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).
Rational Development and Key Features of BiTE Antibodies
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
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).
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)], ...