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Coronel J.,Federal University of Rio de Janeiro | Klausing S.,Xell AG | Heinrich C.,Xell AG | Noll T.,Bielefeld University | And 2 more authors.
Biochemical Engineering Journal | Year: 2016

Aiming at increasing productivity in mammalian cell processes, mild hypothermia and supplementation with short-chain fatty acids have been investigated in literature, but usually separately. The combined effects of butyric acid and hypothermia were investigated in a few studies, but despite the lower cytotoxicity of valeric acid no reports were found on its use under low temperatures. In this work, DOE was used to compare supplementation with both butyrate and valerate at 31, 34 and 37 °C to enhance recombinant protein productivity in a CHO cell process. Due to the promising results obtained with valerate, this fatty acid was further investigated. According to the results obtained, 1 mM valeric acid at 31 °C enables high cell viabilities, higher product titres and increases cell specific productivity (qp) by approximately 4-fold. Cell cycle analysis showed that at 31 °C, especially with valerate, a higher percentage of cells was in G0 + G1 phase. Overall, an inverse relation between qp and cell proliferation state [S/(G0 + G1) ratio] was observed. To our knowledge, this is the first work describing the effects of valeric acid under mild hypothermia on CHO cell cultivations. The results provide a promising tool to increase qp under lower proliferation rates, which can be very useful to develop robust high-cell-density, high-productivity perfusion processes. © 2016 Elsevier B.V. Source

Objectives: To study the maternofetal and milk transfer of an anti-epidermal growth factor receptor (EGFR) monoclonal antibody (MAb) and its effects on conceptus, we administered to pregnant and lactating dams the murine anti-EGFR MAb 7A7 in an autologus model. Study design: For determining the embryo-fetal toxicity, 7A7 at gestational days (GD) 6, 8, 12 and 14 were intravenously administered. Clinical signs and body weights were recorded. On GD 18 pregnant mice were euthanized and the alive and dead fetuses were examined. For measuring the maternofetal transfer mice were dosed on GD 14 with 125I-7A7, after 24 h, mice were euthanized and main maternal organs and fetuses were counted separately for radioactivity. For studying the MAb transferred throughout the milk, lactating dams were intravenously dosed on lactation day (LD) 2 with 125I-7A7. Blood samples were obtained from dams at different times post. One lactating pup from each dam was also euthanized at different times, and their blood and gastric milk were removed and the radioactivities measured. Results: The administration of the 7A7 did not elicit toxicity to adult pregnant mice nevertheless; there was evidence of embryo-fetal toxicity in the 7A7 group characterized by a decrease in litters' body weights and head deformities. The maternofetal transfer of 125I-7A7 antibody on GD 15 was only of a 4%. Conclusion: Results suggest that 7A7 crosses placenta and it is transferred in a superior quantity to pups through the milk and that anti-EGFR MAbs have a potential toxic effect to fetuses. © 2011 Elsevier Ltd. All rights reserved. Source

Figueroa-Morales N.,University of Habana | Leon K.,Center for Molecular Immunology | Mulet R.,University of Habana
Journal of Theoretical Biology | Year: 2012

We develop a stochastic model to study the specific response of the immune system. The model is based on the dynamical interaction between Regulatory and Effector CD4+ T cells in the presence of Antigen Presenting Cells inside a lymphatic node. At a mean field level the model predicts the existence of different regimes where active, tolerant, or cyclic immune responses are possible. To study the model beyond mean field and to understand the specific responses of the immune system we use the Linear Noise Approximation and show that fluctuations due to finite size effects may strongly alter the mean field scenario. Moreover, it was found that the existence of a certain characteristic frequency for the fluctuations. All the analytical predictions were compared with simulations using Gillespie's algorithm. © 2011 Elsevier Ltd. Source

Van Rij C.M.,Radboud University Nijmegen | Lutje S.,Radboud University Nijmegen | Frielink C.,Radboud University Nijmegen | Sharkey R.M.,Immunomedics, Inc. | And 8 more authors.
European Journal of Nuclear Medicine and Molecular Imaging | Year: 2013

Purpose: TF12 is a trivalent bispecific antibody that consists of two anti-TROP-2 Fab fragments and one anti-histamine-succinyl-glycine (HSG) Fab fragment. The TROP-2 antigen is found in many epithelial cancers, including prostate cancer (PC), and therefore this bispecific antibody could be suitable for pretargeting in this cancer. In this study, the characteristics and the potential for pretargeted radioimmunoimaging and radioimmunotherapy with TF12 and the radiolabeled di-HSG peptide IMP288 in mice with human PC were investigated. Methods: The optimal TF12 protein dose, IMP288 peptide dose, and dose interval for PC targeting were assessed in nude mice with s.c. PC3 xenografts. Immuno-positron emission tomography (PET)/CT was performed using TF12/68Ga-IMP288 at optimized conditions. The potential of pretargeted radioimmunotherapy (PRIT) using the TF12 pretargeted 177Lu-IMP288 was determined. Results: TF12 and 111In- IMP288 showed high and fast accumulation in the tumor [20.4 ± 0.6 %ID/g at 1 h post-injection (p.i.)] at optimized conditions, despite the internalizing properties of TF12. The potential for PRIT was shown by retention of 50 % of the 111In-IMP288 in the tumor at 48 h p.i. One cycle of treatment with TF12 and 177Lu-IMP288 showed significant improvement of survival compared to treatment with 177Lu-IMP288 alone (90 vs. 67 days, p < 0.0001) with no renal or hematological toxicity. Conclusion: TROP-2-expressing PC can be pretargeted efficiently with TF12, with very rapid uptake of the radiolabeled hapten-peptide, IMP288, sensitive immuno-PET, and effective therapy. © 2013 Springer-Verlag Berlin Heidelberg. Source

Renaudineau Y.,European University of Brittany | Renaudineau Y.,Brest University Hospital Center | Renaudineau Y.,Brest University Medical School Hospital | Garaud S.,European University of Brittany | And 7 more authors.
Clinical Reviews in Allergy and Immunology | Year: 2010

Autoreactive B cells are central in the pathogenesis of autoimmune diseases (AID) not only by producing autoantibodies but also by secreting cytokines and by presenting autoantigens. Changes in DNA methylation, histone modifications, and miRNA expression, the hallmarks of epigenetic failure, characterize B cells isolated from patients with AID, highlighting the contribution of epigenetic processes to autoreactivity. Additional evidence of epigenetic involvement in the development of B cell autoreactivity comes from in vivo and in vitro studies using DNA demethylating agents as accelerating factors or histone deacetylase inhibitors as repressing factors. As a result, a better understanding of the altered epigenetic processes in AID and in particular in B cells opens perspectives for the development of new therapeutics. © 2009 Humana Press Inc. Source

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