Ibritumomab tiuxetan (pronounced ), sold under the trade name Zevalin, is a monoclonal antibody

radioimmunotherapy Radioimmunotherapy (RIT) uses an antibody labeled with a radionuclide to deliver cytotoxic radiation to a target cell. It is a form of unsealed source radiotherapy. In cancer therapy, an antibody with specificity for a tumor-associated antigen i ...

treatment for non-Hodgkin's lymphoma. The drug uses the monoclonal mouse

IgG1 Immunoglobulin G (Ig G) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG a ...

antibody An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...

ibritumomab in conjunction with the

chelator Chelation is a type of bonding of ions and molecules to metal ions. It involves the formation or presence of two or more separate coordinate bonds between a polydentate (multiple bonded) ligand and a single central metal atom. These ligands are ...

tiuxetan, to which a radioactive isotope (either yttrium-90 or

indium-111 Indium-111 (111In) is a radioactive isotope of indium (In). It decays by electron capture to stable cadmium-111 with a half-life of 2.8 days. Indium-111 chloride (111InCl) solution is produced by proton irradiation of a cadmium target (112Cd(p,2n) ...

) is added. Tiuxetan is a modified version of

DTPA Pentetic acid or diethylenetriaminepentaacetic acid (DTPA) is an aminopolycarboxylic acid consisting of a diethylenetriamine backbone with five carboxymethyl groups. The molecule can be viewed as an expanded version of EDTA and is used similarly ...

whose carbon backbone contains an isothiocyanatobenzyl and a

methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in many ...

group.

Medical use

Ibritumomab is used to treat relapsed or refractory, low grade or transformed

B cell B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...

non-Hodgkin's lymphoma (NHL), a lymphoproliferative disorder, and previously untreated follicular NHL in adult patients who achieve a partial or complete response to first-line

chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...

. The treatment should not be administered to patients with ≥25% lymphoma marrow involvement and/or impaired bone marrow reserve. The treatment starts with an infusions of rituximab. This may be followed by an administration of

labelled ibritumomab tiuxetan (¹¹¹In replaces the ⁹⁰Y component) to allow the distribution of the drug to be imaged on a

gamma camera A gamma camera (γ-camera), also called a scintillation camera or Anger camera, is a device used to image gamma radiation emitting radioisotopes, a technique known as scintigraphy. The applications of scintigraphy include early drug development ...

, before the actual therapy is administered. Seven to nine days later, a second infusion of rituximab is given, followed by the ⁹⁰Y-ibritumomab tiuxetan, by

intravenous infusion Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

over around 10 minutes. The radioactive activity is determined based on patient body weight and platelet count.

Mechanism of action

The antibody binds to the CD20

antigen In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...

found on the surface of normal and malignant

s (but not B cell precursors), allowing radiation from the attached

isotope Isotopes are two or more types of atoms that have the same atomic number (number of protons in their nuclei) and position in the periodic table (and hence belong to the same chemical element), and that differ in nucleon numbers (mass numbers) ...

(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 Complement-dependent cytotoxicity (CDC) is an effector function of IgG and IgM antibodies. When they are bound to surface antigen on target cell (e.g. bacterial or viral infected cell), the classical complement pathway is triggered by bonding protei ...

(CDC), and

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

. Together, these actions eliminate B cells from the body, allowing a new population of healthy B cells to develop from lymphoid

stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...

History

Developed by the IDEC Pharmaceuticals, now part of

Biogen Idec Biogen Inc. is an American multinational biotechnology company based in Cambridge, Massachusetts, specializing in the discovery, development, and delivery of therapies for the treatment of neurological diseases to patients worldwide. History ...

, ibritumomab tiuxetan was the first radioimmunotherapy drug approved by the

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) in 2002 to treat cancer. It was approved for the treatment of patients with relapsed or refractory, low‑grade or follicular B‑cell non‑Hodgkin's lymphoma (NHL), including patients with rituximab refractory follicular NHL. It was given

marketing authorisation Marketing authorisation is the process of reviewing and assessing the evidence to support a medicinal product, such as a drug, in relation to its marketing, finalised by granting of a licence to be sold. This process is performed within a legal fr ...

by the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...

in 2004 for the treatment of adult patients with rituximab relapsed or

refractory In materials science, a refractory material or refractory is a material that is resistant to decomposition by heat, pressure, or chemical attack, and retains strength and form at high temperatures. Refractories are polycrystalline, polyphase, ...

CD20+ follicular B-cell non-Hodgkin's lymphoma. In September 2009, ibritumomab received approval from the FDA for an expanded label to include previously untreated patients with a chemotherapy response.

Availability

Ibritumomab is currently under patent protection and not available in generic form. When first approved, it was the most expensive drug available given in a single dose, costing over US$37,000 (€30,000) for the average dose. However, ibritumomab is essentially an entire course of lymphoma therapy which is delivered in 7–9 days, with one visit for pre-dosing Rituxan, and one visit a week later for the actual Zevalin therapeutic dose preceded by Rituxan. Compared to other monoclonal antibody treatments (many of which are well over US$40,000 for a course of therapy), it may be considered cost effective.

External links

Official Zevalin site

References