Gemtuzumab ozogamicin, sold under the brand name Mylotarg, is an antibody-drug conjugate (a drug-linked

monoclonal antibody A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodie ...

) that is used to treat

acute myeloid leukemia Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with haematopoiesis, normal blood cell production. Sympt ...

(AML). The most common side effects include infection, febrile neutropenia, decreased appetite, hyperglycemia, mucositis, hypoxia, hemorrhage, increased transaminase, diarrhea, nausea, and hypotension. However, the addition of gemtuzumab ozogamicin to standard chemotherapy regimens does not increase infection rates.

Medical uses

In the United States
gemtuzumab ozogamicin
is

indicated In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...

for newly diagnosed CD33-positive ''acute 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.

Mechanism

Gemtuzumab ozogamicin
is a recombinant, humanized anti-

CD33 CD33 or Siglec-3 (sialic acid binding Ig-like lectin 3, SIGLEC3, SIGLEC-3, gp67, p67) is a transmembrane receptor expressed on cells of myeloid lineage. It is usually considered myeloid-specific, but it can also be found on some lymphoid cells. ...

''monoclonal antibody'' (IgG4 κ antibody hP67.6) covalently attached to the cytotoxic antitumor antibioti
''calicheamicin''
(N-acetyl-γ-calicheamicin) ''payload'' via a bifunctional ''linker'' (4-(4-acetylphenoxy)butanoic acid).

Calicheamicin The calicheamicins are a class of enediyne antitumor antibiotics derived from the bacterium '' Micromonospora echinospora'', with calicheamicin γ1 being the most notable. It was isolated originally in the mid-1980s from the chalky soil, or "cal ...

(the ''payload'') is approximately 4,000 times more active than

doxorubicin Doxorubicin, sold under the brand name Adriamycin among others, is a chemotherapy medication used to treat cancer. This includes breast cancer, bladder cancer, Kaposi's sarcoma, lymphoma, and acute lymphocytic leukemia. It is often used toge ...

), and since it also destroys the DNA of normal, healthy, cells, it cannot be used as a single agent to treat patients. However, by linkin
calicheamicin
to a monoclonal antibody, scientists have optimized the features of both components, creating a class of targeted drugs calle
antibody-drug conjugates
(ADC) or ''armed antibodies'' which selectively dispatch highly potent cytotoxic anticancer chemotherapies directly to cancer cells while, at the same time, leaving healthy tissue unaffected.

is expressed in most leukemic blast cells but also in normal hematopoietic cells, the intensity diminishing with maturation of

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

History

Gemtuzumab ozogamicin was created in a collaboration between

Celltech Celltech Group plc was a leading British-based biotechnology business based in Slough. It was listed on the London Stock Exchange and was a constituent of the FTSE 100 Index. Celltech was instrumental in changing the UK's system of technology tr ...

and

Wyeth Wyeth Pharmaceuticals Inc. was a pharmaceutical company until it was purchased by Pfizer in 2009. The company was founded in Philadelphia, Pennsylvania, in 1860 as John Wyeth and Brother. Its headquarters moved to Collegeville, Pennsylvania, a ...

that began in 1991. The same collaboration later produced

inotuzumab ozogamicin Inotuzumab ozogamicin, sold under the brand name Besponsa, is an antibody-drug conjugate medication used to treat relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). It is administered by intravenous infusion. Inotuzum ...

. Celltech was acquired by UCB in 2004 and Wyeth was acquired by

Pfizer Pfizer Inc. ( ) is an American Multinational corporation, multinational Pharmaceutical industry, pharmaceutical and biotechnology corporation headquartered at The Spiral (New York City), The Spiral in Manhattan, New York City. Founded in 184 ...

in 2009. In the United States, gemtuzumab ozogamicin was approved under an accelerated-approval process by the FDA in 2000, for use in patients over the age of 60 with relapsed

acute myelogenous leukemia Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. Symptoms may includ ...

(AML); or those who are not considered candidates for standard chemotherapy. The accelerated approval was based on the

surrogate endpoint In clinical trials, a surrogate endpoint (or surrogate marker) is a Outcome measure, measure of effect of a specific treatment that may correlate with a ''real'' clinical endpoint but does not necessarily have a guaranteed relationship. The Nationa ...

of response rate. It was the first antibody-drug conjugate to be approved. 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 of

veno-occlusive disease Hepatic veno-occlusive disease (VOD) or veno-occlusive disease with immunodeficiency is a potentially life-threatening condition in which some of the small veins in the liver are obstructed. It is a complication of high-dose chemotherapy given be ...

in the absence of

bone marrow transplantation Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood, in order to replicate inside a patient and produce a ...

. Later the onset of VOD was shown to occur at increased frequency in gemtuzumab patients even following bone marrow transplantation. The drug was discussed in a 2008 JAMA article, which criticized the inadequacy of postmarketing surveillance of biologic agents. A randomized Phase III comparative controlled trial (SWOG S0106) was initiated in 2004, by Wyeth in accordance with the FDA accelerated-approval process. The study was stopped on August 20, 2009, prior to completion due to worrisome outcomes. 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).Gemtuzumab Voluntarily Withdrawn From US Market. June 2010
/ref> In June 2010, Pfizer withdrew gemtuzumab ozogamicin from the market at the request of the US FDA. 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". 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. In September 2017, gemtuzumab ozogamicin was approved again for use in the United States and in the European Union.

References

External links

* {{DEFAULTSORT:Gemtuzumab Ozogamicin Antibody-drug conjugates Hepatotoxins Monoclonal antibodies for tumors Orphan drugs Drugs developed by Pfizer Withdrawn drugs Drugs developed by Wyeth