More than 95% of B-precursor ALL cells express CD19 on the leukemic cell surface [12]. Blinatumomab binds to both CD19 on the leukemic cell and to CD3 on T cells, thereby engaging T cells with CD19+ target leukemic cells and inducing cell toxicity. Blinatumomab can bind and activate both CD3 + CD4+ T cells and CD3 + CD8+ T cells. Because the activity of blinatumomab does not depend on the specificity of the T-cell receptor and does not require antigen presentation by major histocompatibility complex, leukemic cells are killed by polyclonal T cells [13]. Blinatumomab has two major effects on the T cell that is connected with the CD19+ leukemic cell through blinatumomab. The first effect is direct activation of the connected T cell, resulting in upregulation of the T-cell activation markers CD25, CD69, CD2, interferon (IFN)-γ, tumor necrosis factor (TNT)-α, interleukin (IL)-2, IL-6, and IL-10. The activated T cell then induces perforin-mediated cytotoxicity via granzyme entry into the CD19-positive leukemic cell. This leads to caspase activation and apoptosis of the CD19-positive leukemic cell. This effect is stronger in CD8-positive T cells than in CD4-positive T cells. The second effect is marked T-cell proliferation, leading to a supply of blinatumomab-activated T cells and serial killing of the CD19-positive target leukemic cells [14] (Fig. 8.2). This proliferation and serial killing of leukemic cells may be the reason why blinatumomab is effective for fully relapsed B-precursor ALL patients, who have so many target CD19-positive leukemic cells compared to the number of T cells. T-cell killing of CD19-positive leukemic cells and activated T-cell proliferation continue for as long as the T cell can make an immune synapse with a CD19-positive leukemic cell via blinatumomab, and they expire following elimination of the CD19-positive leukemic cell. By redirecting unstimulated human T cells to CD19-positive target cells, blinatumomab shows significant cytotoxicity at concentrations of 10–100 pg/ml [9]. This concentration is about 100 times lower than that of rituximab, which shows cytotoxicity at a concentration of 2 μg/ml [15]. In the presence of blinatumomab, the effecter-to-target ratio of the blinatumomab-activated T cell and the CD19-positive target cell is as low as 2:1, which is very low compared with other immunotherapies [9].

The serum half-life (t1/2) of blinatumomab is very short compared with that of a traditional monoclonal antibody such as rituximab, because blinatumomab lacks the Fc region of an antibody. The average t1/2 of blinatumomab and rituximab is 1.25 h and 76.3 h, respectively [14, 16]. This short t1/2 is the reason why continuous intravenous (CIV) administration of blinatumomab is needed, whereas traditional monoclonal antibodies are administered intermittently. The systemic clearance is not affected by creatinine clearance, age, gender, weight, or body surface area [14]. A phase 1 trial of blinatumomab was carried out for 38 patients with relapsed/refractory non-Hodgkin lymphoma. In this trial, blinatumomab was given as CIV administration, using doses ranging from 5 to 60 μg/m² over a period of 4–6 weeks. This trial indicated that the maximum tolerated dose was 60 μg/m² and that the majority of tumor responses were seen during the first 4 weeks [17]. In the cases of patients who received 15 μg/m² of blinatumomab given as CIV administration, its serum concentration reached steady state within a day, and the steady-state concentration was 731 ± 163 pg/ml (mean ± SD; range: 492–1050 pg/ml) [14]. In vitro analysis, a cytolytic effect of blinatumomab was observed at concentrations between 10 and 100 pg/ml [9]. In this phase 1 study, tumor regression was observed in patients who were treated with 5 μg/m² of blinatumomab given as CIV administration [17]. Based on these results, it was recommended that blinatumomab should be given by CIV administration at a dose greater than 15 μg/m² for 4 weeks, with a 2-week rest between cycles.