ipilimumab

Description

Ipilimumab is a CTLA-4 blocking antibody that was approved by the U.S. FDA in March 2011 for the treatment of unresectable or metastatic melanoma. Therefore, ipilimumab has an indirect effect on tumors that is mediated through blockade of CTLA-4 negative signaling and augmentation of T-cell activity. It is one of a handful of immunostimulatory drugs (e.g., aldesleukin and interferon alfa-2b) now approved for cancer therapy.

Originator

Bristol-Myers Squibb (United States)

Uses

Treatment of oncology disease and HIV infection.

brand name

Yervoy

Mechanism of action

Anti-CTLA-4 monoclonal antibodies like ipilimumab inhibit CD80 and CD86 on APCs forms binding to CTLA-4 on T cells. The resulting blockade of CTLA-4 signaling prolongs T-cell activation, restores T-cell proliferation, and thus amplifies T-cell-mediated immunity, which theoretically enhances the patient's capacity to mount an antitumor immune response. Cancer patients with reduced CTLA-4 expression have shown a more pronounced response to blockade of the CTLA-4 pathway and less likelihood of subsequent relapse[1].

Pharmacokinetics

Ipilimumab is a fully human monoclonal IgG1κ antibody. Limited pharmacokinetic data have been presented to date. However, a study of single-dose ipilimumab in patients with castrate-resistant prostate cancer showed that the pharmacokinetics of ipilimumab were consistent with other clinically used monoclonal antibodies tested in humans. The relatively long terminal half-life (12.5 days) means that a single dose of 3?mg/kg results in a serum concentration permitting dosing at 3–4 week intervals. Although the second-line, phase 3 trial used a dose of 3?mg/kg every 3 weeks for four doses without any maintenance, most trials initiated after 2006 use a dose of 10?mg/kg every 3 weeks for four doses and then one dose every 12 weeks for up to at least 3 years. The 10?mg/kg dose was selected based on superior clinical and pharmacokinetic data and a comparable safety profile[1].

Clinical Use

Antineoplastic agent:

Treatment of advanced (unresectable or metastatic) melanoma in adults who have received prior therapy

Side effects

The more common side effects of ipilimumab include Bloody, black, or tarry stools; bone pain; chest pain or tightness; constipation; cough; depressed mood; diarrhea; dry skin and hair; feeling cold; fever; hair loss; heartburn; hoarseness or husky voice; indigestion; itching, skin rash; muscle cramps; nausea; pain in the arms or legs; severe stomach pain, cramping, or burning; slowed heartbeat; sneezing; sore throat; trouble breathing; unusual tiredness or weakness; vomiting; vomiting of material that looks like coffee grounds, severe and continuing; watery or bloody diarrhea.

Drug interactions

Potentially hazardous interactions with other drugs
Live vaccines: risk of generalised infections - avoid.

Metabolism

Most likely removed by opsonisation via the reticuloendothelial system when bound to T lymphocytes, or by human antimurine antibody production.

References

[1] Ahmad Tarhini, David R Minor, Ernest Lo. “Releasing the brake on the immune system: ipilimumab in melanoma and other tumors.” Cancer Biotherapy and Radiopharmaceuticals 25 6 (2010): 601–13.

Raw materials

Preparation Products