The phenomenal growth of the bispecific antibody arena has culminated in 60 unique constructs, more than 30 in clinical development, and two on the market as therapeutics for a wide variety of cancer types and numerous diseases/disorders. Bispecific antibodies are specially engineered antibodies which simultaneously bind to two different epitopes on the same antigen or different antigens, increasing selectivity and effectiveness. 
The focus in incorporating bispecific antibodies within oncology applications has been in either blocking multiple and redundant signaling pathways involved in oncogenesis or redirecting immune effector cells to be in close proximity to tumor cells. In non-oncology applications, a major developmental effort has gone into blocking pro-inflammatory cytokines.[2, 3]
Despite successes in development there are some critical hurdles to overcome and there is a need for innovation and improvement. Manufacturability issues such as low expression yields and product instability/short half-life have hindered development. Challenges lie in the need for rapid discovery of lead bispecific antibodies with optimal selectivity for their targets, and a need for rapid purification techniques. Adverse effects from immunogenicity, mainly caused by a “cytokine storm,” can stifle clinical trials.
Development efforts have provided some solutions to these hurdles. Researchers at Eli Lily are using mathematical modeling parameters to make predictions about how engineered antibody properties will affect binding to cell surface antigens, ultimately optimizing developability. Another novel strategy involves monitoring target/ligand binding of bispecific antibodies through surface plasmon resonance (SPR), which allows users to view the dynamics of bispecific antibody binding and dissociation events with two targets. 
The short half-life of scFv-based bispecific antibodies is a major drawback compared to that of IgG-like bispecific antibodies. Successful half-life extension, and in some cases, recycling, has been achieved by attaching a variety of components: PEG chains , human serum albumin, and Fc fragments . In another novel approach, human mesenchymal stromal cells (MSCs) can be genetically modified to produce and secrete bispecific antibodies that accumulate near tumors continuously throughout the lifetime of the patient.
A plethora of unique applications are being investigated for bispecific antibodies. One is in delivery of therapeutic antibodies across the blood-brain barrier for neurological conditions. Another innovative application involves engaging bispecific antibodies to deliver drug, nanoparticle or radiolabel payloads to tumor sites. Bispecific antibody-based immunoassays are being developed for diagnosis of patients with various infectious diseases: SARS, hepatitis B, tuberculosis, as well as E. coli infections. Another application involves tackling the rising threat of antibiotic resistance through specially designed constructs effective against antibiotic resistant bacteria such as Pseudomonas aeruginosa. 
This exciting and fast moving arena includes many creative design formats, and innovative solutions for numerous development and manufacturing issues. There are still many unmet needs, but the field is bound to yield many more successes.
- Fan, G., et al., Bispecific antibodies and their applications. Journal of Hematology & Oncology, 2015. 8(1): p. 1-14.
- Spiess, C., Q. Zhai, and P.J. Carter, Alternative molecular formats and therapeutic applications for bispecific antibodies. Mol Immunol, 2015. 67(2 Pt A): p. 95-106.
- Spasevska I, D.M., Klein C, Dumontet C, Advances in Bispecific Antibodies Engineering: Novel Concepts for Immunotherapies. J Blood Disord Transfus 2015. 6(243).
- Rhoden, J.J., G.L. Dyas, and V.J. Wroblewski, A Modeling and Experimental Investigation of the Effects of Antigen Density, Binding Affinity, and Antigen Expression Ratio on Bispecific Antibody Binding to Cell Surface Targets. J Biol Chem, 2016.
- Karllson, R., Applications of Surface Plasmon Resonance for Detection of Bispecific Antibody Activity. Biopharm International, 2015. 28(10): p. 38-45.
- Kontermann, R.E., Strategies for extended serum half-life of protein therapeutics. Curr Opin Biotechnol, 2011. 22(6): p. 868-76.
- Aliperta, R., et al., Bispecific antibody releasing-mesenchymal stromal cell machinery for retargeting T cells towards acute myeloid leukemia blasts. Blood Cancer Journal, 2015. 5: p. e348.
- Couch, J.A., et al., Addressing Safety Liabilities of TfR Bispecific Antibodies That Cross the Blood-Brain Barrier. Science Translational Medicine, 2013. 5(183): p. 183ra57-183ra57.
- Byrne, H., et al., A tale of two specificities: bispecific antibodies for therapeutic and diagnostic applications. Trends Biotechnol, 2013. 31(11): p. 621-32.
- DiGiandomenico, A., et al., A multifunctional bispecific antibody protects against Pseudomonas aeruginosa. Science Translational Medicine, 2014. 6(262): p. 262ra155-262ra155.
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