Bispecific Antibodies Mediated Cytotoxicity

The use of antibodies is widely recognized as a well adopted cancer therapy. However, many monoclonal antibodies show shortcomings in effective cancer treatment. To be able to overcome these shortcomings, bispecific antibodies (bsAbs) have been created which combine specificities of two antibodies so they can simultaneously bind to different antigens or epitopes.

Over the past two decades, genetic engineering has resulted in a range of bsAbs formats, with over 50 different formats now available. The different formats can act in different mode of actions.

A range of bispecific antibodies formats. By Anypodetos (Own work) [Public domain], via Wikimedia Commons. A range of bispecific antibodies formats. By Anypodetos (Own work) [Public domain], via Wikimedia Commons.

BiTEs for cancer immunotherapy

Bi-specific T-cell engagers (BiTEs) are a class of artificial bispecific monoclonal antibodies. BiTEs are fusion proteins and consist of two single-chain variable fragments (scFv) connected in tandem by a flexible linker. They are used to physically link a cytotoxic T-cell and a cancer cell with high specificity, upon which the T-cell is activated and induces cytolysis of the cancer cell:

  1. BiTEs can bind to the CD3 receptor of cytotoxic T-cells and to a tumor specific antigen found on the cancer cell, hereby being able to form a link between both cell types.
  2. As a result, the T-cell is activated and produces and excretes proteins like perforin and granzymes.
  3. These proteins enter the tumor cells and initiate death of the cancer cell.

Other bsAbs: how they work in cancer immunotherapy

The overall goal of the different bsABs formats is to serve as a cancer immunotherapy. With so many different bsAbs formats, there are different modes of action to accomplish cancer cell death or inhibit cancer cell growth.

(RTKs) targeting IgGs

Whereas BiTEs serve as a cancer treatment through induction of cancer cell cytotoxicity, receptor tyrosine kinase (RTKs) targeting IgGs are a bsAbs that interfere with two (or more) RTK signaling pathways, by inactivating either the kinases or their ligand. An example is the interference of members of the HER-family by such bsAbs. Result is the inhibition of proliferation of HER-expressing tumor cells and improvement of therapeutic efficacy.

Targeted payload delivery

There are also bsAbs that don't function as a linker between cells or proteins and cells, but rather serve as a vehicle for targeted payload delivery. Such bsAbs are used to bind a small entity that by itself can be labeled with radioactive substances and are directed towards the cancer cells.


Chames and Baty. Bispecific antibodies for cancer therapy: the light at the end of the tunnel? mAbs. Nov/Dec 2009.

Kontermann and Brinkmann. Bispecific Antibodies. Drug Discovery Today; Volume 20, Number 7, July 2015.