Bi-specific T-cell engagers (BiTEs) are a class of artificial bispecific monoclonal antibodies

Bispecific monoclonal antibody

A bispecific monoclonal antibody is an artificial protein that is composed of fragments of two different monoclonal antibodies and consequently binds to two different types of antigen...

 that are investigated for the use as anti-cancer drugs. They direct a host's immune system, more specifically the T cell

T cell

T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...

s' cytotoxic activity, against cancer cells. BiTE is a registered trademark of Micromet AG.

BiTEs are fusion protein

Fusion protein

Fusion proteins or chimeric proteins are proteins created through the joining of two or more genes which originally coded for separate proteins. Translation of this fusion gene results in a single polypeptide with functional properties derived from each of the original proteins...

s consisting of two single-chain variable fragments (scFvs) of different antibodies, or amino acid sequences from four different genes, on a single peptide

Peptide

Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...

 chain of about 55 kilodaltons. One of the scFvs binds to T cells via the CD3 receptor, and the other to a tumor cell via a tumor specific molecule.

Mechanism of action

Like other bispecific antibodies, and unlike ordinary monoclonal antibodies, BiTEs form a link between T cells and tumor cells. This causes T cells to exert cytotoxic activity on tumor cells by producing proteins like perforin

Perforin

Perforin-1 is a protein that in humans is encoded by the PRF1 gene.- Function :Perforin is a cytolytic protein found in the granules of CD8 T-cells and NK cells. Upon degranulation, perforin inserts itself into the target cell's plasma membrane, forming a pore. The lytic membrane-inserting part...

 and granzyme

Granzyme

Granzymes are serine proteases that are released by cytoplasmic granules within cytotoxic T cells and natural killer cells. Their purpose is to induce apoptosis within virus-infected cells, thus destroying them....

s, independently of the presence of MHC I or co-stimulatory

Co-stimulation

During the activation of lymphocytes, co-stimulation is often crucial to the development of an effective immune response. Co-stimulation is required in addition to the antigen-specific signal from their antigen receptors.- Co-stimulation T cells require :...

 molecules. These proteins enter tumor cells and initiate the cell's apoptosis

Apoptosis

Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

.

This action mimics physiological processes observed during T cell attacks against tumor cells.

Clinical trials

The following BiTEs are in clinical trial

Clinical trial

Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...

s :

• Blinatumomab
  Blinatumomab
  Blinatumomab is a drug that has anti-cancer properties. It belongs to a new class of constructed monoclonal antibodies, bi-specific T-cell engagers , that exert action selectively and direct the human immune system to act against tumor cells...
  
   (MT103): for the treatment of non-Hodgkin’s lymphoma and acute lymphoblastic leukemia
  Acute lymphoblastic leukemia
  Acute lymphoblastic leukemia is a form of leukemia, or cancer of the white blood cells characterized by excess lymphoblasts.Malignant, immature white blood cells continuously multiply and are overproduced in the bone marrow. ALL causes damage and death by crowding out normal cells in the bone...
  
  ; directed towards CD19
  CD19
  B-lymphocyte antigen CD19 also known as CD19 , is a protein that in humans is encoded by the CD19 gene.- Function :...
  
  , a surface molecule expressed on B cells
• MT110: for the treatment of gastrointestinal and lung cancer
  Lung cancer
  Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
  
  s; directed towards the EpCAM antigen

Further research

Utilizing the same technology, melanoma

Melanoma

Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...

 (with MCSP specific BiTEs) and acute myeloid leukemia

Acute myeloid leukemia

Acute myeloid leukemia , also known as acute myelogenous leukemia, is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute...

 (with CD33

CD33

CD33 or Siglec-3 is a transmembrane receptor expressed on cells of myeloid lineage. It is usually considered myeloid-specific, but it can also be found on some lymphoid cells.It binds sialic acids, therefore is a member of the SIGLEC family of lectins....

 specific BiTEs) can be targeted. Research in this area is currently ongoing. Another avenue for novel anti-cancer therapies is re-engineering some of the currently used conventional antibodies like trastuzumab

Trastuzumab

Trastuzumab is a monoclonal antibody that interferes with the HER2/neu receptor.The HER receptors are proteins that are embedded in the cell membrane and communicate molecular signals from outside the cell to inside the cell, and turn genes on and off...

 (targeting HER2/neu

HER2/neu

HER-2 also known as proto-oncogene Neu, receptor tyrosine-protein kinase erbB-2, CD340 or p185 is an enzyme that in humans is encoded by the ERBB2 gene. Over expression of this gene is correlated with higher aggressiveness in breast cancers...

), cetuximab

Cetuximab

Cetuximab is a chimeric monoclonal antibody, an epidermal growth factor receptor inhibitor, given by intravenous infusion for treatment of metastatic colorectal cancer and head and neck cancer.- Distribution :Cetuximab is manufactured and distributed in North America by ImClone and Bristol-Myers...

 and panitumumab

Panitumumab

Panitumumab , formerly ABX-EGF, is a fully human monoclonal antibody specific to the epidermal growth factor receptor ....

 (both targeting the EGF receptor), using the BiTE approach. BiTEs against CD66e and EphA2

EPH receptor A2

EPH receptor A2 is a protein that in humans is encoded by the EPHA2 gene.-Interactions:EPH receptor A2 has been shown to interact with PIK3R1, Grb2, ACP1 and SHC1.-References:...

are being developed as well.