Bispecific antibodies: design, therapy, perspectives

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

A promising work on short nonviral minicircle DNA for the synthesis of BsAbs in vivo was recently published. BsAbs against CD3 and CD20 efficiently stimulated T-cell cytotoxicity against CD20 + lymphoma cell lines. Introduction of 5 μg plasmid DNA was sufficient for 1 month's BsAb expression in mice. 120 An oncolytic adenovirus expressing a bispecific single-chain Ab in tumor cells has been constructed. The secreted Abs format is BiTE and BsAbs bind EpCAM on a tumor cell and activate CD4 + and CD8 + T-cell cytotoxicity by directing to CD3. 121 A relatively universal method of BsAb preparation is the exchange of IgG HL fragments, which occurs stochastically between natural IgG 4 , 60 IgG 1 with a mutation in the CH3 domain, 105 and IgG 2 through disulfide linkers. 122 According to the literature, the HL-fragment exchange occurs in human blood, milk, and placenta between IgG of all subclasses, resulting in polyreactive BsAbs. [61] [62] [63] [64] However, the exchange of HL fragments between the therapeutic molecules of bispecific IgG 4 and the patient's IgG 4 leads to the formation of BsAbs that do not possess the original properties, 123 so this imposes significant limitations on this method.