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Ibritumomab tiuxetan

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Ibritumomab tiuxetan, sold under the trade name Zevalin, is a monoclonal antibody radioimmunotherapy treatment for relapsed or refractory, low grade or transformed B cell non-Hodgkin’s lymphoma, a lymphoproliferative disorder. The drug uses the monoclonal mouse IgG1 antibody ibritumomab (pronounced as <ih bri TYOO mo mab>)[1] in conjunction with the chelator tiuxetan, to which a radioactive isotope (either yttrium-90 or indium-111) is added. Tiuxetan is a modified version of DTPA whose carbon backbone contains an isothiocyanatobenzyl and a methyl group.[2][3]

 

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.

Zevalin (Ibritumomab tiuxetan) is a radio-labeled antibody.  The antibody seeks and binds to cells that have a receptor called CD20 — present on both normal and malignant mature b-cells. 

Once bound to the target cells, Zevalin delivers radiation, which enhances the killing effect of the antibody.  

Because immature b-cells do not have the CD20 receptor, normal b-cells will recover in about nine months after treatment.

Rituxan (the naked antibody) is administered prior to Zevalin with the goal of clearing the majority of normal b-cells so that the therapeutic dose (the radio-labeled antibody) is more focused on tumor cells.

 

 

Preparation

Zevalin is supplied as a single dosage kit supplied by IDEC Pharmaceuticals Corp. It consists of Ibritumomab covalently conjugated to the metal chelator tiuxetan, which forms a stable complex with indium-111 for imaging and yttrium-90 for therapy.

The kit is supplied with four vials – a vial containing 3.2 mg of conjugated antibody in 2 ml saline, a vial containing 2 ml 50mM sodium acetate, a vial containing phosphate buffer, and a fourth empty reaction vial. Prior to labeling, a volume of sodium acetate buffer equivalent to 1.2 times the volume of the tracer solution is transferred to the reaction vial. Then 5.5 mCi (203.5 MBq) indium-111 or 40mCi (1.48 GBq) yttrium-90 is added to the reaction vial and mixed thoroughly without shaking. Next, 1.3 ml of conjugated antibody is added. The mixture is incubated for exactly 30min for indium-111 and for 5 min with yttrium-90 labeling, followed by the addition of enough phosphate buffer to make the final volume 10 ml. The labeling yield is determined by ITLC-SG with 0.9% saline as the mobile phase. Labeling efficiency should be greater than 95%.[4]

http://pubs.rsc.org/en/content/articlelanding/2006/cs/b514859f/unauth#!divAbstract

A cartoon depiction of the radiolabelled monoclonal antibody 90Y-ibritumomab tiuxetan 18.

 

Administration

In order to qualify for ibritumomab, a patient needs to have bone marrow involvement of < 25% and > 15% bone marrow cellularity. Since ibritumomab is known to cause cytopenia, platelet and neutrophil counts are also taken pretreatment. Refractory/relapsed patients should have platelet counts of 100,000 per cubic millimetre (100,000/cmm) or greater; consolidation patients should have counts of 150,000/cmm or greater. 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 ibritumomab regimen takes 7–9 days. An imaging dose of the drug is no longer required in the U.S. Rituxan 250 mg/sq.m is given day 1, then on day 7-9 the Rituxan dose is repeated and Zevalin given within four hours. The dose of Zevalin 0.4 mCi/kg (= 14.8MBq/kg) if platelet counts are above 150,000/cmm; 0.3 mCi/kg (= 11.1MBq/kg) if 100,000-150,000/cmm. The Zevalin dose never exceeds 32 mCi (= 1184MBq).[5]

Ibritumomab tiuxetan is administered by intravenous infusion which usually lasts around 10 minutes. Only acrylic shielding is needed, not lead. A trained nuclear medicine technologist performs the infusion and safely disposes of waste.

Efficacy

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

In patients with relapsed or refractory low-grade, follicular, or transformed B-cell NHL, where no prior anti-CD20 therapy was allowed, the ORR was 83% / 55% and CR was 38% / 18%, comparing ibritumomab to rituximab. [6]

Recently, extended follow-up data for the ZEVALIN ([90Y]-ibritumomab tiuxetan) First-line Indolent (FIT) study presented at the American Society of Hematology (ASH) Annual Meeting demonstrated the continued improvement in progression-free survival (PFS) following ibritumomab consolidation therapy for patients with follicular B-cell non-Hodgkin’s lymphoma who achieved a response to first-line therapy over chemotherapy alone. Additionally, ibritumomab consolidation did not adversely affect the use of various effective second-line treatments including stem cell transplants in patients who relapsed.[7]

In a Phase II study on patients with relapsed and refractory mantle cell lymphoma, the OR was 42% and CR was 26%.[8]

A study demonstrated that rituximab followed by single agent ibritumomab in a front-line setting for patients with MALT lymphoma and low-grade follicular lymphoma that primarily involved the conjunctiva or orbit, produced a complete response rate of 83 percent.[9]

http://rd.springer.com/article/10.2165%2F00024669-200201050-00004#page-1

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. 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.

In December 2007, Cell Therapeutics Inc acquired the U.S. rights to sell, market, and distribute this radioimmunotherapy 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.[10] Outside of the U.S., Bayer Schering Pharma continues to have the rights to the drug.

In March 2009, Spectrum Pharmaceuticals acquired 100% control of RIT Oncology, LLC, to commercialize Zevalin in the US. Now Spectrum Pharmaceuticals is responsible for all activities relating to Zevalin in the US.

In September 2009, ibritumomab received approval from the FDA for an expanded label for the treatment of patients with previously untreated follicular non-Hodgkin’s Lymphoma (NHL), who achieve a partial or complete response to first-line chemotherapy.

Costs

Ibritumomab 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$ 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), this drug is priced in the middle for many of these therapies.

Ibritumomab tiuxetan ?
Ibritumomab tiuxetan structure.svg
Monoclonal antibody
Type Whole antibody
Source Mouse
Target CD20
Clinical data
Trade names Zevalin
AHFS/Drugs.com monograph
Licence data US FDA:link
Legal status
Routes intravenous
Identifiers
CAS number 174722-31-7 Yes
ATC code V10XX02 (90Y)
DrugBank DB00078

External links

http://www.fda.gov/ohrms/dockets/ac/01/slides/3782s2_02_idec/sld015.htm

References

  1. Ibritumomab: Pronunciation
  2. Milenic, Diane E.; Brady, Erik D.; Brechbiel, Martin W. (June 2004). “Antibody-targeted radiation cancer therapy”. Nat Rev Drug Discov 3 (6): 488–499. doi:10.1038/nrd1413. ISSN 1474-1776. PMID 15173838.
  3.  WHO Drug Information
  4.  http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/ibriide021902LB.pdf
  5.  Ibritumomab: Indications
  6.  Ibritumomab: Efficacy
  7.  ZEVALIN Consolidation in First-Line Therapy in Patients with Non-Hodgkin’s Lymphoma Resulted in a Progression-Free Survival of Greater Than 67 Months
  8.  Zevalin and mantle cell
  9.  ZEVALIN(R) Produced 83 Percent Complete Response Rate in Mucosa-Associated Lymphoid Tissue (MALT) Orbital Lymphoma Study
  10.  [1]

// // // // //

September 23, 2014

// CASI Signs China Licensing Deal With Spectrum For 3 Cancer Drugs…http://www.outsourcedpharma.com/doc/casi-signs-china-licensing-deal-with-spectrum-for-cancer-drugs-0001

// CASI Signs China Licensing Deal With Spectrum For 3 Cancer Drugs// // // // //

CASI Pharmaceuticals and Spectrum Pharmaceuticals (SPPI) announced the signing of a license agreement that gives CASI exclusive rights to develop three cancer drugs from Spectrum and market them in China, including Macau, Hong Kong, and Taiwan.

The agreement concerns the two approved cancer drugs Zevalin (ibritumomab tiuxetan) Injection non-Hodgkin’s lymphoma (NHL) and Marqibo (vinCRIStine sulfate LIPOSOME injection) for acute lymphoblastic leukemia (ALL) as well as the investigational Phase 3 drug Captisol-Enabled Melphalan (CE melphalan) being studied as a conditioning treatment before autologous stem cell transplant in patients with multiple myeloma. Spectrum recently reported that Melphalan met its primary endpoint in its pivotal safety and efficacy trial. In view of the results, Spectrum said it intends to file a New Drug Application (NDA) with the U.S. Food and Drug Administration (FDA) for the drug in the second half of 2014.

// // // // //

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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