Ibritumomab tiuxetan

Overview
Ibritumomab tiuxetan, also sold under the trade name Zevalin®, is a monoclonal antibody radioimmunotherapy treatment for some forms of B cell non-Hodgkin's lymphoma, a myeloproliferative disorder of the lymphatic system. The drug uses the monoclonal mouse IgG1 antibody ibritumomab (pronounced as ) in conjunction with the chelator tiuxetan, to which a radioactive isotope (either yttrium-90 or indium-111) is added.

Mechanism of action
The antibody binds to the CD20 antigen found on the surface of normal and malignant B cells (but not B cell precursors), allowing radiation from the attached isotope (mostly beta emission) to kill it and some nearby cells. In addition, the antibody itself may trigger cell death via antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis. Together, these actions eliminate B cells from the body, allowing a new population of healthy B cells to develop from lymphoid stem cells.

Administration
In order to qualify for Zevalin, a patient needs to have bone marrow involvement of < 25% and > 15% bone marrow cellularity. Since Zevalin is known to cause cytopenias, platelet and neutrophil counts are also taken pretreatment. Since a murine antibody is used, the patient might also be tested for Human Anti Mouse Antibodies (HAMA). Having bulky disease does not disqualify a patient.

The Zevalin regimen takes 7-9 days, with two administrations of Zevalin. Each dose is preceded by Rituxan, in order to pre-deplete B lymphocytes. The dose of Rituxan given here is less than the usual dose.

The first dose uses Indium-111 Zevalin for imaging. Indium-111 emits some gamma radiation, which can be picked up by the gamma camera. A scan is done to assess biodistribution of the drug. This test dose is used to determine that no excess amounts go to the marrow, liver, etc. in this particular patient.

If the gamma scan shows no altered biodistribution, then the second dose is given, using Yttrium-90 Zevalin as the actual treatment. Yttrium -90 emits the cell-killing beta radiation.

Ibritumomab tiuxetan is administered by intravenous infusion which usually lasts around 10 minutes. Only acrylic shielding is needed, not lead.

Efficacy
Treatment with Zevalin showed higher response rates in clinical trials compared to treatment with only Rituxan (similar to Zevalin, but without the attached radioisotope), and showed very promising results for patients who no longer respond to Rituxan.

In patients With Relapsed or Refractory Low-Grade, Follicular, or Transformed B-cell NHL, where no prior anti-CD20 therapy was allowed, the OR was 80% / 50% and CR was 34% / 20%, comparing Zevalin to Rituxan.

However, in a Phase II study on Zevalin with the more aggressive Mantle Cell Lymphoma, the OR was only 42% and CR was 26%.

History
Developed by the IDEC Pharmaceuticals, which is now part of Biogen Idec, ibritumomab tiuxetan was the first radioimmunotherapy drug approved by the Food and Drug Administration (FDA) in 2002 to treat cancer.

In August 2007, Cell Therapeutics Inc announced plans to buy the U.S. rights to sell, market, and distribute this radioactive antibody from Biogen for approximately US$30 million, or the equivalent of about two years' net sales revenue in the U.S. for the drug. Outside of the U.S., Bayer Schering continues to have the rights to the drug.

Costs
Zevalin®, which is not available in a generic form because it is still under patent protection, is currently the most expensive drug available given in a single dose, costing over US$24,000 for the average dose. However, Zevalin is essentially an entire course of lymphoma therapy which is delivered in 7-9 days, with one visit for imaging, one visit for a gamma scan, and one visit for the actual therapeutic dose. Compared to other monoclonal antibody treatments (many of which are well over US$40,000 for a course of therapy), this drug is priced in the middle for many of these therapies.