Bispecific antibodies: design, therapy, perspectives

Sedykh, Sergey E; Prinz, Victor V; Buneva, Valentina N; Nevinsky, Georgy A

The drug blinatumomab (Amgen) is the first representative of bispecific T-cell engagers (BiTEs) authorized for use in the US. The efficacy of blinatumomab as a therapeutic drug against B-cell tumors was first shown in 2008 in 38 patients with refractory non-Hodgkin's lymphoma, 19 and the results of other preclinical and clinical studies have been published in a number of works. [20] [21] [22] [23] At the end of 2014, the US Food and Drug Administration approved the treatment with blinatumomab of acute lymphoblastic leukemia without the Philadelphia chromosome as a second-line drug. 24 In the EU, the drug was registered in 2015. Therapy with blinatumomab leads to the depletion of B lymphocytes and precursors in peripheral blood, which is gradually restored after the end of treatment. 19 The bispecific blinatumomab molecule has been developed using diabody technology: the first antigen-binding site is directed against a CD19 protein on the surface of B lymphocytes, the second against the CD3 receptor on the surface of cytotoxic T lymphocytes ( Figure 1 ). The singlestranded structure of blinatumomab allows easy protein expression in monomeric form in significant amounts and provides broad therapeutic potential for use in lymphoma and leukemia. 25 Unfortunately, this feature is the reason continuous intravenous administration of the drug is required. The blinatumomab molecule directs primary CD3 + T cells against CD19 + lymphoma cells, and provides cytotoxicity at very low concentrations (~10-100 pg/mL). 26 The direction of cytotoxic T lymphocytes to tumor B cells, bypassing T-cell receptors and major histocompatibility complex, is a significant advantage of the drug. 27 Blinatumomab increases the secretion of anti-inflammatory cytokines (IL2, IL4, IL6, IL10, IFNγ, TNFα). 26 Data from animal models also confirm the high efficacy of blinatumomab against tumor cells in leukemia and lymphoma at very low concentrations. 26, 28 Blinatumomab therapy in adult patients with recurrent acute lymphoblastic leukemia leads to entirely positive results in 72%, achievement of minimal residual disease (tumor cells remaining in the organism after remission) in 88%, and average life expectancy after therapy of 9 months. 21 Therapy for non-Hodgkin's lymphoma with blinatumomab also shows good efficacy: in monotherapy clinical trials, blinatumomab significantly exceeded the effect of mAb therapy at much-lower final blood concentrations. 22 Treatment of non-Hodgkin's lymphoma patients with blinatumomab results in minimal residual disease, even after induction and consolidation, 20 but clinical trials are still under way. In refractory and recurrent acute lymphoblastic leukemia in cases of CD19 absence on the lymphocyte surface and extramedullary hematopoiesis (formation of lymphocytes outside the bone marrow), therapy with blinatumomab is ineffective. 29 After initiation of blinatumomab administration, the number of B lymphocytes decreases to under one cell/μL for 2 days and remains virtually undetectable until the end of therapy. On the contrary, the number of T lymphocytes lowers in all patients to a minimum level for 1 day and is then restored to normal within a few days. Moreover, within 2-3 weeks, the number of T cells doubles in most patients, dominated by an expansion of memory T cells expressing CD45RA. This can be explained by differences in signaling pathways used by memory T cells and naïve T cells. 30 Rapid removal of blinatumomab from the bloodstre