Inotuzumab ozogamicin, sold under the brand name Besponsa, is an

antibody-drug conjugate Antibody-drug conjugates or ADCs are a class of biopharmaceutical drugs designed as a targeted therapy for treating cancer. Unlike chemotherapy, ADCs are intended to target and kill tumor cells while sparing healthy cells. As of 2019, some 56 phar ...

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 Humanized antibodies are antibodies from non-human species whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans. The process of "humanization" is usually applied to monoclonal an ...

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), linked to a

cytotoxic agent Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are an immune cell or some types of venom, e.g. from the puff adder (''Bitis arietans'') or brown recluse spider (''Loxosceles reclusa''). Cell physiology Treating cell ...

from the class of calicheamicins called ozogamicin. 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 fina ...

and

Wyeth Wyeth, LLC was an American pharmaceutical company. The company was founded in Philadelphia, Pennsylvania, in 1860 as ''John Wyeth and Brother''. It was later known, in the early 1930s, as American Home Products, before being renamed to Wyeth in ...

, and it was developed by

Pfizer Pfizer Inc. ( ) is an American multinational pharmaceutical and biotechnology corporation headquartered on 42nd Street in Manhattan, New York City. The company was established in 1849 in New York by two German entrepreneurs, Charles Pfizer ...

which had acquired Wyeth. The U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) considers it to be a

first-in-class medication A first-in-class medication is a pharmaceutical that uses a "new and unique mechanism of action" to treat a particular medical condition. While the Food and Drug Administration's Center for Drug Evaluation and Research tracks first-in-class medicat ...

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 arrhythmia Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adult ...

Adverse effects

The US label for the use of inotuzumab ozagamicin carries an FDA

black box warning In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears on the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administration specifies that it ...

concerning the risk of liver toxicity, in particular

hepatic 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 bef ...

(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 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 of a patient and to produce ...

(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 Leukopenia () is a decrease in the number of leukocytes (WBC). Found in the blood, they are the white blood cells, and are the body's primary defense against an infection. Thus the condition of leukopenia places individuals at increased risk of inf ...

(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 reaction Injection site reactions are allergic reactions that result in cutaneous necrosis that may occur at sites of medication injection, typically presenting in one of two forms, (1) those associated with intravenous infusion or (2) those related to intra ...

Pharmacology

The antibody component of inotuzumab ozogamicin binds to

receptors, which are expressed mostly on

B cells B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...

. The whole conjugate is then drawn into the cell, where the ozogamicin is cleaved from the antibody by the acidic environment of the

lysosome A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane prot ...

. 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 Nucl ...

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

Chemistry

Inotuzumab ozogamicin consists of the

inotuzumab (against

), linked to a

from the class of calicheamicins called ozogamicin. Ozogamicin is N-acetyl-gamma-calicheamicin dimethylhydrazide. It includes the same linker, called "AcBut", and toxin, as

gemtuzumab ozogamicin Gemtuzumab ozogamicin, sold under the brand name Mylotarg, is an antibody-drug conjugate (a drug-linked monoclonal antibody) that is used to treat acute myeloid leukemia. The most common grade 3 and higher adverse reactions that occurred during ...

, 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 region Complementarity-determining regions (CDRs) are part of the variable chains in immunoglobulins (antibodies) and T cell receptors, generated by B-cells and T-cells respectively, where these molecules bind to their specific antigen. A set of CDRs co ...

s 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

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, 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

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