Bispecific antibodies

A bispecific monoclonal antibody (BsMAb, BsAb) is an artificial protein that can simultaneously bind to two different types of antigen. BsMabs can be manufactured in several structural formats, and current applications have been explored for cancer immunotherapy and drug delivery.

There are many formats of bsMab, but the two main categories are IgG-like and non-IgG-like. The main types of manufacturing methods are quadromas, chemical conjugation, and genetic recombination, and each method results in a unique format.

This format retains the traditional monoclonal antibody (mAb) structure of two Fab arms and one Fc region, except the two Fab sites bind different antigens. The most common types are called trifunctional antibodies, as they have three unique binding sites on the antibody: the two Fab regions, and the Fc region. Each heavy and light chain pair is from a unique mAb. The Fc region made from the two heavy chains forms the third binding site. These bsMabs are often manufactured with the quadroma, or the hybrid hybridoma, method.

However, the quadroma method relies on random chance to form usable bsMabs, and can be inefficient. Another method for manufacturing IgG-like bsMabs is called "knobs into holes," and relies on introducing a mutation for a large amino acid in the heavy chain from one mAb, and a mutation for a small amino acid in the other mAb's heavy chain. This allows the target heavy chains (and their corresponding light chains) to fit together better, and makes bsMab production more reliable.

There are other bsMabs that lack an Fc region entirely. These include chemically linked Fabs, consisting of only the Fab regions, and various types of bivalent and trivalent single-chain variable fragments (scFvs). There are also fusion proteins mimicking the variable domains of two antibodies. The furthest developed of these newer formats are the bi-specific T-cell engagers (BiTEs).

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