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Bispecific antibody technology allows for the design of more potent antibody therapies

Bispecific antibodies are thought to have great therapeutic potential in various disease indications. Not all patients respond adequately to antibody therapy with monospecific antibodies. This may be due to the multifactorial nature of disease. Bispecific antibody technology allows for the design of more potent antibody therapies as they enable new therapeutic strategies (Kontermann, 2012). Bispecific antibodies can be employed in a wide range of applications, including:

1. Dual targeting: bispecific antibodies can be used to bind multiple targets, to block multiple pathogenic pathways, target tumor heterogeneity, increase specificity, and/or synergistically induce enhanced therapeutic effects. They can also be used to bind multiple sites on one target (see figure, number 1).

2. Retargeting (see figure, number 2): bispecific antibodies can be designed to redirect and activate effector cells (e.g. T-cells, natural killer [NK] cells) to specifically kill target cells (e.g. tumor cells) (Clark et al., 1987).

3. Monovalent targeting: bispecific antibodies, containing one binding and one non-binding arm, can be used to bind antigens monovalently, thereby preventing crosslinking and/or activation of target molecules (see figure, number 3).

4. Bispecific antibody-drug conjugates: dual targeting strategies with bispecific antibodies that are conjugated to toxins via linkers (see figure, number 4).

5. Bispecific antibodies can be employed for other types of targeted therapy such as pretargeted radioimmunotherapy in which the bispecific antibody binds a tumor target with one arm and captures a radiolabel with the other.


Selected strategies for bispecific therapeutics.

REFERENCES

Kontermann. MAbs. 2012, 4: 182-197.
Clark et al. J Natl Cancer Inst. 1987, 79: 1393-401.


 

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The DuoBody platform revolutionizes bispecific antibody discovery and development by overcoming the limitations of other technologies 

The DuoBody platform is a novel platform for the discovery and development of bispecific antibodies and provides a flexible solution:
• The DuoBody technology is ideally suited for the generation of bispecific IgG1 antibodies with regular human IgG1 structure and using minimal protein engineering (single mutations required).
• The immunogenicity risk profile of bispecific human IgG1 antibodies generated with the DuoBody platform is very low.
• DuoBody molecules of the IgG1 class fully retain Fc-mediated effector functions, including complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC).
• The in vivo serum half-life of IgG1 DuoBody molecules is similar to that of wild-type human IgG1.
• Using the DuoBody technology, novel and existing antigen binding sequences derived from any antibody-generating platform can be combined into a bispecific product.
• The DuoBody technology uses the original antigen binding sites (VH-VL) and hence the full exploitable repertoire of parental mAbs is available.
• The versatile in vitro post-production exchange reaction makes the DuoBody technology platform highly suitable for high throughput generation, screening, and discovery of bispecific antibodies in the final format.
• The DuoBody large scale manufacturing process is compatible with standard unit operations for IgG. In a proof-of-concept study, simple upscaling of the bench scale protocol to large scale results in a high yield of bispecific antibody with excellent quality and stability.
• The DuoBody platform is compatible with currently employed linker-drug technologies and is therefore readily suitable for the generation of bispecific antibody-drug conjugates. The DuoBody technology even allows for combining two different linker-drug technologies.
• The DuoBody technology can be combined with Fc-engineering technologies, to enhance or suppressFc-effector functions.
• The DuoBody technology can be extended to other human IgG subclasses to suit particular applications.
• The DuoBody technology has potential beyond the generation of bispecific antibodies, for instance for Fc-fusion proteins. Asymmetric proteins can thus be generated consisting of any Fc fusion protein involving an antibody Fab, scFv, domain antibody, receptor, ligand, interleukin etc. 

 
REFERENCES
Labrijn et al, PNAS 2013;110(13):5145-5150.
Gramer et al. mAbs 2013;5(6): 962–973.
 

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