Extremely potent, rapid and costimulation‐independent cytotoxic T‐cell response against lymphoma cells catalyzed by a single‐chain bispecific antibody

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Abstract
A recent study reported on an anti‐CD19/anti‐CD3 single‐chain bispecific antibody (bscCD19xCD3) exhibiting high activity against human B lymphoma cell lines (Löffler et al., Blood 2000;95:2098–103). In the present study, we have explored in detail the in vitro efficacy, T‐cell donor variability, binding characteristics, specificity, kinetics and interleukin‐2 (IL‐2) dependence of bscCD19xCD3. We found that a majority of human donor T cells tested (n = 86) gave half‐maximal B‐lymphoma cell lysis (ED50) within a range of 10–50 pg/ml bscCD19xCD3, corresponding to sub‐picomolar concentrations of the bispecific antibody. Under identical experimental conditions, the anti‐CD20 monoclonal antibody rituximab had an at least 100,000‐fold lower in vitro efficacy. The extreme potency of bscCD19xCD3 was in sharp contrast to the relatively low affinity of the anti‐CD3 and anti‐CD19 single‐chain Fv portions in KD ranges of 10−7 and 10−9 M, respectively. Cell lysis by bscCD19xCD3 was predominantly mediated by the population of CD8/CD45RO‐positive T cells. Both immortalized CD4‐ and CD8‐positive human T‐cell clones were highly active effector cells as well. Cell lysis by bscCD19xCD3 was rapid and specific. The respective parental monoclonal antibodies inhibited cell lysis and CD19‐negative cells were not harmed by T cells in the presence of high amounts of bscCD19xCD3. The potent T‐cell stimulus IL‐2 could not markedly augment the activity of bscCD19xCD3‐stimulated T cells. In conclusion, bscCD19xCD3 could redirect unstimulated cytotoxic T cells against CD19‐positive cells in an unexpectedly potent, rapid and specific fashion.