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Antibody with infinite affinity for in vivo tracking of genetically engineered lymphocytes.

There remains an urgent need for the non-invasive tracking of transfused chimeric antigen receptor (CAR) T cells to determine their biodistribution, viability, expansion, and anti-tumor functionality. 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) antibody reporter 1 (DAbR1) comprises a single-chain fragment of the anti-lanthanoid-DOTA antibody 2D12.5/G54C fused to the human CD4-transmembrane domain and binds irreversibly to lanthanoid-(S)-2-(4-acrylamidobenzyl)-DOTA (AABD). The aim of this study was to investigate whether DAbR1 can be expressed on lymphocytes and used as a reporter gene as well as a suicide gene for therapy of immune-related adverse effects. Methods: DAbR1 was sub-cloned together with green fluorescent protein (GFP) into an SFG-retroviral vector and used to transduce CD3/CD28-activated primary human T cells and second-generation 1928z (CAR) T cells. Cell surface expression of DAbR1 was confirmed by cell uptake studies with radiolabeled AABD. In addition, the feasibility of imaging of DAbR1+ T cells in vivo after IV injection of with [86Y]/[177 Lu]-AABD was studied and radiation doses determined. Results: A panel of DAbR1 expressing T cells and CAR T cells exhibited greater than eight-fold increased uptake of [86Y]Y-AABD in vitro when compared to non-transduced cells. Imaging studies showed [86Y]Y-AABD was retained by DAbR1 positive T cells while it continuously cleared from normal tissues allowing for in vivo tracking of intravenously administered CAR T cells. Normal organ dose estimates were favorable for repeated positron emission tomography / computed tomography (PET/CT) studies. Selective T cell ablation in vivo with [177 Lu]Lu-AABD seems feasible for clustered T cell populations. Conclusion: We have demonstrated for the first time that T cells can be modified with DAbR1, enabling their in vivo tracking via PET and single-photon emission computed tomography (SPECT). The favorable biodistribution and high image contrast observed warrant further studies of this new reporter gene.

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