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1.
Renner C Hartmann F Jung W Deisting C Juwana M Pfreundschuh M 《Cancer immunology, immunotherapy : CII》2000,49(3):173-180
Fifteen patients with refractory Hodgkin's disease were treated in a dose-escalation trial with the bispecific monoclonal
antibody (bi-mAb) HRS-3/A9, which is directed against the Fcγ receptor III (CD16 antigen) and the Hodgkin's-associated CD30
antigen. Treatment consisted of four cycles of four bi-mAb infusions given over 1 h every 3–4 days at different dose levels
ranging from 1 mg/m2 to 64 mg/m2. Measurable serum levels (above 0.1 μg/ml) of circulating bi-mAb could be detected in patients treated with doses above 4 mg/m2, reaching peak levels of 9.5 μg/ml immediately after the end of antibody infusion on the highest dose level. Bi-mAb elimination
corresponded to second-order kinetics with a terminal half-life time (t
1/2,β) of 28–32 h. Bi-mAb treatment induced the occurrence of human anti-(mouse Ig) antibodies (HAMA) in 6 out of 13 patients initially
testing negative. All 6 patients not only developed anti-isotypic anti-(mouse Ig) but also anti-idiotypic and anti-anti-idiotypic
antibodies. While no consistent changes of peripheral blood cell counts, or of any lymphocyte subpopulation including natural
killer (NK) cells, has been observed, 4 out of 6 evaluable patients treated with doses of at least 4 mg/m2 showed an increase of NK cell activity within 2 weeks after treatment, which lasted for a maximum of 12 weeks. Circulating
amounts of soluble CD30 antigen could be detected in the serum of 6 patients. However, like the results and time courses of
all the other immunological parameters evaluated, this was not predictive for treatment outcome.
Received: 16 September 1999 / Accepted: 6 January 2000 相似文献
2.
Liewen H Meinhold-Heerlein I Oliveira V Schwarzenbacher R Luo G Wadle A Jung M Pfreundschuh M Stenner-Liewen F 《Experimental cell research》2005,306(1):24-34
The Golgi associated retrograde protein complex (GARP) or Vps fifty-three (VFT) complex is part of cellular inter-compartmental transport systems. Here we report the identification of the VFT tethering factor complex and its interactions in mammalian cells. Subcellular fractionation shows that human Vps proteins are found in the smooth membrane/Golgi fraction but not in the cytosol. Immunostaining of human Vps proteins displays a vesicular distribution most concentrated at the perinuclear envelope. Co-staining experiments with endosomal markers imply an endosomal origin of these vesicles. Significant accumulation of VFT complex positive endosomes is found in the vicinity of the Trans Golgi Network area. This is in accordance with a putative role in Golgi associated transport processes. In Saccharomyces cerevisiae, GARP is the main effector of the small GTPase Ypt6p and interacts with the SNARE Tlg1p to facilitate membrane fusion. Accordingly, the human homologue of Ypt6p, Rab6, specifically binds hVps52. In human cells, the "orphan" SNARE Syntaxin 10 is the genuine binding partner of GARP mediated by hVps52. This reveals a previously unknown function of human Syntaxin 10 in membrane docking and fusion events at the Golgi. Taken together, GARP shows significant conservation between various species but diversification and specialization result in important differences in human cells. 相似文献
3.
Johannes Thoma Patrick Bosshart Moritz Pfreundschuh Daniel J. Müller 《Structure (London, England : 1993)》2012,20(12):2185-2190
Highlights? Mechanical un- and refolding studies of single large transmembrane β-barrel proteins ? FhuA unfolds via highly reproducible steps formed by single β-hairpins ? Once unfolded, FhuA folds into highly irreproducible structures ? To assist folding into the membrane, FhuA may require cofactors 相似文献
4.
Ugur Sahin Sylvia Kraft-Bauer Sascha Ohnesorge M. Pfreundschuh Christoph Renner 《Cancer immunology, immunotherapy : CII》1996,42(1):9-14
The combination of CD16/CD30 bispecific monoclonal antibodies (bi-mAb) and unstimulated human resting natural killer (NK)
cells can cure about 50% of mice with severe combined immunodeficiency (SCID) bearing subcutaneously growing established Hodgkin’s
lymphoma. As interleukin-2 (IL-2) and IL-12 have been shown to increase NK cell activity, we tested the capacity of these
cytokines to increase bi-mAb-mediated NK cell cytotoxicity against two types of human tumors (Hodgkin’s disease and colorectal
carcinoma). Unstimulated NK cells needed a three- to five-times higher antibody concentration than cytokine-stimulated NK
cells to exert similar levels of bi-mAb-mediated cytotoxicity. The augmented tumor cell lysis was achieved with IL-12 at considerably
lower concentrations than with IL-2 and was associated with a significantly increased bi-mAb-mediated intracellular Ca2+ mobilization. The efficiency of IL-12 in this setting together with its low toxicity make it the ideal candidate for a combination
therapy with NK-cell-activating bi-mAb in human tumors that are resistant to standard treatment.
Received: 26 July 1995 / Accepted: 16 November 1995 相似文献
5.
6.
Neumann F Kubuschok B Ertan K Schormann C Stevanovic S Preuss KD Schmidt W Pfreundschuh M 《Cancer immunology, immunotherapy : CII》2011,60(9):1333-1346
Background
Antigen-derived HLA class I-restricted peptides can generate specific CD8+ T-cell responses in vivo and are therefore often used as vaccines for patients with cancer. However, only occasional objective clinical responses have been reported suggesting the necessity of CD4+ T-cell help and possibly antibodies for the induction of an effective anti-tumor immunity in vivo. The SSX2 gene encodes the cancer testis antigen (CTA) HOM-MEL-40/SSX2, which is frequently expressed in a wide spectrum of cancers. Both humoral and cellular immune responses against SSX2 have been described making SSX2 an attractive candidate for vaccine trials.Methods
SYFPEITHI algorithm was used to predict five pentadecamer peptides with a high binding probability for six selected HLA-DRB1 subtypes (*0101, *0301, *0401, *0701, *1101, *1501) which are prevalent in the Caucasian population.Results
Using peripheral blood cells of 13 cancer patients and 5 healthy controls, the HOM-MEL-40/SSX2-derived peptide p101-111 was identified as an epitope with dual immunogenicity for both CD4+ helper and cytotoxic CD8+ T cells. This epitope also reacted with anti-SSX2 antibodies in the serum of a patient with breast cancer. Most remarkably, SSX2/p101-111 simultaneously induced specific CD8, CD4, and antibody responses in vitro.Conclusions
p101-111 is the first CTA-derived peptide which induces CD4+, CD8+, and B-cell responses in vitro. This triple-immunogenic peptide represents an attractive vaccine candidate for the induction of effective anti-tumor immunity. 相似文献7.
Estefania Mulvihill Lorenzo Sborgi Stefania A Mari Moritz Pfreundschuh Sebastian Hiller Daniel J Müller 《The EMBO journal》2018,37(14)
Gasdermin‐D (GSDMD), a member of the gasdermin protein family, mediates pyroptosis in human and murine cells. Cleaved by inflammatory caspases, GSDMD inserts its N‐terminal domain (GSDMDNterm) into cellular membranes and assembles large oligomeric complexes permeabilizing the membrane. So far, the mechanisms of GSDMDNterm insertion, oligomerization, and pore formation are poorly understood. Here, we apply high‐resolution (≤ 2 nm) atomic force microscopy (AFM) to describe how GSDMDNterm inserts and assembles in membranes. We observe GSDMDNterm inserting into a variety of lipid compositions, among which phosphatidylinositide (PI(4,5)P2) increases and cholesterol reduces insertion. Once inserted, GSDMDNterm assembles arc‐, slit‐, and ring‐shaped oligomers, each of which being able to form transmembrane pores. This assembly and pore formation process is independent on whether GSDMD has been cleaved by caspase‐1, caspase‐4, or caspase‐5. Using time‐lapse AFM, we monitor how GSDMDNterm assembles into arc‐shaped oligomers that can transform into larger slit‐shaped and finally into stable ring‐shaped oligomers. Our observations translate into a mechanistic model of GSDMDNterm transmembrane pore assembly, which is likely shared within the gasdermin protein family. 相似文献
8.
The leukocyte alklaine phosphatase (LAP) levels were determined in 183 patients with malignant diseases and 71 normal controls. The median LAP scores were 64 units (range 0 to 290) for the patients and 55 (range 2 to 158) for the controls, respectively, and no significant difference could be established. When analyzed according to primary malignancy, only in patients with Hodgkin's disease (n = 14) was the median value higher than normal (p less than 0.001). In patients with distant metastases (n = 48), higher LAP levels were demonstrated (M = 76, range 21 to 290) as compared to patients with no evidence of metastases (M = 53, range 0 to 229), (p less than 0.01). Thus, LAP activity has very limited value in the diagnosis of malignancies. Its elevation in the presence of malignant disease might, however, indicate metastases. 相似文献
9.
Renner C Stehle I Lee FT Hall C Catimel B Nice EC Mountain A Rigopoulos A Brechbiel MW Pfreundschuh M Scott AM 《Cancer immunology, immunotherapy : CII》2001,50(2):102-108
Bispecific antibodies are currently being used in clinical trials in increasing numbers in the areas of breast cancer, prostate
cancer, non-Hodgkin's lymphoma and Hodgkin's lymphoma. We have previously performed two clinical trials in patients with Hodgkin's
disease with an anti-CD30/anti-CD16 bispecific antibody and demonstrated a 30% response rate in a cohort of patients otherwise
resistant to standard therapeutic modalities. However, no surrogate marker could be defined in these trials indicative of
optimal antibody dosing/scheduling or predictive for favorable response. In order to evaluate accurately the potential biodistribution
properties of bispecific antibody in patients, we have performed a detailed analysis of the binding properties and animal
model in vivo characteristics of these constructs. For this purpose, the parental antibodies (anti-CD30 and anti-CD16) and
the bispecific antibody (anti-CD30/anti-CD16) were radiolabeled with either 125I or 111In. Antibody integrity and binding properties after labeling were confirmed by Scatchard plot and Lindmo analysis. 111In-labeled antibodies revealed superior targeting properties in a standard SCID mouse tumor model. Both the bivalent parental
anti-CD30 monoclonal antibody and the monovalent anti-CD30/anti-CD16 bispecific antibody showed excellent uptake in CD30+ tumors which did not differ significantly between the two (maximum uptake 16.5% ± 4.2% vs. 18.4% ± 3.8% injected dose/gram
tissue). The equivalent targeting properties of the bispecific antibody compared with the parental anti-CD30 antibody encourages
the further clinical development of this bispecific antibody, and might help to explain the clinical responses seen with this
antibody so far in patients suffering from Hodgkin's disease.
Received: 26 October 2000 / Accepted: 15 December 2000 相似文献
10.
Lorenz Thurner Marina Zaks Klaus-Dieter Preuss Natalie Fadle Evi Regitz Mei Fang Ong Michael Pfreundschuh Gunter Assmann 《Arthritis research & therapy》2013,15(6):R211