Daratumumab
(Synonyms: 达雷木单抗; Anti-Human CD38, Human Antibody) 目录号 : GC19785
Daratumumab (DARA) 是一种靶向 CD38 的人 IgG1 mAb，CD38 是一种 46-kDa II 型跨膜糖蛋白，在多发性骨髓瘤 (MM) 的恶性细胞上高水平表达 。
Cas No.:945721-28-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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Purity: >98.00%
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- Datasheet
| Cell experiment [1]: | |
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Cell lines |
bone marrow mononuclear cells (BM-MNC) |
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Preparation Method |
Freshly isolated BM-MNCs, containing 2% to 35% malignant plasma cells as determined by flow cytometry, were immediately used in ex vivo experiments. The BM-MNCs, containing the malignant plasma cells, as well as the patient's own effector cells, were incubated with daratumumab (10 µg/mL), lenalidomide (3 µmol/L), and bortezomib (3 nmol/L) alone or in combination in RPMI + 10% FBS in 96-well round bottom plates in fully humified incubators at 37°C, 5% CO2-air mixture for 48 hours. The survival of primary CD138+ multiple myeloma cells was determined by flow cytometry. |
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Reaction Conditions |
10 µg/mL for 48 hours |
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Applications |
PF-07104091 inhibited T47D and KPL1 cells with IC50s of 0.785 and 0.603 µM, respectively. |
| Animal experiment [2]: | |
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Animal models |
human multiple myeloma model in the RAG2-/-γc-/- mice |
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Preparation Method |
A humanized microenvironment was generated in mice by subcutaneous implantation of ceramic scaffolds that were seeded with human MSC (2 × 105 cells/scaffold) and in vitro cultured for 7 days in osteogenic medium, containing ascorbic acid and dexamethasone. Eight weeks after implantation, mice received a sublethal irradiation dose (3 Gy, 200 kV, 4 mA) and luciferase-gene-marked primary multiple myeloma cells were injected directly into the scaffolds (1 × 106 cells/scaffold). Luciferase transduction of primary multiple myeloma cells was carried out using the lentiviral construct pRRL-cPPT-CMV-Luc2-IRES-GFP-PRE-SIN. When tumors became clearly detectable, mice were distributed over the following treatment groups: (i) control, (ii) T-cell depleted PBMC (PBMC-T), (iii) PBMC-T plus lenalidomide, (iv) PBMC-T plus daratumumab, and (v) PBMC-T plus lenalidomide plus daratumumab. Lenalidomide (1 mg/kg) was given in 5 days on 2 days off schedule for 2 weeks (days 49-53 and 56-60) and both daratumumab (8 mg/kg) and PBMC-T (8 × 106 cells/mouse) were given on days 49 and 56. |
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Dosage form |
8 mg/kg on days 49 and 56. |
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Applications |
Treatment with daratumumab alone suppressed the tumor growth significantly. And the combination of daratumumab plus lenalidomide was able to reduce the tumor volume. |
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References: [1]: Nijhof IS, Groen RW, Noort WA, van Kessel B, de Jong-Korlaar R, Bakker J, Van Bueren JJ, Parren PW, Lokhorst HM, Van De Donk NW, Martens AC. Preclinical evidence for the therapeutic potential of CD38-targeted immuno-chemotherapy in multiple myeloma patients refractory to lenalidomide and bortezomib. Clinical cancer research. 2015 Jun 15;21(12):2802-10. |
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Daratumumab (DARA) is a human IgG1 mAb targeting CD38, a 46-kDa type II transmembrane glycoprotein that is expressed at high levels on malignant cells in multiple myeloma (MM) [1,2].
Daratumumab elicits cell death through complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), induction of apoptosis, and modulation of CD38 enzyme activities [1]. Macrophages to engulf multiple Daratumumab -opsonized target cells in a relatively short time span with a time-lapse imaging microscopy [1]. Daratumumab -dependent phagocytosis is related to CD38 expression levels, uptake into macrophages and substantial elimination of target cells was consistently observed for CD38-transduced UM9-CD38 and L363-CD38 variants with high levels of CD38 expression [1].
Phagocytosis contributed to the antitumor activity of daratumumab in vivo in 2 different xenograft models: subcutaneous Daudi-luc tumor xenograft model and intravenous leukemic Daudi-luc xenograft model [1]. Daratumumab (8 mg/kg, twice) alone suppressed the tumor growth significantly. And the combination of daratumumab plus lenalidomide was able to reduce the tumor volume [3].
References:
[1]. Overdijk MB, Verploegen S, BÖgels M, van Egmond M, van Bueren JJ, Mutis T, Groen RW, Breij E, Martens AC, Bleeker WK, Parren PW. Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. InMAbs 2015 Mar 4 (Vol. 7, No. 2, pp. 311-320). Taylor & Francis.
[2]. Nooka AK, Kaufman JL, Hofmeister CC, Joseph NS, Heffner TL, Gupta VA, Sullivan HC, Neish AS, Dhodapkar MV, Lonial S. Daratumumab in multiple myeloma. Cancer. 2019 Jul 15;125(14):2364-82.
[3]. Nijhof IS, Groen RW, Noort WA, van Kessel B, de Jong-Korlaar R, Bakker J, Van Bueren JJ, Parren PW, Lokhorst HM, Van De Donk NW, Martens AC. Preclinical evidence for the therapeutic potential of CD38-targeted immuno-chemotherapy in multiple myeloma patients refractory to lenalidomide and bortezomib. Clinical cancer research. 2015 Jun 15;21(12):2802-10.
Daratumumab (DARA) 是一种靶向 CD38 的人 IgG1 mAb，CD38 是一种 46-kDa II 型跨膜糖蛋白，在多发性骨髓瘤 (MM) 的恶性细胞上高水平表达 [1,2]。
<p >Daratumumab 通过补体依赖性细胞毒性 (CDC)、抗体依赖性细胞介导的细胞毒性 (ADCC)、抗体依赖性细胞吞噬作用 (ADCP)、细胞凋亡诱导和 CD38 酶活性调节引起细胞死亡 [1] 。使用延时成像显微镜，巨噬细胞在相对较短的时间内吞噬多个 Daratumumab 调理的靶细胞 [1]。 Daratumumab 依赖性吞噬作用与 CD38 表达水平相关，对于具有高 CD38 表达水平的 CD38 转导的 UM9-CD38 和 L363-CD38 变体，一致观察到巨噬细胞摄取和靶细胞的大量消除[1]。
吞噬作用有助于 daratumumab 在 2 种不同异种移植模型中的体内抗肿瘤活性:皮下 Daudi-luc 肿瘤异种移植模型和静脉内白血病 Daudi-luc 异种移植模型[1]。 Daratumumab（8 mg/kg，两次）单独显着抑制肿瘤生长。而daratumumab联合来那度胺能够缩小肿瘤体积[3]。
| Cas No. | 945721-28-8 | SDF | |
| 别名 | 达雷木单抗; Anti-Human CD38, Human Antibody | ||
| 分子式 | 分子量 | ||
| 溶解度 | Soluble in water | 储存条件 | Store at -30℃ |
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Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis
Background: Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease. Methods: We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response. Results: A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P<0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P = 0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy. Conclusions: Among patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.).
Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma
Background: Daratumumab, a human IgG百 monoclonal antibody that targets CD38, induces direct and indirect antimyeloma activity and has shown substantial efficacy as monotherapy in heavily pretreated patients with multiple myeloma, as well as in combination with bortezomib in patients with newly diagnosed multiple myeloma.
Methods: In this phase 3 trial, we randomly assigned 498 patients with relapsed or relapsed and refractory multiple myeloma to receive bortezomib (1.3 mg per square meter of body-surface area) and dexamethasone (20 mg) alone (control group) or in combination with daratumumab (16 mg per kilogram of body weight) (daratumumab group). The primary end point was progression-free survival.
Results: A prespecified interim analysis showed that the rate of progression-free survival was significantly higher in the daratumumab group than in the control group; the 12-month rate of progression-free survival was 60.7% in the daratumumab group versus 26.9% in the control group. After a median follow-up period of 7.4 months, the median progression-free survival was not reached in the daratumumab group and was 7.2 months in the control group (hazard ratio for progression or death with daratumumab vs. control, 0.39; 95% confidence interval, 0.28 to 0.53; P<0.001). The rate of overall response was higher in the daratumumab group than in the control group (82.9% vs. 63.2%, P<0.001), as were the rates of very good partial response or better (59.2% vs. 29.1%, P<0.001) and complete response or better (19.2% vs. 9.0%, P=0.001). Three of the most common grade 3 or 4 adverse events reported in the daratumumab group and the control group were thrombocytopenia (45.3% and 32.9%, respectively), anemia (14.4% and 16.0%, respectively), and neutropenia (12.8% and 4.2%, respectively). Infusion-related reactions that were associated with daratumumab treatment were reported in 45.3% of the patients in the daratumumab group; these reactions were mostly grade 1 or 2 (grade 3 in 8.6% of the patients), and in 98.2% of these patients, they occurred during the first infusion.
Conclusions: Among patients with relapsed or relapsed and refractory multiple myeloma, daratumumab in combination with bortezomib and dexamethasone resulted in significantly longer progression-free survival than bortezomib and dexamethasone alone and was associated with infusion-related reactions and higher rates of thrombocytopenia and neutropenia than bortezomib and dexamethasone alone. (Funded by Janssen Research and Development; ClinicalTrials.gov number, NCT02136134.).
Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma
Background: Lenalidomide plus dexamethasone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. We sought to determine whether the addition of daratumumab would significantly reduce the risk of disease progression or death in this population.
Methods: We randomly assigned 737 patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation to receive daratumumab plus lenalidomide and dexamethasone (daratumumab group) or lenalidomide and dexamethasone alone (control group). Treatment was to continue until the occurrence of disease progression or unacceptable side effects. The primary end point was progression-free survival.
Results: At a median follow-up of 28.0 months, disease progression or death had occurred in 240 patients (97 of 368 patients [26.4%] in the daratumumab group and 143 of 369 patients [38.8%] in the control group). The estimated percentage of patients who were alive without disease progression at 30 months was 70.6% (95% confidence interval [CI], 65.0 to 75.4) in the daratumumab group and 55.6% (95% CI, 49.5 to 61.3) in the control group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.43 to 0.73; P<0.001). The percentage of patients with a complete response or better was 47.6% in the daratumumab group and 24.9% in the control group (P<0.001). A total of 24.2% of the patients in the daratumumab group, as compared with 7.3% of the patients in the control group, had results below the threshold for minimal residual disease (1 tumor cell per 105 white cells) (P<0.001). The most common adverse events of grade 3 or 4 were neutropenia (50.0% in the daratumumab group vs. 35.3% in the control group), anemia (11.8% vs. 19.7%), lymphopenia (15.1% vs. 10.7%), and pneumonia (13.7% vs. 7.9%).
Conclusions: Among patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation, the risk of disease progression or death was significantly lower among those who received daratumumab plus lenalidomide and dexamethasone than among those who received lenalidomide and dexamethasone alone. A higher incidence of neutropenia and pneumonia was observed in the daratumumab group. (Funded by Janssen Research and Development; MAIA ClinicalTrials.gov number, NCT02252172.).
Daratumumab for the treatment of multiple myeloma
Since its initial approval in 2015, daratumumab has had a tremendous impact on the treatment of multiple myeloma. It is a monoclonal antibody that targets CD38, an antigen with high surface expression on multiple myeloma cells. While it initially received approval as a monotherapy for multiply relapsed multiple myeloma, its favorable toxicity profile allowed for combinations with other novel myeloma therapies leading to numerous indications as a component of triplet and quadruplet regimens. These indications now span relapsed/refractory populations and both transplant-eligible and transplant-ineligible patients with newly diagnosed myeloma. Further investigations are underway to continue to expand the reach of daratumumab, including large phase III collaborative trials to assess the efficacy of daratumumab as part of post-transplant maintenance and its impact on smoldering myeloma. The recent introduction of a subcutaneous formulation of daratumumab with proven noninferiority will improve the convenience and accessibility of the drug. In this review, we examine the preclinical development of daratumumab, its pharmacology and clinical investigations that demonstrated its safety and efficacy. Furthermore, we discuss the outstanding questions related to daratumumab and ongoing clinical trials seeking to answer them.
Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma
Background: Daratumumab showed promising efficacy alone and with lenalidomide and dexamethasone in a phase 1-2 study involving patients with relapsed or refractory multiple myeloma.
Methods: In this phase 3 trial, we randomly assigned 569 patients with multiple myeloma who had received one or more previous lines of therapy to receive lenalidomide and dexamethasone either alone (control group) or in combination with daratumumab (daratumumab group). The primary end point was progression-free survival.
Results: At a median follow-up of 13.5 months in a protocol-specified interim analysis, 169 events of disease progression or death were observed (in 53 of 286 patients [18.5%] in the daratumumab group vs. 116 of 283 [41.0%] in the control group; hazard ratio, 0.37; 95% confidence interval [CI], 0.27 to 0.52; P<0.001 by stratified log-rank test). The Kaplan-Meier rate of progression-free survival at 12 months was 83.2% (95% CI, 78.3 to 87.2) in the daratumumab group, as compared with 60.1% (95% CI, 54.0 to 65.7) in the control group. A significantly higher rate of overall response was observed in the daratumumab group than in the control group (92.9% vs. 76.4%, P<0.001), as was a higher rate of complete response or better (43.1% vs. 19.2%, P<0.001). In the daratumumab group, 22.4% of the patients had results below the threshold for minimal residual disease (1 tumor cell per 105 white cells), as compared with 4.6% of those in the control group (P<0.001); results below the threshold for minimal residual disease were associated with improved outcomes. The most common adverse events of grade 3 or 4 during treatment were neutropenia (in 51.9% of the patients in the daratumumab group vs. 37.0% of those in the control group), thrombocytopenia (in 12.7% vs. 13.5%), and anemia (in 12.4% vs. 19.6%). Daratumumab-associated infusion-related reactions occurred in 47.7% of the patients and were mostly of grade 1 or 2.
Conclusions: The addition of daratumumab to lenalidomide and dexamethasone significantly lengthened progression-free survival among patients with relapsed or refractory multiple myeloma. Daratumumab was associated with infusion-related reactions and a higher rate of neutropenia than the control therapy. (Funded by Janssen Research and Development; POLLUX ClinicalTrials.gov number, NCT02076009 .).