Gemtuzumab ozogamicin

Gemtuzumab ozogamicin
Mass / length primary structure	151 to 153  kDa
Identifier
External IDs	CAS number : 220578-59-6
Drug information
ATC code	L01 XC05
DrugBank	DB00056
Drug class	Monoclonal antibody , cytostatic agent

Gemtuzumab ozogamicin (trade name Mylotarg ^® ; manufacturer Wyeth ) is an immunoconjugate that consists of a humanized monoclonal antibody linked to a bacterial toxin . The monoclonal antibody is directed against the CD33 antigen and is used in cancer immunotherapy for the treatment of acute myeloid leukemia (AML). Since April 2018 he has been approved for the treatment of CD33 positive AML in combination with chemotherapy.

Clinical information

Application areas (indications)

Gemtuzumab ozogamicin is used for the first-line therapy of acute myeloid leukemia if CD33 positivity is demonstrated. This is combined as a GO with a corresponding chemotherapy - mostly according to the 7 + 3 scheme. In the US, approval is limited to patients over the age of 60 who are not eligible for conventional chemotherapy . The agent is administered by infusion . Gemtuzumab ozogamicin must not be used in the case of known hypersensitivity to any of the components. The drug is contraindicated in pregnancy; a harmful effect on the fetus can be assumed.

Adverse effects (side effects)

The most common side effects are chills, fever, nausea, vomiting, and headache. Medicines to prevent an infusion reaction are often given before the actual treatment. Treatment with gemtuzumab ozogamicin can adversely affect normal blood formation and lead to long-term myelosuppression . Many patients experience neutropenia and / or thrombocytopenia . Liver toxicity and sinusoidal obstruction syndrome have also been observed.

Pharmacological properties

The antibody gemtuzumab is directed against the CD33 antigen, a sialic acid binding lectin from the SIGLEC family, which can be detected on the cell surface of the leukemic blasts in around 80% of AML patients . When gemtuzumab ozogamicin binds to CD33 on the cell surface of the blasts, a complex is formed which is taken up into the cell. There the toxin is released and the poison effect occurs. The CD33- expressing cells are supposed to be killed selectively in this way.

Other Information

Chemical information

The active ingredient is a conjugate of the humanized, recombinantly produced monoclonal antibody gemtuzumab of type IgG ₄ with the toxin calicheamicin from the bacterium Micromonospora echinospora . The toxin is covalently bound to the antibody via a bifunctional linker. On average, each conjugated antibody molecule should carry four to six toxin molecules; however, around 50% of the antibody molecules are not loaded with toxin molecules at all.

Studies

For approval, the therapeutic efficacy was examined in three phase II clinical studies . All studies were neither controlled nor blinded. A total of 277 patients aged 20 to 87 years participated in these studies. The primary endpoint of the studies was the number of patients who had complete remission ; this was the case in 13% of the patients.

History / Admission Status

Mylotarg was approved by the Food and Drug Administration (FDA) in the United States in May 2000 for the treatment of acute myeloid leukemia. This was the first approval of an antibody-toxin conjugate worldwide. In addition, the drug received orphan drug status in both the United States and the European Union .

An application for approval for the European Union was rejected in 2008. In autumn 2007 the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA) issued a negative assessment of Mylotarg after an unusually long processing time, which was confirmed in a further review at the beginning of 2008. On the basis of this scientific assessment, the European Commission rejected the approval in April 2008. The data presented for the proof of effectiveness primarily contributed to the rejection. The EMA was of the opinion that with the given study design, the heterogeneous patient population and the small number of patients with complete remission, the efficacy in the indicated indication had not been adequately demonstrated; In view of the sometimes severe side effects, the risk-benefit ratio is also unfavorable.

In September 2017, the antibody-toxin conjugate was approved by the FDA for the treatment of AML.

On February 22, 2018, the European Medicines Agency issued a positive approval recommendation for the treatment of AML. Approval took place on April 19, 2018.

literature

• EMA: Mylotarg - gemtuzumab ozogamicin (European public assessment report on the rejection of Mylotarg)
• FDA label for Mylotarg (English, PDF; 351 kB)

swell

1. ↑ FDA approves Mylotarg for treatment of acute myeloid leukemia , PM FDA dated September 1, 2017, accessed September 7, 2017
2. ↑ European Medicines Agency - Human medicines - Mylotarg. Retrieved September 2, 2019 . 

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