Targeted Inhibition of Proinflammatory Cytokines Produced by Myeloid Cells

Abstract Proinflammatory cytokines, in particular IL-6 and TNF, are crucial factors in the development of autoimmune immune response. Their systemic inhibition has been successfully used as a therapy of multiple autoimmune and inflammatory diseases. However, recent data from murine genetic models suggest that the cellular source of proinflammatory cytokines may significantly affect their biological effects. Cytokines derived from particular cellular sources may be pathogenic while the same cytokine produced by other cell may play a protective role. Thus, systemic cytokine inhibition may be far from the optimal therapeutic approach. To independently confirm these findings and to evaluate potentially more effective therapeutic approaches we are developing bispecific antibodies, which may serve as inhibitors of proinfllammatory cytokines targeted to specific cells. Using myeloid-specific TNF inhibitor we have demonstrated that limiting TNF inhibition to macrophages and monocytes results in superior neutralization activity in the TNF-induced hepatotoxicity model. This approach could lower both the required dose and potentially the incidence of side effects. Currently we are developing the similar approach for IL-6. Our bispecific reagents are based on two different VhH antibodies, thus we immunized the lama with recombinant IL-6 and selected high affinity single-domain antibodies by phage display. Funding: Russian Scientific Fund grant 14-25-00160 (anti-IL6 antibodies), RFBR grant 14-04-01656 (anti-TNF).