Blinatumomab: a Bispecific CD19-Directed CD3 T-Cell Engager

Blinatumomab (derived from “B-lineage–specific antitumor mouse monoclonal antibody”) is a bispecific CD19-directed CD3 T-cell engaging antibody that binds to^1-3:

• CD19 (expressed on the surface of cells of B-lineage origin)
• CD3 (expressed on the surface of T cells).

More than 90% of cases of B-cell precursor acute lymphoblastic leukemia (ALL) express CD19 in more than 20% of malignant cells, the intensity of expression being sufficient to make this therapy suitable in ALL.⁴

Blinatumomab activates endogenous T cells by connecting CD3 in the T-cell receptor (TCR) complex with CD19 on benign and malignant B cells (Figure).^1,3 The nonimmunogenic linker protein that binds the anti-CD19 and anti-CD3 antibodies enables a great degree of rotational flexibility, which allows for close proximity of malignant CD19-positive B cells to CD3-positive T cells, favoring direct lysis.⁴



Furthermore, blinatumomab-activated T cells are capable of serial killing of the CD19-positive target cells. One hypothesis for this serial lysis lies in the preferential binding of CD19 compared with CD3, which potentially allows the T cells to be released from the target cells, enabling them to bind to additional target B cells. The T-cell proliferation and the serial killing of CD19-positive B cells induced by blinatumomab explain why this monoclonal antibody is also effective in patients with a limited number of T cells due to prior intensive therapy or early after hematopoietic stem cell transplantation.^5-9

Thus, blinatumomab mediates¹:

• The formation of a synapse between the T cell and the tumor cell
• Upregulation of cell adhesion molecules
• Production of cytolytic proteins
• Release of inflammatory cytokines
• Proliferation of T cells, which result in redirected lysis of CD19-positive cells.

On December 3, 2014, the FDA granted accelerated approval for blinatumomab for the treatment of Philadelphia chromosome–negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (R/R ALL).¹⁰ The approval was based on the achievement of durable complete remission (CR) and response with a reduction in minimal residual disease (MRD) to less than 10^–4 in a multicenter single-arm study (Protocol MT103-211, or the ’211 study) that enrolled 185 patients with R/R ALL.^11,12 Results showed that 32% (95% CI, 26%-40%) of patients with R/R ALL attained a CR with 2 cycles of treatment with single-agent blinatumomab, and the response was durable (median, 6.7 months; range, 0.46-16.5 months). Furthermore, 31% (95% CI, 25%-39%) of patients in the study had a CR with or without complete hematological recovery but with reduction in MRD to <10^–4. Safety was evaluated in 212 patients with R/R ALL treated with blinatumomab. The most common adverse reactions (≥20%) were pyrexia (62%), headache (36%), peripheral edema (25%), febrile neutropenia (25%), nausea (25%), hypokalemia (23%), rash (21%), tremor (20%), and constipation (20%). A neurologic toxicity occurred in approximately 50% of patients and was a frequent reason for interruption of therapy. Blinatumomab activates endogenous T cells when bound to the CD19-expressing target cell, and activation of the immune system results in release of inflammatory cytokines. Cytokine release syndrome, including life-threatening or fatal events, was reported in 11% of the patients.

References

1. Blincyto [package insert]. Thousand Oaks, CA: Amgen Inc; 2014.
2. Ribera JM, Ferrer A, Ribera J, et al. Profile of blinatumomab and its potential in the treatment of relapsed/refractory acute lymphoblastic leukemia. Onco Targets Ther. 2015;8:1567-1574.
3. Wu J, Fu J, Zhang M, et al. Blinatumomab: a bispecific T cell engager (BiTE) antibody against CD19/CD3 for refractory acute lymphoid leukemia. J Hematol Oncol. 2015;8:104.
4. Raponi S, De Propris MS, Intoppa S, et al. Flow cytometric study of potential target antigens (CD19, CD20, CD22, CD33) for antibody-based immunotherapy in acute lymphoblastic leukemia: analysis of 552 cases. Leuk Lymphoma. 2011;52:1098-1107.
5. Klinger M, Brandl C, Zugmaier G, et al. Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19/CD3-bispecific BiTE antibody blinatumomab. Blood. 2012;119:6226–6233.
6. Baeuerle PA, Reinhardt C. Bispecific T-cell engaging antibodies for cancer therapy. Cancer Res. 2009;69:4941-4944.
7. Portell CA, Wenzell CM, Advani AS. Clinical and pharmacologic aspects of blinatumomab in the treatment of B-cell acute lymphoblastic leukemia. Clin Pharmacol. 2013;5(suppl 1):5-11.
8. Rathi C, Meibohm B. Clinical pharmacology of bispecific antibody constructs. J Clin Pharmacol. 2015;55(suppl 3):S21-S28.
9. Ruella M, Gill S. How to train your T cell: genetically engineered chimeric antigen receptor T cells versus bispecific T-cell engagers to target CD19 in B acute lymphoblastic leukemia. Expert Opin Biol Ther. 2015;15:761-766.
10. Przepiorka D, Ko CW, Deisseroth A, et al. FDA approval: blinatumomab. Clin Cancer Res. 2015;21:4035-4039.
11. US Food and Drug Administration. Blinatumomab. www.fda.gov/Drugs/Informa tionOnDrugs/ApprovedDrugs/ucm425597.htm. Accessed November 21, 2015.
12. Onyx Pharmaceuticals. Amgen presents data from pivotal phase 2 study of BLINCYTO™ (blinatumomab) immunotherapy in patients with relapsed/refractory acute lymphoblastic leukemia. www.onyx.com/view.cfm/727/amgen-presents-data-from-pivotal-phase-2-study-of-blincyto-blinatumomab-immunotherapy-in-patients-with-relapsedrefractory-acute-lymphoblastic-leukemia. Accessed November 21, 2015.

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