Daratumumab

Daratumumab, sold under the brand name Darzalex, is an anti-cancer medication. It binds to CD38,[1] which multiple myeloma cells overexpress.[2] 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.[3]

Daratumumab
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetCD38
Clinical data
Trade namesDarzalex
AHFS/Drugs.comMonograph
MedlinePlusa616002
License data
Pregnancy
category
  • AU: C
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
  • EU: Rx-only
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC6466H9996N1724O2010S42
Molar mass145391.67 g·mol−1
 NY (what is this?)  (verify)

Daratumumab was given breakthrough therapy drug status in 2013, for multiple myeloma. It was awarded orphan drug status for multiple myeloma, diffuse large B cell lymphoma, follicular lymphoma, and mantle cell lymphoma.[4]

Medical uses

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.[5][6] In May 2016 daratumumab was also conditionally approved by the European Medicines Agency for treatment of multiple myeloma.[7]

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.[8]

In May 2018, the FDA expanded the approval of 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]

The European Commission granted a marketing authorisation on 20 May 2016.[10]

In the European Union 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.[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

Interference 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.

Interaction 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.[2]

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]

References
  1. World Health Organization (2009). "International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 101" (PDF). WHO Drug Information. 23 (2).
  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): 1207–19. doi:10.1056/NEJMoa1506348. hdl:1874/331934. PMID 26308596.
  3. "Janssen Biotech Announces Global License and Development Agreement for Investigational Anti-Cancer Agent Daratumumab". Janssen Biotech. Retrieved 2013-01-31.
  4. "Archived copy". Archived from the original on 2017-01-13. Retrieved 2017-01-10.CS1 maint: archived copy as title (link)
  5. "Daratumumab Approved for Multiple Myeloma in US". Medscape.
  6. "Darzalex New FDA Drug Approval". CenterWatch.
  7. "Janssen's Single-Agent Darzalex (daratumumab) Approved by European Commission for Treatment of Multiple Myeloma (MM)". Retrieved 2016-05-23 – via Business Wire.
  8. "Daratumumab (Darzalex)". U.S. Food and Drug Administration (FDA). 9 February 2019.
  9. "FDA approves Darzalex for newly diagnosed, transplant-ineligible multiple myeloma". www.healio.com. Retrieved 2018-05-08.
  10. "An overview of Darzalex and why it is authorised in the EU" (PDF). www.ema.europa.eu. 2018. Retrieved 2019-06-04.
  11. "SUMMARY OF PRODUCT CHARACTERISTICS" (PDF). www.ema.europa.eu. Retrieved 2019-06-04.
  12. Nahi H, Chrobok M, Gran C, Lund J (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 (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 (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.
  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): 1545–54. doi:10.1111/trf.13069. PMID 25764134.
  16. Perincheri, Sudhir; Torres, Richard; Tormey, Christopher A.; Smith, Brian R.; Rinder, Henry M.; Siddon, Alexa J. (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 (2020). "Isatuximab: First Approval". Drugs. 80 (9): 905–912. doi:10.1007/s40265-020-01311-1. PMID 32347476. S2CID 216597315.
  18. Konen JM, Fradette JJ, Gibbons DL (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 (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. "Daratumumab - Janssen Biotech - AdisInsight". adisinsight.springer.com.
  21. Mistry, Jayna J; Moore, Jamie A; Kumar, Prakritt; Marlein, Christopher R; Hellmich, Charlotte; Pillinger, Genevra; Jibril, Aisha; Di Palma, Federica; Collins, Angela; Bowles, Kristian M; Rushworth, Stuart A (19 March 2020). "Daratumumab inhibits acute myeloid leukaemia metabolic capacity by blocking mitochondrial transfer from mesenchymal stromal cells". Haematologica: haematol.2019.242974. doi:10.3324/haematol.2019.242974. PMID 32193250.
  22. Martin TG, Corzo K, Chiron M (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 (2019). "Daratumumab in multiple myeloma". Cancer. 125 (14): 2364–2382. doi:10.1002/cncr.32065. PMID 30951198.
  24. Franssen LE, Stege CA, Zweegman S (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. (2016). "Daratumumab, lenalidomide, and dexamethasone for multiple myeloma". 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. (2016). "Daratumumab, bortezomib, and dexamethasone for multiple myeloma". New England Journal of Medicine. 375 (8): 754–766. doi:10.1056/NEJMoa1606038. PMID 27557302.
  • "Daratumumab". Drug Information Portal. U.S. National Library of Medicine.
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