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].
参考文献:
[1]. Overdijk MB, Verploegen S, B?gels 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]。
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]。
| Cell experiment [1]: | |
|
Cell lines |
bone marrow mononuclear cells (BM-MNC) |
|
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. |
|
Reaction Conditions |
10 μg/mL for 48 hours |
|
Applications |
PF-07104091 inhibited T47D and KPL1 cells with IC50s of 0.785 and 0.603 μM, respectively. |
| Animal experiment [2]: | |
|
Animal models |
human multiple myeloma model in the RAG2-/-γc-/- mice |
|
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. |
|
Dosage form |
8 mg/kg on days 49 and 56. |
|
Applications |
Treatment with daratumumab alone suppressed the tumor growth significantly. And the combination of daratumumab plus lenalidomide was able to reduce the tumor volume. |
|
参考文献: [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. |
|
动态评分
0.0