Avelumab (Anti-Human PD-L1, Human Antibody; MSB 0010718C; MSB0010718C; trade name Bavencio) is a fully human IgG1 anti-PD-L1 monoclonal antibody with potential antibody-dependent cell-mediated cytotoxicity. It is developed by Merck KGaA and Pfize as a pharmaceutical drug for use in immunotherapy, originally for the treatment of non-small-cell lung carcinoma (NSCLC). Avelumab targets the protein programmed death-ligand 1 (PD-L1). It has received orphan drug designation by the European Medicines Agency (EMA) for the treatment of gastric cancer in January 2017. The US Food and Drug Administration (FDA) approved it in March 2017 for Merkel-cell carcinoma, an aggressive type of skin cancer. The EMA approved it in September 2017 for the same indication
理化性质和储存条件
| In vitro |
Avelumab is a fully human IgG1 anti-PD-L1 monoclonal antibody with potential antibody-dependent cell-mediated cytotoxicity property. Avelumab increases NK-cell lysis 3.1-fold (P=0.01) in JHC7 cells relative to isotype control. When the cells are treated with IFN-γ, Avelumab markedly enhances NK-cell lysis relative to isotype control in the following cell lines: JHC7 (7.56-fold; P=0.001), UM-Chor1 (7.34-fold; P<0.001), U-CH2 (2.6 fold; P=0.008), MUG-Chor1 (8.38-fold; P=0.0016). Avelumab effectively increases antibody-dependent cell-mediated cytotoxicity (ADCC) of both the non-cancer stem cell (CSC) and CSC subpopulations to the same degree[1]. Results also demonstrate that the addition of Avelumab increases the frequency of antigen-specific multifunctional CD8+ T cells by more than fivefold, relative to the isotype control in CEFT-stimulated peripheral blood mononuclear cells (PBMCs). |
| In Vivo |
Measurement of individual tumors clearly shows a slowing of tumor growth in the Avelumab-treated mice. By day 36 post-tumor implantation, there is a significant (P<0.01) reduction in the average tumor volume of the Avelumab-treated mice. Reduction in MB49 tumor growth in the mice treated with Avelumab is durable and leads to a significant (P<0.05) improvement in percent survival. Avelumab treatment of 10 mice with bladder tumors results in complete tumor regression in 8 mice, confirmed by histopathology. However, in mice depleted of either CD4 or CD8 cells, Avelumab treatment is much less effective in controlling bladder tumor burden with tumor breakthrough occurring in a higher frequency in mice depleted of CD4 T cells. |
| Protocol |
Cell Assay: To examine the relationship between a cancer stem cell (CSC) subpopulation and antibody-dependent cell-mediated cytotoxicity (ADCC) activity, UM-Chor1 cells are left untreated or treated with 50 ng/mL of IFN-γ for 24 h. Cells are then plated as targets at 50,000 cells/well in 6-well round-bottom culture plates and incubated with 2 μg/mL of Avelumab at room temperature for 30 min. NK cells are added at 2500,000 cells/well at an effector-to-target (E:T) ratio of 50:1. After 4 h, tumor cells are harvested and stained with antibodies for flow cytometry.
Animal Studies: Female C57BL/6 mice are used in this study. Subcutaneous tumor injections are carried out by inoculating C57BL/6 mice with 1×105 MB49 parental cells on the right shaved flank. Tumor growth is measured with calipers and 8 days post-inoculation mice are assigned to treatment groups. Tumor-bearing mice are treated with Avelumab (400 μg per 100 μL) and injected i.p. three times, 3 days apart. Since Avelumab is a human IgG1, three injections have to be compressed within a 7 to 9 day window (i.e., days 9, 12, and 15 post-tumor inoculation) to avoid the onset of neutralizing mouse anti-human Ig. |
| References |
Oncotarget. 2016 Jun 7;7(23):33498-511.; Clin Transl Immunology. 2016 May 20;5(5):e83.; Cancer Immunol Res. 2016 May;4(5):452-62. |
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