Bispecific antibodies: design, therapy, perspectives

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

Most of the antitumor BsAbs currently undergoing clinical and preclinical trials, such as blinatumomab and catumaxomab, contain one anti-CD3 antigen-binding site, attracting the T lymphocyte to the tumor cell. The second antigenbinding site can be directed against CD19, CD20, CD33, CD123, HER1, HER2, CEA, disialoganglioside GD2, PSMA, gpA33, and other proteins (Table 1) . Also, many BsAbs with other combinations of antigen-binding sites (usually anticytokines) are in trials: HER2 + HER3, IL1α + IL1β, IL13 + IL17, IL17A/IL17F, and CD30 + CD16A. Data on BsAbs undergoing clinical trials have been published in many reviews and are combined in Table 1 ; the list of terminated clinical trials is combined in Table 2 . The structures of most common BsAbs formats are presented in Figure 3 . Like other methods of therapy for severe diseases, therapeutic BsAbs cause different side effects, the most common of which are nausea, vomiting, abdominal pain, fatigue, leukopenia, neutropenia, and thrombopenia. In many patients, Abs against therapeutic BsAbs appear in the blood during treatment. Most adverse events occur during the beginning of therapy, and in most cases side effects normalize under continued treatment. The majority of data on therapeutic BsAb adverse effects are available on blinatumomab and catumaxomab, since these drugs have undergone numerous clinical trials. A common side effect of blinatumomab and catumaxomab therapy is "cytokine storm", elevation of cytokine levels. Cytokine release-related symptoms are general side effects of many therapeutic mAbs,