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

A recent study reported on an anti-CD19/anti-CD3 single-chain bispecific antibody (bscCD19xCD3) exhibiting high activity against human B lymphoma cell lines (L?ffler 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 (ED(50)) 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 K(D) 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.     

Feasibility and pharmacokinetic study of a chimeric anti-CD20 monoclonal antibody (IDEC-C2B8, rituximab) in relapsed B-cell lymphoma

Background: In clinical trials in the USA, IDEC-C2B8 (a mouse-humanchimeric anti-CD20 monoclonal antibody) has demonstrated high response rateswith only mild toxic effects in relapsed B-cell lymphoma at a dose of fourweekly 375 mg/m² infusions. The aim of the present trial wasto determine whether or not this dose is practically applicable to Japanesepatients with relapsed B-cell lymphoma with respect to safety,pharmacokinetics and efficacy.Patients and methods: Patients with relapsed CD20+ B-cell lymphomareceived intravenous infusions of IDEC-C2B8 once a week for four weeks. Atotal of 12 patients (four at 250 mg/m² and eight at 375mg/m²) were enrolled.Results: All 11 eligible patients treated with either dose leveltolerated IDEC-C2B8 well. Commonly observed adverse drug reactions weregrades 1 or 2 non-hematologic toxicities during the infusion, consistingmostly of flu-like symptoms and skin reactions. All of the observedhematologic toxicities were of grade 3 or less, and transient. A rapid andsustained B-cell decrease in peripheral blood was observed, but noinfectious episodes were encountered. Human anti-mouse and anti-chimericantibodies were not detected. Of the 11 eligible patients (eight withfollicular, two with diffuse large-cell and one with mantle cell lymphoma),two showed a complete response and five showed a partial response, and allof the seven responders had lymphoma with follicular histology. Apharmacokinetic analysis showed that the elimination half-life (T1/2) ofIDEC-C2B8 was 445 ± 361 hours, and that the serum antibody levelsincreased in parallel with the course of infusions, and in most patients wasstill measurable at three months.Conclusions: The dose of four weekly 375 mg/m² infusionsof IDEC-C2B8 is safe and effective in Japanese patients with relapsed B-celllymphoma. Further studies evaluating IDEC-C2B8 are warranted.