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Gene transfer and drug selection systems that enforce ongoing transgene expression  in vitro  and  in vivo  which are compatible with human pharmaceutical drugs are currently underdeveloped. Here, we report on the utility of incorporating human enzyme muteins that confer resistance to the lymphotoxic/immunosuppressive drugs methotrexate (MTX) and mycophenolate mofetil (MMF) in a multicistronic lentiviral vector for  in vivo  T lymphocyte selection. We found that co-expression of human dihydrofolate reductase (DHFR FS ; L22F, F31S) and inosine monophosphate dehydrogenase II (IMPDH2 IY ; T333I, S351Y) conferred T cell resistance to the cytocidal and anti-proliferative effects of these drugs at concentrations that can be achieved clinically (up to 0.1 µM MTX and 1.0 µM MPA). Furthermore, using a immunodeficient mouse model that supports the engraftment of central memory derived human T cells,  in vivo  selection studies demonstrate that huEGFRt + DHFR FS+ IMPDH2 IY+  T cells could be enriched following adoptive transfer either by systemic administration of MTX alone (4.4 -fold), MMF alone (2.9-fold), or combined MTX and MMF (4.9-fold). These findings demonstrate the utility of both DHFR FS /MTX and IMPDH2 IY /MMF for  in vivo  selection of lentivirally transduced human T cells. Vectors incorporating these muteins in combination with other therapeutic transgenes may facilitate the selective engraftment of therapeutically active cells in recipients.

Engineering Human T Cells for Resistance to Methotrexate and Mycophenolate Mofetil as an In Vivo Cell Selection Strategy