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Background  The recently described Designed Ankyrin Repeat Protein (DARPin) technology can produce highly selective ligands to a variety of biological targets at a low production cost.    Methodology/Principal Findings  To investigate the  in vivo  use of DARPins for future application to novel anti-HIV strategies, we identified potent CD4-specific DARPins that recognize rhesus CD4 and followed the fate of intravenously injected CD4-specific DARPin 57.2 in rhesus macaques. The human CD4-specific DARPin 57.2 bound macaque CD4 +  cells and exhibited potent inhibitory activity against SIV infection  in vitro . DARPin 57.2 or the control E3_5 DARPin was injected into rhesus macaques and the fate of cell-free and cell-bound CD4-specific DARPin was evaluated. DARPin-bound CD4 +  cells were detected in the peripheral blood as early as 30 minutes after the injection, decreasing within 6 hours and being almost undetectable within 24 hours. The amount of DARPin bound was dependent on the amount of DARPin injected. CD4-specific DARPin was also detected on CD4 +  cells in the lymph nodes within 30 minutes, which persisted with similar kinetics to blood. More extensive analysis using blood revealed that DARPin 57.2 bound to all CD4 +  cell types (T cells, monocytes, dendritic cells)  in vivo  and  in vitro  with the amount of binding directly proportional to the amount of CD4 on the cell surface. Cell-free DARPins were also detected in the plasma, but were rapidly cleared from circulation.    Conclusions/Significance  We demonstrated that the CD4-specific DARPin can rapidly and selectively bind its target cells  in vivo , warranting further studies on possible clinical use of the DARPin technology.

In Vivo Binding and Retention of CD4-Specific DARPin 57.2 in Macaques