Therapeutic efficacy of FcgammaRI/CD64-directed bispecific antibodies in B-cell lymphoma

CD64 (Fc?RI) receptors represent highly potent trigger molecules for activated polymorphonuclear cells (PMN) and mediate lysis of a range of tumors in the presence of appropriate monoclonal antibodies. An huCD64 transgenic mouse model designed to analyze the therapeutic activity of a panel of bispecific F(ab')2(BsAb) in retargeting granulocyte–colony-stimulating factor (G-CSF)–activated PMN against syngeneic B-cell lymphomas is reported. This model allows careful analysis of the individual elements of the therapeutic process. BsAb were directed against immunoglobulin-idiotype (Id), major histocompatibility class II (MHC II), or CD19 on the tumors and huCD64 on the effectors. In vitro cytotoxicity assays and in vivo tumor tracking showed that, provided effectors were activated with G-CSF, all 3 derivatives destroyed and cleared lymphoma cells, with (huCD64?×?MHC II) proving by far the most cytotoxic in vitro. However, though all derivatives delivered some survival advantage, only the [huCD64?×?Id] BsAb provided long-term protection to tumor-bearing animals. These results demonstrate that CD64-recruited cytotoxic effectors operate in vivo but that the (huCD64?×?Id) conferred an additional anti-tumor function essential for long-term protection. T-cell depletion studies demonstrated that this extra therapeutic activity with [huCD64?×?Id] was totally dependent on CD4 and CD8 T cells and that mice, once “cured” with BsAb, were resistant to tumor rechallenge. These findings indicate that CD64 is an effective trigger molecule for delivering cytokine-activated PMN against tumor in vivo and that, provided tumor targets are selected appropriately, CD64-based BsAb can establish long-term T-cell immunity. <br/

Clinical significance of coexisting antitopoisomerase I and anticentromere antibodies in patients with systemic sclerosis: A EUSTAR group-based study

Objective. To determine the clinical characteristics of simultaneous occurrence of antitopoisomerase (ATA) and anticentromere (ACA) autoantibodies in systemic sclerosis (SSc). Methods. Data of patients (n=4,687) fulfilling the ACR criteria for SSc and followed in the EULAR Scleroderma Trials and Research (EUSTAR) cohort were analysed. Sera from patients with simultaneous ATA and ACA were reanalysed centrally by indirect immunofluorescence, enzyme immunoassay, and immunoblot to confirm antibody status. Results. A total of 29 patients (0.6%) had been documented double-positive for both ATA and ACA in the EUSTAR database. Sera of 14 cases were available for central analysis, of which 8 were confirmed to unequivocally contain both antibodies. The double-positive patients were on average 52.4 years of age, 87.5% were female, and 62.5% had diffuse cutaneous (dc) SSc. Compared with matched ACA single-positive disease, cutaneous and visceral complications were more prevalent in double-positive cases, but this prevalence did not differ significantly in comparison to ATA single-positives. Conclusions. Coexistence of ATA and ACA can be found at low prevalence in SSc. The clinical features of double-positive patients are not clearly dissimilar to those of patients harbouring only ATA. The data do not support a direct involvement of these antibodies in the pathogenesis of established SSc, but may lack statistical power. © Clinical and Experimental Rheumatology 2013

Rituximab Maintenance for a Maximum of 5 Years After Single-Agent Rituximab Induction in Follicular Lymphoma: Results of the Randomized Controlled Phase III Trial SAKK 35/03

PURPOSE Rituximab maintenance therapy has been shown to improve progression-free survival in patients with follicular lymphoma; however, the optimal duration of maintenance treatment remains unknown. PATIENTS AND METHODS Two hundred seventy patients with untreated, relapsed, stable, or chemotherapy-resistant follicular lymphoma were treated with four doses of rituximab monotherapy in weekly intervals (375 mg/m(2)). Patients achieving at least a partial response were randomly assigned to receive maintenance therapy with one infusion of rituximab every 2 months, either on a short-term schedule (four administrations) or a long-term schedule (maximum of 5 years or until disease progression or unacceptable toxicity). The primary end point was event-free survival (EFS). Progression-free survival, overall survival (OS), and toxicity were secondary end points. Comparisons between the two arms were performed using the log-rank test for survival end points. RESULTS One hundred sixty-five patients were randomly assigned to the short-term (n = 82) or long-term (n = 83) maintenance arms. Because of the low event rate, the final analysis was performed after 95 events had occurred, which was before the targeted event number of 99 had been reached. At a median follow-up period of 6.4 years, the median EFS was 3.4 years (95% CI, 2.1 to 5.3) in the short-term arm and 5.3 years (95% CI, 3.5 to not available) in the long-term arm (P = .14). Patients in the long-term arm experienced more adverse effects than did those in the short-term arm, with 76% v 50% of patients with at least one adverse event (P < .001), five versus one patient with grade 3 and 4 infections, and three versus zero patients discontinuing treatment because of unacceptable toxicity, respectively. There was no difference in OS between the two groups. CONCLUSION Long-term rituximab maintenance therapy does not improve EFS, which was the primary end point of this trial, or OS, and was associated with increased toxicity