Introduction

Teplizumab is a humanized monoclonal antibody to CD3 which is used to delay the onset of clinically significant type 1 diabetes (stage 3 diabetes) in a patient at high risk as shown by the presence of anti-pancreatic islet cell autoantibodies and dysglycemia (stage2 diabetes). Teplizumab is given intravenously once daily for 14 days, is generally well tolerated, and is associated with a low rate of serum aminotransferase elevations during therapy, but has not been linked to instances of clinically apparent liver injury with jaundice.

Background

Teplizumab (tep liz’ ue mab) is a humanized monoclonal IgG1 antibody directed against CD3, which results in inhibition of cytotoxic T cell activation and proliferation. Because type 1 diabetes is thought to be caused by cytotoxic T cell destruction of pancreatic islet beta cells that produce insulin, teplizumab was evaluated as a means of therapy and prevention of type 1 diabetes. While a limited course of teplizumab appeared to have little effect on established type 1 diabetes, it did appear to delay the onset of clinically apparent type 1 diabetes. In preregistration trials, stage 2 diabetes was defined by the presence of at least two anti-pancreatic islet cell autoantibodies and dysglycemia without frank hyperglycemia (stage 3 diabetes). Patients with stage 2 diabetes were generally identified among relatives of patients with type 1 diabetes by screening for anti-pancreatic islet cell autoantibodies. Natural history studies demonstrated that almost all subjects with stage 2 diabetes develop stage 3 diabetes, generally within 1 to 5 years. In a single, randomized controlled trial of teplizumab given as daily intravenous infusions daily for 14 days, therapy was associated with a subsequent median delay in onset of stage 3 diabetes of 24 months. On the basis of this trial, teplizumab was approved in 2022 the United States for use in preventing stage 3 diabetes in adults and children (8 years of age or older) with stage 2 diabetes. Teplizumab is available in single use vials of 2 mg per 2 mL (1 mg/mL). The recommended regimen is a daily infusion in escalating doses for the first 5 days from 65 to 1,030 µg/m², which is then continued for another 9 days. Premedication is recommended at least during the first 5 days using an oral analgesic (acetaminophen or a nonsteroid antiinflammatory agent), antihistamine, and antiemetic. Monitoring of symptoms, blood counts and liver enzymes is also recommended during the 14 days. Common side effects during and for the several weeks after treatment include mild local injection reactions, nasopharyngitis, fatigue, headache, nausea, diarrhea, arthralgia and skin rash. Uncommon, potentially severe adverse reactions include cytokine release syndrome, severe hypersensitivity reactions, lymphopenia, and reactivation of latent viral infections or tuberculosis.

Hepatotoxicity

Mild-to-moderate serum aminotransferase elevations arise in up to 25% of patients treated with teplizumab, usually during the 14 days of therapy and often associated with evidence of mild-to-moderate cytokine release syndrome. The ALT and AST elevations are usually mild, transient and asymptomatic, rising to above 3 times the upper limit of normal (ULN) in 5% of patients and rarely necessitating drug discontinuation. Serum bilirubin levels also rise, particularly in patients with cytokine release syndrome, but clinically apparent liver injury with jaundice has not been reported, and liver test abnormalities resolve in almost all patients within days or a few weeks of ending the 14 day course. There has been limited clinical experience with use of teplizumab and scant information on the safety and efficacy of repeated courses of treatment. Development of antibodies to teplizumab is not uncommon (up to 50%), but the clinical significance of drug antibodies has not been defined.

Likelihood score: E (unlikely cause of clinically apparent acute liver injury).

Mechanism of Injury

The possible mechanisms of liver injury due to teplizumab are unclear, but probably relate to cytokine release induced by the binding of the monoclonal antibody to activated T cells that then release cytokines into the circulation that can cause transient liver injury. There is no evidence that the cytokine release induced by teplizumab can result in prolonged or chronic liver injury.

Outcome and Management

Drug Class: Monoclonal Antibodies, Antidiabetic Agents