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Bispecific Antibodies

The term ‘bispecific antibodies’ or ‘bsAbs’ covers a multitude of different compound classes, all possess the ability to bind or target two specific antigens or epitopes.

Bispecific antibodies are not new and were in fact first described and devised back in the late 20th century. [1]  Morrison and co-workers realized the benefits of targeting two binding sites and placing targets in close proximity to one another.  This closeness can trigger contact between cells or enhance protein complexation on the one cell. [1] 

The large complexity and technical issues associated with producing bispecific antibodies limited development to R&D functions.  However, with the keen interest in biologics from the pharmaceutical industry and the vast improvements in biopharmaceutical engineering technologies, there are a number of bispecific antibodies on the market, with many, many more in development undergoing clinical trials.

The first bispecific antibody, Removab (Catumaxomab – Fresenius Biotech), achieved regulatory approval in the EU in April 2009 for the treatment of malignant ascites with a second, Blincyto (Blinatumamab – Amgen) gaining FDA approval in December 2014 for specific types of leukemia.

Structure of Removab

Figure 1: Structure of Removab, the first bispecific antibody to achieve approval. [2]

Early work focused on the rather crude, but effective, conjunction of two monoclonal antibodies as depicted on the left hand-side of the figure below.


bispecific antibodies

Figure 2: Schematic overview of the different strategies used to generate bispecific antibodies (bsAbs) derived from the antigen-binding sites of two different antibodies. Symmetric bsAbs are generated by the assembly of antibodies with unmodified heavy chain constant regions, such as by the heterodimerization of heavy chains from two different antibodies or homodimerization of heavy chains extended by an additional binding site resulting in bivalent or tetravalent molecules. Using heavy chains modified to force heterodimerization (e.g. using a knobs-into-holes strategy) results in asymmetric bsAbs. Alternatively, two different antibody fragments, such as scFv, can be fused to a non-immunoglobulin protein, such as albumin. Furthermore, two antigen-binding fragments can be directly fused, resulting in small bsAbs molecules. Finally, bsAbs can also be generated by chemical conjugation of two different antibodies. [1]


Huge advances in the genetic engineering technologies over the last 20 years has led to over 50 different formats being developed with the main classification shown below. [1]

bispecific antibodies

Figure 3: Various bispecific antibodies (bsAbs) are currently in clinical development or are already approved for cancer therapy. The upper two lines depict immunoglobulin (Ig)-like bsAbs comprising an IgG Fc region, either as bivalent or tetravalent molecules. Furthermore, several small bsAbs and bsAbs fusion proteins have entered clinical trials. Abbreviations: BiTE, bispecific T cell engager; DART, dual affinity retargeting; DNL, dock-and-lock; DVD-Ig, dual variable domain immunoglobulins; HSA, human serum albumin; kih, knobs into holes. [1]

The main distinction is the presence of an IgG Fc region in the species depicted in the top two lines.  These ‘newer’ classes show improvements in terms of size, valency, flexibility, half-life and biodistribution in order to achieve the target-product profile sought. [1] The presence of the Fc region not only aids purification but also solubility and stability.  The Fc region is also know to facilitate ADCC and complement-dependent cytotoxicity (CDC, which is a function of the complement system. It is the processes in the immune system that kill pathogens by damaging their membranes without the involvement of antibodies or cells of the immune system) whereas, bispecific antibodies without the presence of an Fc region are only therapeutically active by the direct result of their antigen binding sites.  Their smaller size does, however, facilitate enhanced tissue penetration for tumour destruction, although more frequent dosing is generally required due to their short plasmatic half-life due to their rapid elimination.  Improvements have been made in this area, and continue to be made, typically by binding half-life extension moieties, such as polypropylene glycol (PEG) or albumin binding groups.


[1] Ulrich Brinkmann et al., Bispecific antibodies, Nat Biotechnol. Drug Discovery Today, Volume 20, Number 7, July 2015

[2] Walsh. G., Biopharmaceutical benchmarks 2010, Nature Biotechnology, Volume 28 Number 9 September 2010 Source: Fresenius Biotech, Munich

 
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