte globulin treatment for patients with recent-onset type 1 diabetes:12-month results of a randomised,placebo-controlled,phase 2 trial.Lancet Diabetes Endocrinol.2013;1(4):306-16. 51.Gonder-Frederick L,Nyer M,Shepard JA.Assessing fear of hypoglycemia in children with Type 1 diabetes and their parents.Diabetes Manag(Lond).2011;1(6):627-639. 52.Greenbaum CJ,Beam CA,Boulware D et al.Fall in C peptide during first 2 years from diagnosis:evidence of at least two distinct phases from composite type 1 diabetes TrialNet data.Diabetes.2012;61:2066-2073. 53.Hagopian W,Ferry RJ Jr,Sherry N et al,Protege Trial Investigators.Teplizumab preserves C-peptide in recent-onset type 1 diabetes:two-year results from the randomized,placebo-controlled Protege trial.Diabetes.2013;62(11):3901-8.doi:10.2337 / db13-0236.Epub 2013 Jun 25. 54.Helminen O,Pokka T,Tossavainen P,et al.Continuous glucose monitoring andHbA1c in the evaluation of glucose metabolism in children at high risk for type 1 diabetes mellitus.Diabetes Res Clin Pract.2016;120:89-96. 55.Herold KC,Hagopian W,Auger JA,Poumian-Ruiz E,Taylor L,Donaldson D,Gitelman SE,Harlan DM,Xu D,Zivin RA,Bluestone JA.Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus.N Engl J Med.2002 May 30;346(22):1692-1698. 56.Herold KC,Gitelman SE,Umest M et al.A single course of anti-CD3 monoclonal antibody hOKT3γ1(Ala-Ala)results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes.Diabetes.2005;54:1-7. 57.Herold KC,Gitelman SE,Ehlers MR,et al.Teplizumab(anti-CD3 mAb)treatment preserves C-peptide responses in patients with new-onset type 1 diabetes in a randomized controlled trial:metabolic and immunologic features at baseline identify a subgroup of responders.Diabetes.2013(a);62(11):3766-3774. 58.Herold KC,Gitelman SE,Willi SM,et al.Teplizumab treatment may improve C-peptide responses in participants with type 1 diabetes after the new-onset period:a randomised controlled trial.Diabetologia.2013(b);56(2):391-400. 59.Herold KC,Bundy BN,Long SA,et al.An Anti-CD3 Antibody,Teplizumab,in Relatives at Risk for Type 1 Diabetes.N Engl J Med.2019 Jun 9.doi:10.1056 / NEJMoa1902226.[Epub ahead of print] 60.Huo L,Harding JL,Peeters A,et al.Life expectancy of type 1 diabetic patients during 1997-2010:a national Australian registry-based cohort study.Diabetologia.2016;59(6):1177-85. 61.InternationalHypoglycaemia Study Group.Glucose Concentrations of Less Than 3.0 mmol / L(54 mg / dL)Should Be Reported in Clinical Trials:A Joint Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes.Diabetes Care.2016;dc162215. 62.Joint Commission.High Alert Medications and Patient Safety.Sentinel Event Alert.Issue 11.November 19,1999.https: / / www.jointcommission.org / assets / 1 / 18 / SEA_11.pdf.Accessed August 21,2018. 63.Karvonen M,Viik-Kajander M,Moltchanova E,et al.Incidence of childhood type 1 diabetes worldwide.Diabetes Mondiale(DiaMond)Project Group.Diabetes Care.2000;23(10):1516-1526. 64.Kuhtreiber WM,Washer SL,Hsu E,et al.Low levels of C-peptide have clinical significance for established Type 1 diabetes.Diabet Med.2015 Oct;32(10):1346-53. 65.Lachin JM,McGee P,Palmer JP;DCCT / EDIC Research Group.Impact of C-peptide preservation on metabolic and clinical outcomes in the Diabetes Control and Complications Trial.Diabetes.2014;63(2):739-748. 66.Laitinen OH,HonkanenH,Pakkanen O,et al.Coxsackievirus B1 is associated with induction of β-cell autoimmunity that portends type 1 diabetes.Diabetes.2014;63(2):446-455. 67.Lebastchi J,Deng S,Lebastchi AH,et al.Immune therapy and β-cell death in type 1 diabetes.Diabetes.2013;62(5):1676-1680. 68.Lin A,Northam EA,Werther GA,Cameron FJ.Risk factors for decline in IQ in youth with type 1 diabetes over the 12 years from diagnosis / illness onset.Diabetes Care.2015;38:236-242. 69.Lind M,Svensson AM,Kosiborod M,et al.Glycemic control and excess mortality in type 1 diabetes.N Engl J Med.2014;371:1972-1982. 70.Long SA,Thorpe J,DeBerg HA,et al.Partial exhaustion of CD8 T cells and clinical response to teplizumab in new-onset type 1 diabetes.Sci.Immunol.2016;1(5):1-23. 71.Long SA,Thorpe J,Herold KC,et al.Remodeling T cell compartments during anti-CD3 immunotherapy of type 1 diabetes.Cell Immunol.2017 Sep;319:3-9. 72.Ludvigsson J,Carlsson A,Deli A,et al.Decline of C-peptide during the first year after diagnosis of Type 1 diabetes in children and adolescents.Diabetes Res Clin Pract.2013;100(2):203-209. 73.Masharani UB,Becker J.Teplizumab therapy for type 1 diabetes.Expert Opin Biol Ther.2010;10(3):459-465. 74.Matveyneko AV and Butler PC.Relationship between β cell mass and diabetes onset.Diabetes Obes Metab.2008;10:23-31. 75.Mittermayer F,Caveney E,De Oliveira C,et al.Addressing Unmet Medical Needs in Type 1 Diabetes:A Review of Drugs Under Development.Curr Diabetes Rev.2017;13(3):300-314. 76.Monaghan M,Helgeson V,Wiebe D.Type 1 diabetes in young adulthood.Curr Diabetes Rev.2015;11(4):239-250. 77.MortensenHB,Hougaard P,Swift P,et al.New definition for the partial remission period in children and adolescents with type 1 diabetes.Diabetes Care.2009;32:1384-1390. 78.National Cancer Institute.Common Terminology Criteria for Adverse Events(CTCAE).https: / / ctep.cancer.gov / protocolDevelopment / electronic_applications / ctc.htm.Updated March 1,2018.Accessed September 27,2018. 79.Orban T,Bundy B,Becker DJ,et al.Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes:a randomised,double-blind,placebo-controlled trial.Lancet 2011;378(9789):412-419. 80.Palmer JP,Fleming GA,Greenbaum CJ,et al.C-peptide is the appropriate outcome measure for type 1 diabetes clinical trials to preserve beta-cell function:report of an ADA workshop,21-22 October 2001.Diabetes.2004;53(1):250-264. 81.Palmer JP.C-peptide in the natural history of type 1 diabetes.Diabetes Metab Res Rev.2009;25(4):325-328. 82.Rawshani A,Rawshani A,Franzen S,et al.Mortality and Cardiovascular Disease in Type 1 and Type 2 Diabetes.N Engl J Med.2017;376(15):1407-1418. 83.Rawshani A,Sattar N,Franzen S,et al.Excess mortality and cardiovascular disease in young adults with type 1 diabetes in relation to age at onset:a nationwide,register-based cohort study.Lancet.2018;392(10146):477-486. 84.Rigby MR,DiMeglio LA,Rendell MS,et al.Targeting of memory T cells with alefacept in new-onset type 1diabetes(T1DAL study):12-month results of a randomised,double-blind,placebo-controlled phase 2 trial.Lancet Diabetes Endocrinol.2013;1(4):284-294. 85.Rigby MR,Ehlers MR.Targeted Immune Interventions for Type 1 Diabetes:Not as Easy as it Looks! Curr Opin Endocrinol Diabetes Obes.2014;21(4):271-278. 86.Rigby MR,Harris KM,Pinckney A,et al.Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients.J Clin Invest.2015;125(8):3285-3296. 87.Roark CL,Anderson KM,Simon LJ,et al.Multiple HLA epitopes contribute to type 1 diabetes susceptibility.Diabetes.2014;63(1):323-331. 88.Rosenzweig M,Rosenthal CA,Torres VM,Vaickus L.Development of a quantitative assay to measure EBV viral load in patients with autoimmune type 1 diabetes and healthy subjects.J Virol Methods.2010;164(1-2):111-115. 89.Seaquist ER,Anderson J,Childs B,et al.Hypoglycemia and diabetes:a report of a workgroup of the American Diabetes Association and the Endocrine Society.Diabetes Care.2013;36(5):1384-1395. 90.Secrest AM,Becker DJ,Kelsey SF,LaPorte RE,and Orchard TJ.Characterising sudden death and dead-in-bed syndrome in Type 1 diabetes:analysis from 2 childhood-onset Type 1 diabetes registries.Diabet Med.2011;28(3):293-300. 91.Sherry N,Hagopian W,Ludvigsson J,et al.,Protege Trial Investigators.Teplizumab for treatment of type 1 diabetes(Protege study):1-year results from a randomised,placebo-controlled trial.Lancet.2011;378(9790):487-97. 92.Sorensen JS,Johannesen J,Pociot F,et al.Residual β-cell function 3-6 years after onset of type 1 diabetes reduces risk of severe hypoglycemia in children and adolescents.Diabetes Care.2013;36:3454-3459. 93.Sosenko JM,Skyler JS,Herold KC,et al.The metabolic progression to type 1 diabetes as indicated by serial oral glucose tolerance testing in the Diabetes Prevention Trial-type 1.Diabetes.2012;61(6):1331-7. 94.Steck AK,Dong F,Taki I,et al.Early hyperglycemia detected by continuous glucose monitoring in children at risk for type 1 diabetes.Diabetes Care.2014;37:2031-2033. 95.Steffes MW,Sibley S,Jackson M,Thomas W.Beta-cell function and the development of diabetes-related complications in diabetes control and complications trial.Diabetes Care.2003;26:832-836. 96.Streisand R.Young children with type 1 diabetes:challenges,research,and future directions.Curr Diab Rep.2014;14(9):520.pp1-16. 97.Trancone A,Bonfanti R,Iafusco D,et al.Evaluating the experience of children with type 1 diabetes and their parents taking part in an artificial pancreas clinical trial over multiple days in a diabetes camp setting.Diabetes Care.2016;39:2158-2164. 98.Varni JW,Delamater AM,Hood KK,et al.PedsQL 3.2 Diabetes Module for children,adolescents,and young adults:reliability and validity in type 1 diabetes.Diabetes Care.2018;dc172707. 99.Verkruyse LA,Storch GA,Devine SM,et al.Once daily ganciclovir as initial pre-emptive therapy delayed until threshold CMV load > or =10000 copies / ml:a safe and effective strategy for allogeneic stem cell transplant patients.Bone Marrow Transplant.2006;37(1):51-6. 100.Waldron-Lynch F,Henegariu O,Deng S,et al.Teplizumab induces human gut-tropic regulatory cells in humanized mice and patients.Sci Transl Med.2012;4(118):118ra12. 101.Wherrett DK,Chiang JL,Delamater AM,et al.Defining pathways for development of disease-modifying therapies in children with type 1 diabetes:a consensus report.Diabetes Care.2015;38(10):1975-85. 102.Ziegler AG and Nepom GT.Prediction and pathogenesis in type 1 diabetes.Immunity.2010;32:468-478.

Claims

1. A method for reducing the use of exogenous insulin in a subject requiring the method, wherein the method involves approximately 9000 μg / m³ ２ ~Approx. 14000μg / m ２ A method comprising administering a course of teplizumab for 12 to 14 days in a total dose to the subject, wherein the administration of teplizumab results in a reduction of at least 0.08 U / kg / day of exogenous insulin use.

2. The method according to claim 1, wherein administration of teplizumab reduces the amount of exogenous insulin used by at least 0.08 U / kg / day in the first year.

3. The method according to claim 1, wherein administration of teplizumab reduces the amount of exogenous insulin used by at least 0.10 U / kg / day in the second year.

4. The method according to claim 1, comprising administering a 12-day course of teprizumab to the subject.

5. The aforementioned 12-day course of teplizumab administration, Approximately 106 μg / m³ on day 1 ２ The first dose of teprizumab and Approximately 425 μg / m³ on the second day ２ The second dose of teprizumab, Approximately 850 μg / m² on each of the 3rd to 12th days. ２ The method according to claim 4, comprising a single dose of teplizumab.

6. The method according to claim 1, comprising administering a 14-day course of teprizumab to the subject.

7. The aforementioned 14-day course of teplizumab administration, Approximately 100 μg / m² on day 1 ２ The first dose of teprizumab and Approximately 425 μg / m³ on the second day ２ The second dose of teprizumab, Approximately 850 μg / m² on the third day ２ The third dose of teprizumab, The fourth administration of teprotumumab at about 850 μg / m ２ and, Approximately 1000 μg / m² on each of the 5th to 14th days. ２ The method according to claim 6, comprising a single dose of teprizumab.

8. The method according to any one of claims 1 to 7, comprising administering a first and second course of teprizumab for 12 to 14 days.

9. The method according to any one of claims 1 to 7, comprising administering a first and second 12-day course of teprizumab.

10. The method according to claim 8 or 9, wherein the two courses of teplizumab are administered at intervals of approximately six months.

11. The method according to any one of claims 1 to 10, wherein the subject requiring the method has stage 3 type 1 diabetes.

12. The method according to any one of claims 1 to 11, comprising administering teplizumab by intravenous infusion.

13. A method according to any one of claims 1 to 12, wherein the subject requiring the method is approximately 7.5 years of age or older.

14. The method according to any one of claims 1 to 13, wherein the reduction in exogenous insulin use is carried out over a period of one year or more.

15. Teplizumab for use in reducing exogenous insulin use in subjects requiring a reduction in exogenous insulin use, according to any one of claims 1 to 14.

16. The use of teplizumab for the manufacture of a pharmacopoeia for reducing the use of exogenous insulin in a subject requiring it, according to any one of claims 1 to 14.

Images