Daratumumab

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Daratumumab
Daratumumab CD38 7DHA.png
Fab fragment of daratumumab (teal/green) binding CD38 (pale pink). From PDB entry 7DHA
Monoclonal antibody
Type Whole antibody
Source Human
Target CD38
Clinical data
Trade names Darzalex
AHFS/Drugs.com Monograph
MedlinePlus a616002
License data
Pregnancy
category
  • AU:C
Routes of
administration 		Intravenous [Subcutaneous]
ATC code
Legal status
Legal status
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C6466H9996N1724O2010S42
Molar mass 145391.67 g·mol−1
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Daratumumab, sold under the brand name Darzalex, is an anti-cancer monoclonal antibody medication. It binds to CD38, [5] which is overexpressed in multiple myeloma cells. [6] Daratumumab was originally developed by Genmab, but it is now being jointly developed by Genmab along with the Johnson & Johnson subsidiary Janssen Biotech, which acquired worldwide commercialization rights to the drug from Genmab. [7]

Contents

Daratumumab was granted breakthrough therapy drug status in 2013, for multiple myeloma. It was granted orphan drug status for multiple myeloma, diffuse large B cell lymphoma, follicular lymphoma, and mantle cell lymphoma. [8]

Medical uses

In May 2018, the U.S. Food and Drug Administration (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. [9]

In the European Union it is indicated as monotherapy for the treatment of adults with relapsed and refractory multiple myeloma, [10] whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy. [11]

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). [12] Daratumumab frequently causes human cytomegalovirus (CMV) reactivation by an unknown mechanism. [13] Injection related reactions (inflammation-like) are also common. [14]

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 (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. 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. [15] 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. [16]

Pharmacology

Mechanism of action

Daratumumab is an IgG1k monoclonal antibody directed against CD38. CD38 is overexpressed in multiple myeloma cells. Daratumumab binds to a different CD38 epitope amino-acid sequence than does the anti-CD38 monoclonal antibody isatuximab. [17] Daratumumab binds to CD38, causing cells to apoptose via antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, inhibition of mitochondrial transfer or antibody-dependent cellular phagocytosis. [18] [19] [20] [21]

These effects are dependent upon fragment crystallizable region immune effector mechanisms. [22] Antibody-dependent cellular cytotoxicity is by means of natural killer cells. [23]

Unlike isatuximab which causes apoptosis directly, daratumumab only induces apoptosis indirectly. [22]

Multiple myeloma cells with higher levels of CD38 show greater daratumumab-mediated cell lysis than cells with low CD38 expression. [24] CD38 enzyme results in the formation of the immunosuppressive substance adenosine, so eliminating CD38-containing cells increases the ability of the immune system to eliminate cancer. [18]

History

Encouraging preliminary results were reported in June 2012, from a Phase I/II clinical trial in relapsed multiple myeloma participants. [25] Updated trial results presented in December 2012, indicate daratumumab is continuing to show promising single-agent anti-myeloma activity. [26] A 2015 study compared monotherapy 8 and 16 mg/kg at monthly to weekly intervals. [6]

Daratumumab was given priority review status by the U.S. Food and Drug Administration (FDA) for multiple myeloma as a combination therapy (second line). [20]

Daratumumab phase III trials for multiple myeloma show great promise in combination therapy with lenalidomide and dexamethasone, [27] as well as with bortezomib and dexamethasone. [28] [ needs update ]

In November 2015, the U.S. Food and Drug Administration (FDA) approved daratumumab for treatment of multiple myeloma in people who had received at least three prior therapies. [29] [30] In May 2016 daratumumab was also conditionally approved by the European Medicines Agency for treatment of multiple myeloma. [31]

In November 2016, the FDA approved daratumumab in combination with lenalidomide or bortezomib and dexamethasone for the treatment of people with multiple myeloma who have received at least one prior therapy. [32]

The European Commission granted a marketing authorisation in May 2016. [33]

Related Research Articles

<span class="mw-page-title-main">Multiple myeloma</span> Cancer of plasma cells

Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, anemia, renal insuficiency, and infections may occur. Complications may include hypercalcemia and amyloidosis.

<span class="mw-page-title-main">Lenalidomide</span> Pair of enantiomers

Lenalidomide, sold under the brand name Revlimid among others, is a medication used to treat multiple myeloma, smoldering myeloma, and myelodysplastic syndromes (MDS). For multiple myeloma, it is a first line treatment, and is given with dexamethasone. It is taken by mouth.

<span class="mw-page-title-main">Bortezomib</span> Chemical compound

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 generally used together with other medications. It is given by injection.

<span class="mw-page-title-main">CD38</span> Protein-coding gene in the species Homo sapiens

CD38 (cluster of differentiation 38), also known as cyclic ADP ribose hydrolase is a glycoprotein found on the surface of many immune cells (white blood cells), including CD4+, CD8+, B lymphocytes and natural killer cells. CD38 also functions in cell adhesion, signal transduction and calcium signaling.

Amyloid light-chain (AL) amyloidosis, also known as primary amyloidosis, is the most common form of systemic amyloidosis. The disease is caused when a person's antibody-producing cells do not function properly and produce abnormal protein fibers made of components of antibodies called light chains. These light chains come together to form amyloid deposits which can cause serious damage to different organs. An abnormal light chain in urine is known as Bence Jones protein.

Elotuzumab, sold under the brand name Empliciti, is a humanized IgG1 monoclonal antibody medication used in combination with lenalidomide and dexamethasone, for adults that have received 1 to 3 prior therapies for the treatment of multiple myeloma. It is also indicated for adult patients in combination with pomalidomide and dexamethasone, who have received 2 prior therapies including lenalidomide and a protease inhibitor. Administration of elotuzumab is done intravenously. Each intravenous injection of elotuzumab should be premedicated with dexamethasone, diphenhydramine, ranitidine and acetaminophen. It is being developed by Bristol Myers Squibb and AbbVie.

<span class="mw-page-title-main">Pomalidomide</span> Chemical compound

Pomalidomide, sold under the brand names Pomalyst and Imnovid, is an anti-cancer medication used for the treatment of multiple myeloma and AIDS-related Kaposi sarcoma.

<span class="mw-page-title-main">Carfilzomib</span> Chemical compound

Carfilzomib, sold under the brand name Kyprolis, is an anti-cancer medication acting as a selective proteasome inhibitor. Chemically, it is a tetrapeptide epoxyketone and an analog of epoxomicin. It was developed by Onyx Pharmaceuticals.

<span class="mw-page-title-main">Filanesib</span> Chemical compound

Filanesib is a kinesin spindle protein (KIF11) inhibitor which has recently been proposed as a cancer treatment, specifically for multiple myeloma.

MDX-1097 is a monoclonal antibody therapy that in 2023 has been assessed in a Phase IIb clinical trial in conjunction with lenalidomide and dexamethasone as a treatment for multiple myeloma, a type of white blood cell cancer. MDX-1097 was originally developed by scientists at Immune System Therapeutics Ltd. In 2015, Haemalogix Ltd acquired the rights to MDX-1097 and are taking it through clinical testing.

<span class="mw-page-title-main">Isatuximab</span> Monoclonal antibody

Isatuximab, sold under the brand name Sarclisa, is a monoclonal antibody (mAb) medication for the treatment of multiple myeloma.

<span class="mw-page-title-main">Ixazomib</span> Chemical compound

Ixazomib is a drug for the treatment of multiple myeloma, a type of white blood cell cancer, in combination with other drugs. It is taken by mouth in the form of capsules.

<span class="mw-page-title-main">Melphalan flufenamide</span> Alkylating type cancer drug

Melphalan flufenamide, sold under the brand names Pepaxto and Pepaxti, is an anticancer medication used to treat multiple myeloma.

<span class="mw-page-title-main">Selinexor</span> Anti-cancer drug

Selinexor sold under the brand name Xpovio among others, is a selective inhibitor of nuclear export used as an anti-cancer medication. It works by blocking the action of exportin 1 and thus blocking the transport of several proteins involved in cancer-cell growth from the cell nucleus to the cytoplasm, which ultimately arrests the cell cycle and leads to apoptosis. It is the first drug with this mechanism of action.

Daratumumab/hyaluronidase, sold under the brand name Darzalex Faspro, is a fixed-dose combination medication for the treatment of adults with newly diagnosed or relapsed/refractory multiple myeloma. It is a combination of daratumumab and hyaluronidase. It is administered via subcutaneous injection.

Belantamab mafodotin, sold under the brand name Blenrep, is a medication for the treatment of relapsed and refractory multiple myeloma.

Monoclonal gammopathy of renal significance (MGRS) are a group of kidney disorders that present with kidney damage due to nephrotoxic monoclonal immunoglobulins secreted by clonal plasma cells or B cells. By definition, people with MGRS do not meet criteria for multiple myeloma or other hematologic malignancies. The term MGRS was introduced in 2012 by the International Kidney and Monoclonal Gammopathy Research Group (IKMG). MGRS is associated with monoclonal gammopathy of undetermined significance (MGUS). People with MGUS have a monoclonal gammopathy but does not meet the criteria for the clonal burden nor the presence of end organ damage seen in hematologic malignancies. In a population based study based on the NHANES III health survey; 6% of patients with MGUS were subsequently classified as having MGRS. The prevalence and incidence of MGRS in the general population or in specific populations is not known but it is more prevalent in those over the age of 50 as there is a monoclonal protein (M-protein) present in 3% of those 50 and years older and 5% of those 70 years and older, placing those 50 and older at increased risk of MGRS.

Ciltacabtagene autoleucel, sold under the brand name Carvykti, is an anti-cancer medication used to treat multiple myeloma. Ciltacabtagene autoleucel is a BCMA -directed genetically modified autologous chimeric antigen receptor (CAR) T-cell therapy. Each dose is customized using the recipient's own T-cells, which are collected and genetically modified, and infused back into the recipient.

Teclistamab, sold under the brand name Tecvayli, is a human bispecific monoclonal antibody used for the treatment of relapsed and refractory multiple myeloma. It is a bispecific antibody that targets the CD3 receptor expressed on the surface of T-cells and B-cell maturation antigen (BCMA), which is expressed on the surface of malignant multiple myeloma B-lineage cells.

Talquetamab, sold under the brand name Talvey, is a humanized monoclonal antibody used for the treatment of multiple myeloma. It is a bispecific GPRC5D-directed CD3 T-cell engager. Talquetamab is a bispecific antibody against two targets: human CD3, a T-cell surface antigen, and human G-protein coupled receptor family C group 5 member D (GPRC5D), a tumor-associated antigen with potential antineoplastic activity. Talquetamab binds both targets, drawing the T cells close to the tumor cells, causing a cytotoxic T-lymphocyte response. It is being developed by Janssen Pharmaceuticals.

References

  1. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 9 April 2023.
  2. ↑ "Prescription medicines and biologicals: TGA annual summary 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 31 March 2024.
  3. ↑ "Health Canada New Drug Authorizations: 2016 Highlights". Health Canada . 14 March 2017. Retrieved 7 April 2024.
  4. ↑ "Darzalex- daratumumab injection, solution, concentrate Darzalex IV- daratumumab injection, solution, concentrate". DailyMed. Retrieved 18 December 2021.
  5. ↑ World Health Organization (2009). "International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 101" (PDF). WHO Drug Information. 23 (2). Archived from the original (PDF) on December 17, 2010.
  6. 1 2 Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, et al. (September 2015). "Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma". The New England Journal of Medicine. 373 (13): 1207–1219. doi: 10.1056/NEJMoa1506348 . hdl: 1874/331934 . PMID   26308596.
  7. ↑ "Janssen Biotech Announces Global License and Development Agreement for Investigational Anti-Cancer Agent Daratumumab". Janssen Biotech. Retrieved 2013-01-31.
  8. ↑ "Daratumumab Receives Breakthrough Therapy Designation from US Food and Drug Administration". Genmab A/S. 1 May 2013. Archived from the original on 2017-01-13. Retrieved 2017-01-10.
  9. ↑ "FDA approves Darzalex for newly diagnosed, transplant-ineligible multiple myeloma". www.healio.com. Retrieved 2018-05-08.
  10. ↑ Vincent L, Gras L, Ceballos P, Finke J, Passweg J, Harel S, et al. (March 2022). "Daratumumab after allogeneic hematopoietic cell transplantation for multiple myeloma is safe and synergies with pre-existing chronic graft versus host disease. A retrospective study from the CMWP EBMT" (PDF). Bone Marrow Transplantation. 57 (3): 499–501. doi:10.1038/s41409-021-01560-y. PMID   35013536. S2CID   245861546.
  11. ↑ "SUMMARY OF PRODUCT CHARACTERISTICS" (PDF). www.ema.europa.eu. Retrieved 2019-06-04.
  12. ↑ Nahi H, Chrobok M, Gran C, Lund J, Gruber A, Gahrton G, et al. (2019). "Infectious complications and NK cell depletion following daratumumab treatment of Multiple Myeloma". PLOS ONE. 14 (2): e0211927. Bibcode:2019PLoSO..1411927N. doi: 10.1371/journal.pone.0211927 . PMC   6374018 . PMID   30759167.
  13. ↑ Nakagawa R, Onishi Y, Kawajiri A, Onodera K, Furukawa E, Sano S, et al. (August 2019). "Preemptive therapy for cytomegalovirus reactivation after daratumumab-containing treatment in patients with relapsed and refractory multiple myeloma". Annals of Hematology. 98 (8): 1999–2001. doi:10.1007/s00277-019-03645-7. PMID   30824957. S2CID   71146150.
  14. ↑ Jain A, Ramasamy K (September 2020). "Evolving Role of Daratumumab: From Backbencher to Frontline Agent". Clinical Lymphoma, Myeloma & Leukemia. 20 (9): 572–587. doi:10.1016/j.clml.2020.03.010. PMID   32331971. S2CID   216131042.
  15. ↑ Chapuy CI, Nicholson RT, Aguad MD, Chapuy B, Laubach JP, Richardson PG, et al. (June 2015). "Resolving the daratumumab interference with blood compatibility testing". Transfusion. 55 (6 Pt 2): 1545–1554. doi: 10.1111/trf.13069 . PMID   25764134.
  16. ↑ Perincheri S, Torres R, Tormey CA, Smith BR, Rinder HM, Siddon AJ (2016-12-02). "Daratumumab Interferes with Flow Cytometric Evaluation of Multiple Myeloma". Blood. 128 (22): 5630. doi:10.1182/blood.V128.22.5630.5630. ISSN   0006-4971.
  17. ↑ Dhillon S (June 2020). "Isatuximab: First Approval". Drugs. 80 (9): 905–912. doi:10.1007/s40265-020-01311-1. PMID   32347476. S2CID   216597315.
  18. 1 2 Konen JM, Fradette JJ, Gibbons DL (December 2019). "The Good, the Bad and the Unknown of CD38 in the Metabolic Microenvironment and Immune Cell Functionality of Solid Tumors". Cells. 9 (1): 52. doi: 10.3390/cells9010052 . PMC   7016859 . PMID   31878283.
  19. ↑ Roccatello D, Fenoglio R, Sciascia S, Naretto C, Rossi D, Ferro M, et al. (June 2020). "CD38 and Anti-CD38 Monoclonal Antibodies in AL Amyloidosis: Targeting Plasma Cells and beyond". International Journal of Molecular Sciences. 21 (11): 4129. doi: 10.3390/ijms21114129 . PMC   7312896 . PMID   32531894.
  20. 1 2 "Daratumumab - Janssen Biotech - AdisInsight". adisinsight.springer.com.
  21. ↑ Mistry JJ, Moore JA, Kumar P, Marlein CR, Hellmich C, Pillinger G, et al. (February 2021). "Daratumumab inhibits acute myeloid leukaemia metabolic capacity by blocking mitochondrial transfer from mesenchymal stromal cells". Haematologica. 106 (2): 589–592. doi: 10.3324/haematol.2019.242974 . PMC   7849566 . PMID   32193250.
  22. 1 2 Martin TG, Corzo K, Chiron M, Velde HV, Abbadessa G, Campana F, et al. (November 2019). "Therapeutic Opportunities with Pharmacological Inhibition of CD38 with Isatuximab". Cells. 8 (12): 1522. doi: 10.3390/cells8121522 . PMC   6953105 . PMID   31779273.
  23. ↑ Nooka AK, Kaufman JL, Hofmeister CC, Joseph NS, Heffner TL, Gupta VA, et al. (July 2019). "Daratumumab in multiple myeloma". Cancer. 125 (14): 2364–2382. doi: 10.1002/cncr.32065 . PMID   30951198.
  24. ↑ Franssen LE, Stege CA, Zweegman S, van de Donk NW, Nijhof IS (April 2020). "Resistance Mechanisms Towards CD38-Directed Antibody Therapy in Multiple Myeloma". Journal of Clinical Medicine. 9 (4): 1195. doi: 10.3390/jcm9041195 . PMC   7230744 . PMID   32331242.
  25. ↑ "ASCO: Drug Shows Promise in Myeloma". MedPage Today.
  26. ↑ "Daratumumab Continues To Show Promise For Relapsed/Refractory Myeloma Patients (ASH 2012)". The Myeloma Beacon. Retrieved 2013-01-31.
  27. ↑ Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, et al. (October 2016). "Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma". The New England Journal of Medicine. 375 (14): 1319–1331. doi: 10.1056/NEJMoa1607751 . PMID   27705267.
  28. ↑ Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, et al. (August 2016). "Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma". The New England Journal of Medicine. 375 (8): 754–766. doi: 10.1056/NEJMoa1606038 . hdl: 11343/240283 . PMID   27557302.
  29. ↑ "Daratumumab Approved for Multiple Myeloma in US". Medscape.
  30. ↑ "Darzalex New FDA Drug Approval". CenterWatch. Archived from the original on 2019-08-05. Retrieved 2019-06-04.
  31. ↑ "Janssen's Single-Agent Darzalex (daratumumab) Approved by European Commission for Treatment of Multiple Myeloma (MM)" (Press release). 23 May 2016. Retrieved 2016-05-23– via Business Wire.
  32. ↑ "Daratumumab (Darzalex)". U.S. Food and Drug Administration (FDA). 9 February 2019.
  33. ↑ "An overview of Darzalex and why it is authorised in the EU" (PDF). www.ema.europa.eu. 2018. Retrieved 2019-06-04.
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