Abstract
We discuss in this chapter the recently developed two-in-one antibody format (Bostrom et al. 2009). In contrast to bi-specific antibodies, which assemble two different monospecific binding units into one molecule, two-in-one antibodies are dual-specific antibodies that can be produced as conventional IgG, in which each of the two identical Fab arms recognizes two distinct antigen epitopes. The first proof-of-concept two-in-one bH1 has been selected from the phage-displayed libraries of a human epidermal growth factor (Her2)-specific antibody with varying CDR sequences based on its ability to recognize vascular endothelial growth factor (VEGF) in addition to Her2. The in-depth structural and biophysical analysis of the bH1 binding site shows that although the two paratopes against the two different antigens overlap extensively, structural plasticity – rearrangement of the CDR-L1 loop as well conformational changes in amino acid side chains – allows the binding site to adapt with high shape complementary to the two structurally unrelated antigens. Further, the dual binding function of bH1 has been improved to high affinity and validated by the potent dual action in vitro and in vivo, showing the therapeutic potential of such antibodies. The approach taken to generate bH1 is applicable for producing dual-specific antibodies against other antigen pairs. The two-in-one antibodies have certain advantages, which are also discussed here, and thereby provide a new option for antibody therapeutic development.
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We thank Charles Eigenbrot for helpful input and discussion.
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Koenig, P., Fuh, G. (2011). Two-in-One Antibodies. In: Kontermann, R. (eds) Bispecific Antibodies. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-20910-9_11
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DOI: https://doi.org/10.1007/978-3-642-20910-9_11
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