Bispecific antibodies: design, therapy, perspectives

Sedykh, Sergey E; Prinz, Victor V; Buneva, Valentina N; Nevinsky, Georgy A

BsAbs can be generated by the attachment of light or heavy chains, single-domain Abs, single-chain variable fragment (scFv), or other genetic engineering structures with additional antigen-binding sites to the amino or carboxyl ends of monospecific IgG molecules. 2 The most widely format used is IgG with dual-variable domains (DVD-Ig), 76 in which a variable part of HL fragment is added to another variable part of another Ab with a short peptide linker. The resulting molecules are bispecific and bivalent with regard to each antigen. 77 For example, tetravalent tetraspecific Abs binding EGFR, HER2, HER3, and VEGF are constructed by combining DVD-Ig technology with other methods. 78 One of the advantages of BsAbs designed with DVD-Ig technology is their ability simultaneously to bind antigens with all variable domains. This is especially true in cases of binding cytokines and other proteins present in the blood in low concentrations. Also, this allows less frequent administration of these BsAbs. 79 Chemical conjugation for the BsAb generation was used for the first time in 1985: two Fab 2 obtained by pepsinolysis of rabbit IgG were reduced and then oxidized, resulting in bispecific Fab 2 . 66 Subsequently, homo-and heterobifunctional reagents interacting with cysteine residues 67 and Fab obtained by genetic engineering 80 were used. CovX-Body technology is the most modern approach for the preparation of BsAbs based on the site-specific attachment of low-molecular-weight ligands to IgG. 81 The half-life of low-molecular-weight drugs