Teplizumab Overview

Introduction of Teplizumab

Teplizumab (also known as MGA031 and hOKT3γ1(Ala-Ala)) is a humanized anti-CD3 monoclonal antibody (mAb) developed at Columbia University, and was then further developed at MacroGenics, Inc. 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. The Fc region of this antibody has been engineered to have Fc receptor non-binding (FNB) properties. This antibody has been used in clinical trials with the aim of protecting the remaining β-cells in newly diagnosed type 1 diabetes mellitus patients, but "these agents [i. e. anti-CD3-antibodies] alone do not restore normal glucose control". On November 2022, teplizumab was approved by the U.S. Food and Drug Administration (FDA) as the first drug that can delay the onset of T1D.

Know more about type I diabetes.

Biological and Chemical Properties of Teplizumab

Protein Structure

Figure 1 Structure of Teplizumab

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|QVQLVQSGGGVVQPGRSLRLSCKASGYTFTRYTMHWVRQAPGKGLEWIGYINPSRGYTNYNQKVKDRFTISRDNSKNTAFLQMDSLRPEDTGVYFCARYYDDHYCLDYWGQGTPVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

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

Protein Chemical Formula

C₆₄₆₂H₉₉₃₈N₁₇₃₈O₂₀₂₂S₄₆

Protein Average Weight

150000.0 Da (approximate)

Mechanism of Action of Teplizumab

Teplizumab is an anti-CD3 monoclonal antibody specifically designed to target and modulate T cells, which play a crucial role in the immune response. The CD3 complex is a key component of the T cell receptor (TCR) that transmits activation signals upon recognizing antigens. In autoimmune diseases like type 1 diabetes (T1D), T cells mistakenly attack the body's own tissues, such as the insulin-producing beta cells in the pancreas. By binding to the CD3 epsilon chain, teplizumab interferes with T cell activation and reduces the immune system's attack on these cells.

Figure 2 Mechanism of action of Teplizumab

Teplizumab works through several mechanisms to achieve this modulation. It induces a state of partial inactivation in T cells, reducing their aggressive autoimmune response while preserving their ability to fight infections. Additionally, teplizumab promotes the development and function of regulatory T cells (Tregs), which help maintain immune tolerance by suppressing overactive immune responses. The drug also modulates effector T cells, decreasing their production of inflammatory cytokines and altering their trafficking patterns to reduce their infiltration into the pancreas. This multi-faceted approach helps to preserve the function of pancreatic beta cells, delaying the progression of T1D and maintaining endogenous insulin production for a longer period.

Targeting the CD3 Complex

The CD3 complex is an integral part of the T cell receptor (TCR) complex, which is crucial for T cell activation. This complex is made up of several protein chains that work together to transduce activation signals from the T cell surface to its interior. When T cells recognize antigens presented by the body's own cells, the CD3 complex plays a key role in initiating the immune response. In autoimmune diseases like T1D, this response becomes misdirected against the body's own tissues. Teplizumab's ability to bind specifically to the CD3 epsilon chain disrupts this signaling process, leading to a reduction in T cell activation and proliferation.

Inducing Partial Inactivation of T Cells

Teplizumab does not completely deactivate T cells; instead, it induces a state of partial inactivation. This means that T cells are still functional but less likely to launch a full-scale autoimmune attack. This partial inactivation is beneficial because it reduces the harmful immune response against pancreatic beta cells while preserving the immune system's ability to respond to infections. By striking this balance, teplizumab helps to maintain immune function without exacerbating autoimmune activity.

Promoting Regulatory T Cells (Tregs)

Regulatory T cells (Tregs) play a crucial role in maintaining immune tolerance by suppressing overactive immune responses. Teplizumab has been shown to increase the number and activity of Tregs, thereby promoting a more balanced immune environment. Tregs help to prevent the immune system from attacking the body's own tissues, which is particularly important in autoimmune diseases like T1D. By enhancing the function of Tregs, teplizumab contributes to the preservation of pancreatic beta cells and the delay in disease progression.

Modulating Effector T Cells

Effector T cells are responsible for carrying out immune attacks, including those against the body's own tissues in autoimmune diseases. Teplizumab modulates the activity of effector T cells by reducing their production of inflammatory cytokines, which are signaling molecules that promote inflammation and tissue destruction. By decreasing the levels of these cytokines, teplizumab helps to mitigate the damage caused by the immune system to pancreatic beta cells. This modulation of effector T cells is a key mechanism by which teplizumab protects beta cell function.

Altering T Cell Trafficking

Teplizumab also affects the movement and localization of T cells within the body. By altering the expression of certain surface molecules on T cells, teplizumab reduces their ability to migrate into the pancreas. This limits the infiltration of autoreactive T cells into the pancreatic islets, where beta cells reside. By preventing these cells from reaching and attacking the beta cells, teplizumab further helps to preserve insulin production and delay the onset of T1D.

Fc Receptor Non-Binding

A critical feature of teplizumab is its Fc receptor non-binding modification. Fc receptors are found on various immune cells and bind to the Fc region of antibodies, leading to different immune responses, such as antibody-dependent cellular cytotoxicity (ADCC) or phagocytosis. By engineering teplizumab to be Fc receptor non-binding, researchers have minimized the risk of these unwanted immune responses. This modification reduces the likelihood of broad immune activation and potential adverse effects, enhancing the safety profile of teplizumab. The Fc receptor non-binding characteristic ensures that teplizumab specifically targets T cells without triggering additional immune system activation that could exacerbate autoimmune conditions or lead to other complications.

Long-Term Immune Modulation

The effects of teplizumab extend beyond the immediate modulation of T cell activity. Studies have shown that a short course of teplizumab can lead to lasting changes in the immune system. These long-term effects are thought to result from the induction of immune tolerance and the establishment of a more regulatory immune environment. The drug's ability to promote long-term immune regulation and balance is a significant factor in its efficacy for delaying the onset of T1D.

Clinical Projects of Teplizumab*

* The table was excerpted from the following website:
https://clinicaltrials.gov/ct2/results?cond=&term=Teplizumab

Approved Drugs of Teplizumab**

INN (trade name)	Therapeutic area	Dose	Strength	sRoute	Company	Marketing start	Market
Tzield	Stage 3 type 1 diabetes	Injection	1 mg/1mL	Intravenous	Provention Bio, Inc.	2022-11-17

** Information presented in the table were collected from the following website:
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=761183

What We Provide

TeplizumabAntibodies targeting T1DServices

Anti-Human CD3 Recombinant Antibody (Teplizumab)

We provide high-quality Teplizumab for use in WB, FC, IP, ELISA, Neut, FuncS, IF and most other immunological methods. For lab research use only, not for diagnostic, therapeutic or any in vivo human use.

SpecificationTested Data

• Immunogen
• The details of the immunogen for this antibody are not available.

• Host Species
• Mouse

• Derivation
• Humanized (from mouse)

• Type
• IgG1 - kappa

• Specificity
• Tested positive against native human antigen.

• Species Reactivity
• Human

• Applications
• Neut, ELISA, IF, IP, FuncS, FC, ICC

• CAS
• 876387-05-2

• Generic Name
• Teplizumab

• UNII
• S4M959U2IJ

• MW
• 145.8 kDa

• Related Disease
• Type 1 diabetes

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ELISA

Figure 1 Anti-Human CD3 Antibody (TAB-159) in ELISA

ELISA analysis of TAB-159 was performed by coating with recombinant human CD3e protein (His Tag). Then blocked with BSA and incubated with TAB-159. The HRP-conjugated goat anti-human IgG as a secondary antibody (1:5000). Detection was performed using TMB substrate and stopped with sulfuric acid. The absorbances were read on a spectrophotometer at 450 nm.

FC

Figure 2 Anti-Human CD3 Antibody (TAB-159) in FC

Flow cytometry analysis of Jurkat cells with purified antibody TAB-159 (Lot#CB2101Y13). Cells were blocked with Human TruStain FcXTM and washed with 0.5% BSA-PBS. An FITC-conjugated goat anti-human IgG secondary antibody was added.
PC: Positive Control, Blue (Biolegend, 317306)
Lot#CB2101Y13: CB2101Y13 batch, Blue (TAB-159)

• CD3D
• INS
• PRPH
• b96.11
• MRPS31

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For research use only. Not intended for any clinical use.