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 Acute lymphoblastic leukemia (ALL) is a cancer of the lymphoid line of blood cells characterized by the development of large numbers of immature lymphocytes. Symptoms may include feeling tired, pale skin color, fever, easy bleeding or bruisin ...

(ALL). The medication consists of a humanized monoclonal antibody against

CD22 CD22, or cluster of differentiation-22, is a molecule belonging to the SIGLEC family of lectins. It is found on the surface of mature B cells and to a lesser extent on some immature B cells. Generally speaking, CD22 is a regulatory molecule that ...

(

inotuzumab 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). The medication consists of a humanized monoclonal antib ...

), linked to a cytotoxic agent from the class of

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 "calich ...

s called

ozogamicin The term ozogamicin in the names of monoclonal antibodies or antibody-drug conjugates indicates that they are linked to a cytotoxic agent from the class of calicheamicins. See also *Gemtuzumab ozogamicin Gemtuzumab ozogamicin, sold under the ...

. This drug was discovered by scientists collaborating at

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. History Celltech was founded by Gerard Fairtlough in 1980 with financ ...

and Wyeth, and it was developed by Pfizer which had acquired Wyeth. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.

Medical use

Inotuzumab ozogamicin is used to treat relapsed or refractory B-cell precursor

. It is administered by intravenous infusion in a doctor's office or clinic. In studies in pregnant animals, the drug caused harm to the fetus at doses less than those used clinically, and so the drug has not been tested in pregnant women. Pregnant women should not take inotuzumab ozogamicin and must not become pregnant while taking it. It is unknown if the drug or its metabolites are secreted in breast milk, but women should not breastfeed while taking it, and should wait two months after the last dose to start breastfeeding. The drug prolongs the QT interval in some people, so it should be used with caution in people with heart arrhythmias.

Adverse effects

The US label for the use of inotuzumab ozagamicin carries an FDA black box warning concerning the risk of

liver toxicity Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn fro ...

, in particular hepatic veno-occlusive disease (VOD), which has been fatal in some people. The risk of this is higher in people who take the drug before having hematopoietic stem cell transplantation (HSCT) and more people die who have HSCT following treatment with this drug, than people who have HSCT taking other chemotherapies. The risk gets higher as more rounds of treatment with inotuzumab ozogamicin are administered. The most common serious adverse reactions in people taking the drug in the clinical trial leading to approval were infections (23%), loss of neutrophils with fever (11%), hemorrhage (5%), stomach pain (3%), fever (3%), VOD (2%), and tiredness (2%). More than 20% of people had the following adverse reactions: loss of platelets (51%), loss of neutrophils (49%), infections (48%), anemia (36%), leukopenia (35%), tiredness (35%), hemorrhage (33%), fever (32%), nausea (31%), headache (28%), loss of neutrophils with fever (26%),

elevated transaminases In medicine, the presence of elevated transaminases, commonly the transaminases alanine transaminase (ALT) and aspartate transaminase (AST), may be an indicator of liver dysfunction. Other terms include transaminasemia, transaminitis, and elevated ...

(26%), stomach pain (23%), and

jaundice Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme meta ...

(21%). Between 10% and 20% of people also had loss of appetite, vomiting, diarrhea, mouth sores, constipation, chills, and injection site reactions.

Pharmacology

The antibody component of inotuzumab ozogamicin binds to

receptors, which are expressed mostly on B cells. The whole conjugate is then drawn into the cell, where the ozogamicin is cleaved from the antibody by the acidic environment of the lysosome. The ozogamicin eventually travels to the

nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucle ...

where it breaks up DNA, causing the cell to die.

Chemistry

Inotuzumab ozogamicin consists of the humanized monoclonal antibody inotuzumab (against

), linked to a cytotoxic agent from the class of

s called ozogamicin. Ozogamicin is N-acetyl-gamma-calicheamicin dimethylhydrazide. It includes the same linker, called "AcBut", and toxin, as gemtuzumab ozogamicin, which arose from the same collaboration. The linker is a carbonyl-containing carboxylic acid. The antibody, originally called G5/44, was created by grafting the complementarity-determining regions and some

framework A framework is a generic term commonly referring to an essential supporting structure which other things are built on top of. Framework may refer to: Computing * Application framework, used to implement the structure of an application for an op ...

residues from the murine anti-CD22 mAb m5/44, onto human acceptor frameworks.

History

and Wyeth entered into a collaboration in 1991 to develop antibody-drug conjugates. The humanized antibody portion was generated at Celltech and the DNA encoding it was transfected into

CHO cells Chinese hamster ovary (CHO) cells are an epithelial cell line derived from the ovary of the Chinese hamster, often used in biological and medical research and commercially in the production of recombinant therapeutic proteins. They have foun ...

, which were sent to Wyeth, where chemists expressed and purified the antibodies and conjugated them with the linker to the cytotoxin; the work was published in 2004. Celltech was acquired by UCB in 2004 and Wyeth was acquired by Pfizer in 2009. In May 2013, a phase III trial in patients with relapsed or refractory CD22+ aggressive non-Hodgkin lymphoma (NHL) who were not candidates for intensive high-dose chemotherapy was terminated for futility. In 2017, inotuzumab ozogamicin was approved by the European Commission and the FDA for the treatment of adults with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia (ALL) in 2017 under the trade name Besponsa (Pfizer/Wyeth).

References

External links

* * * {{Portal bar , Medicine Antibody-drug conjugates Monoclonal antibodies for tumors Wyeth brands Pfizer brands