Methods of reducing exogenous insulin use

Abstract

Provided herein is a method of reducing exogenous insulin use. In some embodiments, such methods may comprise administering tilizumab to a subject in need thereof at a total dose of from about 9000 [mu] g / m2 to about 14000 [mu] g / m2 for a course of 12 to 14 days.

Description

Cross-references to related applications

[0001] This application claims priority to U.S. Provisional Application 63 / 493,113, filed March 30, 2023, the contents of which are incorporated herein by reference in their entirety. sequence list

[0002] This application contains a sequence list that has been filed electronically in .XML format, and the full text of that sequence list is hereby incorporated by reference. The .XML copy created on March 21, 2024, is named "122548.TW060.xml" and is 3,387 bytes in size. Technical Background

[0003] Type 1 diabetes (T1D) is caused by the autoimmune destruction of insulin-producing beta cells on the Langerhans islands, leading to a dependence on exogenous insulin injections for survival. Approximately 1.6 million Americans have T1D, making it one of the most common childhood diseases after asthma. Despite improvements in care, most people with T1D still struggle to consistently achieve their target blood sugar levels. The increased risk of morbidity and mortality for people with T1D remains a significant concern. Summary of the Invention

[0004] Some aspects of this disclosure relate to methods for reducing the use of exogenous insulin in subjects in need, methods comprising administering insulin at approximately 9000 μg / m². 2 Approximately 14000 μg / m 2 The total dose of teplizumab was administered to the subject for a course of 12 to 14 days, during which the administration of teplizumab resulted in a reduction of exogenous insulin use of at least 0.08 U / kg / day.

[0005] In some implementations, administration of telizumab resulted in a reduction of exogenous insulin use by at least 0.08 U / kg / day in the first year. In some implementations, administration of telizumab resulted in a reduction of exogenous insulin use by at least 0.10 U / kg / day in the second year.

[0006] In some embodiments, the method includes administering a 12-day course of telizumab to the subject. In other embodiments, the 12-day course of telizumab includes a first dose of approximately 106 μg / m² telizumab on day 1, a second dose of approximately 425 μg / m² telizumab on day 2, and one dose of approximately 850 μg / m² telizumab daily from day 3 to day 12.

[0007] In other embodiments, the method includes administering a 14-day course of telizumab to the subject. In yet another embodiment, the 14-day course of telizumab includes a first dose of approximately 100 μg / m² telizumab on day 1, a second dose of approximately 425 μg / m² telizumab on day 2, a third dose of approximately 850 μg / m² telizumab on day 3, a fourth dose of approximately 850 μg / m² telizumab on day 4, and one daily dose of approximately 1000 μg / m² telizumab from days 5 to 14.

[0008] In some implementations, the method includes administering a first and a second 12- to 14-day course of telizumab. In some implementations, the first and second 12- to 14-day courses are administered at an interval of approximately 6 months.

[0009] In some implementations, the method includes administering a first and a second 12-day course of telizumab. In some implementations, the first and second 12-day courses are administered at an interval of approximately 6 months.

[0010] In some implementation schemes, the required subjects are approximately 7.5 years of age or older.

[0011] In some implementations, the method includes administering telizumab via intravenous infusion.

[0012] In some implementation schemes, the reduction in exogenous insulin use lasts for one year or longer.

[0013] Some aspects of this disclosure relate to telizumab for use in methods for reducing exogenous insulin use in subjects in need, said methods comprising administering telizumab at approximately 9000 μg / m 2 Approximately 14000 μg / m 2 The total dose of telizumab was administered to the subject for a course of 12 to 14 days, during which the administration of telizumab resulted in a reduction of exogenous insulin use of at least 0.08 U / kg / day.

[0014] This disclosure also provides the use of telizumab in the manufacture of a medicine for reducing the use of exogenous insulin in subjects in need of the methods described herein. Brief description of the attached diagram

[0015] Figure 1 Forest plot of the least-squares mean difference between the teglizumab group and the control group relative to the change in baseline C-peptide AUC. Inset A: Analysis includes 5 clinical trials with Year 1 data. Analysis of imputed data with and without missing values. Inset B: Analysis includes 3 clinical trials with Year 1 and Year 2 data available. Analysis of imputed data with and without missing values.

[0016] Figure 2 : Mean C-peptide and insulin use observed in clinical trials (SE). Inset A: C-peptide AUC levels at year 1 from 5 studies with 1-year data. The p-values ​​at year 1 are from the ANCOVA model with aggregated 1-year observational data. Inset B: C-peptide AUC levels at year 2 from 3 studies with year 2 data. The p-values ​​at year 2 are from the ANCOVA model with aggregated 2-year observational data. Inset C: Mean insulin use at year 1. The p-values ​​at year 1 are from the ANCOVA model with aggregated 1-year observational data. Inset D: Mean insulin use at year 2. The p-values ​​at year 2 are from the ANCOVA model with aggregated 2-year observational data.

[0017] Figure 3 Forest plot of the least-squares mean difference between the telizumab group and the control group relative to changes in baseline insulin use. Inset A: Analysis includes 5 clinical trials with year 1 data. Imputed data with and without missing values ​​are analyzed. Inset B: Analysis includes 3 clinical trials with year 1 and year 2 data available. Imputed data with and without missing values ​​are analyzed. Specific implementation details I. definition

[0018] Some terms are defined as follows. Other definitions are provided throughout the application.

[0019] As used herein, the articles “a” and “an” refer to one or more (e.g., at least one) grammatical object of the article. When used with the term “including” in this text, the use of “a” and “an” may mean “one”, but it is also consistent with the meanings of “one or more”, “at least one”, and “more than one”.

[0020] As used herein, “about” and “approximately” generally refer to the acceptable degree of error of a measured quantity given the nature or precision of the measurement. Exemplary error levels are within 20% (%) of a given range, typically within 10%, and more typically within 5%. The term “substantially” means more than 50%, preferably more than 80%, and most preferably more than 90% or 95%.

[0021] As used herein, the term "comprising" refers to compositions, methods, and their respective components that are present in a given embodiment but may contain unspecified elements.

[0022] As used herein, the term "consistently of" refers to those elements required for a given embodiment. This term allows for the presence of additional elements that do not materially affect the basic and novel or functional characteristics of that embodiment of the disclosure.

[0023] The term “composed of” means the compositions, methods and their respective components described herein, excluding any elements not mentioned in the description of the embodiments.

[0024] The term “antibody” is used in the broadest sense in this article and includes 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.

[0025] "Antibody fragment" refers to a molecule other than a complete antibody that contains a portion of the complete antibody that binds to the antigen that binds to the complete antibody. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; biantibodies; linear antibodies; single-chain antibody molecules (e.g., scFv); and multispecific antibodies formed from antibody fragments.

[0026] As used in this article, the term “onset” for 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).

[0027] As used herein, “regimen” includes a dosing schedule and a dosing regimen. A regimen in this document is a method of use and includes a treatment regimen. A “dosing regimen,” “dosing regimen,” or “course of treatment” can include the administration of multiple doses of a therapeutic agent over a period of 1 to 20 days.

[0028] As used herein, the terms “subject” and “patient” are used interchangeably. As used herein, the term “subject” refers to an animal, preferably a mammal, including 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 6 weeks of T1D diagnosis. In some embodiments, the patient population includes children who are positive for at least one T1D-related autoantibody and have a peak stimulating C-peptide of ≥0.2 pmol / mL at screening.

[0029] As used in this article, the term “child” (and its variations) includes children aged 8 to 17 years.

[0030] As used in this article, the term "effective amount" refers to an amount of telizumab sufficient to delay or prevent the development, recurrence, or onset of one or more symptoms of T1D.

[0031] As used herein, the terms "treat," "treatment," and "treating" refer to the improvement of one or more symptoms associated with T1D resulting from the administration of one or more CD3-binding molecules. In some embodiments, such terms refer to a reduction in the average number of hypoglycemic episodes in humans. In other embodiments, such terms refer to maintaining reference levels of C-peptide in peripheral blood.

[0032] In some implementations, the effective dose reduces one or more T1D symptoms by at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%.

[0033] The various aspects of this disclosure are described in further detail below. Other definitions are listed in the specification. II. Anti-CD3 antibody and pharmaceutical composition

[0034] The terms "anti-CD3 antibody" and "CD3-binding antibody" refer to antibodies or antibody fragments capable of binding to differentiation cluster 3 (CD3) with sufficient affinity, making the antibody usable as a prophylactic, diagnostic, and / or therapeutic agent targeting CD3. In some embodiments, the anti-CD3 antibody binds to less than about 10% of unrelated non-CD3 proteins, for example, as measured by radioimmunoassay (RIA). In some embodiments, the dissociation constant (Kd) of the CD3-binding antibody is <1 μM, <100 nM, <10 nM, <1 nM, <0.1 nM, <0.01 nM, or <0.001 nM (e.g., 10 μM, <100 nM, <100 nM, <10 nM, <1 nM, <0.1 nM, <0.01 nM, or <0.001 nM). -8 M or smaller, for example, 10 -8 M to 10 -13 M, for example, 10 -9 M to 10 -13 M). In some implementations, the anti-CD3 antibody binds to an epitope of CD3 that is conserved in CD3 from different species.

[0035] In some implementations, the anti-CD3 antibody may be ChAglyCD3 (oxizumab). Oxizumab is a humanized Fc-nonbinding anti-CD3 antibody, initially evaluated by the Belgian Diabetes Registry (BDR) in a phase 2 study, then developed by Tolerx, and subsequently in collaboration with GSK for phase 3 DEFEND new-onset T1D trials (NCT00678886, NCT01123083, NCT00763451). Oxizumab is administered via intravenous infusion over 8 days. See, for example, Wiczling et al., J. Clin. Pharmacol. (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., 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., Br J Clin. 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.

[0036] In some implementations, the anti-CD3 antibody may be visilizumab (also known as HuM291; Nuvion). Vicizumab is a humanized anti-CD3 monoclonal antibody characterized by a mutated IgG2 isotype lacking binding to the Fcγ receptor and capable of selectively inducing apoptosis in activated T cells. It has been evaluated in patients with graft-versus-host disease (NCT00720629; NCT00032279), ulcerative colitis (NCT00267306), and Crohn's disease (NCT00267709). See, for example, Sandborn et al., (2010) Gut 59(11):1485-92. III. telizumab

[0037] In some implementations, the anti-CD3 antibody may be telizumab. Telizumab, also known as hOKT3yl(Ala-Ala) (containing alanine at positions 234 and 235), is an anti-CD3 antibody engineered to alter the function of T lymphocytes that mediate the destruction of insulin-producing β cells in the pancreatic islets. Telizumab binds to epitopes on the CD3ε chain expressed on mature T cells, thereby altering their function. Following telizumab treatment, circulating T cells (and other lymphocytes) are temporarily reduced, potentially including marginalization and exhaustion (Long 2017, Sherry 2011). In addition to reducing T cell effector function, telizumab appears to increase the number and function of regulatory T cells (Tregs) (Ablamunits 2010, Bisikirska 2005, Long 2017, Waldron-Lynch 2012). Recent studies have shown that telimumab induces immune “exhaustion” in effector CD8+ T cell subsets, potentially making them more susceptible to regulation or loss (Long 2016, Long 2017). In summary, these mechanistic data suggest that telimumab not only “inhibits” the β-cell immune destruction process but also acts as an immune “modulator,” facilitating the rebalancing of effectors and regulatory arms associated with T1D autoimmunity, and supporting the idea that telimumab may have the ability to reintroduce β-cell self-tolerance (Lebastchi 2013).

[0038] The sequence and composition of telizumab are disclosed in U.S. Patent Nos. 6,491,916; 8,663,634; and 9,056,906. The molecular weight of telizumab is approximately 150 kDa. The complete sequences of the light and heavy chains are shown below. The bolded portions are complementarity-determining regions. Tselituzumab light chain (SEQ ID NO:1): DIQMTQSPSSLSASVGDRVTITCSASSSVSYMNWYQQTPGKAPKRWIYDTSKLASGVP SRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSNPFTFGQGTKLQITRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSS TLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Tislelizumab heavy chain (SEQ ID NO:2): QVQLVQSGGGVVQPGRSLRLSCKASGYTFTRYTMHWVRQAPGKGLEWIGYINPSRG YTNYNQKVKDRFTISRDNSKNTAFLQMDSLRPEDTGVYFCARYYDDHYCLDYWGQ GTPVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0039] In some embodiments, pharmaceutical compositions are provided herein. Such compositions comprise an effective amount of an anti-CD3 antibody and a pharmaceutically acceptable carrier. In some embodiments, the term "pharmaceuticalally acceptable" means approved by a U.S. federal or state regulatory agency or listed in the United States Pharmacopeia (US Pharmacopeia) or other recognized pharmacopoeia for use in animals, and more particularly humans. The term "carrier" refers to a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient, or mediator administered with the therapeutic agent. Such drug carriers may be sterile liquids, such as water and oils, including liquids of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous solutions of glucose and glycerol may also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerin, propylene, ethylene glycol, water, ethanol, etc. (see, for example, Handbook of Pharmaceutical Excipients, Arthur H. Kibbe (ed., 2000, incorporated in its entirety by reference), Am. Pharmaceutical Association, Washington, DC).

[0040] If desired, the composition may also contain small amounts of wetting agents or emulsifiers, or pH buffers. These compositions can be in the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations, etc. Oral formulations may include standard carriers such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. EWMartin describes examples of suitable drug carriers in "Remington's Pharmaceutical Sciences". Such compositions contain a therapeutically effective amount of the therapeutic agent, preferably in purified form, and an appropriate amount of carrier to provide a suitable form of administration to the patient. The formulation should be suitable for the mode of administration. In some embodiments, the pharmaceutical composition is sterile and administered to a subject in a suitable form, preferably an animal subject, more preferably a mammalian subject, and most preferably a human subject.

[0041] In some embodiments, it may be desirable to apply the pharmaceutical composition topically to the area requiring treatment; this can be achieved, for example, but not limited to, local infusion, injection, or via an implant, which is a porous, non-porous, or gel-like material, including membranes such as saliva membranes or fibers. Preferably, when administering anti-CD3 antibodies, care must be taken to use materials that are not absorbed by the anti-CD3 antibodies.

[0042] In some embodiments, the composition can be delivered in vesicles, particularly liposomes (see Langer, Science (1990) 249:1527-33; Treat et al., Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; generally see ibid.).

[0043] In some embodiments, the composition can be delivered in a controlled-release or sustained-release system. In some embodiments, a pump can be used to achieve controlled-release or sustained-release (see Langer, ibid.; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:20; Buchwald et al., (1980) Surgery 88:507; Saudek et al., (1989) N. Engl. J. Med. 321:574). In some embodiments, polymeric materials may be used to achieve controlled or sustained release of the antibodies or fragments thereof disclosed herein (see, for example, Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Press, Pocaraton, Florida (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, J Macromol. Sci. Rev. Macromol. Chem. (1983) 23:61; see also Levy et al., (1985) Science 228:190; During et al., (1989) Ann Neurol. 25:351; Howard et al., (1989) J Neurosurg. 71:105); US Patent Nos. 5,679,377, 5,916,597, 5,912,015, 5,989,463, 5,128,326, PCT Publication No. WO 99 / 15154, and PCT Publication No. WO 99 / 20253. Examples of polymers for use in sustained-release formulations include, but are not limited to, poly(2-hydroxyethyl methacrylate), poly(methyl methacrylate), poly(acrylic acid), poly(ethylene-co-vinyl acetate), poly(methacrylic acid), polyglycolic acid (PLG), polyanhydride, poly(N-vinylpyrrolidone), poly(vinyl alcohol), polyacrylamide, poly(ethylene glycol), polylactide (PLA), poly(lactide-co-glycolic acid) (PLGA), and polyorthoesters. In some embodiments, the polymers used in sustained-release formulations are inert, free of leaching impurities, stable during storage, sterile, and biodegradable. In some implementations, the controlled-release or sustained-release system can be placed near the therapeutic target (i.e., the lungs), so that only a portion of the systemic dose is needed (see, for example, Goodson, in Medical Applications of Controlled Release, ibid., Vol. 2, pp. 115-138 (1984)).

[0044] Langer (1990, Science 249:1527-1533) discussed controlled-release systems in a review. Any technique known to those skilled in the art can be used to prepare sustained-release formulations comprising one or more antibodies or fragments thereof disclosed herein. See, for example, U.S. Patent No. 4,526,938; PCT Publication No. WO 91 / 05548; PCT Publication No. WO 96 / 20698; Ning et al., (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.

[0045] Pharmaceutical compositions can be formulated to be compatible with their intended route of administration. Examples of routes of administration include, but are not limited to, parenteral, such as intravenous, intradermal, subcutaneous, oral, intranasal (e.g., inhalation), transdermal (topical), mucosal, and rectal administration. In some embodiments, the composition is formulated according to conventional procedures for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to humans. In some embodiments, the pharmaceutical composition is formulated according to conventional procedures for subcutaneous administration to humans. Typically, compositions for intravenous administration are solutions in sterile isotonic buffer solutions. Where necessary, the composition may also include a solubilizer and a local anesthetic, such as lidocaine, to reduce pain at the injection site.

[0046] The composition can be formulated for parenteral administration by injection, such as by bolus or continuous infusion. Injectable formulations can be provided in unit dosage forms, such as in ampoules or multi-dose containers, with added preservatives. The composition can be in the form of a suspension, solution, or emulsion, for example, in an oily or aqueous medium, and can contain formulations containing, for example, suspending agents, stabilizers, and / or dispersants. Alternatively, the active ingredient can be in powder form for reconstitution with a suitable medium (e.g., sterile, pyrogen-free water) prior to use.

[0047] In some embodiments, this disclosure provides dosage forms that allow for continuous administration of anti-CD3 antibodies over hours or days (e.g., associated with a pump or other device for such delivery), for example, over 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 20 hours, 24 hours, 30 hours, 36 hours, 4 days, 5 days, 7 days, 10 days, or 12 days. In some embodiments, this disclosure provides dosage forms that allow for administration of continuously increasing doses, for example, from 106 μg / m² over 24 hours, 30 hours, 36 hours, 4 days, 5 days, 7 days, 10 days, or 12 days. 2 / day increased to 850μg / m 2 / day or from 211μg / m 2 / day increased to 840μg / m 2 / sky.

[0048] The composition can be formulated into neutral or salt form. Pharmaceutically acceptable salts include those that form with anions, such as those derived from hydrochloric acid, phosphoric acid, acetic acid, oxalic acid, tartaric acid, etc., and those that form with cations, such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxide, isopropylamine, triethylamine, 2-ethylaminoethanol, histidine, procaine, etc.

[0049] Typically, the components of the compositions disclosed herein are provided individually or in combination in unit dosage forms, for example, as lyophilized powders or anhydrous concentrates in sealed containers such as ampoules or sachets indicating the amount of active agent. When the composition is administered by infusion, it can be dispensed using an infusion bottle containing sterile pharmaceutical-grade water or saline. When the composition is administered by injection, ampoules of sterile water or saline for injection can be provided to allow mixing of the components prior to administration.

[0050] Specifically, this disclosure provides that anti-CD3 antibodies or pharmaceutical compositions thereof can be packaged in sealed containers, such as ampoules or pouches, indicating the amount of the drug. In some embodiments, the anti-CD3 antibody or pharmaceutical composition thereof is provided in a sealed container as a dry, sterile lyophilized powder or anhydrous concentrate, and can be reconstituted, for example, with water or saline to an appropriate concentration for administration to a subject. Preferably, the anti-CD3 antibody or pharmaceutical composition thereof is provided in a sealed container as a dry, sterile lyophilized powder at a unit dose of at least 5 mg, more preferably at least 10 mg, at least 15 mg, at least 25 mg, at least 35 mg, at least 45 mg, at least 50 mg, at least 75 mg, or at least 100 mg. The lyophilized agents or pharmaceutical compositions herein should be stored in their original containers at 2°C to 8°C, and the therapeutic agents or pharmaceutical compositions of this disclosure should be administered within one week after reconstitution, preferably within 5 days, 72 hours, 48 ​​hours, 24 hours, 12 hours, 6 hours, 5 hours, 3 hours, or 1 hour. In some embodiments, the pharmaceutical composition is supplied in liquid form in a sealed container indicating the amount and concentration of the agent. Preferably, the liquid form of the composition is supplied in a sealed container at a concentration of at least 0.25 mg / ml, more preferably at least 0.5 mg / ml, at least 1 mg / ml, at least 2.5 mg / ml, at least 5 mg / ml, at least 8 mg / ml, at least 10 mg / ml, at least 15 mg / ml, at least 25 mg / ml, at least 50 mg / ml, at least 75 mg / ml, or at least 100 mg / ml. The liquid form should be stored in its original container at a temperature of 2°C to 8°C.

[0051] In some embodiments, this disclosure provides that the compositions of this disclosure are packaged in sealed containers such as ampoules or pouches indicating the amount of anti-CD3 antibody.

[0052] If desired, the composition may be provided in a packaging or dispenser device, which may contain one or more unit dosage forms containing the active ingredient. The packaging may include, for example, metal or plastic foil, such as blister packs.

[0053] The amount of the composition of this disclosure that is effective in treating one or more symptoms associated with T1D can be determined using standard clinical techniques. The precise dosage used in the formulation may also depend on the route of administration and the severity of the condition, and should be determined based on the physician's judgment and the individual patient's situation. The effective dosage can be inferred from dose-response curves derived from in vitro or animal model testing systems. IV. Methods and uses

[0054] This article provides methods for reducing exogenous insulin use in subjects in need. In some implementations, the method includes using approximately 9000 μg / m². 2 Approximately 14000 μg / m2 The total dose of telizumab was administered to the subjects for a course of 12 to 14 days, during which the administration of telizumab resulted in a reduction of exogenous insulin use of at least 0.08 U / kg / day.

[0055] In some implementations, administration of telizumab resulted in a reduction of exogenous insulin use by at least 0.08 U / kg / day in the first year. In some implementations, administration of telizumab resulted in a reduction of exogenous insulin use by at least 0.10 U / kg / day in the second year.

[0056] In some implementations, administration of telizumab results in the maintenance of C-peptide levels, as reflected by increased endogenous insulin production and reduced exogenous insulin requirements.

[0057] In some embodiments, the method includes administering telizumab to the subject for a 12-day course of treatment. In other embodiments, the method includes administering telizumab to the subject for a 14-day course of treatment.

[0058] In some implementations, the method includes administering a first and a second 12- to 14-day course of telizumab. In some implementations, the first and second 12- to 14-day courses are administered at an interval of approximately 6 months.

[0059] In some implementations, the method includes administering a first and a second 12-day course of telizumab. In some implementations, the first and second 12-day courses are administered at an interval of approximately 6 months.

[0060] In some implementations, the recipient has stage 3 type 1 diabetes. In some implementations, the recipient has been diagnosed with stage 3 type 1 diabetes within 5 to 31 weeks prior to the administration step. In some implementations, the recipient is approximately 7.5 years of age or older.

[0061] In some implementations, the method includes administering telizumab via intravenous infusion.

[0062] In some implementation schemes, the reduction in exogenous insulin use lasts for one, two, or longer years.

[0063] In some implementations, the methods described herein result in reduced insulin requirements or independence from exogenous insulin.

[0064] Type 1 diabetes typically occurs in childhood and adolescence; however, it can also occur in the fifth and sixth decades of adulthood, although at a much lower frequency (Atkinson 2014, Bluestone 2010, Streisand 2014).

[0065] In some implementations, an anti-human CD3 antibody (e.g., telizumab) is administered to patients aged 8 to 17 years 6 weeks after a T1D diagnosis who have a peak C-peptide level ≥0.2 pmol / mL during a mixed diet tolerance test (MMTT). In some implementations, the peak C-peptide level at screening is in the range of 0.2 pmol / mL (inclusive) to 0.7 pmol / mL (inclusive).

[0066] In some implementations, T1D diagnosis is based on the American Diabetes Association (ADA) criteria. According to the ADA's definition of a clinical diagnosis of diabetes, an individual must meet one of the following four criteria:

[0067] Fasting plasma glucose (FPG) ≥126 mg / dL (7.0 mmol / L). Fasting is defined as abstaining from calorie intake for at least 8 hours.

[0068] A 2-hour postprandial glucose (PG) level ≥200 mg / dL (11.1 mmol / L) is required during the oral glucose tolerance test (OGTT). The test should be performed as described by the World Health Organization (WHO) using a glucose load containing the equivalent of 75 g of anhydrous glucose dissolved in water.

[0069] Heme A1C (HbA1c) ≥ 6.5% (48 mmol / mol). This test should be performed in a laboratory using a method certified and standardized by the National Glycohemoglobin Standardization Program (NGSP) for the Diabetes Control and Complications Trial (DCCT).

[0070] In patients with typical symptoms of hyperglycemia or hyperglycemic crisis, randomized PG ≥200 mg / dL (11.1 mmol / L) was selected.

[0071] For the diagnosis of clinical type 1 diabetes (T1D), the ADA recommends that plasma glucose, rather than HbA1c, should be used to diagnose acute T1D episodes in individuals with symptoms of hyperglycemia.

[0072] According to the ADA, for patients with typical symptoms, a blood glucose test is sufficient to diagnose clinical diabetes (hyperglycemic symptoms or a hyperglycemic crisis plus a random blood glucose level ≥200 mg / dL [11.1 mmol / L]). In these cases, knowing the blood glucose level is crucial because it not only confirms that the symptoms are caused by diabetes but also informs management decisions. Some providers may also want to know HbA1c to determine when the patient has had hyperglycemia. Furthermore, T1D, formerly known as “insulin-dependent diabetes” or “juvenile-onset diabetes,” accounts for 5%–10% of diabetes and is caused by cell-mediated autoimmune destruction of pancreatic β-cells. Autoimmune markers include islet cell autoantibodies and autoantibodies against GAD (GAD65), insulin, tyrosine phosphatase IA-2 and IA-2β, and ZnT8. T1D is defined as the presence of one or more of these autoimmune markers.

[0073] In some implementations, the diagnosis of T1D is performed using a continuous glucose monitoring system (CGM) that reveals a high average blood glucose level from the sensor (>=110 mg / dL), or high variability in blood glucose (CV>=15), or a short time within the range (>=10% of the time above 140 mg / dL).

[0074] In some embodiments, patients diagnosed with clinical T1D are positive for at least one of the following T1D-related autoantibodies: glutamate decarboxylase 65 (GAD65) autoantibody, islet antigen 2 (IA-2) autoantibody, zinc carrier protein 8 (ZnT8) autoantibody, islet cell cytoplasmic autoantibody (ICA), or insulin autoantibody (if tested within the first 14 days of insulin therapy). In some embodiments, the presence of autoantibodies is detected by ELISA, electrochemiluminescence (ECL), radiometric assay (see, for example, Yu et al., 1996, J Clin Endocrinol Metab. 81:4264-4267), agglutination PCR (Tsai et al., ACS Central Science 2016 2(3):139-147), or any other method of immunospecific detection of antibodies described herein or known to those skilled in the art.

[0075] It has been recognized that β-cells continue to be lost after a T1D diagnosis. To maximize the effect of β-cell preservation on patients with recoverable endogenous insulin production levels, in some implementations, patients to be treated have peak C-peptide levels of ≥0.2 pmol / mL within 6 weeks after a T1D diagnosis and during a mixed diet tolerance test (MMTT).

[0076] In some implementations, the methods described herein reduce, prevent, or delay the need for patients to administer exogenous insulin.

[0077] Pre-treatment, during-treatment, and post-treatment β-cell function can be assessed using the methods described herein or any method known to those skilled in the art. For example, the Diabetes Control and Complications Trial (DCCT) study group has established monitoring of glycated heme percentages (HA1 and HA1c) as a standard for assessing glycemic control (DCCT, 1993, N. Engl. J. Med. 329: 977-986). Alternatively, characterization of daily insulin requirements, C-peptide levels / response, hypoglycemic episodes, and / or FPIR can be used as markers of β-cell function or for establishing treatment 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 values ​​at 1 minute and 3 minutes after IGTT, which is performed according to the pancreatic islet cell antibody registry user study protocol (see, for example, Bingley et al., (1996) Diabetes 45:1720-8 and McCulloch et al., (1993) DiabetesCare 16:911-5).

[0078] In some implementations, an effective amount of an anti-CD3 antibody, such as telizumab, is administered via subcutaneous (SC) injection, intravenous (IV) infusion, or oral administration for a course of 10 to 14 days, with a cumulative dose greater than 10,000 micrograms per square meter (μg / m²). 2 ).

[0079] In some implementations, an effective amount of an anti-CD3 antibody, such as telizumab, is administered subcutaneously (SC) or intravenously (IV) or orally for a course of 10 to 14 days, at a dose of approximately 9,500 to approximately 14,000 μg / m². 2 Approximately 9,500 to approximately 13,500 μg / m 2 Approximately 9,500 to approximately 13,000 μg / m 2 Approximately 9,500 to approximately 12,500 μg / m 2 Approximately 9,500 to approximately 12,000 μg / m 2 Approximately 9,500 to approximately 11,500 μg / m 2 Approximately 9,500 to approximately 11,000 μg / m 2Approximately 9,500 to approximately 10,500 μg / m 2 Approximately 9,500 to approximately 10,000 μg / m 2 In some implementations, an effective amount of an anti-CD3 antibody, such as telizumab, is administered via subcutaneous (SC) injection, intravenous (IV) infusion, or oral administration for a course of 10 to 14 days, at a dose of approximately 10,000 μg / m². 2 10,500 μg / m 2 11,000 μg / m 2 11.500 μg / m 2 12,000 μg / m 2 12,500 μg / m 2 13,000 μg / m 2 13,500 μg / m 2 Or 14,000 μg / m 2 In some implementations, the anti-CD3 antibody is or contains telizumab.

[0080] In some implementations, the effective amount includes a dose of 106-850 micrograms per square meter (μg / m²). 2 A 12- to 14-day course of subcutaneous intravenous (IV) infusion of an anti-CD3 antibody, such as teglizumab, is administered. In some implementations, the total dose over the duration of the regimen is approximately 14,000 μg / m². 2 13500μg / m 2 13000μg / m 2 12500μg / m 2 12000μg / m 2 11500μg / m 2 11000μg / m 2 10500μg / m 2 10000μg / m 2 9500μg / m 2 9000μg / m 2 8000μg / m 2 7000μg / m 2 6000μg / m 2 And it can be less than 5000 μg / m 2 4000μg / m 2 3000μg / m 2 2000μg / m 2 or 1000 μg / m 2 In some implementations, the total dose over the duration of the regimen is approximately 9030 μg / m². 2 Approximately 14000 μg / m2 Approximately 9030 μg / m 2 Approximately 13500 μg / m 2 Approximately 9000 μg / m 2 Approximately 13000 μg / m 2 Approximately 9000 μg / m 2 Approximately 12500 μg / m 2 Approximately 9000 μg / m 2 Approximately 12000 μg / m 2 Approximately 9000 μg / m 2 Approximately 11500 μg / m 2 Approximately 9000 μg / m 2 Approximately 11000 μg / m 2 Approximately 9000 μg / m 2 Approximately 10500 μg / m 2 Approximately 9000 μg / m 2 Approximately 10000 μg / m 2 Approximately 9000 μg / m 2 Approximately 9500 μg / m 2 In some implementations, the total dose over the duration of the regimen is approximately 9030 μg / m². 2 Approximately 14000 μg / m 2 Approximately 9030 μg / m 2 Approximately 13500 μg / m 2 Approximately 9030 μg / m 2 Approximately 13000 μg / m 2 Approximately 9030 μg / m 2 Approximately 12500 μg / m 2 Approximately 9030 μg / m 2 Approximately 12000 μg / m 2 Approximately 9030 μg / m 2 Approximately 11500 μg / m2, approximately 9030 μg / m 2 Approximately 11000 μg / m 2 Approximately 9030 μg / m 2 Approximately 10500 μg / m 2 Approximately 9030 μg / m 2 Approximately 10000 μg / m 2 Approximately 9030 μg / m 2 Approximately 9500 μg / m 2 .

[0081] Unbound by this theory, the cumulative dose exceeds approximately 9,000 μg / m². 2The efficacy of teglizumab in terms of C-peptide retention is expected to be comparable to that shown at approximately 9,000 mg. This is because the exposure / response curve unexpectedly reached a plateau, beyond which dose increases did not lead to an increase in efficacy. C-peptide retention was assessed using data from the Protégé study. The model-predicted changes in teglizumab AUC and C-peptide relative to baseline were plotted, and an Emax analysis was performed. These data indicate that the Emax model describes the relationship between 2-year teglizumab exposure and C-peptide changes. At teglizumab AUC levels greater than approximately 1500 ng*hr / mL (below approximately 9,000 μg / mL), the C-peptide retention was significantly reduced. 2 At the dose-predicted lowest AUC (1,789 ng*hr / mL), no further improvement in C-peptide was observed with increasing teglizumab exposure. Therefore, these data suggest that doses of teglizumab above approximately 9,000 mg have comparable efficacy in terms of C-peptide retention to those shown at approximately 9,000 mg.

[0082] In some implementations, the effective dose includes a 12-day course of intravenous infusion of telizumab, with the first dose on day 1 being 106 μg / m². 2 Teglituzumab, second dose on day 2, 425 μg / m². 2 Teglituzumab, and one dose of 850 μg / m² daily from days 3 to 12. 2 .

[0083] In some implementations, the effective dose includes a 12-day course of intravenous infusion of telizumab, with the first dose on day 1 being 211 μg / m². 2 Teglituzumab, second dose on day 2, 423 μg / m². 2 Teglituzumab, and one dose of 840 μg / m² daily from days 3 to 12. 2 .

[0084] In some implementations, the effective dose includes a 12-day course of intravenous infusion of telizumab, with the first dose on day 1 being approximately 100 μg / m². 2 Teglituzumab, second dose on day 2, approximately 400 μg / m². 2 Teglitumab, third dose on day 3, approximately 850 μg / m². 2 and approximately 1,200 μg / m² per day from day 4 to 12. 2 .

[0085] In some implementations, the effective dose includes a 12-day course of intravenous infusion of telizumab, with the first dose on day 1 being approximately 100 μg / m². 2 Teglituzumab, second dose on day 2, approximately 400 μg / m². 2 Teglitumab, third dose on day 3, approximately 850 μg / m². 2and approximately 1,300 μg / m² per day from day 4 to 12. 2 .

[0086] In some implementations, the effective dose includes a 12-day course of intravenous infusion of telizumab, with the first dose on day 1 being approximately 100 μg / m². 2 Teglituzumab, second dose on day 2, approximately 400 μg / m². 2 Teglitumab, third dose on day 3, approximately 850 μg / m². 2 and approximately 1,400 μg / m² per day from day 4 to 12. 2 .

[0087] In some implementations, the effective dose includes a 12-day course of intravenous infusion of telizumab, with the first dose on day 1 being approximately 200 μg / m². 2 Teglituzumab, second dose on day 2, approximately 400 μg / m². 2 Teglitumab, third dose on day 3, approximately 850 μg / m². 2 and approximately 1,200 μg / m² per day from day 4 to 12. 2 .

[0088] In some implementations, the effective dose includes a 12-day course of intravenous infusion of telizumab, with the first dose on day 1 being approximately 200 μg / m². 2 Teglituzumab, second dose on day 2, approximately 400 μg / m². 2 Teglitumab, third dose on day 3, approximately 850 μg / m². 2 and approximately 1,300 μg / m² per day from day 4 to 12. 2 .

[0089] In some implementations, the effective dose includes a 12-day course of intravenous infusion of telizumab, with the first dose on day 1 being approximately 200 μg / m². 2 Teglituzumab, second dose on day 2, approximately 400 μg / m². 2 Teglitumab, third dose on day 3, approximately 850 μg / m². 2 and approximately 1,400 μg / m² per day from day 4 to 12. 2 .

[0090] In some implementations, the method includes administering approximately 60 μg / m² on days 1–4. 2 Approximately 125 μg / m 2 Approximately 250 μg / m 2 and approximately 500 μg / m 2 And approximately 1,000 μg / m² per day from day 5 to 14. 2 The dose was administered to the subject via IV infusion over a 14-day course. In some implementations, the cumulative dose was approximately 10,935 μg / m².2 .

[0091] In some implementations, the method includes administering approximately 60 μg / m² on days 1–4. 2 Approximately 125 μg / m 2 Approximately 250 μg / m 2 and approximately 500 μg / m 2 And approximately 1,030 μg / m² per day from day 5 to 14. 2 The dose was administered to the subject via IV infusion over a 14-day course. In some implementations, the cumulative dose was approximately 11,235 μg / m². 2 .

[0092] In some implementations, the method includes administering approximately 100 μg / m² on days 1–4. 2 Approximately 425 μg / m 2 Approximately 850 μg / m 2 and approximately 850 μg / m 2 And approximately 1,000 μg / m² per day from day 5 to 14. 2 The dose was administered to the subject via IV infusion over a 14-day course. In some implementations, the cumulative dose was approximately 12,225 μg / m².

[0093] In some implementations, the method includes administering approximately 65 μg / m² on days 1–4. 2 Approximately 125 μg / m 2 Approximately 250 μg / m 2 and approximately 500 μg / m 2 And approximately 1,070 μg / m² per day from day 5 to 14. 2 The dose was administered to the subject via IV infusion over a 14-day course. In some implementations, the cumulative dose was approximately 11,640 μg / m². 2 .

[0094] In some implementations, the method includes administering approximately 65 μg / m² on days 1–4. 2 Approximately 125 μg / m 2 Approximately 250 μg / m 2 and approximately 500 μg / m 2 And approximately 1,030 μg / m² per day from day 5 to 14. 2 The dose was administered to the subject via IV infusion over a 14-day course. In some implementations, the cumulative dose was approximately 11,240 μg / m². 2 .

[0095] The dosing regimens described herein include two or more cycles of anti-CD3 antibody administration such as telizumab, comprising a first cycle administered in week 1 and a second cycle administered in week 26. In some embodiments, telizumab is administered via IV infusion in two cycles, with the first cycle beginning on day 1 (week 1) and the second cycle beginning at approximately day 182 (week 26). Each cycle consists of daily infusions lasting 10 to 14 days (e.g., 12 or 14 days), wherein the cumulative telizumab dose in each cycle is 9000 μg / m². 2 In some implementations, telixirmab is administered via intravenous infusion in two cycles. The first cycle begins on day 1 (week 1), and the second cycle begins at approximately day 182 (week 26). Each cycle consists of daily infusions lasting 10 to 14 days (e.g., 12 or 14 days), with a cumulative telixirmab dose of 9500 μg / m² per cycle. 2 In some implementations, telizumab is administered via intravenous infusion in two cycles. The first cycle begins on day 1 (week 1), and the second cycle begins at approximately day 182 (week 26). Each cycle consists of daily infusions lasting 10 to 14 days (e.g., 12 or 14 days), with a cumulative telizumab dose of 10,000 μg / m² per cycle. 2 In some implementations, teliximab is administered via intravenous infusion in two cycles. The first cycle begins on day 1 (week 1), and the second cycle begins at approximately day 182 (week 26). Each cycle consists of daily infusions lasting 10 to 14 days (e.g., 12 or 14 days), with a cumulative teliximab dose of 10,500 μg / m² per cycle. 2 In some implementations, telixirmab is administered via intravenous infusion in two cycles. The first cycle begins on day 1 (week 1), and the second cycle begins at approximately day 182 (week 26). Each cycle consists of daily infusions lasting 10 to 14 days (e.g., 12 or 14 days), with a cumulative telixirmab dose of 11,000 μg / m² per cycle. 2 In some implementations, telizumab is administered via intravenous infusion in two cycles. The first cycle begins on day 1 (week 1), and the second cycle begins at approximately day 182 (week 26). Each cycle consists of daily infusions lasting 10 to 14 days (e.g., 12 or 14 days), with a cumulative telizumab dose of 11,500 μg / m² per cycle. 2In some implementations, teliximab is administered via intravenous infusion in two cycles. The first cycle begins on day 1 (week 1), and the second cycle begins at approximately day 182 (week 26). Each cycle consists of daily infusions lasting 10 to 14 days (e.g., 12 or 14 days), with a cumulative teliximab dose of 12,000 μg / m² per cycle. 2 In some implementations, teliximab is administered via intravenous infusion in two cycles. The first cycle begins on day 1 (week 1), and the second cycle begins at approximately day 182 (week 26). Each cycle consists of daily infusions lasting 10 to 14 days (e.g., 12 or 14 days), with a cumulative teliximab dose of 12,500 μg / m² per cycle. 2 In some implementations, teliximab is administered via intravenous infusion in two cycles. The first cycle begins on day 1 (week 1), and the second cycle begins at approximately day 182 (week 26). Each cycle consists of daily infusions lasting 10 to 14 days (e.g., 12 or 14 days), with a cumulative teliximab dose of 13,000 μg / m² per cycle. 2 In some implementations, teliximab is administered via intravenous infusion in two cycles. The first cycle begins on day 1 (week 1), and the second cycle begins at approximately day 182 (week 26). Each cycle consists of daily infusions lasting 10 to 14 days (e.g., 12 or 14 days), with a cumulative teliximab dose of 13,500 μg / m² per cycle. 2 In some implementations, telizumab is administered via intravenous infusion in two cycles. The first cycle begins on day 1 (week 1), and the second cycle begins at approximately day 182 (week 26). Each cycle consists of daily infusions lasting 10 to 14 days (e.g., 12 or 14 days), with a cumulative telizumab dose of 14,000 μg / m² per cycle. 2 In some implementations, the 12-day treatment course has a 2-day escalation phase and a fixed 10-day maximum dosing period. In some implementations, 106 μg / m² is administered on day 1. 2 Telizumab, administered on day 2 at 425 μg / m². 2 Tegliotumab, administered at 850 μg / m² daily from days 3 to 12. 2 Tilizumab.

[0096] In other embodiments, the treatment course may be repeated at intervals of 2 months, 4 months, 5 months, 6 months, 8 months, 9 months, 10 months, 12 months, 15 months, 18 months, 24 months, 30 months, or 36 months. In some embodiments, the efficacy of treatment with an anti-CD3 antibody such as telizumab is determined as described herein, or as known in the art, at 2 months, 4 months, 5 months, 6 months, 9 months, 12 months, 15 months, 18 months, 24 months, 30 months, or 36 months after prior treatment.

[0097] In some implementation schemes, at approximately 5-1200 μg / m 2 For example, 106-850 μg / m 2 Administering one or more doses, such as 12 daily doses of an anti-CD3 antibody like telizumab, to a subject to treat one or more symptoms of T1D, or to slow the progression of T1D or improve one or more symptoms of T1D.

[0098] In some implementations, the treatment regimen comprises administering to the subject a daily effective dose of an anti-CD3 antibody, such as teglizumab, for two cycles, wherein the cycle is administered over 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. In some implementations, the treatment regimen comprises administering an effective dose daily, every 2 days, every 3 days, or every 4 days.

[0099] In some implementations, subjects are administered a treatment regimen comprising one or more doses of a prophylactic effective amount of an anti-CD3 antibody, such as tegizumab, wherein the prophylactic effective amount is 200 μg / kg / day, 175 μg / kg / day, 150 μg / kg / day, 125 μg / kg / day, 100 μg / kg / day, 95 μg / kg / day, 90 μg / kg / day, 85 μg / kg / day, 80 μg / kg / day, 75 μg / kg / day, 70 μg / kg / day, 65 μg / kg / day, 60 μg / kg / day, 55 μg / kg / day, 50 μg / kg / day, 45 μg / kg / day, 40 μg / kg / day, 3 ... 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 where the preventive effective dose is 1200 μg / m2 / day, 1150μg / m 2 / day, 1100μg / m 2 / day, 1050μg / m 2 / day, 1000μg / m 2 / day, 950μg / m 2 / day, 900μg / m 2 / day, 850μg / m 2 / day, 800μg / m 2 / day, 750μg / m 2 / day, 700μg / m 2 / day, 650μg / m 2 / day, 600μg / m 2 / day, 550μg / m2 / day, 500μg / m2 / day, 450μg / m 2 / day, 400μg / m 2 / day, 350μg / m 2 / day, 300 μg / m 2 / day, 250μg / m 2 200μg / m 2 / day, 150μg / m 2 / day, 100μg / m 2 / day, 50μg / m 2 / day, 40μg / m 2 / day, 30μg / m 2 / day, 20μg / m 2 / day, 15μg / m 2 / day, 10μg / m 2 / day or 5μg / m 2 / sky.

[0100] In some implementations, the intravenous dose is 1200 μg / m². 2 or less, 1150 μg / m 2 or less, 1100 μg / m 2 Or even shorter, 1050 μg / m 2 or less, 1000 μg / m 2 or less, 950 μg / m 2 or less, 900 μg / m 2 or less, 850 μg / m 2 or less, 800 μg / m 2 or less, 750 μg / m 2 or less, 700 μg / m 2 or less, 650 μg / m 2 or less, 600 μg / m2 or less, 550 μg / m 2 or less, 500 μg / m 2 or less, 450 μg / m 2 or less, 400 μg / m 2 or less, 350 μg / m 2 or less, 300 μg / m 2 or less, 250 μg / m 2 or less, 200 μg / m2 or less, 150 μg / m 2 or less, 100 μg / m 2 or less, 50 μg / m 2 or less, 40 μg / m 2 or less, 30 μg / m2 or less, 20 μg / m 2 or less, 15 μg / m 2 or less, 10 μg / m 2 or less, or 5 μg / m 2 Or fewer anti-CD3 antibodies such as telixirmab may be administered over approximately 24 hours, approximately 22 hours, approximately 20 hours, approximately 18 hours, approximately 16 hours, approximately 14 hours, approximately 12 hours, approximately 10 hours, approximately 8 hours, approximately 6 hours, approximately 4 hours, approximately 2 hours, approximately 1.5 hours, approximately 1 hour, approximately 50 minutes, approximately 40 minutes, approximately 30 minutes, approximately 20 minutes, approximately 10 minutes, approximately 5 minutes, approximately 2 minutes, approximately 1 minute, approximately 30 seconds, or approximately 10 seconds to prevent, treat, or improve one or more symptoms of type 1 diabetes. In some embodiments, the total dose over the duration of the regimen is less than approximately 14,000 μg / m². 2 13500μg / m 2 13000μg / m 2 12500μg / m 2 12000μg / m 2 11500μg / m 2 11000μg / m 2 10500μg / m 2 10000μg / m 2 9500μg / m 2 9000μg / m 2 8000μg / m 2 7000μg / m 2 6000μg / m 2 And it can be less than 5000 μg / m 2 4000μg / m 2 3000μg / m 2 2000μg / m 2or 1000 μg / m 2 In some implementation schemes, the daily dose administered is approximately 100 μg / m². 2 Approximately 200 μg / m 2 Approximately 100 μg / m 2 Approximately 500 μg / m 2 Approximately 100 μg / m 2 Approximately 1000 μg / m 2 or approximately 500 μg / m 2 Approximately 1000 μg / m 2 .

[0101] In some implementations, the dose is increased in the first three, or first quarter doses of the treatment regimen (e.g., the first three days of a 12-day regimen with one dose daily), until the effective daily dose of the anti-CD3 antibody, such as telizumab, is reached. In some implementations, the subject is administered a treatment regimen comprising one or more effective doses of an anti-CD3 antibody, such as telizumab, wherein the effective dose is increased daily, for example, by 0.01 μg / kg, 0.02 μg / kg, 0.04 μg / kg, 0.05 μg / kg, 0.06 μg / kg, 0.08 μg / kg, 0.1 μg / kg, 0.2 μg / kg, 0.25 μg / kg, 0.5 μg / kg, 0.75 μg / kg, 1 μg / kg, 1.5 μg / kg, 2 μg / kg, 4 μg / kg, etc. kg, 5 μg / kg, 10 μg / kg, 15 μg / kg, 20 μg / kg, 25 μg / kg, 30 μg / kg, 35 μg / kg, 40 μg / kg, 45 μg / kg, 50 μg / kg, 55 μg / kg, 60 μg / kg, 65 μg / kg, 70 μg / kg, 75 μg / kg, 80 μg / kg, 85 μg / kg, 90 μg / kg, 95 μg / kg, 100 μg / kg, or 125 μg / kg; or increase daily, for example, by 100 μg / kg as treatment progresses. 2 150μg / m 2 200μg / m 2 250μg / m 2 300μg / m 2 350μg / m 2 400μg / m 2 450μg / m 2 500μg / m 2 550μg / m 2 600μg / m 2 Or 650 μg / m 2In some implementations, a treatment regimen comprising one or more effective doses of an anti-CD3 antibody, such as telizumab, is administered to the subject, wherein the effective dose is increased by 1.25-fold, 1.5-fold, 2-fold, 2.25-fold, 2.5-fold, or 5-fold until the daily effective dose of the anti-CD3 antibody, such as telizumab, is reached.

[0102] In some embodiments, one or more doses of 200 μg / kg or less are administered intramuscularly to the subject, preferably 175 μg / kg or less, 150 μg / kg or less, 125 μg / kg or less, 100 μg / kg or less, 95 μg / kg or less, 90 μg / kg or less, 85 μg / kg or less, 80 μg / kg or less, 75 μg / kg or less, 70 μg / kg or less, 65 μg / kg or less, 60 μg / kg or less, 55 μg / kg or less, 50 μg / kg or less. Anti-CD3 antibodies such as telizumab at doses of 45 μg / kg or less, 40 μg / kg or less, 35 μg / kg or less, 30 μg / kg or less, 25 μg / kg or less, 20 μg / kg or less, 15 μg / kg or less, 10 μg / kg or less, 5 μg / kg or less, 2.5 μg / kg or less, 2 μg / kg or less, 1.5 μg / kg or less, 1 μg / kg or less, 0.5 μg / kg or less, or 0.2 μg / kg or less, are used to treat or improve one or more symptoms of T1D.

[0103] In some embodiments, one or more doses of 200 μg / kg or less are administered subcutaneously to the subject, preferably 175 μg / kg or less, 150 μg / kg or less, 125 μg / kg or less, 100 μg / kg or less, 95 μg / kg or less, 90 μg / kg or less, 85 μg / kg or less, 80 μg / kg or less, 75 μg / kg or less, 70 μg / kg or less, 65 μg / kg or less, 60 μg / kg or less, 55 μg / kg or less, 50 μg / kg or less. Anti-CD3 antibodies such as telizumab at doses of 45 μg / kg or less, 40 μg / kg or less, 35 μg / kg or less, 30 μg / kg or less, 25 μg / kg or less, 20 μg / kg or less, 15 μg / kg or less, 10 μg / kg or less, 5 μg / kg or less, 2.5 μg / kg or less, 2 μg / kg or less, 1.5 μg / kg or less, 1 μg / kg or less, 0.5 μg / kg or less, or 0.2 μg / kg or less, are used to treat or improve one or more symptoms of T1D.

[0104] In some embodiments, one or more doses of 100 μg / kg or less are administered intravenously to the subject, preferably 95 μg / kg or less, 90 μg / kg or less, 85 μg / kg or less, 80 μg / kg or less, 75 μg / kg or less, 70 μg / kg or less, 65 μg / kg or less, 60 μg / kg or less, 55 μg / kg or less, 50 μg / kg or less, 45 μg / kg or less, 40 μg / kg or less, 3 Anti-CD3 antibodies such as telizumab at doses of 5 μg / kg or less, 30 μg / kg or less, 25 μg / kg or less, 20 μg / kg or less, 15 μg / kg or less, 10 μg / kg or less, 5 μg / kg or less, 2.5 μg / kg or less, 2 μg / kg or less, 1.5 μg / kg or less, 1 μg / kg or less, 0.5 μg / kg or less, or 0.2 μg / kg or less, are used to treat or improve one or more symptoms of T1D. In some embodiments, the intravenous dose is 100 μg / kg or less, 95 μg / kg or less, 90 μg / kg or less, 85 μg / kg or less, 80 μg / kg or less, 75 μg / kg or less, 70 μg / kg or less, 65 μg / kg or less, 60 μg / kg or less, 55 μg / kg or less, 50 μg / kg or less, 45 μg / kg or less, 40 μg / kg or less, 35 μg / kg or less, 30 μg / kg or less, 25 μg / kg or less, 20 μg / kg or less, or 15 μg / kg. Anti-CD3 antibodies such as telixirumab, administered at or less than 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, may be administered over approximately 6 hours, approximately 4 hours, approximately 2 hours, approximately 1.5 hours, approximately 1 hour, approximately 50 minutes, approximately 40 minutes, approximately 30 minutes, approximately 20 minutes, approximately 10 minutes, approximately 5 minutes, approximately 2 minutes, approximately 1 minute, approximately 30 seconds, or approximately 10 seconds, to treat or improve one or more symptoms of T1D.

[0105] In some embodiments, the subject is orally administered one or more doses of 100 μg / kg or less, preferably 95 μg / kg or less, 90 μg / kg or less, 85 μg / kg or less, 80 μg / kg or less, 75 μg / kg or less, 70 μg / kg or less, 65 μg / kg or less, 60 μg / kg or less, 55 μg / kg or less, 50 μg / kg or less, 45 μg / kg or less, 40 μg / kg or less, 3 ...40 μg / kg or less, 35 μg / kg or less, 40 μg / kg or less, 40 μg / kg or less, 35 μg / kg or less, 40 μg / kg or less, 40 μg / kg or less, 35 μg / kg or less, 40 μg / kg or less, 40 μg / kg or less, 40 μg / kg or less, 35 μg / kg or less, 40 μg / kg or less, 40 μg / kg or less, 40 Anti-CD3 antibodies such as telixirzab at doses of μg / kg or less, 30 μg / kg or less, 25 μg / kg or less, 20 μg / kg or less, 15 μg / kg or less, 10 μg / kg or less, 5 μg / kg or less, 2.5 μg / kg or less, 2 μg / kg or less, 1.5 μg / kg or less, 1 μg / kg or less, 0.5 μg / kg or less, or 0.2 μg / kg or less, are used to treat or improve one or more symptoms of T1D. In some embodiments, the oral dose is 100 μg / kg or less, 95 μg / kg or less, 90 μg / kg or less, 85 μg / kg or less, 80 μg / kg or less, 75 μg / kg or less, 70 μg / kg or less, 65 μg / kg or less, 60 μg / kg or less, 55 μg / kg or less, 50 μg / kg or less, 45 μg / kg or less, 40 μg / kg or less, 35 μg / kg or less, 30 μg / kg or less, 25 μg / kg or less, 20 μg / kg or less, or 15 μg / kg. Anti-CD3 antibodies such as telixirumab, administered at or less than 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, may be administered over approximately 6 hours, approximately 4 hours, approximately 2 hours, approximately 1.5 hours, approximately 1 hour, approximately 50 minutes, approximately 40 minutes, approximately 30 minutes, approximately 20 minutes, approximately 10 minutes, approximately 5 minutes, approximately 2 minutes, approximately 1 minute, approximately 30 seconds, or approximately 10 seconds, to treat or improve one or more symptoms of T1D.

[0106] In some implementations, an escalating dose is administered during the first few days of the dosing regimen, with the dose on day 1 being 100-250 μg / m². 2 / day, and increasing to the daily dose just described above on days 2 and 3. For example, administer the following dose to the subject: approximately 106 μg / m² on day 1. 2 / day, approximately 425μg / m² on the second day. 2 / day, and for the following days of the regimen (e.g., days 3-12) 850 μg / m 2 / day. In some implementations, the following dose is administered to the subject: approximately 211 μg / m² on day 1. 2 / day, approximately 423μg / m² on day 2. 2 Approximately 840 μg / m² per day, on day 3 and the following days of the regimen (e.g., days 3–12). 2 / sky.

[0107] In some embodiments, an escalating dose is administered during the first few days of the dosing regimen, with a dose of approximately 5-150 μg / m² / day on day 1, preferably approximately 55-150 μg / m² / day, for example, approximately 60-100 μg / m² / day, and escalating to the daily dose just described above on days 3, 4, 5, 6, or 7. In some embodiments, the following doses are administered to the subject: approximately 60 μg / m² / day on day 1, approximately 125 μg / m² / day on day 2, approximately 250 μg / m² / day on day 3, and approximately 500 μg / m² / day on day 4. 2 / day, and for the following days of the regimen (e.g., days 5-14) 1,000 μg / m 2 / day. In some implementations, the following dose is administered to the subject: approximately 60 μg / m² on day 1. 2 / day, approximately 125μg / m² on the second day. 2 / day, approximately 250μg / m² on day 3. 2 / day, approximately 500μg / m² on day 4. 2 / day, and for the following days of the regimen (e.g., days 5-14) 1,030 μg / m 2 / day. In some implementations, the following dose is administered to the subject: approximately 100 μg / m² on day 1. 2 / day, approximately 425μg / m² on the second day. 2 / day, approximately 850μg / m³ on day 3. 2 / day, approximately 850μg / m² on day 4. 2 / day, and for the following days of the regimen (e.g., days 5-14) 1,000 μg / m 2 / day. In some implementations, the following dose is administered to the subject: approximately 60 μg / m² on day 1. 2 / day, approximately 125μg / m² on the second day. 2 / day, approximately 250μg / m² on day 3. 2 / day, approximately 500μg / m² on day 4. 2 / day, and for the following days of the regimen (e.g., days 5-14) 1,070 μg / m 2 / sky.

[0108] In some implementations, to reduce the likelihood of cytokine release and other adverse reactions, the initial 1, 2, or 3 doses, or all doses, are administered more slowly via intravenous administration. For example, 106 μg / m². 2 The daily dose can be administered over approximately 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, and 22 hours. In some embodiments, the dose is administered by slow infusion over a period of, for example, 20 to 24 hours. In some embodiments, the dose is infused in a pump, preferably with the concentration of the antibody being administered increasing as the infusion proceeds.

[0109] In some implementation schemes, the aforementioned 106 μg / m 2 / day up to 850μg / m 2 The set dose portion of the / day regimen is administered in incremental doses.

[0110] In some implementations, anti-CD3 antibodies such as teglizumab are not administered at daily doses over several days, but rather via infusion over uninterrupted intervals of 4, 6, 8, 10, 12, 15, 18, 20, 24, 30, or 36 hours. The infusion may be constant, or it may begin with a lower dose, for example, at the initial 1, 2, 3, 5, 6, or 8 hours of infusion, and then increase to a higher dose. During the infusion, the patient receives a dose equal to the amount administered in the aforementioned 5- to 20-day regimen. For example, approximately 150 μg / m² may be administered. 2 200μg / m 2 250μg / m 2 500μg / m 2 750μg / m 2 1000μg / m 2 1500μg / m 2 2000μg / m 2 3000μg / m 2 4000μg / m 2 5000μg / m 2 6000μg / m 2 7000μg / m 2 8000μg / m 2 9000μg / m 2 9500μg / m 2 10000μg / m 2 10500μg / m 2 11000μg / m 211500μg / m 2 12000μg / m 2 12500μg / m 2 13000μg / m 2 13500μg / m 2 Or 14000μg / m 2 The dosage. Specifically, the infusion rate and duration are designed to minimize the level of free anti-CD3 antibodies, such as teglizumab, in the subject after administration. In some embodiments, the level of free anti-CD3 antibodies, such as teglizumab, should not exceed 200 ng / ml of free antibody. Furthermore, the infusion is designed to achieve at least 50%, 60%, 70%, 80%, 90%, 95%, or 100% combined T-cell receptor coating and modulation.

[0111] In some implementations, long-term administration of anti-CD3 antibodies such as telizumab is used to treat one or more symptoms of type 1 diabetes, or to slow the progression of type 1 diabetes or improve one or more symptoms of type 1 diabetes. For example, in some implementations, low doses of anti-CD3 antibodies such as telizumab are administered once a month, twice a month, three times a month, once a week, or even more frequently, as an alternative to the aforementioned 6 to 14-day dosing regimens, or after administration of such regimens, to enhance or maintain their effect. Such low doses can be as low as 1 μg / m². 2 Up to 100 μg / m 2 Within a range, for example, approximately 5 μg / m 2 10μg / m 2 15μg / m 2 20μg / m 2 25μg / m 2 30μg / m 2 35μg / m 2 40μg / m 2 45μg / m 2 or 50 μg / m 2 .

[0112] In some implementations, subjects may be re-dosed at some point after two cycles of an anti-CD3 antibody, such as telizumab, administration, for example, based on one or more physiological or biomarker parameters, or as a matter of course. Re-dosing and / or assessment of the need for such re-dosing may be performed at 2, 4, 6, 8, 9, 1, 15, 18, 2, 30, or 3 years after administration of the dosing regimen, and may include indefinite administration of a cycle every 6 months, 9 months, 1 year, 15 months, 18 months, 2 years, 30 months, or 3 years.

[0113] In some embodiments, before and / or after administration of a 12-day course of tegizumab (e.g., at intervals of 1–6 months, 2–5 months, or approximately 3 months), the level (or relative amount) of phenotypically exhausted T cells, such as TIGIT+KLRG1+CD8+CD3+ cells, relative to all CD3+ T cells, is measured, for example, by flow cytometry. In some embodiments, the level of TIGIT+KLRG1+CD8+CD3+ T cells may be monitored, for example, by flow cytometry. In some embodiments, when the level of TIGIT+KLRG1+CD8+CD3+ T cells corresponds to (e.g., returns to) baseline levels, an additional 12-day course of an anti-CD3 antibody, such as tegizumab, is administered. In some embodiments, the TIGIT+KLRG1+CD8+CD3+ T cell assay is performed approximately 3 months (or approximately 1–6 months) after administration of a second 12-day course of treatment. In some implementations, if the subject has more than about 10% TIGIT+KLRG1+CD8+ T cells in all CD3+ T cells, monitoring can be performed annually. In some implementations, if the subject has less than about 10% TIGIT+KLRG1+CD8+ T cells in all CD3+ T cells, monitoring can be performed approximately every 3-6 months.

[0114] In some implementations, re-dosing includes administering additional (e.g., a second, third, or more) 12- to 14-day courses of telizumab, each with a total dose exceeding approximately 9000 μg / m². 2 As described herein. In some implementations, an additional 12-day course of telixirmab includes a first dose of 106 μg / m² on day 1. 2 Tilizumab, second dose 425 μg / m2 on day 2, and one dose 850 μg / m2 daily from day 3 to 12. 2 And the total dose was approximately 9031 μg / m 2 In other implementations, an additional 12-day course of telixirmab includes a first dose of 211 μg / m² on day 1. 2 Telizumab, second dose on day 2, 423 μg / m² 2 Teglituzumab, and one dose of 840 μg / m² daily from days 3 to 12. 2 The total dose was approximately 9034 μg / m³. 2 .

[0115] In some implementations, additional (e.g., a second, third, or more) 12- to 14-day courses of anti-CD3 antibodies such as telizumab may be administered approximately 12 to approximately 24 months (e.g., 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.

[0116] This article provides methods for reducing exogenous insulin use and telizumab dosing regimens. In some embodiments, an anti-CD3 antibody such as telizumab is administered to reduce exogenous insulin use by at least 0.08 U / kg / day (e.g., a reduction of 0.08 U / kg / day, 0.09 U / kg / day, 0.10 U / kg / day, 0.11 U / kg / day, or more).

[0117] In some implementations, subjects treated with an anti-CD3 antibody, such as telizumab, have lower exogenous insulin use (e.g., a reduction of at least 0.08 U / kg / day in exogenous insulin use) compared to pre-treatment levels. In some implementations, administration of an anti-CD3 antibody, such as telizumab, leads to the discontinuation of exogenous insulin use.

[0118] In some implementations, anti-CD3 antibodies, such as telizumab, are administered to achieve or maintain glycated heme (HA1 or HA1c) levels below 8%, below 7.5%, below 7%, below 6.5%, below 6%, below 5.5%, or 5% or lower. At the start of treatment, the patient's HA1 or HA1c level is below 8%, below 7.5%, below 7%, below 6.5%, below 6%, or more preferably 4%-6% (preferably measured in the absence of other diabetes treatments, such as exogenous insulin). Such patients preferably retain at least 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, or 20% of β-cell function before initiating treatment. In some implementations, the administration of anti-CD3 antibodies prevents damage, thereby slowing disease progression and reducing the need for insulin administration. In some embodiments, the treatment methods described 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 at 6, 9, 12, 15, 18, or 24 months after prior treatment, respectively. In some embodiments, administration of anti-CD3 antibodies according to the methods described herein reduces the average HA1 or HA1c level in patients by approximately 5%, approximately 10%, approximately 15%, approximately 20%, approximately 25%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, or approximately 70%, compared to pre-treatment levels at 6, 9, 12, 15, 18, or 24 months after prior treatment. In some implementations, administration of anti-CD3 antibodies according to the methods provided herein increases the average 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 pre-treatment levels at 6, 9, 12, 15, 18, or 24 months after prior treatment.

[0119] In some embodiments, administration of anti-CD3 antibodies, particularly telizumab, according to the methods provided herein, slows β-cell loss and / or preserves β-cell function (as demonstrated by, for example, C-peptide levels, episodes of hypoglycemia or hyperglycemia, duration within a range of 2 months, 2 months, 24 months, or longer) in children and adolescents aged 8–17 years diagnosed with T1D within the first 6 weeks. In some embodiments, administration of anti-CD3 antibodies, particularly telizumab, according to the methods provided herein, slows β-cell loss and / or preserves β-cell function within 18 months (78 weeks) in children and adolescents aged 8–17 years diagnosed with T1D within the first 5 to 31 weeks.

[0120] In some embodiments, the subjects are adults. In some embodiments, the subjects are pediatric subjects. In some embodiments, the pediatric subjects are 7 years of age or older. In some embodiments, the pediatric subjects are 6 years of age or older. In some embodiments, the pediatric subjects are 5 years of age or older. In some embodiments, the pediatric subjects are 4 years of age or older. In some embodiments, the pediatric subjects are 3 years of age or older. In some embodiments, the pediatric subjects are 1 year of age or older. In some embodiments, the pediatric subjects are infants.

[0121] Some implementation schemes involve the use of telizumab in methods for treating clinical type 1 diabetes (T1D), which includes administration at a dose greater than about 9000 μg / m². 2 The total dose of tesilizumab was administered to subjects in need for a 12-day course.

[0122] In some implementations, the total dose is between approximately 9000 and approximately 9500 μg / m². 2 Between [specific values]. In some implementations, the total dose is between approximately 9000 and approximately 14000 μg / m³. 2 between.

[0123] In some implementations, the 12-day treatment course includes a first dose of 106 μg / m² on day 1. 2 Teglituzumab, second dose on day 2, 425 μg / m². 2 Teglituzumab, and one dose of 850 μg / m² daily from days 3 to 12. 2 And the total dose was approximately 9031 μg / m 2 .

[0124] In some implementations, the 12-day treatment course includes a first dose of 211 μg / m² on day 1. 2 Telizumab, second dose on day 2, 423 μg / m²2 Teglituzumab, and one dose of 840 μg / m² daily from days 3 to 12. 2 And the total dose was approximately 9034 μg / m 2 .

[0125] In some implementations, the method may include administering a first and a second 12-day course of telizumab. In some implementations, the first and second 12-day courses are administered at intervals of approximately 1–6 months, approximately 2–5 months, or approximately 3 months.

[0126] In some implementations, the method may include administering a third or more 12-day cycles of telizumab to subjects in need, with a total dose of more than about 9000 μg / m² per cycle. 2 .

[0127] In some implementations, the third or more 12-day cycles of telixirmab include a first dose of 106 μg / m² on day 1. 2 Teglituzumab, second dose on day 2, 425 μg / m² 2 Teglituzumab, and one dose of 850 μg / m² daily from days 3 to 12. 2 And the total dose for each course of treatment is approximately 9031 μg / m². 2 .

[0128] In some implementations, the third or more 12-day cycles of telixirmab include a first dose of 211 μg / m² on day 1. 2 Telizumab, second dose on day 2, 423 μg / m² 2 Teglituzumab, and one dose of 840 μg / m² daily from days 3 to 12. 2 And the total dose for each course of treatment is approximately 9034 μg / m². 2 .

[0129] In some implementations, a third or more 12-day cycles of telixirumab are administered at intervals of approximately 12 months to approximately 24 months.

[0130] In some embodiments, the method may further include determining a baseline level of TIGIT+KLRG1+CD8+ cells relative to all CD3+ T cells after each 12-day treatment cycle, monitoring the level of TIGIT+KLRG1+CD8+CD3+ T cells, and administering an additional 12-day cycle of teglitzumab when the level of TIGIT+KLRG1+CD8+CD3+ T cells returns to baseline. In some embodiments, TIGIT+KLRG1+CD8+CD3+ T cells are measured by flow cytometry. In some embodiments, TIGIT+KLRG1+CD8+CD3+ T cells are monitored by flow cytometry. In some embodiments, the measurement of TIGIT+KLRG1+CD8+CD3+ T cells is performed approximately 1–6 months, approximately 2–5 months, or approximately 3 months after each 12-day treatment cycle. In some implementations, if the subject has more than approximately 10% TIGIT+KLRG1+CD8+ T cells in all CD3+ T cells, follow-up monitoring is performed annually. In some implementations, if the subject has less than approximately 10% TIGIT+KLRG1+CD8+ T cells in all CD8+ T cells, follow-up monitoring is performed approximately every 3-6 months.

[0131] In some implementations, the subjects in need have been diagnosed with T1D within 6 weeks prior to the administration step.

[0132] In some implementations, the administration step results in a reduction of at least 10% in insulin use, HbA1c levels, hypoglycemic episodes, or a combination thereof, compared to pre-treatment levels.

[0133] In some implementations, each dose is administered parenterally.

[0134] In some implementations, each dose is administered via intravenous infusion.

[0135] In some implementation schemes, the required subjects are approximately 8 to 17 years old.

[0136] In some implementations, during the Mixed Diet Tolerance Trial (MMTT), subjects in need have a peak C-peptide level of ≥0.2 pmol / mL.

[0137] In some implementations, subjects receiving telizumab had higher mean C-peptide values ​​compared to controls receiving placebo.

[0138] In some implementations, the method also includes assessing the area under the time-concentration curve (AUC) of C-peptide at 78 weeks following a mixed dietary tolerance test (MMTT).

[0139] In some implementations, the subject in need has at least 20% β-cell function prior to administration of the first dose.

[0140] In some implementations, the reduction in insulin use, HbA1c levels, hypoglycemic episodes, or a combination thereof lasts for 12 months or longer.

[0141] Some aspects involve methods for treating clinical type 1 diabetes (T1D), which include using doses greater than approximately 9000 μg / m². 2 The total dose is administered to subjects in need for a 12-day course of telizumab. Some aspects involve the use of telizumab in methods for treating clinical type 1 diabetes (T1D), which includes administration at doses greater than approximately 9000 μg / m². 2 The total dose of tesilizumab was administered to subjects in need for a 12-day course.

[0142] In some implementations, a method for treating clinical type 1 diabetes (T1D) is provided, which includes administering approximately 9000 to approximately 9500 μg / m². 2 The total dose is administered to subjects in need for a 12-day course of telizumab. In some implementations, a method of treating clinical type 1 diabetes (T1D) is provided, comprising administering telizumab at a dose of approximately 9000 to approximately 14000 μg / m². 2 The total dose of tesilizumab was administered to subjects in need for a 12-day course. V. Exemplary Implementation

[0143] The following are further examples of non-limiting exemplary embodiments of this disclosure. 1. A method for reducing exogenous insulin use in a subject in need, the method comprising administering telizumab to the subject for a course of 12 to 14 days at a total dose of about 9000 μg / m2 to about 14000 μg / m2, wherein administration of telizumab results in a reduction of exogenous insulin use by at least 0.08 U / kg / day. 2. The method as described in implementation scheme 1, wherein administration of tellizumab resulted in a reduction of exogenous insulin use by at least 0.08 U / kg / day in the first year. 3. The method as described in implementation scheme 1, wherein the administration of telizumab resulted in a reduction of exogenous insulin use by at least 0.10 U / kg / day in the second year. 4. The method as described in implementation scheme 1, wherein the method comprises administering telizumab to the subject for a 12-day course of treatment. 5. The method as described in implementation scheme 1, wherein the method comprises administering a 14-day course of telizumab to the subject. 6. The method as described in implementation scheme 1, wherein the method comprises administering telizumab for a first and a second 12- to 14-day treatment course. 7. The method as described in implementation scheme 6, wherein the first and second 12- to 14-day treatment courses are administered at intervals of approximately 6 months. 8. The method as described in implementation scheme 1, wherein the method comprises administering telizumab for a first and a second 12-day course of treatment. 9. The method as described in embodiment 8, wherein the first and second 12-day treatment courses are administered at intervals of approximately 6 months. 10. The method as described in implementation scheme 1, wherein the subject in need has stage 3 type 1 diabetes. 11. The method of any one of embodiments 1-10, wherein the method comprises administering telizumab by intravenous infusion. 12. The method as described in any one of embodiments 1-10, wherein the subject in need is about 7.5 years of age or older. 13. The method as described in any one of embodiments 1-10, wherein the reduction in exogenous insulin use lasts for one year or longer. 14. The telizumab used in a method of reducing exogenous insulin use in a subject in need, the method comprising administering telizumab to the subject for 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 telizumab results in a reduction of exogenous insulin use of at least 0.08 U / kg / day. Example

[0144] In November 2022, based on data from the pivotal TN-10 study, tesalizumab became the first drug approved for delaying the onset of stage 3 type 1 diabetes in adults with stage 2 type 1 diabetes and pediatric patients aged 8 years and older. To evaluate the effect of tesalizumab on maintaining endogenous insulin production, a meta-analysis of C-peptide data from 609 patients (375 tesalizumab patients and 234 control patients) from five phase 3 clinical trials was performed. The primary outcome of the meta-analysis was that, after one or two cycles of tesalizumab, the change in stimulated C-peptide relative to baseline was significantly improved in 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 was also conducted, showing an overall reduction of 0.08 U / kg / day in year 1 (p<0.0001) and 0.10 U / kg / day in year 2 (p=0.0001). A comprehensive safety analysis was performed on five clinical trials that enrolled 1018 patients in phase 2 or 3 trials (approximately 1500 patients are visited annually for tislelizumab treatment). This analysis showed that the most common adverse events included lymphopenia, rash, and headache, most of which occurred in the first few weeks after tislelizumab administration and typically resolved without intervention. These data confirm the consistency of β-cell function preservation as measured by C-peptide across multiple clinical trials, and the safety profile characterized by self-limiting adverse events after one or two cycles of tislelizumab treatment. introduction

[0145] Tiglizamab was the first drug approved for altering the autoimmune progression of type 1 diabetes and the first approved for delaying any autoimmune disease in patients before clinical onset. This approval came after decades of research, beginning with preclinical studies and followed by six clinical trials, including five in post-clinical diagnosis patients (Phase 3) and one in patients with two or more islet autoantibodies and abnormal blood glucose levels before clinical diagnosis (Phase 2).

[0146] Tilizumab is a humanized IgG1 monoclonal antibody (mAb) that binds with high affinity to the ε chain of CD3 (CD3ε). Its complementarity-determining region (CDR) is derived from Ortho Kung T3 (OKT3), the first mAb licensed for use in humans for acute solid graft rejection. OKT3 was humanized to minimize immunogenicity. Two Leu-to-Ala substitutions were introduced into the Fc region to minimize Fc receptor binding, resulting in a 100-1,000-fold reduction in T cell activation, T cell proliferation, and cytokine release in human peripheral blood mononuclear cell cultures compared to OKT3. 1-5Early studies of its mechanism have shown that partial activation leads to the action of CD8+ T cells, which are an integral part of autoimmune-mediated destruction of pancreatic β cells. 6-10

[0147] Telizumab was initially investigated for the treatment of acute graft rejection and psoriatic arthritis. 11-14 Meanwhile, experiments in spontaneous and chemically induced diabetic mouse models provide evidence for reversing or preventing autoimmune diabetes and immune tolerance, as continuous administration (as required by previous immunotherapies) is not required. 15-17

[0148] The first randomized clinical trial for stage 3 type 1 diabetes was a phase 2 clinical study (Study 1), which evaluated the safety, tolerability, and efficacy of a single 12- or 14-day course of telixirumab in patients with newly diagnosed stage 3 diabetes compared to standard of care. 18 Efficacy was assessed based on the preservation of β-cell function by evaluating the response of C-peptide to the Mixed Diet Tolerance Test (MMTT). The success of this trial led to a randomized phase 2 trial (AbATE[NCT00129259]) that administered a second course of telizumab after one year in an effort to prolong the duration of response. 18-20 Subsequently, two phase 3 trials (Protégé and Encore [NCT00385697 and NCT00920582]) were conducted to test three telizumab dosing regimens, administered in two cycles with a 6-month interval. These trials used a novel, unproven composite primary endpoint of exogenous insulin use and HbA1c. In the interim analysis, the Protégé study failed to meet its primary endpoint, leading to the termination and discontinuation of further clinical development. 21 At the time these two studies were terminated, another phase 2 trial (Delay[NCT00378508]) evaluated the effect of tilimizumab on patients with clinically significant C-peptide levels (e.g., >0.2 pmol / ml) 4–12 months after diagnosis of type 1 diabetes. 22 All five clinical studies showed promising C-peptide retention.

[0149] The phase 2 study TN-10 (NCT01030861), sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and conducted via TrialNet for type 1 diabetes, aimed to evaluate whether a single course of telixizumab could delay or prevent the clinical diagnosis of type 1 diabetes in patients with early-stage (phase 2) type 1 diabetes.23 The study recruited relatives of patients with type 1 diabetes (aged 8 to 49 years) who had two or more pancreatic autoantibodies and abnormal blood glucose levels. Results showed that, compared to placebo patients, a statistically significant delay of approximately 2 years in the median time to onset of type 1 diabetes was observed in the phase 3 clinical trial, indicating stable β-cell decline leading to preserved β-cell function. The latest analysis reported a further delay in progression of 2.7 years. 23,24

[0150] While clinical study results support assessments of β-cell function retention using C-peptide (a measure of endogenous insulin production), individual studies have different protocol designs, including different eligibility criteria and the nature of control groups, which may affect the overall interpretation of the results. 25

[0151] Therefore, the primary objective of this comprehensive analysis was to confirm the consistency of tilimuzumab's effects on β-cell function, as measured by C-peptide levels stimulated in five clinical trials in patients with type 1 diabetes in phase 3. Secondary efficacy analyses of exogenous insulin use were performed. A comprehensive review of the safety experience of tilimuzumab in patients with type 1 diabetes in phases 2 and 3 was also evaluated. method 1. Clinical trials

[0152] The designs of six clinical trials have been previously disclosed (Table 1). 19,20,22,23,26 The dosing regimen evolved over time to suit pediatric patients and, based on safety experience, progressed from a 14-day dosing regimen (Study 1: 4 increments, 10 days full dose based on body weight) to 12 days (Study 1: 2-day increments, 10 days full dose based on body surface area [BSA]) and then to 14 days (AbATE, Delay, Protégé, Encore: 4-day increments, 10 days full dose based on BSA). All patients in the trials received standard care management for type 1 diabetes with insulin therapy. Investigators are advised to follow the recommendations of the American Diabetes Association for target glycemic control. No specific algorithm for insulin administration is provided.

[0153] Most patients received the full 14-day regimen of teliximab via intravenous infusion, including 51 μg / mcg on day 1. 2 Day 2: 103 μg / m 2 Day 3: 206 μg / m 2 Day 4: 413 μg / m 2 and 826 μg / m² on days 5 to 14 2 The cumulative dose was 9,034 μg / m². 2Patients were randomized to receive two cycles of Protégé, Encore (at randomization and at month 6), and AbATE (at randomization and at month 12), as well as a single cycle in Study 1 and Delay, with the option of a second cycle (open-label) in the Delay study. The Protégé and Encore studies also investigated lower cumulative dose regimens (6 days [2426 μg / m²]). 2 Or a 14-day regimen of one-third of the dose [2985 μg / m] 2 The lower dosing regimen in Protégé and the second course in Delay were not included in the efficacy analysis, but were included in the safety analysis. 2. Therapeutic effect analysis Analysis of aC peptide reaction

[0154] All five studies included in the comprehensive efficacy analysis were conducted in patients with stage 3 type 1 diabetes who received the full 14-day protocol and were designed as randomized, placebo- or standard-of-care fixed-timeframe studies (Table 1). For Studies 1, AbATE, Protégé, and Encore, patients were recruited at 6, 8, 12, and 12 weeks after type 1 diabetes diagnosis, or 4–12 months after type 1 diabetes diagnosis in the Delay study. All patients had detectable levels of stimulating C-peptide. Studies 1 and AbATE were open-label, randomized to either the investigational drug or standard of care, while Delay, Protégé, and Encore were double-blind, randomized, placebo-controlled. Studies 1, AbATE, and Delay were conducted by academic researchers at research sites in the United States, while Protégé and Encore were conducted by MacroGenics at research sites in the United States, Eastern Europe, and India.

[0155] A phase one integrated intention-to-treat (ITT) analysis was performed using individual patient data from all five studies with 1-year follow-up and three studies with 2-year follow-up (Study 1, AbATE, and Protégé). The ITT population included all patients who were randomized to the 12-day and 14-day telizumab regimen in Study 1 and to the full 14-day telizumab regimen in AbATE, Protégé, Encore, and Delay, as well as patients who were randomized to standard care or placebo (e.g., control group) in all five studies (Table 2).

[0156] The primary endpoint was the change in the area under the curve (AUC) of C-peptide relative to baseline. Baseline was defined as the C-peptide measurement obtained prior to the initial dose of telithrumab. The AUC in the 4-hour MMTT was divided by 240 or the last measurement time of C-peptide and converted (ln(AUC+1)). C-peptide was measured by radioimmunoassay (Study 1), TOSOH assay (AbATE and Delay), and at... The measurements were performed using chemiluminescence assays (Protégé and Encore) on the 2000.

[0157] Under the assumptions of "random missing" and "non-random missing," two analyses were performed on the observed data and the imputed missing data using multiple imputation methods. Analysis of covariance (ANCOVA) was used to analyze the change in C-peptide relative to baseline. ANCOVA included treatment as the primary effect, with age, baseline C-peptide, study, and the interaction between treatment and study as covariates. The treatment-study interaction term was included to assess whether there were effect differences dependent on individual study characteristics, and these differences were adjusted for. The results of ANCOVA were used to estimate the least squares mean (LSM) and 95% confidence interval (CI) of the change in the corresponding C-peptide relative to baseline AUC due to treatment. The number of treatment cycles and their duration were determined by the study and therefore were not included as separate covariates in ANCOVA. Parameter estimates and 95% CIs were generated for the imputed dataset by averaging the estimates from 100 imputations performed. All parameter estimates and their respective 95% CIs for the treatment LSM differences are presented in a forest plot. b. Analysis of exogenous insulin use

[0158] The second meta-analysis assessed daily exogenous insulin use (U / kg / day) in the same studies. The mean daily total insulin dose (all insulins) was used in this analysis. Individual patient data on insulin use included data from all five studies with a 1-year follow-up, as well as from studies 1, AbATE, and Protégé where 2-year data were available. ANCOVA was used to assess treatment variability in insulin use, with covariates including baseline insulin use, treatment, age, study, and the interaction between treatment and study. Observational and imputed data were also analyzed. 3. Security Analysis

[0159] All five studies included in the comprehensive safety analysis were conducted in phase 2 (TN-10) or phase 3 (AbATE, Protégé, Encore, and Delay) clinical trials using BSA-based dosing regimens (Supplementary Tables 1 and 3). Safety data from Study 1 are not included because it included weight-based dosing. Safety assessments included analyses of adverse events (AEs), mechanism-related adverse events considered as adverse events of particular concern (AESIs), and serious adverse events (SAEs). The safety cohort included all patients who received at least one dose of telixirumab in all three dosing regimens (full 14-day, 6-day, and one-third-dose 14-day regimens) or were randomized to placebo or standard of care (e.g., control group). Descriptive statistics were used to describe the data. All analyses were performed using SAS software version 9.4. result 1. Therapeutic effect analysis Analysis of aC peptide reaction

[0160] A total of 609 patients from 5 clinical trials were included in the ITT population for efficacy analysis, with 375 in the teglizumab group and 234 in the control group. In the teglizumab group, 88% of patients completed their respective studies. In the teglizumab group, three patients (0.8%) withdrew early due to adverse events, and 17 patients (4.5%) were lost to follow-up. In the control group, no subjects withdrew early due to adverse events, and 6 subjects (2.6%) were lost to follow-up.

[0161] Baseline demographics and clinical characteristics were similar across treatment groups, but numerous differences existed between study cohorts (Table 2). Patients in the Protégé and Encore trials were older and had longer time elapsed since diagnosis compared to Study 1 and AbATE. By design, patients in the Delay trial had a duration of 4–12 months from diagnosis.

[0162] Forest plots of LSM differences and respective 95% CIs for changes in C-peptide relative to baseline from a meta-analysis of five studies are shown. Figure 1In inset A. These data showed that, in the 1-year and 2-year data (observational and imputational), the retention of C-peptide with telizumab treatment was highly statistically significant compared with placebo or standard of care (p < 0.0001). For the observational data, the difference in treatment effect between telizumab and the control group was 0.0 (95% CI: 0.04, 0.12) pmol / mL in year 1 and 0.12 (95% CI: 0.07, 0.17) pmol / mL in year 2. For the imputational data, the difference in treatment effect between telizumab and the control group was 0.09 (95% CI: 0.05, 0.13) pmol / mL in year 1 and 0.10 (95% CI: 0.05, 0.16) pmol / mL in year 2.

[0163] Analysis by individual study and by year shows Figure 1 In small figure B. Except for Encore, which had significant missing data due to early termination of the study, C-peptide levels were significantly improved in every other study. In each of the three studies with available 2-year data, telizumab treatment significantly preserved C-peptide levels compared to placebo.

[0164] C-peptide plots of 1-year and 2-year data are shown in the figures below. Figure 2 In insets A and B, C-peptide AUC levels at the 6-month time point were elevated in the telizumab group (mean increases of 5% and 8% in 1-year and 2-year data, respectively), but decreased in the control group. At 1 year, C-peptide AUC decreased by 8% and 27% relative to baseline in both the telizumab and control groups (p < 0.0001). For studies with 2-year data, the decreases relative to baseline were 34% and 51% in telizumab and control, respectively (p < 0.0001). b. Comprehensive analysis of exogenous insulin use

[0165] Each clinical trial uses a targeted therapy approach to manage diabetes, so any effect of tesilizumab treatment on endogenous β-cell function will be reflected through changes in exogenous insulin requirements.

[0166] Forest plots of a comprehensive analysis of insulin use showed that, compared with those in the control group, patients treated with telizumab had statistically significant reductions 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) (respectively). Figure 3(See insets A and B). In individual studies, Studies 1 and AbATE showed statistically significant reductions in insulin use in patients treated with telizumab compared to controls (p < 0.0001 at 1 and 2 years for both studies). However, point estimates from all studies tended to favor lower insulin use in patients treated with telizumab.

[0167] Insulin usage over time is displayed graphically. Figure 2 In insets C and D. Baseline levels were similar in both groups. Significantly reduced insulin use was observed at 1 year (0.58 vs. 0.65 U / kg / day; p<0.0001) and in three studies with 2-year data (AbATE, Protégé, and Encore) (0.66 vs. 0.74 U / kg / day; p=0.0001). Insulin discontinuation data are only available from the Protégé study, in which patients were not allowed to discontinue insulin unless instructed to do so by the investigator. Despite being unaware of treatment, at 1 year, 5.3% (11 / 207) of patients in the full-dose 14-day telixirumab group were not taking insulin, compared to 0% (0 / 98) in the control group (p=0.02). At year 2, 3 of these 11 patients were still on insulin discontinuation, while all control patients were still on insulin (p<0.05). 2. Security Analysis a. Comprehensive analysis of security

[0168] The comprehensive safety analysis included 1,018 patients with stage 2 and 3 type 1 diabetes, of whom 773 were randomized to teglizumab treatment and 245 were randomized to controls (Table 3). Approximately 1,500 patients treated with teglizumab were followed up annually. Baseline demographics and clinical characteristics were similar between the treatment groups in this expanded cohort.

[0169] A summary of adverse events (AEs) is shown in Table 4. Almost all patients in either treatment group experienced AEs, most of which were grade 1 or 2 in severity, typically occurring during or immediately after administration. Most AEs resolved without intervention. AEs leading to permanent discontinuation of the study drug were reported in 14.3% of the telizumab group and 3.7% of the control group. The most common causes of discontinuation in the telizumab group were laboratory tests (7.7%; primarily elevated liver enzymes reaching the protocol-defined discontinuation threshold) and hematologic and lymphatic disorders (3.2%; including neutropenia, thrombocytopenia, lymphopenia, and anemia). [Table 4]. Summary of adverse events in the safety group

[0170] SAEs were reported in 12.4% of patients in the telizumab group and 8.2% in the control group, but the majority (76.7%) were considered unrelated to treatment. The most common SAEs were associated with underlying type 1 diabetes pathophysiology, most notably diabetic ketoacidosis (DKA) (n=18, 2.3% telizumab; n=1, 0.4% control) and ketoacidosis (n=1, 0.1% telizumab; n=0, control). These events were reported at a mean of 10 months after the end of telizumab treatment, with a mean HbA1c level of 11.9% at the time of the event, indicating underlying poor glycemic control. SAEs with hypoglycemic events were observed only in stage 3 patients and did not occur in stage 2 patients. The incidence of hypoglycemic altered consciousness and hypoglycemic coma was comparable between the two groups.

[0171] The most common adverse events (AEs) reported by 10% or more patients in both groups are shown in Table 4. AEs reported more frequently in the teglizumab group compared to the control group included lymphopenia, leukopenia, neutropenia, decreased serum bicarbonate, and rash, all of which occurred during dosing and typically resolved within 4 weeks of initiation of dosing. Lymphopenia was observed in approximately 80% of patients treated with teglizumab, reaching its lowest point on day 5 of treatment and resolving with continued dosing, consistent with lymphocyte marginalization rather than cellular exhaustion.

[0172] Cytokine release syndrome (CRS) was reported in 5.8% (46 / 791) of telizumab patients and 1.2% (3 / 245) of control patients. 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 over-the-counter medications.

[0173] Infection rates were similar in patients treated with telimumab (53.0%) and control patients (52.7%), with severe infections occurring in 3.5% and 2% of telimumab and control patients, respectively. Novel Epstein-Barr virus (EBV) infections were reported in 18 (2.3%) telimumab patients and 10 (4.1%) control patients. EBV reactivation was reported in 40 (5.1%) telimumab patients and 6 (2.4%) control patients. EBV viremia was detected in 25 (3.2%) telimumab patients and 3 (1.2%) control patients 2 to 3 weeks after administration; it was usually asymptomatic and resolved spontaneously without antiviral treatment. Novel cytomegalovirus (CMV) infections were detected in 5 (0.6%) patients treated with telimumab and 2 (0.8%) patients in the control group. Four patients (0.5%) who received telizumab experienced CMV reactivation, none of which were symptom-related, and all cases resolved spontaneously without the need for antiviral treatment.

[0174] Patients treated with telizumab reported hypersensitivity reactions including allergic reactions (0.1%), angioedema (0.3%), peripheral edema (1.6%), and urticaria (1.9%); rashes were observed in 48% of telizumab patients and 15% of control patients, respectively. discuss

[0175] Disease Improvement Therapy (Telizumab-mzwv) was first approved for delaying the onset of type 1 diabetes in clinical stage 3. Tiglizumab is believed to improve disease progression from stage 2 to stage 3 in type 1 diabetes by preserving β-cell function. Over the past 20 years, five clinical trials of telizumab in stage 3 type 1 diabetes have demonstrated the preservation of β-cell function, as measured by C-peptide levels. To assess the consistency of β-cell preservation, a meta-analysis of C-peptide data from these five clinical trials was performed, supported by an analysis of exogenous insulin use. A review of the comprehensive safety experience was evaluated by integrating data from 791 patients treated with telizumab (representing approximately 1,500 patients followed annually). 18-23 This represents the most extensive data to date on the use of a single drug in improving type 1 diabetes.

[0176] Comprehensive efficacy analysis showed that, at 1 and 2 years post-treatment, patients treated with tilimuzumab exhibited significantly greater preservation of C-peptide levels compared to controls. Reduced exogenous insulin use supported the higher C-peptide levels (a measure of endogenous insulin production).

[0177] It is noteworthy that patients exhibit heterogeneity in terms of age (a possible determinant of the rate of decline in C-peptide), location (North America, India, and Eastern Europe), clinical practice, and other patient characteristics (such as adolescent status, which may affect insulin sensitivity). 27 Patients' autoimmune processes may also exhibit biological differences, as some patients received treatment shortly after diagnosis, while others received treatment up to one year after diagnosis. Furthermore, different assays were used to measure C-peptide. However, all studies followed the same MMTT protocol, and the analysis involved changes in β-cell function relative to baseline. An exploratory analysis of data from the Protégé study showed a greater decline in telixirmab response to C-peptide in patients diagnosed less than 6 weeks prior to randomization and in patients from the United States, whose baseline metabolic parameters indicated less severe disease than those from other regions. 21 In the Delay study, which investigated telizumab in patients diagnosed with stage 3 type 1 diabetes within the past 4 to 12 months, the time from diagnosis onset did not significantly improve the treatment effect on C-peptide response. 22 However, in this study, the magnitude of the C-peptide response between teglizumab and control patients was smaller than that observed in studies where teglizumab was used within weeks of diagnosis. Therefore, treatment may need to be initiated shortly after or even before a clinical diagnosis to achieve the best response to the drug. In the Protégé and Delay trials, teglizumab was effective in all age groups, but younger patients treated with teglizumab showed better C-peptide responses than older patients. Data from these trials have been incorporated into the PROTECT study (NCT03875729). 28 Designed to evaluate telizumab in newly diagnosed stage 3 type 1 diabetes patients aged 8 to 17 years with evidence of residual β-cell function, this study is evaluating the efficacy of telizumab. The results of the meta-analysis demonstrated significant differences in C-peptide retention across multiple studies, supporting the consistency of telizumab's therapeutic effects both between and within studies, indicating that its biological effects are robust, reproducible, and not unique to any particular study or patient characteristic.

[0178] The safety profile of telizumab is characterized by mild to moderate self-limiting adverse events. CRS was observed in 5.8% of adverse events, which may be attributed to the partial agonist effect of telizumab. 1,29 A higher rate of serious infections was observed (3.5% in telizumab compared to 2% in the control group), although the overall infection rate was similar between the treatment groups. Most patients treated with telizumab experienced lymphopenia (approximately 80%), which resolved even with continued administration and uninterrupted treatment. 30,31Importantly, the development of transient lymphopenia did not appear to be associated with an overall increase in the risk of infection. Although not included in the meta-analysis, 7-year follow-up of patients in the AbATE study showed no increased risk of infection and no malignancies were observed. 32 Previous preclinical studies and analyses of cells from patients treated with telizumab have suggested that this partial agonist signaling may lead to partial exhaustion of CD8+ T cells. Indeed, investigations of patients from the AbATE and rTN-10 studies showed that CD8+TIGIT+KLRG1+ memory T cells in patients treated with telizumab exhibited signs of exhaustion and produced lower levels of the inflammatory cytokines TNFα and IFNγ, which are associated with T cell-mediated β-cell death. 24 Because tesilizumab targets activated effector cells and preserves regulatory T cells and memory T cells to fight previously encountered pathogens, the preservation of β cells does not have a long-term effect on immunity. 32

[0179] A comprehensive C-peptide analysis could not resolve whether the benefit of a second cycle of telizumab outweighed the benefit of a single cycle; future trials may help address this question. The targeted therapy glycemic study design limited the ability to assess the effect of treatment on HbA1c levels. Nevertheless, improvements in HbA1c levels were observed at certain time points in Studies 1 and AbATE.

[0180] In summary, the comprehensive efficacy analysis provides strong evidence for the statistically significant preservation of β-cell function in patients with stage 3 type 1 diabetes, which is 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 tilimuzumab as a promising treatment addressing the potential autoimmune pathogenesis of type 1 diabetes. Based on the data presented in this article, the recent approval for delaying the onset of stage 3 type 1 diabetes in adults with stage 2 type 1 diabetes and pediatric patients aged 8 years and older represents a first advance towards achieving the goal of developing disease-modifying therapies.

[0181] Modifications and variations of the methods and compositions described herein will be apparent to those skilled in the art without departing from the scope and spirit of this disclosure. Although this disclosure has been described in conjunction with specific embodiments, it should be understood that the claimed disclosure should not be unduly limited to such specific embodiments. In fact, various modifications to the methods of implementing this disclosure are intended and understood by those skilled in the art to be within the scope of this disclosure as expressed in the claims of this application. By incorporating via reference

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Claims

1. A method for reducing the use of exogenous insulin in subjects in need, the method comprising administering insulin at approximately 9000 μg / m². 2 Approximately 14000 μg / m 2 The total dose of telizumab was administered to the subject for a course of 12 to 14 days, during which the administration of telizumab resulted in a reduction of exogenous insulin use of at least 0.08 U / kg / day.

2. The method of claim 1, wherein administration of tellizumab resulted in a reduction of exogenous insulin use by at least 0.08 U / kg / day in the first year.

3. The method of claim 1, wherein administration of tellizumab resulted in a reduction of exogenous insulin use by at least 0.10 U / kg / day in the second year.

4. The method of claim 1, wherein the method comprises administering telizumab to the subject for a 12-day course of treatment.

5. The method of claim 4, wherein the 12-day course of telizumab comprises: The first dose on day 1 was approximately 106 μg / m³. 2 telizumab The second dose on day 2 was approximately 425 μg / m². 2 Tefalizumab, and One dose of approximately 850 μg / m² per day from days 3 to 12. 2 Tilizumab.

6. The method of claim 1, wherein the method comprises administering telizumab to the subject for a 14-day course of treatment.

7. The method of claim 6, wherein the 14-day course of telizumab comprises: The first dose on day 1 is approximately 100 μg / m 2 telizumab The second dose on day 2 was approximately 425 μg / m². 2 telizumab The third dose on day 3 was approximately 850 μg / m³. 2 telizumab The fourth dose on day 4 was approximately 850 μg / m. 2 Tefalizumab, and One dose of approximately 1000 μg / m² per day from days 5 to 14. 2 Tilizumab.

8. The method of any one of claims 1-7, wherein the method comprises administering telizumab for a first and a second 12- to 14-day treatment course.

9. The method of any one of claims 1-7, wherein the method comprises administering telizumab for a first and a second 12-day course of treatment.

10. The method of claim 8 or 9, wherein the two courses of telizumab are administered at an interval of approximately 6 months.

11. The method of any one of claims 1-10, wherein the subject in need suffers from stage 3 type 1 diabetes.

12. The method of any one of claims 1-11, wherein the method comprises administering telizumab via intravenous infusion.

13. The method of any one of claims 1-12, wherein the subject in need is about 7.5 years of age or older.

14. The method of any one of claims 1-13, wherein the reduction in exogenous insulin use lasts for one year or longer.

15. Tilizumab, used to reduce the use of exogenous insulin in a subject in need of the method as described in any one of claims 1-14.

16. Use of tellizumab in the manufacture of a medicament for reducing the use of exogenous insulin in a subject in need of the method as described in any one of claims 1-14.

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