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We recently reported that triplebody 19-3-19 can engage and activate T cells as cytolytic
effectors via a central OKT3-derived single chain variable fragment (scFv) domain
(Roskopf et al., 2014).
Antibody-derivatives in the triplebody format can simultaneously target two different
tumour cell antigens (“dual-targeting”), while concomitantly recruiting immune effector
cells. To take full advantage of this dual-targeting capacity, a triplebody 33-3-19,
designed for lysis of CD19+ CD33+ biphenotypic leukaemia cells with enhanced selectivity,
was also constructed and analysed.
33-3-19 was produced in suspension-adapted 293F cells, purified and tested using standard
molecular biology and flow cytometric techniques.
33-3-19 activated T cells as efficiently as 19-3-19 and induced the specific lysis
of established myeloid (MOLM13, THP-1) as well as B cell lines (SEM, Raji) and of
primary patient cells at picomolar concentrations. However, 33-3-19 achieved a lower
maximal specific lysis of the B lymphoid cell lines (35–55 %) than 19-3-19 (55–90
%) in 3 h. This may in part be due to its monovalent affinity for CD19. Importantly, 33-3-19
induced the preferential lysis of double- over single-positive leukaemia cells (i.e.
BV173 versus SEM cells) in a target cell mixture. Finally, 33-3-19 led to the elimination
of >95% colony-forming leukaemia-initiating cells.
These results highlight the potential of dual-targeting triplebodies for efficient
and selective immune-intervention.
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