Bispecific antibodies: design, therapy, perspectives

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

Monoclonal Abs (mAbs) are secreted by identical immune cells, clones of a single parent cell. mAbs are not just monospecific bivalent molecules, but in contrast to polyclonal Abs, bind the same epitope (antigen fragment recognized by Abs). In this regard, mAbs are widely used for the treatment of cancer: Avastin (bevacizumab, anti-VEGF), Herceptin (trastuzumab, anti-HER2-receptor antagonist), and rituximab (anti-CD20) have been on the pharmaceutical market for more than 15 years. However, these and other drugs based on mAbs are not able to cure some cases of cancer in monotherapy, particularly due to T lymphocytes not taking an active part in the destruction of tumors, while mAb molecules only prevent the binding of growth factors to the receptors. mAbs blocking the inhibitory signals that protect tumors from immune cells show excellent results in the treatment of particular types of tumors. Nevertheless, high expectations are focused on Abs binding two or more antigens (BsAbs), as well as conjugated to agents for chemo-and radiotherapy. 1 BsAbs have been developed in which one antigen-binding site is directed against the CD3 receptor (activates cytotoxic T lymphocytes) and the other against specific antigens of tumor cells (CD19, CD20, CD33, CD123, HER2, epithelial cell adhesion molecule [EpCAM] , BCMA, CEA, and others). 2 The convergence of cytotoxic T lymphocytes and tumor cells due to BsAb binding activates cytotoxic T cells and promotes the destruction of tumor cells. In addition to a wide range BsAbs directed against tumors, several bispecific molecules for the treatment of other diseases have been developed. The BsAb for the treatment of osteoporosis blocks the factors of Wnt signal-transduction pathway (sclerostin and Dkk1); it enhances the formation of osteoblasts and growth of bone tissue. 3 ACE910 binds blood-coagulation factors IX and X and is designed to reduce bleeding rate in hemophilia A. The convergence of coagulation factors enhances the coagulation cascade. 4 A BsAb against the transferrin receptor (provides passage through the blood-brain barrier) and protease BACE1 (accumulates amyloid peptides) is a candidate for an anti-Alzheimer's disease drug. 5 BsAbs that are focused on autoimmune diseases usually bind cytokines: TNF, IL1, IL4, IL14, IL17, IL23, and others. 2, 6 It has been shown that simultaneous use of two mAbs against cytokines in autoimmune diseases has severe side effects without superior efficiency. In this regard, BsAbs against autoimmune diseases usually combine two anticytokine antigen-binding sites and provide higher therapeutic potential than a mixture of two mAbs. 7, 8 In particular, the most therapeutically important cytokines in psoriasis are IL17, IL23, IL6, and TNF. 9 ABT122 against TNFα and IL17A has clinical effects in rheumatoid arthritis and psoriatic arthritis. 10 In contrast, Phase I/II clinical trials of COVA322 (same specificity as ABT122) in psoriasis 11 were preliminary terminated, due to safety concerns. 8 Antigenbinding sites of ABT981 are directed against IL1α and IL1β, inflammatory cytokines found in the cartilage and synovial fluid of patients with osteoarthritis. 12 BsAbs have several significant advantages over monospecific Abs. BsAbs direct specific effectors of the immune system to target tumor cells, enhancing their cytotoxicity. BsAbs can provide higher binding specificity, since in contrast to monospecific Abs, they interact with two different surface antigens. The use of B