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 Lymphocyte, lymphoid line of blood cells characterized by the development of large numbers of lymphoblast, immature lymphocytes. Symptoms may include feeling tired, pale skin color, fever, ...

(ALL). It is administered by

intravenous infusion Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...

. Inotuzumab ozogamicin 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 ant ...

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 tha ...

( inotuzumab), linked to a

cytotoxic agent Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are toxic metals, toxic chemicals, microbe neurotoxins, radiation particles and even specific neurotransmitters when the system is out of balance. Also some types of dru ...

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 "cal ...

s called ozogamicin. The US

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 respo ...

considers it to be a

first-in-class medication A first-in-class medication is a prototype drug 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 medic ...

Medical use

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

. In March 2024, the US

approved inotuzumab ozogamicin for the treatment of children aged one year and older with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia.

Adverse effects

The US

label for the use of inotuzumab ozagamicin carries a

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

concerning the risk of

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

, 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 be ...

, 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 a patient and produce ...

and more people die who have hematopoietic stem cell transplantation following treatment with this drug, than people who have hematopoietic stem cell transplantation, 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 include 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 white blood cells (leukocytes). It places individuals at increased risk of infection as white blood cells are the body's primary defense against infections. Signs and symptoms Symptoms may include: * s ...

(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, and elevated liver enzym ...

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

jaundice Jaundice, also known as icterus, is a yellowish or, less frequently, 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 ...

(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 (ISRs) are reactions that occur at the site of injection of a drug. They may be mild or severe and may or may not require medical intervention. Some reactions may appear immediately after injection, and some may be delayed ...

s. 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.

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 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 inserted into the plasm ...

. 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 that is found in all mammalian cells, with the exception of red blood cells (erythrocytes). There are normally hundreds of lysosomes in the cytosol, where they function as the cell’s degradation cent ...

. 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 Nucleu ...

where it breaks up

DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...

, causing the cell to die.

Chemistry

Inotuzumab ozogamicin consists of the

inotuzumab (against

), linked to a

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

Inotuzumab ozogamicin 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. 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 ...

, and it was developed 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 ...

which had acquired Wyeth.

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 Chinese hamster ovary (CHO) cells are a family of immortalized cell lines derived from epithelial cells of the ovary of the Chinese hamster, often used in biological and medical research and commercially in the production of recombinant therapeu ...

, 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 participants with relapsed or refractory CD22+ aggressive non-Hodgkin lymphoma (NHL) who were not candidates for intensive high-dose chemotherapy was terminated for futility. In March 2024, the FDA approved inotuzumab ozogamicin for the treatment of children aged one year and older with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia. Efficacy was evaluated in a multicenter, single-arm, open-label study in 53 pediatric participants aged one year and older with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia. Two dose levels were evaluated--an initial dose of 1.4 mg/m2/cycle in 12 participants and 1.8 mg/m2/cycle in 41 participants. Premedications included methylprednisolone 1 mg/kg (maximum of 50 mg), an antipyretic, and an antihistamine. Participants received a median of 2 cycles of therapy (range: 1 to 4 cycles). The application was granted

priority review Priority review is a program of the United States Food and Drug Administration (FDA) to expedite the review process for drugs that are expected to have a particularly great impact on the treatment of a disease. The priority review voucher program ...

and

orphan drug An orphan drug is a medication, pharmaceutical agent that is developed to treat certain rare medical conditions. An orphan drug would not be profitable to produce without government assistance, due to the small population of patients affected by th ...

designations.

Society and culture

Legal status

In 2017, inotuzumab ozogamicin was approved by the European Commission and the US

for the treatment of adults with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia under the brand name Besponsa (Pfizer/Wyeth).

References

External links

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