Daratumumab, sold under the brand name Darzalex, is an anti-cancer
monoclonal antibody
A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.
Monoclonal antibodies ...
medication. It binds to
CD38, which is overexpressed in
multiple myeloma cells.
Daratumumab was originally developed by
Genmab
Genmab A/S is a Danish biotechnology company, founded in February 1999 by Florian Schönharting, at the time managing director of BankInvest Biomedical venture fund. The company is based in Copenhagen, Denmark - internationally, it operates thr ...
, but it is now being jointly developed by Genmab along with the
Johnson & Johnson subsidiary
Janssen Biotech
Janssen Pharmaceuticals is a pharmaceutical company headquartered in Beerse, Belgium, and wholly-owned by Johnson & Johnson. It was founded in 1953 by Paul Janssen.
In 1961, Janssen Pharmaceuticals was purchased by New Jersey-based American c ...
, which acquired worldwide commercialization rights to the drug from Genmab.
Daratumumab was granted
breakthrough therapy
Breakthrough therapy is a United States Food and Drug Administration designation that expedites drug development that was created by Congress under Section 902 of the 9 July 2012 Food and Drug Administration Safety and Innovation Act. The FDA's "br ...
drug status in 2013, for
multiple myeloma. It was granted
orphan drug status
An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases.
The assignment o ...
for multiple myeloma,
diffuse large B cell lymphoma,
follicular lymphoma
Follicular lymphoma (FL) is a cancer that involves certain types of white blood cells known as lymphocytes. The cancer originates from the uncontrolled division of specific types of B-cells known as centrocytes and centroblasts. These cells norma ...
, and
mantle cell lymphoma
Mantle cell lymphoma (MCL) is a type of non-Hodgkin's lymphoma (NHL), comprising about 6% of NHL cases. There are only about 15,000 patients presently in the United States with mantle cell lymphoma. It is named for the mantle zone of the lymph n ...
.
Medical uses
In May 2018, 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) approved daratumumab for use in combination with bortezomib, melphalan and prednisone to include the treatment of people with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.
In the
European Union
The European Union (EU) is a supranational political and economic union of member states that are located primarily in Europe. The union has a total area of and an estimated total population of about 447million. The EU has often been de ...
it is indicated as monotherapy for the treatment of adults with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy.
Side effects
Treatment of multiple myeloma with daratumumab potentially increases the patient's susceptibility to bacterial and viral infections, due to the killing of
natural killer cells (which are the main
innate immune system defense against virus).
Daratumumab frequently causes
human cytomegalovirus
''Human betaherpesvirus 5'', also called human cytomegalovirus (HCMV), is species of virus in the genus '' Cytomegalovirus'', which in turn is a member of the viral family known as ''Herpesviridae'' or herpesviruses. It is also commonly calle ...
(CMV) reactivation by an unknown mechanism.
Injection related reactions (inflammation-like) are also common.
Interactions
With blood compatibility testing
Daratumumab can also bind to
CD38 present on red blood cells and interfere with routine testing for clinically significant antibodies. People will show a panreactive antibody panel, including a positive auto-control, which tends to mask the presence of any clinically significant antibodies. Treatment of the antibody panel cells with
dithiothreitol
Dithiothreitol (DTT) is the common name for a small-molecule redox reagent also known as Cleland's reagent, after W. Wallace Cleland. DTT's formula is C4H10O2S2 and the chemical structure of one of its enantiomers in its reduced form is shown o ...
(DTT) and repeating testing will effectively negate the binding of daratumumab to CD38 on the red blood cell surface; however, DTT also inactivates/destroys many antigens on the red blood cell surface by disrupting
disulfide bonds
In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...
. The only antigen system affected that is associated with common, clinically significant antibodies is
Kell, making crossmatch testing with K-negative RBCs a reasonable alternative when urgent transfusion is indicated.
It is therefore advisable to do a baseline antibody screen and Rh & Kell phenotyping (type and screen) before starting the therapy. If antibody screen is negative, proceed with phenotype matched transfusions during therapy. If antibody screen is positive, give specific antigen negative blood. The incompatibility may persist for up to 6 months after stopping the medicine. Furthermore, blood transfusion centers should be routinely notified when sending such a sample.
With flow cytometry testing
Daratumumab can also interfere with flow cytometric evaluation of multiple myeloma, causing an apparent lack of plasma cells.
Pharmacology
Mechanism of action
Daratumumab is an IgG1k
monoclonal antibody
A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.
Monoclonal antibodies ...
directed against
CD38. CD38 is overexpressed in multiple myeloma cells. Daratumumab binds to a different CD38
epitope
An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The epitope is the specific piece of the antigen to which an antibody binds. The p ...
amino-acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ami ...
sequence than does the anti-CD38 monoclonal antibody
isatuximab.
Daratumumab binds to CD38, causing cells to apoptose via
antibody-dependent cellular cytotoxicity
Antibody-dependent cellular cytotoxicity (ADCC), also referred to as antibody-dependent cell-mediated cytotoxicity, is a mechanism of cell-mediated immune defense whereby an effector cell of the immune system actively lyses a target cell, whose ...
,
complement-dependent cytotoxicity Complement-dependent cytotoxicity (CDC) is an effector function of IgG and IgM antibodies. When they are bound to surface antigen on target cell (e.g. bacterial or viral infected cell), the classical complement pathway is triggered by bonding prot ...
, inhibition of mitochondrial transfer or
antibody-dependent cellular phagocytosis.
These effects are dependent upon
fragment crystallizable region immune effector mechanisms.
Antibody-dependent cellular cytotoxicity is by means of
natural killer cells.
Unlike
isatuximab which causes apoptosis directly, daratumumab only induces apoptosis indirectly.
Multiple myeloma cells with higher levels of CD38 show greater daratumumab-mediated cell lysis than cells with low CD38 expression.
CD38 enzyme results in the formation of the
immunosuppressive
Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reacti ...
substance
adenosine, so eliminating CD38-containing cells increases the ability of the immune system to eliminate cancer.
History
Encouraging preliminary results were reported in June 2012, from a Phase I/II clinical trial in relapsed
multiple myeloma participants. Updated trial results presented in December 2012, indicate daratumumab is continuing to show promising single-agent anti-myeloma activity. A 2015 study compared monotherapy 8 and 16 mg/kg at monthly to weekly intervals.
[
Daratumumab was given priority review status by 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) for multiple myeloma as a combination therapy (second line).
Daratumumab phase III trials for multiple myeloma show great promise in combination therapy
Combination therapy or polytherapy is therapy that uses more than one medication or modality. Typically, the term refers to using multiple therapies to treat a ''single'' disease, and often all the therapies are pharmaceutical (although it can also ...
with lenalidomide and dexamethasone
Dexamethasone is a glucocorticoid medication used to treat rheumatic problems, a number of skin diseases, severe allergies, asthma, chronic obstructive lung disease, croup, brain swelling, eye pain following eye surgery, superior vena ...
, as well as with bortezomib
Bortezomib, sold under the brand name Velcade among others, is an anti-cancer medication used to treat multiple myeloma and mantle cell lymphoma. This includes multiple myeloma in those who have and have not previously received treatment. It is ...
and dexamethasone
Dexamethasone is a glucocorticoid medication used to treat rheumatic problems, a number of skin diseases, severe allergies, asthma, chronic obstructive lung disease, croup, brain swelling, eye pain following eye surgery, superior vena ...
.
In November 2015, 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) approved daratumumab for treatment of multiple myeloma in people who had received at least three prior therapies. In May 2016 daratumumab was also conditionally approved by the European Medicines Agency for treatment of multiple myeloma.
In November 2016, the FDA approved daratumumab in combination with lenalidomide or bortezomib
Bortezomib, sold under the brand name Velcade among others, is an anti-cancer medication used to treat multiple myeloma and mantle cell lymphoma. This includes multiple myeloma in those who have and have not previously received treatment. It is ...
and dexamethasone
Dexamethasone is a glucocorticoid medication used to treat rheumatic problems, a number of skin diseases, severe allergies, asthma, chronic obstructive lung disease, croup, brain swelling, eye pain following eye surgery, superior vena ...
for the treatment of people with multiple myeloma who have received at least one prior therapy.
The European Commission
The European Commission (EC) is the executive of the European Union (EU). It operates as a cabinet government, with 27 members of the Commission (informally known as "Commissioners") headed by a President. It includes an administrative body ...
granted a marketing authorisation on 20 May 2016.
References
External links
*
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