Enzyme Kinetics and Drugs as Enzyme Inhibitors
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
Elotuzumab and daratumumab are two relatively new mAbs approved by the FDA in 2015 for treatment of patients with relapsed or refractory MM. Elotuzumab targets directly the glycoprotein receptor SLAMF7 (Signalling Lymphocyte Activation Molecule Family Member 7) that is overexpressed on the surface of myeloma and NK cells but is not found on normal cells. It exerts a dual effect in that it activates NK cells directly and also mediates antibody-dependent cell-mediated cytotoxicity (ADCC) by recruiting activated NK cells on MM cells (Lonial et al., 2015). Daratumumab is a human anti-CD38 IgG1 (κ subclass) antibody. It targets the protein CD38 (also an enzyme that catalyzes the metabolism of cyclic adenosine diphosphate ribose and nicotinic acid adenine dinucleotide phosphate) that is overexpressed on multiple myeloma cells and also expressed on many types of immune cells. Its antimyeloma effect mainly relies on its prominent ADCC and complement-dependent cytotoxicity (CDC) activities (Phipps et al., 2015). This topic is discussed in more detail in Section 21.2.3.4.3.
Plasma Cell Neoplasms
Tariq I. Mughal in Precision Haematological Cancer Medicine, 2018
The licensing of the first monoclonal antibody, as a monotherapy for the treatment of relapsed-and-refractory myeloma, daratumumab, which targets CD38, an antigen uniformly expressed in all myeloma cells, has generally been considered to be a breakthrough. The antibody when used as a single agent in patients who have had at least three previous treatments, accorded about 30% responses rates and a survival benefit. This remarkable activity appears to be arise from the drug, triggering long-term memory T-cell function, and the associated anti-MM immunity, by targeting the CD38 immunosuppressive cells. This is unprecedented in patients with relapsed-and-refractory disease, and there is much enthusiasm to test the agent in first-line setting in combination with a chemotherapy-free regimen. The challenge in the first-line use is of course formidable, given an overall survival of about 88% at 3 years with VRD. A second monoclonal antibody, elotuzumab, which targets the signalling lymphocytic activation molecule F7 (SLAMF7) has also been approved for use as a combination for relapsed-and-refractory myeloma. Panobinostat, a deacetylase inhibitor, is also licensed for this indication, and in a randomized trial in combination with VD had a longer progression-free survival and more near or complete responses, compared to VD plus placebo. The principal side effect appears to be grade 3 diarrhoea, which occurs in about a quarter of all patients.
Antibody-Based Therapies
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
Daratumumab (Darzalex™) is a first-in-class humanized IgG1 antibody targeting the CD38 epitope. It is used for the treatment of multiple myeloma and non-Hodgkin’s lymphomas. CD38 is expressed on multiple immune system cell types, and is highly expressed in hematological malignancies, including multiple myeloma. Daratumumab was approved in the USA in 2015 for patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent. The US FDA granted breakthrough therapy designation to daratumumab in 2013, and approval in 2015 was made via the agency’s accelerated approval program. In 2018, the FDA expanded the approval of daratumumab for use in combination with bortezomib, melphalan, and prednisone to include the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.
Long-term storage protocol of reagent red blood cells treated with 0.01M dithiothreitol (DTT) for pre-transfusion testing of patients receiving anti-CD38 therapy, daratumumab
Published in Hematology, 2023
Yuyuan Li, Chengyao Li, Ling Zhang, Jiao Li, Qixin Li, Haining Ouyang, Jiaona Luo, Linrui Zhu, Kui Cai
In conclusion, daratumumab is increasingly being used in the therapy of patients with relapsed and refractory multiple myeloma [18]. This study provides transfusion departments and blood banks with a storage protocol of reagent RBCs for the pre-transfusion examinations of patients treated with daratumumab. This protocol enables stable storage of DTT-treated reagent RBCs for 18 days without affecting the detection of most antibodies, which is significantly better than other current treatment methods. In clinical applications, it can guarantee that patients receive safe, timely, and effective blood transfusion treatment. And as alloantibodies can be rapidly detected, current expert recommendations such as phenotyping and genotyping of patients’ RBCs prior to the daratumumab therapy and the provision of phenotype-matching or K-negative RBCs may be unnecessary [6–8, 17]. Hosokawa named his research protocol the ‘Osaka method’, and similarly, our group named the described protocol the ‘Foshan method’.
The pharmacologic management of multiple myeloma in older adults
Published in Expert Opinion on Pharmacotherapy, 2019
Jessica L. Dempsey, Andrew Johns, Ashley E. Rosko, Hillard M. Lazarus
Daratumumab is a CD38-targeted monoclonal antibody that causes myeloma cell death through a variety of immune-mediated mechanisms [102]. As previously discussed, daratumumab recently was approved to be administered in combination with VMP in the frontline setting in patients unable to receive an AHCT [39]. It is difficult to identify how approval of this will effect treatment decisions in the United States as VMP is not common as an initial treatment in older adult patients. In the relapsed, refractory disease setting, daratumumab currently is approved to be administered as monotherapy with dexamethasone or in combination with bortezomib, lenalidomide or pomalidomide [56,103,104]. Daratumumab is well-tolerated with infusion-related reactions during the first infusion being the most significant toxicity. Daratumumab may interfere with identification of antibodies during the blood product crossmatch process. Thus, clear communication between the provider and blood bank are crucial so proper steps to account for this interference, such as treatment of patient blood samples with dithiothreitol can be undertaken [105].
The safety of current and emerging therapies for multiple myeloma
Published in Expert Opinion on Drug Safety, 2020
Omar Nadeem, Kenneth C. Anderson
Daratumumab is given as an intravenous infusion typically on a weekly basis for the first 2 months, followed by biweekly administration for 4 months, and then monthly until progression or unacceptable toxicity (Table 3). The first infusion of daratumumab is given at a slow rate to avoid infusion-related reactions, which have been observed are in up to 50% of patients, mostly grade 1 or 2 in nature. Premedication regimens consisting of corticosteroids (methylprednisolone or dexamethasone), acetaminophen, and an antihistamine given 1–3 h prior to the infusion can abrogate these reactions. Montelukast use is encouraged, as it has shown to reduce the risk of IRR. Delayed infusion reactions are occasionally seen after the first two infusions, prompting corticosteroid use on the day after the infusion. The risk of IRR after the first two infusions is low. Other adverse events associated with daratumumab include infections (20%, mostly sinopulmonary in nature), fatigue, and fever. Hematologic toxicity is noted including lymphopenia, neutropenia, and thrombocytopenia in 72%, 60%, and 48%, respectively; as well as depletion of normal immunoglobulins, especially in patients on long-term therapy.
Related Knowledge Centers
- Cd38
- Follicular Lymphoma
- Innate Immune System
- Mantle Cell Lymphoma
- Monoclonal Antibody
- Natural Killer Cell
- Orphan Drug
- Multiple Myeloma
- Breakthrough Therapy
- Diffuse Large B-Cell Lymphoma