Research Progress of Diabody Drugs

The research of diabody began from the birth of monoclonal antibody technology in the 1920s to the 1980s. The development of genetic engineering antibody technology, especially the wide application of phage display library technology, can reconstruct the binding surface of antibody, thus giving it a high affinity for binding to the second antigen. The diabody constructed by this technology is called DAF (dual action fab fragment).

The mechanism of action of diabody

Mediation of T cell killing

An important mechanism of diabody is mediation of T cell killing. In recent years, with the deepening of the understanding of the mechanism of immune escape of cancer cells and the rise of cancer immunotherapy, the research of antibody drugs to activate T cells has attracted much attention. The expression of MHC on the surface of most cancer cells is down-regulated or even absent, thus escaping immune killing. CD3 * diabody can bind to T cell surface CD3 molecule and cancer cell surface antigen respectively, thus shortening the distance between cytotoxic T cell (Tc or CTL) and cancer cells, and guiding T cells to kill cancer cells directly without relying on the dual activation signals of T cells. The unique T_cell activation mode of CD3_diabody is considered to be an important advantage in its mechanism of action.

Double Target Blocking

Another important mechanism of diabody is the simultaneous binding of dual targets to block the dual signaling pathway. The mechanism has a wider range of applications, including the treatment of tumors, autoimmune diseases, inhibition of vascular growth and anti-infection. Take the transmembrane tyrosine kinase receptor HER family, which plays an important role in regulating cell physiological process, as an example. It includes HER1 (erbB1, EGFR), HER2 (erbB2, NEU), HER3 (erbB3) and HER4 (erbB4), which are abnormally high expressed on the surface of many epithelial-derived solid tumor targeting and are important targets for targeted therapy of tumors. Antibodies already on the market include Herceptin monoclonal antibody binding to HER2 D4 domain, Patuzumab binding to HER2 D2 domain (Perjeta) and Erbitux binding to HER1 / EGFR domain, which are widely used in the clinical treatment of solid tumors such as breast cancer, gastric cancer and colorectal cancer.

Pre-clinical studies showed that the anti-tumor activity of the diabody FAE structure HER2 HER2 binding domain of HER2 antigen was better than that of the anti-Herceptin antibody [11]. The DAF diabody, which can combine EGFR and HER3 simultaneously, also shows better efficacy than single targeting EGFR antibody Erbitux. In the field of autoimmune disease treatment, diabody combining IL-13 and IL-4 double-target structure IgG4 have also entered clinical research.

Concluding remarks and Prospects

The design of diabody depends on the in-depth study of the molecular mechanism of disease, the action mechanism of diabody and their side effects. There are still many problems to be solved in this field, such as how to avoid the cytokine storm and how to balance the affinity of double targets after the combination of CD3 *diabody CD3 and so on. A kind of Bifunctional antibodies have irreplaceable advantages in the mechanism of dual blocking and inducing T cell tumor killing. With the development of upstream genetic engineering technology and downstream production technology, it is possible to construct diabody with the same or similar molecular structure as conventional whole antibodies, and to achieve large-scale production, paving the way for the wider application of diabody in the future; more and more diabody have entered clinical research. It can be predicted that diabody drugs will become a new growth point in the development of antibody drugs in the future.