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Zimmermann S.,Hanover Clinical Trial Center GmbH | Hollmann C.,Glaxosmithkline | Stachelhaus S.A.,Human Gesellschaft fur Biochemica und Diagnostica mbH
Experimental Cell Research | Year: 2013

Background: Continuing efforts in development of non-invasive prenatal genetic tests have focused on the isolation of fetal nucleated red blood cells (NRBCs) from maternal blood for decades. Because no fetal cell-specific antibody has been described so far, the present study focused on the development of monoclonal antibodies (mAbs) to antigens that are expressed exclusively on fetal NRBCs. Methods: Mice were immunized with fetal erythroid cell membranes and hybridomas screened for Abs using a multi-parameter fluorescence-activated cell sorting (FACS). Selected mAbs were evaluated by comparative FACS analysis involving Abs known to bind erythroid cell surface markers (CD71, CD36, CD34), antigen-i, galactose, or glycophorin-A (GPA). Specificity was further confirmed by extensive immunohistological and immunocytological analyses of NRBCs from umbilical cord blood and fetal and adult cells from liver, bone marrow, peripheral blood, and lymphoid tissues. Results: Screening of 690 hybridomas yielded three clones of which Abs from 4B8 and 4B9 clones demonstrated the desired specificity for a novel antigenic structure expressed on fetal erythroblast cell membranes. The antigenic structure identified is different from known surface markers (CD36, CD71, GPA, antigen-i, and galactose), and is not present on circulating adult erythroid cells, except for occasional detectability in adult bone marrow cells. © 2013 The Authors.

Budde S.,Hannover Medical School | Noll Y.,Hannover Medical School | Zieglschmid V.,Hanover Clinical Trial Center GmbH | Schroeder C.,Hannover Medical School | And 2 more authors.
Trials | Year: 2015

Background: After total knee replacement, overall blood loss is often underestimated, although it exceeds the visible blood loss caused by bleeding into the tissues or into the joint. The use of fibrin sealants during surgery has been suggested to reduce perioperative blood loss and transfusion rates and may be beneficial for patient recovery and the postoperative function of the joint. Methods/Design: This will be a single-centre, single-blinded, randomised controlled trial with a parallel design, for which 68 patients undergoing total knee replacement will be recruited and followed up at 3, 6 and 12 months; 34 will be control patients who will receive the standard orthopaedic surgery treatment (electrocoagulation), and the other 34 will receive the same treatment plus 5 ml EVICEL™ applied during surgery and used according to the manufacturer's instructions. The primary objective is to test the null hypothesis that the effect of EVICEL™ for controlling haemostasis and reducing postoperative blood loss in patients undergoing total knee replacement is not superior to the use of electrocoagulation alone. The secondary objective is to show that EVICEL™ reduces the need for transfusion, increases range of motion, improves clinical outcome and wound healing, and reduces the need for analgesics. The tertiary objective is to show that EVICEL™ reduces the costs of total knee replacement treatment. Discussion: So far, studies on the effect of fibrin sealants in total knee replacement have delivered inconsistent and ambivalent results, indicating that there is still a need for high-evidence studies as proposed in the presented study protocol. © 2015 Budde et al.

Voelkel C.,Hannover Medical School | Voelkel C.,Hanover Clinical Trial Center GmbH | Luhrmann A.,Hanover Clinical Trial Center GmbH | Baum C.,Hannover Medical School | And 2 more authors.
Cellular Therapy and Transplantation | Year: 2010

Retrovirus mediated gene therapy has already proven to be more than just a theoretical option to treat patients with severe genetic defects. Clinical gene therapy trials of X-linked severe combined immunodeficiency or adenosine deaminase deficiency have demonstrated the success and potential benefit of the therapy. Nevertheless, the complexity of the therapeutic products and their biological origin, as well as virus-related safety concerns require the need of a strict regulatory framework in order to guarantee the quality of the individual products and safety of the patients. The aim of this review is to give an overview of the rapidly evolving regulatory framework of Advanced Therapy Medicinal Products in Europe. We will summarize the most important regulatory documents to be considered before entering the clinical development phase-not only from a German but also from a European perspective. © The Authors.

Pincha M.,Hannover Medical School | Sai Sundarasetty B.,Hannover Medical School | Salguero G.,Hannover Medical School | Gutzmer R.,Hannover Medical School | And 14 more authors.
Human Gene Therapy Methods | Year: 2012

SmartDCs (Self-differentiated Myeloid-derived Antigen-presenting-cells Reactive against Tumors) consist of highly viable dendritic cells (DCs) induced to differentiate with lentiviral vectors (LVs) after an overnight ex vivo transduction. Tricistronic vectors co-expressing cytokines (granulocyte- macrophage-colony stimulating factor [GM-CSF], interleukin [IL]-4) and a melanoma antigen (tyrosine related protein 2 [TRP2]) were used to transduce mouse bone marrow cells or human monocytes. Sixteen hours after transduction, the cells were dispensed in aliquots and cryopreserved for identity, potency, and safety analyses. Thawed SmartDCs readily differentiated into highly viable cells with a DC immunophenotype. Prime/boost subcutaneous administration of 1×106 thawed murine SmartDCs into C57BL/6 mice resulted into TRP2-specific CD8+ T-cell responses and protection against lethal melanoma challenge. Human SmartDC-TRP2 generated with monocytes obtained from melanoma patients secreted endogenous cytokines associated with DC activation and stimulated TRP2-specific autologous T-cell expansion in vitro. Thawed human SmartDCs injected subcutaneously in NOD.Rag1-/-.IL2rγ -/- mice maintained DC characteristics and viability for 1 month in vivo and did not cause any signs of pathology. For development of good manufacturing practices, CD14+ monocytes selected by magnetic-activated cell separation were transduced in a closed bag system (multiplicity of infection of 5), washed, and cryopreserved. Fifty percent of the monocytes used for transduction were recovered for cryopreservation. Thawed SmartDCs produced in two independent runs expressed the endogenous cytokines GM-CSF and IL-4, and the resulting homogeneous SmartDCs that self-differentiated in vitro contained approximately 1.5-3.0 copies of integrated LVs per cell. Thus, this method facilitates logistics, standardization, and high recovery for the generation of viable genetically reprogrammed DCs for clinical applications. © 2012, Mary Ann Liebert, Inc.

Walter C.,Hanover Clinical Trial Center GmbH | Rohde B.,Hanover Clinical Trial Center GmbH | Wicke D.C.,Hanover Clinical Trial Center GmbH | Pohler C.,Hanover Clinical Trial Center GmbH | And 2 more authors.
Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz | Year: 2011

Novel therapies, e.g., cell and gene therapy or tissue engineering, are summarized in the European Union as advanced therapy medicinal products (ATMPs). In terms of composition and product properties, ATMPs are highly complex, and given their multiple potential actions they are subject to continuously developing regulatory requirements. Due to promising basic research findings, there are high expectations by the society toward the therapeutic potential of ATMPs. It is of utmost importance to develop a scientifically sound preclinical and clinical development plan before entering into the first clinical trial. Due to the complex features of ATMPs, this development plan should be discussed early with the regulatory authorities to define the specifics and challenges of each individual product. For planning as well as operational realization of the initial clinical trial involving ATMPs, specific requirements that need to be addressed are discussed in this paper. © 2011 Springer Medizin Verlag.

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