Inotuzumab ozogamicin

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Inotuzumab ozogamicin
Mass / length primary structure 95347.07  Da
Identifier
External IDs
Drug information
ATC code L01 XC26
DrugBank DB05889
Drug class Monoclonal Antibodies , Cytostatics , Other Antineoplastic Agents, and Protective Agents

Inotuzumab-ozogamicin is an antibody-drug conjugate and is used as a drug in the treatment of acute lymphoblastic leukemia in certain patients.

Chemistry and properties

Inotuzumab-ozogamicin is a conjugate consisting of a monoclonal antibody (inotuzumab) and a cytotoxic agent , which are covalently linked via a hydrazone linker . Inotuzumab is a recombinant and humanized IgG  4κ antibody. The cytotoxic component is represented by N-acetyl-gamma-calicheamicin-dimethylhydrazide, a calicheamicin derivative and hereinafter referred to as calicheamicin. Gemtuzumab ozogamicin is a comparable active ingredient .

pharmacology

background

In acute lymphocytic leukemia (ALL), the precursor cells of lymphocytes are malignantly degenerated, which leads to disorders of blood formation with complex symptoms. If left untreated, the disease can quickly become fatal . Overall survival (adults) in relapsed or refractory ALL (cannot be influenced by therapy) is given as an average of three to six months. The previous standard for patients affected in this way is repeated polychemotherapy , to which less than half of the patients in remission respond. For more information, see the main article, Acute Lymphocytic Leukemia .

Mechanism of action

Inotuzumab ozogamicin binds specifically to the CD22 receptor on the surface of B lymphocytes via the antibody component . This is followed by absorption into the cell interior. No cytotoxic effects are mediated via the antibody and CD22 signaling pathway. Intracellularly , calicheamicin is split off from the linker by hydrolysis in the acidic environment of the lysozymes and can now develop its effect. The activated substance causes double-strand breaks in the DNA and thus initiates apoptosis , i.e. the death of the cell. The aim of therapy is normalized blood values ​​and complete remission of the disease. In the approval and phase III study INO-VATE ALL (326 patients), 80.7 percent of the subjects achieved a complete remission (29.4 percent under chemotherapy). Inotuzumab ozogamicin is provisionally rated as a leap innovation (Pharm. Ztg.)

Pharmacokinetics

During therapy with inotuzumab ozogamicin, a steady-state state is established after four treatment cycles . The active ingredient has a mean maximum serum level of 308  ng / ml. The volume of distribution of inotuzumab ozogamicin is approximately 12 liters. Calicheamicin has a high plasma protein binding (97%) in vitro and is a substrate of P-glycoprotein , a transporter protein. The serum level of unconjugated calicheamicin is mostly below the quantification limit of 50  pg / ml, but measurable values ​​of up to 276 pg / ml have occasionally occurred.

The metabolism of calicheamicin is primarily non-enzymatic through reduction . A steady-state clearance of 0.0333 l / h and a plasma half-life (end of the fourth therapy cycle  ) of 12.3 days were determined for inotuzumab ozogamicin .

Since the cytotoxic active ingredient is largely only released in the target cell, a minimal dosage is possible and systemic effects are reduced. Because callicheamicins are extremely toxic, they can be used simply by coupling them to an antibody.

application

Inotutumab ozogamicin is used in adults with acute lymphoblastic leukemia (relapsed or refractory) with CD22-positive B progenitor cells. If a Philadelphia chromosome is present, inotuzumab ozogamicin is only indicated after a therapy with tyrosine kinase inhibitors has failed . It is used as an intravenous infusion in up to six cycles (21 or 28 days). Premedication with corticosteroids , antipyretics and antihistamines is often used as a prophylactic countermeasure against side effects and immune reactions.

unwanted effects

Common side effects of inotuzumab ozogamicin are changes in the blood count ( thrombocytopenia , neutropenia , leukopenia ), infections , haemorrhages , abdominal pain , hyperthermia and fatigue . An important and serious side effect is venous occlusive liver disease , which can lead to venous occlusion, blood congestion and damage to the liver as a result of the destruction of liver sinusoids . In the event of this side effect, the therapy should be discontinued. Serious pre-existing liver diseases are a contraindication for the use of the active ingredient. Since there is the possibility of tumor lysis syndrome , drugs to lower the uric acid level should be given preventively to patients with a particularly high tumor burden .

Inotuzumab ozogamicin can influence cardiac physiology and thus lead to a prolongation of the QT interval . Thus there is a potential for interaction with other drugs that affect the QT interval. Regular checks of the ECG and electrolytes are recommended.

Inotuzumab ozogamicin has been shown to be genotoxic, clastogenic and toxic to reproduction in animal experiments (rats) . Sexual contraceptive measures are required during therapy and for eight (women) or five (men) months after the last application.

Finished medicinal products

Inotuzumab ozogamicin was developed by Pfizer and UCB and launched on the German market by Pfizer in 2017 under the trade name Besponsa ® . The medicinal product contains powder (equivalent to 1 mg inotuzumab ozogamicin) for a concentrate for solution for infusion. The cost of a vial is EUR 12,314.32 (German, as of 2019). It was approved in both the European Union and the USA in 2017.

Individual evidence

  1. a b c d Entry on Inotuzumab ozogamicin in the DrugBank of the University of Alberta , accessed on August 8, 2019.
  2. a b c d e f g h i j k Pharm. Ztg. Online, drug profile : Inotuzumab-Ozogamicin (accessed on August 8, 2019)
  3. a b c d e Pfizer Pharma , Pharmaceutical Information on Besponsa ® , as of August 2019 ( link , accessed June 13, 2020; restricted access)
  4. ADC Review: Inotuzumab ozogamicin (CMC-544) Drug Description (accessed August 11, 2019)
  5. Besponsa ® in Red List online ( link , accessed August 8, 2019; restricted access)