Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-43256
Pugach, P; Krarup, A; Gettie, A; Kuroda, M; Blanchard, J; Piatak Jr., M; Lifson, J D; Trkola, A; Robbiani, M (2010). In vivo binding and retention of CD4-specific DARPin 57.2 in macaques. PLoS ONE, 5(8):e12455.
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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.
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|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > Institute of Medical Virology|
|DDC:||570 Life sciences; biology
610 Medicine & health
|Deposited On:||26 Jan 2011 16:46|
|Last Modified:||27 Nov 2013 21:43|
|Publisher:||Public Library of Science|
|Funders:||Campbell Foundation, National Institutes of Health (NIH) grants AI040877 and AI084133 and in part with federal funds from the National Cancer Institute, NIH, under contract HHSN261200800001E. , PP is an F.M. Kirby Foundation fellow. MR is a 2002 and AT is a 2006 Elizabeth Glaser Scientist|
|Free access at:||Publisher DOI. An embargo period may apply.|
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