Development of the Bispecific Antibody in Fab-scFv Format Based on an Antibody to Human Interferon Beta-1 and Antibody t
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lopment of the Bispecific Antibody in Fab-scFv Format Based on an Antibody to Human Interferon Beta-1 and Antibody to HER2 Receptor A. A. Paninaa, 1, V. A. Toporovaa, V. S. Rybchenkob, D. S. Balabashina, V. V. Argentovab, S. A. Yakimova, O. N. Solopovac, d, T. K. Alievb, D. A. Dolgikha, P. G. Sveshnikovc, and M. P. Kirpichnikova, b aShemyakin–Ovchinnikov
Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997 Russia b Moscow State University, Moscow, 119991 Russia c Russian Research Center for Molecular Diagnostics and Therapy, Moscow, 117149 Russia dBlokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, 115478 Russia Received December 27, 2019; revised January 11, 2020; accepted January 20, 2020
Abstract—The development of new therapies for malignant tumors is an urgent task. Currently, the humanized antibody trastuzumab is considered the “gold standard” in the complex treatment of breast tumors with overexpression of HER2, human epidermal growth factor receptor 2. However, in some cases, resistance to the specified preparation is observed. The search for new therapies for HER2-associated tumors seems to be an important area of research. A number of clinical studies are currently underway on the use of human interferon-beta (IFN-beta) in oncology. Most of these studies use viral vectors carrying the interferon-beta gene to reduce the systemic effect of this cytokine. The immunocytokine complex of the bispecific antibody and IFN-beta we developed can also avoid the systemic action of IFN-beta. Part of the development of such a complex is the creation of bispecific antibodies of various formats. Based on the neutralizing B16 antibody to IFN-beta and the trastuzumab (Tz) antibody specific for the HER2 receptor, we obtained various variants of bispecific antibodies in Fab-scFv format. It was shown that the proteins obtained bind and neutralize IFNbeta, and they also bind the HER2 receptor in tumor cell lysates and as a recombinant extracellular domain. Such molecules in the immunocytokine complex can be used as delivery vehicles of IFN-beta to HER2-positive tumor cells. Keywords: IFN-beta, CHO, trastuzumab, Fab-scFv, HER2 DOI: 10.1134/S1068162020040159
INTRODUCTION Malignant neoplasms take the second place among all causes of death after cardiovascular diseases. Respiratory tumors are in the first place in men, and breast tumors in women, and a significant part of both are tumors with overexpression of the epidermal growth factor receptor HER2, which is an indicator of an unfavorable prognosis of the disease outcome. In addition, HER2 can be overexpressed on tumors of the bladder, pancreas, ovary, uterus, colon, kidney, Abbreviations: L, light chain of the antibody; H, heavy chain of the antibody; VH, variable domain of the H chain; VL, variable domain of the L chain; Ch1, first constant domain of an IgG1 antibody; Fab fragment, antigen-binding fragment of antibody; scFv, single chain antibody variants; HER2, human epidermal growth factor rec
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