This Laboratory is dedicated to the design of potentially therapeutic recombinant proteins and antibodies, including anticancer proteins, antiviral and anti-cytokine antibodies. It is working on the development of next- generation peptides and protein anti-cancer drugs. According to World Health Organization estimates, by 2020 cancer diseases will rank first in the world in terms of mortality outstripping the "traditional mortality leader", cardiovascular diseases. Currently, the treatment regimens used for malignant tumors are primarily surgery and chemotherapy individually or in combination. Unfortunately, a number of tumors cannot be surgically eliminated, and the chemotherapy drugs that are available are not effective in all cases due to their high toxicity. In addition, with the development of multi-drug resistance, recurrence of the disease occurs in a more severe and often incurable form. Therefore, it is important to search for new low-toxicity antitumor drugs that ensure high selectivity and effectiveness of treatment. It should be noted that any new drug that meets these requirements will provide an undeniable competitive advantage to its developers. These requirements, effect specificity and effective mechanisms that differ from traditional antitumor drugs, are met by therapeutic antibodies and peptides that serve as the focus for research being conducted by the Laboratory for Therapeutic Proteins and Antibodies.
Today, one of the most actively developing areas of anticancer therapy is the development of antitumor drugs based on natural proteins and peptides capable of causing apoptotic death of cancer cells and selectively inhibiting tumor growth. The basis of antitumor drugs that are introduced into clinical practice or undergo different stages of preclinical and clinical trials are such proapoptotic proteins and peptides as the cytokines of the family of tumor necrosis factor (Mahalingam et al., 2011, Dimberg et al., 2013, Prasad et al., 2014), interferons (George et al., 2012), interleukin-24 (Tian et al., 2012), some viral proteins (apoptin - a nonstructural protein of the chicken anemia virus, rodent NS1 protein, human E4orf4 protein) (Argiris et al., 2011; Backendorf & Noteborn, 2014), ribonuclease (ribonuclease from the frog leopard Rana pipiens, bacterial ribonuclease binase and barnase) (Fang & Ng, 2011; Smolewski et al., 2014), a croton-peptide from the cascavela venom Crotalus durissus (Hayashi et al., 2012), proteins and milk epitopes (Barbana et al., 2011; Gibbons et al., 2011; Koval et al., 2014). Antibody-based drugs, such as MabThera, Herceptin, Avastin, that are highly specific to cellular targets, are actively used in the clinic and open the prospect of creating personalized anti-cancer drugs.
Earlier at the Institute of Chemical Biology and Fundamental Medicine SB RAS (ICBFM SB RAS), the protein lactaptin-proteolytic fragment of kappa-casein, that is capable of inducing the apoptotic death of cancer cells, was isolated from human milk (Nekipelaya et al., 2008; Vlasov et al. 2008). An E. coli producing strain synthesizing a recombinant analogue of a native peptide, also has the ability to induce apoptosis of human cancer cells in a culture and inhibit the growth and metastasis of animal and human tumors in the xenograft model (Tikunova et al., 2010; Semenov et al., 2010, Koval et al., 2012; Koval et al., 2012; Koval et al., 2014). Based on the resulting recombinant peptide, a new antitumor drug "Lactaptin" was created and its preclinical studies conducted. However, lactaptine, like other protein therapeutic drugs, has a significant drawback - it is evenly distributed across organs and tissues which reduces its concentration in the target tumor and, as a result decreases the effectiveness of the antitumor effect.
An increase in the antitumor efficacy of therapeutic proteins may be related to targeted delivery of the drug to tumor cells. The targeted approach is used, for example, in the development of anti-cancer drugs based on monoclonal antibodies or fragments thereof having a specificity for cancer cell antigens, as well as tumor-specific receptor ligands. In addition, the ICBFM SB RAS staff have extensive experience in the development of full-length recombinant antibodies. Specifically, they have constructed full-length antibodies against human cytokines and developed antiviral antibodies (Levanov et al., 2010, Tikunova et al., 2012; Baykov et al, 2014; Levanov et al., 2010; Khlusevich et al., 2014). At the present time, preclinical trials of a humanized antibody against tick-borne encephalitis virus are being completed.
Head of the laboratory – Doctor of Biological Sciences, Nina Tikunova