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| Monoclonal antibody | |
|---|---|
| Type | Whole antibody |
| Source | Humanized (frommouse) |
| Target | CD33 |
| Clinical data | |
| Trade names | Mylotarg |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a618005 |
| License data | |
| Pregnancy category | |
| Routes of administration | Intravenous |
| ATC code | |
| Legal status | |
| Legal status | |
| Identifiers | |
| CAS Number | |
| DrugBank |
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| ChemSpider |
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| UNII | |
| KEGG |
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| ChEMBL | |
| Chemical and physical data | |
| Molar mass | 151500 g·mol−1 |
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Gemtuzumab ozogamicin, sold under the brand nameMylotarg, is anantibody-drug conjugate (a drug-linkedmonoclonal antibody) that is used to treatacute myeloid leukemia (AML).[5][7][8]
The most common side effects include infection, febrile neutropenia, decreased appetite, hyperglycemia, mucositis, hypoxia, hemorrhage, increased transaminase, diarrhea, nausea, and hypotension.[9] However, the addition of gemtuzumab ozogamicin to standard chemotherapy regimens does not increase infection rates.[10]
In the United States,gemtuzumab ozogamicin isindicated for newly diagnosed CD33-positiveacute myeloid leukemia (AML) for adults and children one month and older and for the treatment of relapsed or refractory CD33-positive AML in adults and children two years and older.[5][9]
Gemtuzumab ozogamicin is a recombinant, humanized anti-CD33monoclonal antibody (IgG4 κ antibody hP67.6) covalently attached to the cytotoxic antitumor antibioticcalicheamicin (N-acetyl-γ-calicheamicin)payload via a bifunctionallinker (4-(4-acetylphenoxy)butanoic acid).
Calicheamicin (thepayload) is approximately 4,000 times more active thandoxorubicin, and since it also destroys the DNA of normal, healthy, cells, it cannot be used as a single agent to treat patients. However, by linkingcalicheamicin to a monoclonal antibody, scientists have optimized the features of both components, creating a class of targeted drugs calledantibody-drug conjugates (ADC) orarmed antibodies which selectively dispatch highly potent cytotoxic anticancer chemotherapies directly to cancer cells while, at the same time, leaving healthy tissue unaffected.[11]
CD33 is expressed in most leukemic blast cells but also in normal hematopoietic cells, the intensity diminishing with maturation ofstem cells.
Gemtuzumab ozogamicin was created in a collaboration betweenCelltech andWyeth that began in 1991.[12][13] The same collaboration later producedinotuzumab ozogamicin.[14] Celltech was acquired byUCB in 2004[15] and Wyeth was acquired byPfizer in 2009.[16]
In the United States, gemtuzumab ozogamicin was approved under anaccelerated-approval process by the FDA in 2000, for use in patients over the age of 60 with relapsedacute myelogenous leukemia (AML); or those who are not considered candidates for standard chemotherapy.[17]The accelerated approval was based on thesurrogate endpoint ofresponse rate.[18] It was the firstantibody-drug conjugate to be approved.[19]
Within the first year after approval, the FDA required a black box warning be added to gemtuzumab packaging. The drug was noted to increase the risk ofveno-occlusive disease in the absence ofbone marrow transplantation.[20] Later the onset of VOD was shown to occur at increased frequency in gemtuzumab patients even following bone marrow transplantation.[21] The drug was discussed in a 2008 JAMA article, which criticized the inadequacy of postmarketing surveillance ofbiologic agents.[22]
A randomized Phase III comparative controlled trial (SWOG S0106) was initiated in 2004, by Wyeth in accordance with theFDA accelerated-approval process. The study was stopped on August 20, 2009, prior to completion due to worrisome outcomes.[23] Among the patients evaluated for early toxicity, fatal toxicity rate was significantly higher in the gemtuzumab combination therapy group vs the standard therapy group. Mortality was 5.7% with gemtuzumab and 1.4% without the agent (16/283 = 5.7% vs 4/281 = 1.4%; P = .01).[18]
In June 2010, Pfizer withdrew gemtuzumab ozogamicin from the market at the request of the US FDA.[24][25] However, some other regulatory authorities did not agree with the FDA decision, with Japan's Pharmaceuticals and Medical Devices Agency stating in 2011 that the "risk-benefit balance of gemtuzumab ozogamicin has not changed from its state at the time of approval".[26]
In 2017, Pfizer reapplied for US and EU approval, based on a meta-analysis of prior trials and results of the ALFA-0701 clinical trial, an open-label Phase III trial in 280 older people with AML.[19] In September 2017, gemtuzumab ozogamicin was approved again for use in the United States[7][27] and in the European Union.[6]
This article incorporates text from this source, which is in thepublic domain.
