The Experts below are selected from a list of 25710 Experts worldwide ranked by ideXlab platform

Jennifer S Davis - One of the best experts on this subject based on the ideXlab platform.

  • immunoglobulin fc domain fusion to trail significantly prolongs its Plasma Half Life and enhances its antitumor activity
    Molecular Cancer Therapeutics, 2014
    Co-Authors: Haizhen Wang, Jennifer S Davis
    Abstract:

    TRAIL (Apo2L) is a potent inducer of cell death. Interest in TRAIL has increased, following the observation that TRAIL can selectively kill a wide variety of human cancer cells without killing normal cells both in vitro and when grown as xenografts. Therefore, TRAIL has been proposed as a promising anticancer agent and currently is being tested in clinical trials. However, recombinant TRAIL has a very short Plasma Half-Life, which limits its therapeutic potential. To overcome this limitation, we investigated the ability of the human IgG1 fragment crystallizable region (Fc) to enhance TRAIL stability. In this report, we show that Fc-TRAIL chimeric protein displays higher specific activity in vitro and a significantly longer Half-Life in mice than recombinant human TRAIL (rh-TRAIL). No short-term toxicity, especially liver toxicity, was observed. More importantly, Fc-TRAIL was much more effective in inhibiting tumor growth in a xenograft tumor model compared with rh-TRAIL. Our data suggest that fusion of Fc to TRAIL is able to improve the bioavailability and activity of TRAIL both in vitro and in vivo, and Fc-TRAIL may be explored for future clinical applications in cancer treatment and prevention.

  • immunoglobulin fc domain fusion to trail significantly prolongs its Plasma Half Life and enhances its antitumor activity
    Molecular Cancer Therapeutics, 2014
    Co-Authors: Haizhen Wang, Jennifer S Davis, Xiangwei Wu
    Abstract:

    TRAIL (Apo2L) is a potent inducer of cell death. Interest in TRAIL has increased, following the observation that TRAIL can selectively kill a wide variety of human cancer cells without killing normal cells both in vitro and when grown as xenografts. Therefore, TRAIL has been proposed as a promising anticancer agent and currently is being tested in clinical trials. However, recombinant TRAIL has a very short Plasma Half-Life, which limits its therapeutic potential. To overcome this limitation, we investigated the ability of the human IgG1 fragment crystallizable region (Fc) to enhance TRAIL stability. In this report, we show that Fc-TRAIL chimeric protein displays higher specific activity in vitro and a significantly longer Half-Life in mice than recombinant human TRAIL (rh-TRAIL). No short-term toxicity, especially liver toxicity, was observed. More importantly, Fc-TRAIL was much more effective in inhibiting tumor growth in a xenograft tumor model compared with rh-TRAIL. Our data suggest that fusion of Fc to TRAIL is able to improve the bioavailability and activity of TRAIL both in vitro and in vivo , and Fc-TRAIL may be explored for future clinical applications in cancer treatment and prevention. Mol Cancer Ther; 13(3); 643–50. ©2014 AACR .

Arne Skerra - One of the best experts on this subject based on the ideXlab platform.

  • zr labeled versus i labeled αher2 fab with optimized Plasma Half Life for high contrast tumor imaging in vivo
    The Journal of Nuclear Medicine, 2015
    Co-Authors: Claudia T Mendler, Hansjurgen Wester, Torben Gehring, Markus Schwaiger, Arne Skerra
    Abstract:

    Immuno-PET imaging of the tumor antigen HER2/neu allows for the noninvasive detection and monitoring of oncogene expression; such detection and monitoring are of prognostic value in patients with breast cancer. Compared with the full-size antibody trastuzumab, smaller protein tracers with more rapid blood clearance permit higher imaging contrast at earlier time points. Antigen-binding fragments (Fabs) of antibodies with moderately prolonged circulation achieved through the genetic fusion with a long, conformationally disordered chain of the natural amino acids Pro, Ala, and Ser (PASylation)—a biologic alternative to chemical conjugation with polyethylene glycol, PEG—offer a promising tracer format with improved pharmacokinetics for in vivo imaging. Recently, the transition metal radionuclide 89Zr has attracted increasing interest for immuno-PET studies, complementing the conventional halogen radionuclide 124I. Methods: To allow direct comparison of these 2 radioactive labels for the same protein tracer, the recombinant αHER2 Fab fused with 200 Pro, Ala, and Ser (PAS200) residues was either conjugated with 124I via an iodination reagent or coupled with deferoxamine (Df) and complexed with 89Zr. After confirmation of the stability of both radioconjugates and quality control in vitro, immuno-PET and biodistribution studies were performed with CD1-Foxn1nu mice bearing HER2-positive human tumor xenografts. Results:89Zr⋅Df-Fab-PAS200 and 124I-Fab-PAS200 showed specific tumor uptake of 11 and 2.3 percentage injected dose per gram 24 h after injection, respectively; both led to high tumor-to-blood (3.6 and 4.4, respectively) and tumor-to-muscle (20 and 43, respectively) ratios. With regard to off-target accumulation, overt 124I activity was seen in the thyroid, as expected, whereas high kidney uptake was evident for 89Zr; the latter was probably due to glomerular filtration and reabsorption of the protein tracer in proximal tubular cells. Conclusion: Both 89Zr- and 124I-labeled versions of αHER2 Fab-PAS200 allowed PET tumor imaging with high contrast. With its residualizing radiometal, the tracer 89Zr⋅Df-Fab-PAS200 showed better in vivo stability and higher tumor uptake.

  • pasylation of murine leptin leads to extended Plasma Half Life and enhanced in vivo efficacy
    Molecular Pharmaceutics, 2015
    Co-Authors: Florian Bolze, Martin Schlapschy, S Schneider, F Sedlmayer, Katrin Seyfarth, Martin Klingenspor, Arne Skerra
    Abstract:

    Leptin plays a central role in the control of energy homeostasis and appetite and, thus, has attracted attention for therapeutic approaches in spite of its limited pharmacological activity owing to the very short circulation in the body. To improve drug delivery and prolong Plasma Half-Life, we have fused murine leptin with Pro/Ala/Ser (PAS) polypeptides of up to 600 residues, which adopt random coil conformation with expanded hydrodynamic volume in solution and, consequently, retard kidney filtration in a similar manner as polyethylene glycol (PEG). Relative to unmodified leptin, size exclusion chromatography and dynamic light scattering revealed an approximately 21-fold increase in apparent size and a much larger molecular diameter of around 18 nm for PAS(600)-leptin. High receptor-binding activity for all PASylated leptin versions was confirmed in BIAcore measurements and cell-based dual-luciferase assays. Pharmacokinetic studies in mice revealed a much extended Plasma Half-Life after ip injection, fro...

  • pasylation a biological alternative to pegylation for extending the Plasma Half Life of pharmaceutically active proteins
    Protein Engineering Design & Selection, 2013
    Co-Authors: Martin Schlapschy, Uli Binder, Claudia Borger, Ina Theobald, Klaus Wachinger, Sigrid Kisling, Dirk Haller, Arne Skerra
    Abstract:

    A major limitation of biopharmaceutical proteins is their fast clearance from circulation via kidney filtration, which strongly hampers efficacy both in animal studies and in human therapy. We have developed conformationally disordered polypeptide chains with expanded hydrodynamic volume comprising the small residues Pro, Ala and Ser (PAS). PAS sequences are hydrophilic, uncharged biological polymers with biophysical properties very similar to poly-ethylene glycol (PEG), whose chemical conjugation to drugs is an established method for Plasma Half-Life extension. In contrast, PAS polypeptides offer fusion to a therapeutic protein on the genetic level, permitting Escherichia coli production of fully active proteins and obviating in vitro coupling or modification steps. Furthermore, they are biodegradable, thus avoiding organ accumulation, while showing stability in serum and lacking toxicity or immunogenicity in mice. We demonstrate that PASylation bestows typical biologics, such as interferon, growth hormone or Fab fragments, with considerably prolonged circulation and boosts bioactivity in vivo.

  • fusion of a recombinant antibody fragment with a homo amino acid polymer effects on biophysical properties and prolonged Plasma Half Life
    Protein Engineering Design & Selection, 2007
    Co-Authors: Martin Schlapschy, Ina Theobald, Hildegard I D Mack, Margret Schottelius, Hansjurgen Wester, Arne Skerra
    Abstract:

    Chemical conjugation of small recombinant proteins with polyethylene glycol (PEG) is an established strategy to extend their typically short circulation times to a therapeutically useful range. We have investigated the production of a genetic fusion with a glycine-rich homo-amino-acid polymer (HAP) as an alternative way to attach a solvated random chain with large hydrodynamic volume. The anti-HER2 Fab fragment 4D5 was used as a model system and fused with either 100 or 200 residue polymers of the repetitive sequence (Gly(4)Ser)(n) to its light chain. Both fusion proteins were successfully produced in the periplasm of Escherichia coli and obtained as homogeneous preparations after two-step affinity chromatography via the His(6) tag fused to the heavy chain and the Strep-tag II fused to the extended light chain. Both modified Fab fragments showed binding activity towards the HER2 antigen indistinguishable from the conventional recombinant Fab fragment. When compared with the unfused Fab fragment, a significantly increased hydrodynamic volume, by ca. 120%, was observed during gel filtration for the 200 residue HAP fusion protein and, to a lesser extent, in the case of the 100 residue HAP. Difference CD measurements revealed a characteristic random coil spectrum for the 100 and 200 residue HAP fusion moieties. Finally, pharmacokinetic experiments were carried out in mice after radioiodination of the recombinant Fab fragments. Although the 100 residue HAP fusion showed a behavior very similar to the unfused Fab fragment, with a terminal Plasma Half-Life of ca. 2 h, the 200 residue HAPylated Fab fragment gave rise to a significantly prolonged Half-Life of ca. 6 h. While this moderate effect may so far be most beneficial for specialized medical applications, such as in vivo imaging, the genetic engineering of optimized HAP sequences should yield pharmacokinetic properties similar to PEGylation, yet without necessitating in vitro modification steps.

Haizhen Wang - One of the best experts on this subject based on the ideXlab platform.

  • immunoglobulin fc domain fusion to trail significantly prolongs its Plasma Half Life and enhances its antitumor activity
    Molecular Cancer Therapeutics, 2014
    Co-Authors: Haizhen Wang, Jennifer S Davis
    Abstract:

    TRAIL (Apo2L) is a potent inducer of cell death. Interest in TRAIL has increased, following the observation that TRAIL can selectively kill a wide variety of human cancer cells without killing normal cells both in vitro and when grown as xenografts. Therefore, TRAIL has been proposed as a promising anticancer agent and currently is being tested in clinical trials. However, recombinant TRAIL has a very short Plasma Half-Life, which limits its therapeutic potential. To overcome this limitation, we investigated the ability of the human IgG1 fragment crystallizable region (Fc) to enhance TRAIL stability. In this report, we show that Fc-TRAIL chimeric protein displays higher specific activity in vitro and a significantly longer Half-Life in mice than recombinant human TRAIL (rh-TRAIL). No short-term toxicity, especially liver toxicity, was observed. More importantly, Fc-TRAIL was much more effective in inhibiting tumor growth in a xenograft tumor model compared with rh-TRAIL. Our data suggest that fusion of Fc to TRAIL is able to improve the bioavailability and activity of TRAIL both in vitro and in vivo, and Fc-TRAIL may be explored for future clinical applications in cancer treatment and prevention.

  • immunoglobulin fc domain fusion to trail significantly prolongs its Plasma Half Life and enhances its antitumor activity
    Molecular Cancer Therapeutics, 2014
    Co-Authors: Haizhen Wang, Jennifer S Davis, Xiangwei Wu
    Abstract:

    TRAIL (Apo2L) is a potent inducer of cell death. Interest in TRAIL has increased, following the observation that TRAIL can selectively kill a wide variety of human cancer cells without killing normal cells both in vitro and when grown as xenografts. Therefore, TRAIL has been proposed as a promising anticancer agent and currently is being tested in clinical trials. However, recombinant TRAIL has a very short Plasma Half-Life, which limits its therapeutic potential. To overcome this limitation, we investigated the ability of the human IgG1 fragment crystallizable region (Fc) to enhance TRAIL stability. In this report, we show that Fc-TRAIL chimeric protein displays higher specific activity in vitro and a significantly longer Half-Life in mice than recombinant human TRAIL (rh-TRAIL). No short-term toxicity, especially liver toxicity, was observed. More importantly, Fc-TRAIL was much more effective in inhibiting tumor growth in a xenograft tumor model compared with rh-TRAIL. Our data suggest that fusion of Fc to TRAIL is able to improve the bioavailability and activity of TRAIL both in vitro and in vivo , and Fc-TRAIL may be explored for future clinical applications in cancer treatment and prevention. Mol Cancer Ther; 13(3); 643–50. ©2014 AACR .

Florence Dixmerias - One of the best experts on this subject based on the ideXlab platform.

  • prolonged qt interval and torsade de pointes following astemizole overdose
    Clinical Toxicology, 1993
    Co-Authors: Philippe Saviuc, Vincent Danel, Florence Dixmerias
    Abstract:

    AbstractA 26 year-old woman was admitted to the hospital two hours after astemizole overdose. Electrocardiograph showed a prolonged QT interval. Torsade de pointes occurred 13 h after ingestion. Plasma levels of astemizole plus hydroxylated metabolites showed an apparent Plasma Half-Life of 17 h. The possible occurrence of torsade de pointes in astemizole overdose, and the long elimination time of astemizole and hydroxylated metabolites, makes it necessary to maintain ECG monitoring until QT interval has returned to normal.

  • prolonged qt interval and torsade de pointes following astemizole overdose
    Clinical Toxicology, 1993
    Co-Authors: Philippe Saviuc, Vincent Danel, Florence Dixmerias
    Abstract:

    AbstractA 26 year-old woman was admitted to the hospital two hours after astemizole overdose. Electrocardiograph showed a prolonged QT interval. Torsade de pointes occurred 13 h after ingestion. Plasma levels of astemizole plus hydroxylated metabolites showed an apparent Plasma Half-Life of 17 h. The possible occurrence of torsade de pointes in astemizole overdose, and the long elimination time of astemizole and hydroxylated metabolites, makes it necessary to maintain ECG monitoring until QT interval has returned to normal.

Xiangwei Wu - One of the best experts on this subject based on the ideXlab platform.

  • immunoglobulin fc domain fusion to trail significantly prolongs its Plasma Half Life and enhances its antitumor activity
    Molecular Cancer Therapeutics, 2014
    Co-Authors: Haizhen Wang, Jennifer S Davis, Xiangwei Wu
    Abstract:

    TRAIL (Apo2L) is a potent inducer of cell death. Interest in TRAIL has increased, following the observation that TRAIL can selectively kill a wide variety of human cancer cells without killing normal cells both in vitro and when grown as xenografts. Therefore, TRAIL has been proposed as a promising anticancer agent and currently is being tested in clinical trials. However, recombinant TRAIL has a very short Plasma Half-Life, which limits its therapeutic potential. To overcome this limitation, we investigated the ability of the human IgG1 fragment crystallizable region (Fc) to enhance TRAIL stability. In this report, we show that Fc-TRAIL chimeric protein displays higher specific activity in vitro and a significantly longer Half-Life in mice than recombinant human TRAIL (rh-TRAIL). No short-term toxicity, especially liver toxicity, was observed. More importantly, Fc-TRAIL was much more effective in inhibiting tumor growth in a xenograft tumor model compared with rh-TRAIL. Our data suggest that fusion of Fc to TRAIL is able to improve the bioavailability and activity of TRAIL both in vitro and in vivo , and Fc-TRAIL may be explored for future clinical applications in cancer treatment and prevention. Mol Cancer Ther; 13(3); 643–50. ©2014 AACR .