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OVERVIEW

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Blinatumomab (blincyto) is a first-in-class bispecific antibody with high affinity toward both CD19 (expressed primarily on surface B cells) and CD3 (found on T lymphocytes) receptors. Blinatumomab received accelerated approval for treatment of Philadelphia chromosome-negative (Ph–) B-cell acute lymphoblastic leukemia (B-ALL) in December 2014.1 It was the second cancer immunotherapeutic to gain breakthrough therapy designation and accelerated approval in 2014 (see Update: Programmed Cell Death-1 Pathway Checkpoint Inhibition: Immuno-oncology for Advanced Melanoma).

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Rational Development and Key Features of BiTE Antibodies

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Directing native T cells to engage and clear specific tumor cells in vivo has long been a goal of antitumor immunotherapy. BiTE antibodies represent the first immunotherapy with the ability to bind to and sustain T-cell engagement in vivo using an anti-CD3 T-cell single-chain antibody linked to a second tumor-specific antibody.2 The first bispecific single-chain antibody was described in 1995 and was developed with the goal of directing CD3 T cells to tumor cells expressing the epithelial cell adhesion/activating molecule (EpCAM) cell surface antigen in colorectal cancer.3, 4 A promising cancer-specific target, EpCAM expression is prevalent in cancers of epithelial origin, and a BiTE therapy (MT110, eFigure 62-2.1B) is currently in phase I clinical evaluation for lung, gastric, colorectal, breast, prostate, and ovarian cancers.5, 6 A related bispecific trifunctional monoclonal antibody, catumaxomab, is approved in Europe and currently in trials in the U.S.7

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eFigure 62–2.1.

Structure and function of blinatumomab. A. The structural features of blinatumomab (MT103, AMG103) arise from monoclonal antibodies (mAbs) directed against CD19 and CD3. Single-chain antibodies are constructed from the light and heavy variable immunoglobulin domains (VL and VH) for each protein and connected using a long amino acid linker (Gly4Ser1)3.4, 12 Two single-chain antibodies are joined using a short amino acid linker (Gly4Ser1)1.31 B. Aggregation of T and B cells in the presence of blinatumomab. A cytotoxic T lymphocyte (blue) is associated with chronic lymphocytic leukemia cells (pink).14 The EpCAM BiTE MT110 can facilitate T-lymphocyte interaction with solid tumor cells, which have high expression levels of the EpCAM antigen (e.g., pancreatic cancer cells32).

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Blinatumomab features a CD3 T-cell engaging single-chain antibody linked to a CD19 single-chain antibody (eFigure 62–2.1A). In normal hematopoiesis, the CD19 cluster differentiation epitope is expressed on B cells beginning at the pro-B cell stage in development and persists until differentiation into terminal plasma cells.8 B-cell lineage malignancies include leukemias and lymphomas, and, importantly, many express the CD19 epitope. Moreover, the majority of patients with these malignancies are not well managed on conventional chemotherapies, with a significant percentage succumbing to disease relapse.9 A different B cell–specific therapeutic, rituximab [an anti-CD20 monoclonal antibody (mAb)], has ...

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