Teplizumab

Identification

Summary

Teplizumab is a CD3-directed monoclonal antibody indicated to delay the onset of Stage 3 type 1 diabetes in patients with Stage 2 type 1 diabetes.

Brand Names

Tzield

Generic Name

Teplizumab

DrugBank Accession Number

DB06606

Background

Teplizumab (teplizumab-mzwv) is a humanized IgG1 kappa CD3-directed monoclonal antibody used to delay the onset of type 1 diabetes (T1D).^3,4,5,11 T1D is an autoimmune condition in which T cell-mediated destruction of pancreatic β cells leads to loss of insulin production, impaired glycemic control, and reliance on exogenous insulin.¹ Anti-CD3 therapy has traditionally been used to prevent graft-versus-host-disease in organ transplantation but more recently has been explored to prolong the onset of (T1D) in high-risk patients.^3,6 Targeting T cells can be achieved through antibodies against the T cell receptor (TCR) component CD3. Although the mechanism of action of teplizumab has not been fully elucidated, it may involve partial agonistic signaling and deactivation of pancreatic beta cell autoreactive T lymphocytes.¹¹ Fc-receptors can bind to the "tail-end" anti-CD3 antibodies in an antigen-non-specific manner and lead to severe adverse effects related to cytokine release syndrome (CRS). Teplizumab was designed as an Fc-non-binding antibody in order to reduce the incidence of CRS.³ On November 2022, teplizumab was approved by the FDA as the first drug that can delay the onset of type 1 diabetes.¹²

Type

Biotech

Groups

Approved, Investigational

Biologic Classification

Protein Based Therapies
Monoclonal antibody (mAb)

Protein Structure

Protein Chemical Formula: C₆₄₆₂H₉₉₃₈N₁₇₃₈O₂₀₂₂S₄₆
Protein Average Weight: 150000.0 Da (approximate)

Sequences

>8869_H|teplizumab|Humanized||H-GAMMA-1 (VH(1-119)+CH1(120-217)+HINGE-REGION(218-232)+CH2(233-342)+CH3(343-449))|||||||449||||MW 49611.9|MW 49611.9|
QVQLVQSGGGVVQPGRSLRLSCKASGYTFTRYTMHWVRQAPGKGLEWIGYINPSRGYTNY
NQKVKDRFTISRDNSKNTAFLQMDSLRPEDTGVYFCARYYDDHYCLDYWGQGTPVTVSSA
STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGP
SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS
TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDEL
TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ
QGNVFSCSVMHEALHNHYTQKSLSLSPGK

>8869_L|teplizumab|Humanized||L-KAPPA (V-KAPPA(1-105)+C-KAPPA(107-213))|||||||213||||MW 23304.7|MW 23304.7|
DIQMTQSPSSLSASVGDRVTITCSASSSVSYMNWYQQTPGKAPKRWIYDTSKLASGVPSR
FSGSGSGTDYTFTISSLQPEDIATYYCQQWSSNPFTFGQGTKLQITRTVAAPSVFIFPPS
DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL
SKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

References:

American Medical Association: Statement on a nonproprietary name adopted by the USAN council [Link]

Download FASTA Format

Synonyms

hOKT3 gamma1(Ala-Ala)
Humanized OKT3
Teplizumab-mzwv

External IDs

MGA-031
MGA031

Pharmacology

Indication

Teplizumab is indicated to delay the onset of Stage 3 type 1 diabetes (T1D) in adults and pediatric patients aged 8 years and older with Stage 2 T1D.¹¹

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Associated Conditions

Stage 3 Type 1 Diabetes Mellitus

Contraindications & Blackbox Warnings

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Pharmacodynamics

Teplizumab is a monoclonal antibody that binds to CD3 molecules on the surface of CD4+ and CD8+ T cells, both involved in the destruction of pancreatic β cells.¹¹ Several studies have detected an increase in C-peptide levels in early-onset type 1 diabetes (T1D) patients treated with teplizumab, suggesting an improved β cell function.^9,10 The exposure-response relationship and the safety and effectiveness pharmacodynamic time-response of teplizumab have not been fully elucidated.¹¹

In the absence of T cell depletion, the use of teplizumab in a 14-day course of treatment can lead to the development of lymphopenia. Cytokine release syndrome (CRS) has also been detected in patients treated with teplizumab. The main manifestations of CRS include fever, nausea, fatigue, headache, myalgia, arthralgia, increased alanine aminotransferase, increased aspartate aminotransferase, and increased total bilirubin; these manifestations occurred in the first 5 days of treatment. In addition, the use of teplizumab may lead to the development of serious infections and hypersensitivity reactions.¹¹

Mechanism of action

Type 1 diabetes (T1D) is an autoimmune condition in which T cell-mediated destruction of pancreatic β cells leads to loss of insulin production, impaired glycemic control, and reliance on exogenous insulin. T1D is a progressive disease with three recognizable stages and in which only Stage 3 is associated with clinically apparent symptoms.¹ The earliest indication of T1D risk is the presence of at least two autoantibodies against relevant antigens, confirming an important role for B cells in what has traditionally been considered a T cell-dominated condition.^1,2 Combined with other observations from animal and human studies, it is clear that T and B cells play a role in T1D; treatment has focussed on targeting each of them independently, as well as their interactions.²

The T cell receptor (TCR) comprises TCR α and β chains together with six CD3 molecules, including two CD3 ε chains. It is responsible for recognizing antigens displayed on the MHC complex of other cells to elicit a response.³ Teplizumab, a humanized IgG1κ Fc-nonbinding version of an existing mouse OKT3 antibody (also designated huOKT3γala-ala), is specific for the ε chain of CD3 and inhibits T cell activation through steric inhibition of antigen recognition.^3,4,5 Recently, teplizumab has shown efficacy in delaying the time to diagnosis in patients at high risk of developing T1D.⁶ However, the exact mechanism underlying this effect remains clear.

One hypothesis is that teplizumab acts as a partial agonist at the TCR, increasing the number of exhausted T cells positive for KLRG1, TIGIT, and CD8. These exhausted T cells persist but cannot perform effector functions and, therefore, would be unlikely to contribute to further β cell destruction.^1,7 Other studies have noted changes in the T cell populations of clinical responders, including an increase in circulating CD8⁺ central memory (CD8CM) T cells.⁸ It is clear, however, that treatment is most effective in patients who have not yet progressed to Stage 3 and who have an active immune response.¹

Target	Actions	Organism
AT-cell surface glycoprotein CD3 epsilon chain	antibody	Humans

Absorption

During the 14-day treatment course of teplizumab, steady-state concentrations are not expected to be achieved.¹¹

Volume of distribution

In a 60 kg subject, teplizumab has a central volume of distribution (Vd) of 2.27 L.¹¹

Protein binding

Not Available

Metabolism

As a monoclonal antibody, teplizumab is expected to be metabolized into small peptides by proteases throughout the body.¹¹

Route of elimination

Teplizumab showed saturable binding and elimination.¹¹

Half-life

In a 60 kg subject, teplizumab has a mean terminal elimination half-life of 4.5 days.¹¹

Clearance

In a 60 kg subject, teplizumab has a clearance of 2.7 L/day.¹¹

Adverse Effects

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Toxicity

Toxicity information regarding teplizumab is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as serious infections, lymphopenia and cytokine release syndrome.¹¹ Symptomatic and supportive measures are recommended. The mutagenic and carcinogenic potential of teplizumab has not been evaluated. As an antibody, teplizumab is not expected to interact directly with DNA. In female and male mice, teplizumab did not have significant effects in fertility and reproductive performance when administered subcutaneously at doses up to 20 mg/kg.¹¹

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
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Abciximab	The risk or severity of adverse effects can be increased when Abciximab is combined with Teplizumab.
Adalimumab	The risk or severity of adverse effects can be increased when Adalimumab is combined with Teplizumab.
Aducanumab	The risk or severity of adverse effects can be increased when Teplizumab is combined with Aducanumab.
Alemtuzumab	The risk or severity of adverse effects can be increased when Alemtuzumab is combined with Teplizumab.
Alirocumab	The risk or severity of adverse effects can be increased when Teplizumab is combined with Alirocumab.
Amivantamab	The risk or severity of adverse effects can be increased when Teplizumab is combined with Amivantamab.
Anifrolumab	The risk or severity of adverse effects can be increased when Teplizumab is combined with Anifrolumab.
Ansuvimab	The risk or severity of adverse effects can be increased when Teplizumab is combined with Ansuvimab.
Anthrax immune globulin human	The risk or severity of adverse effects can be increased when Teplizumab is combined with Anthrax immune globulin human.
Antilymphocyte immunoglobulin (horse)	The risk or severity of adverse effects can be increased when Teplizumab is combined with Antilymphocyte immunoglobulin (horse).

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Food Interactions

No interactions found.

Products

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International/Other Brands

Tzield (Provention Bio, Inc)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Tzield	Injection	1 mg/1mL	Intravenous	Provention Bio, Inc.	2022-11-17	Not applicable

Chemical Identifiers

UNII: S4M959U2IJ
CAS number: 876387-05-2

References

Synthesis Reference

Koenig, S, et al. (2014). Methods for the treatment of autoimmune disorders using immunosuppressive monoclonal antibodies with reduced toxicity. (U.S. Patent No. 8,663,634 B2). U.S. Patent and Trademark Office. https://patentimages.storage.googleapis.com/53/4f/2f/7b8a017220d8b8/US8663634.pdf

General References

Dayan CM, Korah M, Tatovic D, Bundy BN, Herold KC: Changing the landscape for type 1 diabetes: the first step to prevention. Lancet. 2019 Oct 5;394(10205):1286-1296. doi: 10.1016/S0140-6736(19)32127-0. Epub 2019 Sep 15. [Article]
Felton JL, Conway H, Bonami RH: B Quiet: Autoantigen-Specific Strategies to Silence Raucous B Lymphocytes and Halt Cross-Talk with T Cells in Type 1 Diabetes. Biomedicines. 2021 Jan 6;9(1). pii: biomedicines9010042. doi: 10.3390/biomedicines9010042. [Article]
Gaglia J, Kissler S: Anti-CD3 Antibody for the Prevention of Type 1 Diabetes: A Story of Perseverance. Biochemistry. 2019 Oct 8;58(40):4107-4111. doi: 10.1021/acs.biochem.9b00707. Epub 2019 Sep 24. [Article]
Kaplon H, Reichert JM: Antibodies to watch in 2021. MAbs. 2021 Jan-Dec;13(1):1860476. doi: 10.1080/19420862.2020.1860476. [Article]
Xu D, Alegre ML, Varga SS, Rothermel AL, Collins AM, Pulito VL, Hanna LS, Dolan KP, Parren PW, Bluestone JA, Jolliffe LK, Zivin RA: In vitro characterization of five humanized OKT3 effector function variant antibodies. Cell Immunol. 2000 Feb 25;200(1):16-26. doi: 10.1006/cimm.2000.1617. [Article]
Herold KC, Bundy BN, Long SA, Bluestone JA, DiMeglio LA, Dufort MJ, Gitelman SE, Gottlieb PA, Krischer JP, Linsley PS, Marks JB, Moore W, Moran A, Rodriguez H, Russell WE, Schatz D, Skyler JS, Tsalikian E, Wherrett DK, Ziegler AG, Greenbaum CJ: An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes. N Engl J Med. 2019 Aug 15;381(7):603-613. doi: 10.1056/NEJMoa1902226. Epub 2019 Jun 9. [Article]
Linsley PS, Long SA: Enforcing the checkpoints: harnessing T-cell exhaustion for therapy of T1D. Curr Opin Endocrinol Diabetes Obes. 2019 Aug;26(4):213-218. doi: 10.1097/MED.0000000000000488. [Article]
Tooley JE, Vudattu N, Choi J, Cotsapas C, Devine L, Raddassi K, Ehlers MR, McNamara JG, Harris KM, Kanaparthi S, Phippard D, Herold KC: Changes in T-cell subsets identify responders to FcR-nonbinding anti-CD3 mAb (teplizumab) in patients with type 1 diabetes. Eur J Immunol. 2016 Jan;46(1):230-41. doi: 10.1002/eji.201545708. Epub 2015 Dec 14. [Article]
Sims EK, Bundy BN, Stier K, Serti E, Lim N, Long SA, Geyer SM, Moran A, Greenbaum CJ, Evans-Molina C, Herold KC: Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals. Sci Transl Med. 2021 Mar 3;13(583):eabc8980. doi: 10.1126/scitranslmed.abc8980. [Article]
Smigoc Schweiger D: Recent Advances in Immune-based Therapies for Type 1 Diabetes. Horm Res Paediatr. 2022 May 9. doi: 10.1159/000524866. [Article]
FDA Approved Drug Products: TZIELD (teplizumab-mzwv) injection for intravenous use [Link]
US Food & Drug Administration: FDA Approves First Drug That Can Delay Onset of Type 1 Diabetes [Link]

External Links

RxNav: 2621880
Wikipedia: Teplizumab

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
3	Active Not Recruiting	Treatment	Type 1 Diabetes Mellitus	1
3	Completed	Treatment	Type 1 Diabetes Mellitus	1
2	Completed	Treatment	Autoantibody Positive / High Risk / Impaired Glucose Tolerance / Non-diabetic Relatives at Risk for Type 1 Diabetes	1
2	Completed	Treatment	Type 1 Diabetes Mellitus	2
2	Recruiting	Treatment	Type 1 Diabetes Mellitus	1
2	Terminated	Treatment	Type 1 Diabetes Mellitus	1
2, 3	Completed	Treatment	Type 1 Diabetes Mellitus	1
2, 3	Terminated	Treatment	Type 1 Diabetes Mellitus	1
1, 2	Completed	Treatment	Type 1 Diabetes Mellitus	1
1, 2	Terminated	Treatment	Psoriasis (PsO)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection	Intravenous	1 mg/1mL

Prices

Not Available

Patents

Not Available

Properties

State: Solid
Experimental Properties: Not Available

Targets

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Details1. T-cell surface glycoprotein CD3 epsilon chain

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Antibody

General Function: Transmembrane signaling receptor activity
Specific Function: The CD3 complex mediates signal transduction, resulting in T cell activation and proliferation. Required for normal immune responses (PubMed:15546002, PubMed:8490660).
Gene Name: CD3E
Uniprot ID: P07766
Uniprot Name: T-cell surface glycoprotein CD3 epsilon chain
Molecular Weight: 23147.09 Da

References

Xu D, Alegre ML, Varga SS, Rothermel AL, Collins AM, Pulito VL, Hanna LS, Dolan KP, Parren PW, Bluestone JA, Jolliffe LK, Zivin RA: In vitro characterization of five humanized OKT3 effector function variant antibodies. Cell Immunol. 2000 Feb 25;200(1):16-26. doi: 10.1006/cimm.2000.1617. [Article]
Gaglia J, Kissler S: Anti-CD3 Antibody for the Prevention of Type 1 Diabetes: A Story of Perseverance. Biochemistry. 2019 Oct 8;58(40):4107-4111. doi: 10.1021/acs.biochem.9b00707. Epub 2019 Sep 24. [Article]
FDA Approved Drug Products: TZIELD (teplizumab-mzwv) injection for intravenous use [Link]

Drug created at March 19, 2008 16:40 / Updated at November 24, 2022 22:21

Teplizumab

Identification

References:

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Targets

References