Cell type-restricted cytokine targeting in disease
Proinflammatory cytokines, such as TNF and IL-6, contribute to pathogenesis of several autoimmune diseases with an inflammatory component. Systemic neutralization of these molecules is the basis for therapeutic intervention and has already made a revolution in medicine. Howeverm studies in experimental arthritis suggested that TNF from one particular cellular source may play a protective role. If so, systemic cytokine inhibition is a double-edged sword disrupting both pathogenic and protective signaling. On the other hand, in several disease models in mice TNF produced by myeloid cells is pathogenic. Based on these findings we have developed an approach to cell type-restricted cytokine neutralization. We are utilizing bispecific antibodies that would attach to the cell surface of a particular type of immune cells, and capture the cytokine released by these cells, preventing its systemic dissemination. Our inhibitors are based on single domain antibodies (VHH) specific for human or mouse TNF, human IL6 and for cell type-specific markers, in particular, for F4/80 surface molecule expressed on the surface of macrophages. We demonstrate that such antibodies can effectively attach to the cell surface, capture and retain the released cytokine. Using mice humanized for the TNF system and macrophages isolated from such mice we assessed activity of such bi-specific constructs in vitro and in vivo. Our findings indicate that macrophage-restricted TNF neutralization has advantages over systemic TNF inhibition, paving the way to bioengineering of a new type of cytokine inhibitors.