Comparison of the pharmacodynamic profiles of a biosimilar filgrastim and Amgen filgrastim: results from a randomized, phase I trial

Further to the patent expiry of Neupogen® (Amgen filgrastim), Hospira has developed a biosimilar filgrastim (Nivestim™) that may offer a clinically effective alternative for multiple hematologic and oncologic indications. Here results are reported from a phase I trial, primarily designed to compare the pharmacodynamic profiles of Hospira filgrastim and Amgen filgrastim. A phase I, single-center, double-blind, randomized trial was undertaken to demonstrate equivalence of the pharmacodynamic characteristics of Hospira filgrastim and Amgen filgrastim. Fifty healthy volunteers were randomized to receive 5 or 10 µg/kg dosing, before further randomization to treatment sequence. All volunteers received five daily subcutaneous doses of Hospira filgrastim or Neupogen, with subsequent crossover to the alternative treatment. Bioequivalence was evaluated by analysis of variance; if the estimated 90% confidence intervals (CIs) for the ratio of ‘test’ to ‘reference’ treatment means were within the conventional equivalence limits of 0.80–1.25, then bioequivalence was concluded. Forty-eight volunteers completed the study. Geometric mean absolute neutrophil count area under the curve from time 0 to the last time point at day 5 (primary endpoint) was comparable in volunteers given Hospira filgrastim or Amgen filgrastim at 5 µg/kg (ratio of means, 0.98; 90% CI, 0.92–1.05) or 10 µg/kg (ratio, 0.97; 90% CI, 0.93–1.01); 90% CIs were within the predefined range necessary to demonstrate bioequivalence. Hospira filgrastim was well tolerated with no additional safety concerns over Amgen filgrastim. Hospira filgrastim is bioequivalent with Amgen filgrastim with regard to its pharmacodynamic characteristics

An artificial intelligence method using FDG PET to predict treatment outcome in diffuse large B cell lymphoma patients

Convolutional neural networks (CNNs) may improve response prediction in diffuse large B-cell lymphoma (DLBCL). The aim of this study was to investigate the feasibility of a CNN using maximum intensity projection (MIP) images from 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) baseline scans to predict the probability of time-to-progression (TTP) within 2 years and compare it with the International Prognostic Index (IPI), i.e. a clinically used score. 296 DLBCL 18F-FDG PET/CT baseline scans collected from a prospective clinical trial (HOVON-84) were analysed. Cross-validation was performed using coronal and sagittal MIPs. An external dataset (340 DLBCL patients) was used to validate the model. Association between the probabilities, metabolic tumour volume and Dmaxbulk was assessed. Probabilities for PET scans with synthetically removed tumors were also assessed. The CNN provided a 2-year TTP prediction with an area under the curve (AUC) of 0.74, outperforming the IPI-based model (AUC = 0.68). Furthermore, high probabilities (> 0.6) of the original MIPs were considerably decreased after removing the tumours (< 0.4, generally). These findings suggest that MIP-based CNNs are able to predict treatment outcome in DLBCL

Ubiquitin fusion expression and tissue-dependent targeting of hG-CSF in transgenic tobacco

<p>Abstract</p> <p>Background</p> <p>Human granulocyte colony-stimulating factor (hG-CSF) is an important human cytokine which has been widely used in oncology and infection protection. To satisfy clinical needs, expression of recombinant hG-CSF has been studied in several organisms, including rice cell suspension culture and transient expression in tobacco leaves, but there was no published report on its expression in stably transformed plants which can serve as a more economical expression platform with potential industrial application.</p> <p>Results</p> <p>In this study, hG-CSF expression was investigated in transgenic tobacco leaves and seeds in which the accumulation of hG-CSF could be enhanced through fusion with ubiquitin by up to 7 fold in leaves and 2 fold in seeds, leading to an accumulation level of 2.5 mg/g total soluble protein (TSP) in leaves and 1.3 mg/g TSP in seeds, relative to hG-CSF expressed without a fusion partner. Immunoblot analysis showed that ubiquitin was processed from the final protein product, and ubiquitination was up-regulated in all transgenic plants analyzed. Driven by <it>CaMV </it>35S promoter and phaseolin signal peptide, hG-CSF was observed to be secreted into apoplast in leaves but deposited in protein storage vacuole (PSV) in seeds, indicating that targeting of the hG-CSF was tissue-dependent in transgenic tobacco. Bioactivity assay showed that hG-CSF expressed in both seeds and leaves was bioactive to support the proliferation of NFS-60 cells.</p> <p>Conclusions</p> <p>In this study, the expression of bioactive hG-CSF in transgenic plants was improved through ubiquitin fusion strategy, demonstrating that protein expression can be enhanced in both plant leaves and seeds through fusion with ubiquitin and providing a typical case of tissue-dependent expression of recombinant protein in transgenic plants.</p

Response to rituximab induction is a predictive marker in B-cell post-transplant lymphoproliferative disorder and allows successful stratification into rituximab or r-chop consolidation in an international, prospective, multicenter Phase II trial

Purpose The Sequential Treatment of CD20-Positive Posttransplant Lymphoproliferative Disorder (PTLD-1) trial ( ClinicalTrials.gov identifier, NCT01458548) established sequential treatment with four cycles of rituximab followed by four cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy as a standard in the management of post-transplant lymphoproliferative disorder (PTLD) and identified response to rituximab induction as a prognostic factor for overall survival. We hypothesized that rituximab consolidation might be sufficient treatment for patients with a complete response after rituximab induction. Patients and Methods In this prospective, international, multicenter phase II trial, 152 treatment-naive adult solid organ transplant recipients, with CD20+ PTLD unresponsive to immunosuppression reduction, were treated with four weekly doses of rituximab induction. After restaging, complete responders continued with four courses of rituximab consolidation every 21 days; all others received four courses of rituximab plus CHOP chemotherapy every 21 days. The primary end point was treatment efficacy measured as the response rate in patients who completed therapy and the response duration in those who completed therapy and responded. Secondary end points were frequency of infections, treatment-related mortality, and overall survival in the intention-to-treat population. Results One hundred eleven of 126 patients had a complete or partial response (88%; 95% CI, 81% to 93%), of whom 88 had a complete response (70%; 95% CI, 61% to 77%). Median response duration was not reached. The 3-year estimate was 82% (95% CI, 74% to 90%). Median overall survival was 6.6 years (95% CI, 5.5 to 7.6 years). The frequency of grade 3 or 4 infections and of treatment-related mortality was 34% (95% CI, 27% to 42%) and 8% (95% CI, 5% to 14%), respectively. Response to rituximab induction remained a prognostic factor for overall survival despite treatment stratification. Conclusion In B-cell PTLD, treatment stratification into rituximab or rituximab plus CHOP consolidation on the basis of response to rituximab induction is feasible, safe, and effective

Stage- and Gender-Specific Proteomic Analysis of Brugia malayi Excretory-Secretory Products

To succeed in infection, parasites must have ways to reach the host, penetrate its tissues and escape its defense systems. As they are not necessarily fatal, most helminth parasites remain viable within their host for many years, exerting a strong influence over the host immune function. Many of these functions are performed by products that are released from the parasite. We exploited the remarkable sensitivity of modern proteomics tools together with the availability of a sequenced genome to identify and compare the proteins released in vitro by adult males, adult females and the microfilariae of the filarial nematode Brugia malayi. This parasite is one of the etiological agents of lymphatic filariasis, a disease that poses continuing and significant threats to human health. The different forms of the parasite inhabit different compartments in the mammalian host. We found that the set of proteins released by each form is unique; they must reflect particular developmental processes and different strategies for evasion of host responses. The identification of these proteins will allow us to illuminate the biology of secretory processes in this organism and to establish a path for developing an understanding of how these parasite proteins function in immune evasion events