The Experts below are selected from a list of 3402 Experts worldwide ranked by ideXlab platform
Ira Pastan - One of the best experts on this subject based on the ideXlab platform.
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engineered anti gpc3 immunotoxin hn3 abd t20 produces regression in mouse liver cancer xenografts through prolonged serum retention
Hepatology, 2020Co-Authors: Bryan D Fleming, Tim F Greten, Daniel J Urban, Matthew D Hall, Thomas Longerich, Ira PastanAbstract:BACKGROUND AND AIMS Treatment of hepatocellular carcinomas using our glypican-3 (GPC3)-targeting human nanobody (HN3) immunotoxins causes potent tumor regression by blocking protein synthesis and down-regulating the Wnt signaling pathway. However, immunogenicity and a short serum half-life may limit the ability of immunotoxins to transition to the clinic. APPROACH AND RESULTS To address these concerns, we engineered HN3-based immunotoxins to contain various deimmunized Pseudomonas exotoxin (PE) domains. This included HN3-T20, which was modified to remove T-cell epitopes and contains a PE domain II truncation. We compared them to our previously reported B-cell deimmunized immunotoxin (HN3-mPE24) and our original HN3-immunotoxin with a wild-type PE domain (HN3-PE38). All of our immunotoxins displayed high affinity to human GPC3, with HN3-T20 having a KD value of 7.4 nM. HN3-T20 retained 73% enzymatic activity when compared with the wild-type immunotoxin in an adenosine diphosphate-ribosylation assay. Interestingly, a real-time cell growth inhibition assay demonstrated that a single dose of HN3-T20 at 62.5 ng/mL (1.6 nM) was capable of inhibiting nearly all cell proliferation during the 10-day experiment. To enhance HN3-T20's serum retention, we tested the effect of adding a streptococcal albumin-binding domain (ABD) and a llama single-domain antibody fragment specific for mouse and human serum albumin. For the detection of immunotoxin in mouse serum, we developed a highly sensitive enzyme-linked immunosorbent assay and found that HN3-ABD-T20 had a 45-fold higher serum half-life than HN3-T20 (326 minutes vs. 7.3 minutes); consequently, addition of an ABD resulted in HN3-ABD-T20-mediated tumor regression at 1 mg/kg. CONCLUSION These data indicate that ABD-containing deimmunized HN3-T20 immunotoxins are high-potency therapeutics ready to be evaluated in clinical trials for the treatment of liver cancer.
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Immunotoxin Therapy for Brain Tumors
Translational Immunotherapy of Brain Tumors, 2017Co-Authors: Vidyalakshmi Chandramohan, Ira Pastan, John H. Sampson, Darellâ D BignerAbstract:Despite a multimodal approach involving surgery, radiotherapy, and chemotherapy, the median survival for malignant brain tumor patients is limited to 15–19 months. To improve glioblastoma patient survival, novel therapies targeting the heterogeneous tumor cell population are needed. Advances in understanding the molecular features of patients' tumors have led to the development of personalized tumor-targeted therapies that are more effective and less toxic. Immunotoxins, a novel class of antibody/ligand-toxin conjugates, have been developed during the last two decades for the treatment of brain tumors. The antibody/ligand domain of the immunotoxin binds to the target antigen on the tumor cell surface, whereas the toxin payload kills the tumor cells by inhibiting protein synthesis. Advances in immunotoxin delivery and monitoring of immunotoxin distribution in tumors are overcoming the challenges in the brain tumor therapy field. Herein, we summarize the different antiglioma immunotoxins that are at the preclinical and clinical stages of development.
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NEOPLASIA Sensitization
2016Co-Authors: Thomas Decker, Ira Pastan, Robert J Kreitman, Christian Peschel, Thomas LichtAbstract:of B-cell chronic lymphocytic leukemia cells to recombinant immunotoxin by immunostimulatory phosphorothioate oligodeoxynucleotide
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quantification of recombinant immunotoxin delivery to solid tumors allows for direct comparison of in vivo and in vitro results
Scientific Reports, 2015Co-Authors: Kevin Hollevoet, Emily Masonosann, Gerhard Niederfellner, Ira PastanAbstract:Quantification of recombinant immunotoxin delivery to solid tumors allows for direct comparison of in vivo and in vitro results
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whole genome rnai screen highlights components of the endoplasmic reticulum golgi as a source of resistance to immunotoxin mediated cytotoxicity
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Matteo Pasetto, Antonella Antignani, Ira Pastan, Rajarshi Guha, Pinar Ormanoglu, Eugen Buehler, Scott E Martin, David J FitzgeraldAbstract:Immunotoxins (antibody–toxin fusion proteins) target surface antigens on cancer cells and kill these cells via toxin-mediated inhibition of protein synthesis. To identify genes controlling this process, an RNAi whole-genome screen (∼22,000 genes at three siRNAs per gene) was conducted via monitoring the cytotoxicity of the mesothelin-directed immunotoxin SS1P. SS1P, a Pseudomonas exotoxin-based immunotoxin, was chosen because it is now in clinical trials and has produced objective tumor regressions in patients. High and low concentrations of SS1P were chosen to allow for the identification of both mitigators and sensitizers. As expected, silencing known essential genes in the immunotoxin pathway, such as mesothelin, furin, KDEL receptor 2, or members of the diphthamide pathway, protected cells. Of greater interest was the observation that many RNAi targets increased immunotoxin sensitivity, indicating that these gene products normally contribute to inefficiencies in the killing pathway. Of the top sensitizers, many genes encode proteins that locate to either the endoplasmic reticulum (ER) or Golgi and are annotated as part of the secretory system. Genes related to the ER-associated degradation system were not among high-ranking mitigator or sensitizer candidates. However, the p97 inhibitor eeyarestatin 1 enhanced immunotoxin killing. Our results highlight potential targets for chemical intervention that could increase immunotoxin killing of cancer cells and enhance our understanding of toxin trafficking.
Zhirui Wang - One of the best experts on this subject based on the ideXlab platform.
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diphtheria toxin based anti human cd19 immunotoxin for targeting human cd19 tumors
Molecular Oncology, 2017Co-Authors: Qian Zheng, Qi Huang, Zhaohui Wang, Huiping Zhang, Christene A. Huang, Joren C. Madsen, David H. Sachs, Zhirui WangAbstract:CD19 is expressed on normal and neoplastic B cells and is a promising target for immunotherapy. However, there is still an unmet need to further develop novel therapeutic drugs for the treatment of the refractory/relapsing human CD19+ tumors. We have developed a diphtheria toxin-based anti-human CD19 immunotoxin for targeting human CD19+ tumors. We have constructed three isoforms of the CD19 immunotoxin: monovalent, bivalent, and foldback diabody. In vitro binding affinity and efficacy analysis demonstrated that the bivalent isoform had the highest binding affinity and in vitro efficacy. The in vivo efficacy of the CD19 immunotoxins was assessed using human CD19+ JeKo-1 tumor-bearing NOD/SCID IL-2 receptor γ-/- (NSG) mouse model. In these animals, CD19 immunotoxins significantly prolonged the median survival from 31 days in controls to 34, 36, and 40 days in animals receiving the monovalent isoform, foldback diabody isoform, and bivalent isoform, respectively. The bivalent CD19 immunotoxin is a promising therapeutic drug candidate for targeting relapsing/refractory human CD19+ tumors.
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porcine treg depletion with a novel diphtheria toxin based anti human ccr4 immunotoxin
Veterinary Immunology and Immunopathology, 2016Co-Authors: Zhaohui Wang, Qi Huang, Huiping Zhang, Christene A. Huang, Joren C. Madsen, David H. Sachs, Qian Zheng, Nalu Navarroalvarez, Jigesh A Shah, Zhirui WangAbstract:Abstract Regulatory T cells (Tregs) are known to play an important role in immunoregulation and have been shown to facilitate induction of transplantation tolerance. Chemokine (C-C motif) receptor 4 (CCR4) is expressed on the surface of effector Tregs involved in controlling alloimmune and autoimmune responses. Recently we have developed a novel diphtheria-toxin based anti-human CCR4 immunotoxin for depleting CCR4 + cells in vivo. In this study, we have demonstrated that the anti-human CCR4 immunotoxin bound to porcine lymphocytes including CD4 + FoxP3 + Tregs. Anti-human CCR4 immunotoxin effectively depleted CCR4 + Foxp3 + porcine Tregs in vivo . We observed depletion of up to 70–85% of the CCR4 + Foxp3 + porcine Tregs in the peripheral blood and 85–91% in the lymph nodes following the anti-human CCR4 immunotoxin treatment in Massachusetts General Hospital (MGH) miniature swine. The depletion lasted for about one week with no significant reduction observed within CCR4 − cell populations including CD8α + T cells, CCR4 − CD4 + T cells and B cells. In summary, anti-human CCR4 immunotoxin effectively depleted CCR4 + Foxp3 + porcine Tregs in both peripheral blood and lymph nodes.
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recombinant anti monkey cd3 immunotoxin depletes peripheral lymph node t lymphocytes more effectively than rabbit anti thymocyte globulin in naive baboons
Transplant Immunology, 2013Co-Authors: Isaac Wamala, Christene A. Huang, Zhirui Wang, Abraham J Matar, Evan A Farkash, David H. SachsAbstract:Abstract T cell depletion is an important procedure for both experimental and therapeutic immune modulation. Rabbit anti-thymocyte globulin (ATG), which is a commonly used T cell depletion antibody in clinical organ and cell transplantation protocols, is effective in temporarily depleting peripheral blood T lymphocytes but only moderately effective in depleting peripheral lymph node T cells which comprise the majority of T lymphocytes. A recombinant anti-CD3 immunotoxin, A-dmDT390-scfbDb (C207), has been developed and shown in an initial study to retain the lymph node depleting properties of conjugated CD3 immunotoxin. This agent could potentially be used synergistically with or as a replacement for rabbit ATG in preclinical primate models of transplantation. We directly compared the peripheral blood and lymph node depleting abilities of this recombinant anti-CD3 immunotoxin and rabbit ATG in naive animals at clinically tolerated doses. Baboons were treated with a full course of either rabbit ATG (n = 2) or CD3 immunotoxin (n = 3). Peripheral blood and lymph node T lymphocytes were measured before and following treatment. Peripheral blood CD3 + cells fell below 100 cells/μL in every animal. In the two animals receiving ATG, CD3 + cells represented 53% and 68% of lymph node cells two days following a full course of rabbit ATG. In contrast, CD3 + cells represented 3%, 5%, and 38% in lymph nodes following a full course of CD3-IT. Thus, recombinant anti-monkey CD3 immunotoxin showed improved peripheral lymph node T lymphocyte depletion to rabbit ATG and spared other immune cells.
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development of a diphtheria toxin based antiporcine cd3 recombinant immunotoxin
Bioconjugate Chemistry, 2011Co-Authors: Zhirui Wang, David M Neville, David H. Sachs, Raimon Duranstruuck, R Crepeau, Abraham J Matar, Isabel Hanekamp, Srimathi Srinivasan, Christene A. HuangAbstract:Anti-CD3 immunotoxins, which induce profound but transient T-cell depletion in vivo by inhibiting eukaryotic protein synthesis in CD3+ cells, are effective reagents in large animal models of transplantation tolerance and autoimmune disease therapy. A diphtheria toxin based antiporcine CD3 recombinant immunotoxin was constructed by fusing the truncated diphtheria toxin DT390 with two identical tandem single chain variable fragments (scFv) derived from the antiporcine CD3 monoclonal antibody 898H2-6-15. The recombinant immunotoxin was expressed in a diphtheria-toxin resistant yeast Pichia pastoris strain under the control of the alcohol oxidase promoter. The secreted recombinant immunotoxin was purified sequentially with hydrophobic interaction chromatography (Butyl 650 M) followed by strong anion exchange (Poros 50 HQ). The purified antiporcine CD3 immunotoxin was tested in vivo in four animals; peripheral blood CD3+ T-cell numbers were reduced by 80% and lymph node T-cells decreased from 74% CD3+ cells pretreatment to 24% CD3+ cells remaining in the lymph node following 4 days of immunotoxin treatment. No clinical toxicity was observed in any of the experimental swine. We anticipate that this conjugate will provide an important tool for in vivo depletion of T-cells in swine transplantation models.
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a fold back single chain diabody format enhances the bioactivity of an anti monkey cd3 recombinant diphtheria toxin based immunotoxin
Protein Engineering Design & Selection, 2007Co-Authors: Geunbae Kim, Yuanyi Liu, Zhirui Wang, Askale Mathias, Scott Stavrou, Judith M Thomas, Jeanine K Goodwin, David M NevilleAbstract:T-cell depleting anti-CD3 immunotoxins have utility in non-human primate models of transplantation tolerance and autoimmune disease therapy. We recently reported that an affinity matured single-chain (scFv) anti-monkey CD3 antibody, C207, had increased binding to T-cells and increased bioactivity in a diphtheria toxin (DT)-based biscFv immunotoxin compared with the parental antibody, FN18. However, FN18 scFvs and their mutant derivatives such as C207 did not exhibit robust bivalent character in the biscFv format. We now report that C207 in a diabody format exhibits a 7-fold increase in binding to T-cells over scFv (C207) indicating considerable divalent character for the diabody. This construct was formed by reducing the VL/VH linker to five residues and was secreted from Pichia pastoris as the non-covalent dimer. An immunotoxin based on this diabody format was secreted as a non-covalent dimer but was devoid of bioactivity and failed to bind T-cells, suggesting steric hindrance from the two large closely positioned truncated DT moieties. We constructed a single-chain diabody immunotoxin by fusing to the truncated DT C-terminus L1-VL-L1VH-L2-VL-L1-VH where L1 is a five-residue linker and L2 is the longer (G4S)3 linker permitting interactions between the distal and proximal VL/VH domains. This ‘fold-back’ immunotoxin was secreted predominantly as the monomer and exhibited a 5- to 7-fold increase in bioactivity over DT390biscFv(C207) and depleted monkey T-cells in vivo.
Christene A. Huang - One of the best experts on this subject based on the ideXlab platform.
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Dosing optimization of CCR4 immunotoxin for improved depletion of CCR4+ Treg in nonhuman primates
Wiley, 2018Co-Authors: Zhaohui Wang, Huiping Zhang, Christene A. Huang, Joren C. Madsen, Shannon G Pratts, Nathan J. Louras, Alexandre G. Lellouch, Haoyu Wang, Curtis L. Cetrulo, David H. SachsAbstract:Recently, we have developed a diphtheria toxin‐based recombinant anti‐human CCR4 immunotoxin for targeting CCR4+ tumors and Tregs. In this study, we further optimized the dosing schedule for improved CCR4+ Treg depletion. We have demonstrated that up to a 90% depletion was achieved and the depletion extended to approximately 2 weeks in the peripheral blood and more than 48 days in the lymph node at 25 μg·kg−1, BID for 8 consecutive days in cynomolgus monkeys. Expansion was observed including monocytes and NK cells. Antibody against the CCR4 immunotoxin was detected after approximately 2 weeks, affecting further depletion efficacy for multiple course treatment
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diphtheria toxin based anti human cd19 immunotoxin for targeting human cd19 tumors
Molecular Oncology, 2017Co-Authors: Qian Zheng, Qi Huang, Zhaohui Wang, Huiping Zhang, Christene A. Huang, Joren C. Madsen, David H. Sachs, Zhirui WangAbstract:CD19 is expressed on normal and neoplastic B cells and is a promising target for immunotherapy. However, there is still an unmet need to further develop novel therapeutic drugs for the treatment of the refractory/relapsing human CD19+ tumors. We have developed a diphtheria toxin-based anti-human CD19 immunotoxin for targeting human CD19+ tumors. We have constructed three isoforms of the CD19 immunotoxin: monovalent, bivalent, and foldback diabody. In vitro binding affinity and efficacy analysis demonstrated that the bivalent isoform had the highest binding affinity and in vitro efficacy. The in vivo efficacy of the CD19 immunotoxins was assessed using human CD19+ JeKo-1 tumor-bearing NOD/SCID IL-2 receptor γ-/- (NSG) mouse model. In these animals, CD19 immunotoxins significantly prolonged the median survival from 31 days in controls to 34, 36, and 40 days in animals receiving the monovalent isoform, foldback diabody isoform, and bivalent isoform, respectively. The bivalent CD19 immunotoxin is a promising therapeutic drug candidate for targeting relapsing/refractory human CD19+ tumors.
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porcine treg depletion with a novel diphtheria toxin based anti human ccr4 immunotoxin
Veterinary Immunology and Immunopathology, 2016Co-Authors: Zhaohui Wang, Qi Huang, Huiping Zhang, Christene A. Huang, Joren C. Madsen, David H. Sachs, Qian Zheng, Nalu Navarroalvarez, Jigesh A Shah, Zhirui WangAbstract:Abstract Regulatory T cells (Tregs) are known to play an important role in immunoregulation and have been shown to facilitate induction of transplantation tolerance. Chemokine (C-C motif) receptor 4 (CCR4) is expressed on the surface of effector Tregs involved in controlling alloimmune and autoimmune responses. Recently we have developed a novel diphtheria-toxin based anti-human CCR4 immunotoxin for depleting CCR4 + cells in vivo. In this study, we have demonstrated that the anti-human CCR4 immunotoxin bound to porcine lymphocytes including CD4 + FoxP3 + Tregs. Anti-human CCR4 immunotoxin effectively depleted CCR4 + Foxp3 + porcine Tregs in vivo . We observed depletion of up to 70–85% of the CCR4 + Foxp3 + porcine Tregs in the peripheral blood and 85–91% in the lymph nodes following the anti-human CCR4 immunotoxin treatment in Massachusetts General Hospital (MGH) miniature swine. The depletion lasted for about one week with no significant reduction observed within CCR4 − cell populations including CD8α + T cells, CCR4 − CD4 + T cells and B cells. In summary, anti-human CCR4 immunotoxin effectively depleted CCR4 + Foxp3 + porcine Tregs in both peripheral blood and lymph nodes.
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treg depletion in non human primates using a novel diphtheria toxin based anti human ccr4 immunotoxin
Molecular Oncology, 2016Co-Authors: Zhaohui Wang, Huiping Zhang, Christene A. Huang, Jigesh A Shah, Shannon G Pratts, Philip J Spencer, Makoto Tonsho, Tatsu Tanabe, Harrison Powell, Joren C. MadsenAbstract:Regulatory T cells (Treg) play an important role in modulating the immune response and has attracted increasing attention in diverse fields such as cancer treatment, transplantation and autoimmune diseases. CC chemokine receptor 4 (CCR4) is expressed on the majority of Tregs, especially on effector Tregs. Recently we have developed a diphtheria-toxin based anti-human CCR4 immunotoxin for depleting CCR4(+) cells in vivo. In this study, we demonstrated that the anti-human CCR4 immunotoxin bound and depleted monkey CCR4(+) cells in vitro. We also demonstrated that the immunotoxin bound to the CCR4(+)Foxp3(+) monkey Tregs in vitro. In vivo studies performed in two naive cynomolgus monkeys revealed 78-89% CCR4(+)Foxp3(+) Treg depletion in peripheral blood lasting approximately 10 days. In lymph nodes, 89-96% CCR4(+)Foxp3(+) Tregs were depleted. No effect was observed in other cell populations including CD8(+) T cells, other CD4(+) T cells, B cells and NK cells. To our knowledge, this is the first agent that effectively depleted non-human primate (NHP) Tregs. This immunotoxin has potential to deplete effector Tregs for combined cancer treatment.
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recombinant anti monkey cd3 immunotoxin depletes peripheral lymph node t lymphocytes more effectively than rabbit anti thymocyte globulin in naive baboons
Transplant Immunology, 2013Co-Authors: Isaac Wamala, Christene A. Huang, Zhirui Wang, Abraham J Matar, Evan A Farkash, David H. SachsAbstract:Abstract T cell depletion is an important procedure for both experimental and therapeutic immune modulation. Rabbit anti-thymocyte globulin (ATG), which is a commonly used T cell depletion antibody in clinical organ and cell transplantation protocols, is effective in temporarily depleting peripheral blood T lymphocytes but only moderately effective in depleting peripheral lymph node T cells which comprise the majority of T lymphocytes. A recombinant anti-CD3 immunotoxin, A-dmDT390-scfbDb (C207), has been developed and shown in an initial study to retain the lymph node depleting properties of conjugated CD3 immunotoxin. This agent could potentially be used synergistically with or as a replacement for rabbit ATG in preclinical primate models of transplantation. We directly compared the peripheral blood and lymph node depleting abilities of this recombinant anti-CD3 immunotoxin and rabbit ATG in naive animals at clinically tolerated doses. Baboons were treated with a full course of either rabbit ATG (n = 2) or CD3 immunotoxin (n = 3). Peripheral blood and lymph node T lymphocytes were measured before and following treatment. Peripheral blood CD3 + cells fell below 100 cells/μL in every animal. In the two animals receiving ATG, CD3 + cells represented 53% and 68% of lymph node cells two days following a full course of rabbit ATG. In contrast, CD3 + cells represented 3%, 5%, and 38% in lymph nodes following a full course of CD3-IT. Thus, recombinant anti-monkey CD3 immunotoxin showed improved peripheral lymph node T lymphocyte depletion to rabbit ATG and spared other immune cells.
Philippe Grandjean - One of the best experts on this subject based on the ideXlab platform.
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severity of covid 19 at elevated exposure to perfluorinated alkylates
PLOS ONE, 2020Co-Authors: Clara Amalie Gade Timmermann, Flemming Nielsen, Philippe Grandjean, Marie Kruse, L Boding, C Heilmann, Kare Molbak, Pernille Just VinholtAbstract:BACKGROUND: The course of coronavirus disease 2019 (COVID-19) seems to be aggravated by air pollution, and some industrial chemicals, such as the perfluorinated alkylate substances (PFASs), are Immunotoxic and may contribute to an association with disease severity. METHODS: From Danish biobanks, we obtained plasma samples from 323 subjects aged 30-70 years with known SARS-CoV-2 infection. The PFAS concentrations measured at the background exposures included five PFASs known to be Immunotoxic. Register data was obtained to classify disease status, other health information, and demographic variables. We used ordered logistic regression analyses to determine associations between PFAS concentrations and disease outcome. RESULTS: Plasma-PFAS concentrations were higher in males, in subjects with Western European background, and tended to increase with age, but were not associated with the presence of chronic disease. Of the study population, 108 (33%) had not been hospitalized, and of those hospitalized, 53 (16%) had been in intensive care or were deceased. Among the five PFASs considered, perfluorobutanoic acid (PFBA) showed an unadjusted odds ratio (OR) of 2.19 (95% confidence interval, CI, 1.39-3.46) for increasing severities of the disease. Among those hospitalized, the fully adjusted OR for getting into intensive care or expiring was 5.18 (1.29, 20.72) when based on plasma samples obtained at the time of diagnosis or up to one week before. CONCLUSIONS: Measures of individual exposures to Immunotoxic PFASs included short-chain PFBA known to accumulate in the lungs. Elevated plasma-PFBA concentrations were associated with an increased risk of a more severe course of COVID-19. Given the low background exposure levels in this study, the role of exposure to PFASs in COVID-19 needs to be ascertained in populations with elevated exposures.
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severity of covid 19 at elevated exposure to perfluorinated alkylates
medRxiv, 2020Co-Authors: Clara Amalie Gade Timmermann, Flemming Nielsen, Philippe Grandjean, Marie Kruse, Just P Vinholt, L Boding, C Heilmann, Kare MolbakAbstract:Background The course of coronavirus disease 2019 (COVID-19) seems to be aggravated by air pollution, and some industrial chemicals, such as the perfluorinated alkylate substances (PFASs), are Immunotoxic and may contribute as well. Methods From Danish biobanks, we obtained plasma samples from 323 subjects aged 30-70 years with known SARS-CoV-2 infection. The PFAS concentrations measured at the background exposures included five PFASs known to be Immunotoxic. Register data was obtained to classify disease status, other health information, and demographic variables. We used ordinal and ordered logistic regression analyses to determine associations between PFAS concentrations and disease outcome. Results Plasma-PFAS concentrations were higher in males, in subjects with Western European background, and tended to increase with age, but were not associated with the presence of chronic disease. Of the study population, 108 (33%) had not been hospitalized, and of those hospitalized, 53 (16%) had been in intensive care or were deceased. Among the five PFASs considered, perfluorobutanoic acid (PFBA) showed an odds ratio (OR) of 2.19 (95% confidence interval, CI, 1.39-3.46) for increasing severities of the disease, although the OR decreased to 1.77 (95% CI, 1.09, 2.87) after adjustment for age, sex, sampling site and interval between blood sampling and diagnosis. Conclusions Measures of individual exposures to Immunotoxic PFASs included PFBA that accumulates in the lungs. Elevated plasma-PFBA concentrations were associated with an increased risk of more severe course of CIVID-19. Given the low background exposure levels in this study, the role of PFAS exposure in COVID-19 needs to be ascertained in populations with elevated exposures.
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serum perfluoroalkyl substances vaccine responses and morbidity in a cohort of guinea bissau children
Environmental Health Perspectives, 2020Co-Authors: Clara Amalie Gade Timmermann, Kristoffer Jarlov Jensen, Flemming Nielsen, Esben Budtzjorgensen, Fiona R M Van Der Klis, Christine Stabell Benn, Philippe GrandjeanAbstract:Background: Perfluoroalkyl substances (PFAS) are a group of widely used persistent chemicals with suspected Immunotoxic effects. Objectives: The present study aimed to examine the association betwe...
David H. Sachs - One of the best experts on this subject based on the ideXlab platform.
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Dosing optimization of CCR4 immunotoxin for improved depletion of CCR4+ Treg in nonhuman primates
Wiley, 2018Co-Authors: Zhaohui Wang, Huiping Zhang, Christene A. Huang, Joren C. Madsen, Shannon G Pratts, Nathan J. Louras, Alexandre G. Lellouch, Haoyu Wang, Curtis L. Cetrulo, David H. SachsAbstract:Recently, we have developed a diphtheria toxin‐based recombinant anti‐human CCR4 immunotoxin for targeting CCR4+ tumors and Tregs. In this study, we further optimized the dosing schedule for improved CCR4+ Treg depletion. We have demonstrated that up to a 90% depletion was achieved and the depletion extended to approximately 2 weeks in the peripheral blood and more than 48 days in the lymph node at 25 μg·kg−1, BID for 8 consecutive days in cynomolgus monkeys. Expansion was observed including monocytes and NK cells. Antibody against the CCR4 immunotoxin was detected after approximately 2 weeks, affecting further depletion efficacy for multiple course treatment
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diphtheria toxin based anti human cd19 immunotoxin for targeting human cd19 tumors
Molecular Oncology, 2017Co-Authors: Qian Zheng, Qi Huang, Zhaohui Wang, Huiping Zhang, Christene A. Huang, Joren C. Madsen, David H. Sachs, Zhirui WangAbstract:CD19 is expressed on normal and neoplastic B cells and is a promising target for immunotherapy. However, there is still an unmet need to further develop novel therapeutic drugs for the treatment of the refractory/relapsing human CD19+ tumors. We have developed a diphtheria toxin-based anti-human CD19 immunotoxin for targeting human CD19+ tumors. We have constructed three isoforms of the CD19 immunotoxin: monovalent, bivalent, and foldback diabody. In vitro binding affinity and efficacy analysis demonstrated that the bivalent isoform had the highest binding affinity and in vitro efficacy. The in vivo efficacy of the CD19 immunotoxins was assessed using human CD19+ JeKo-1 tumor-bearing NOD/SCID IL-2 receptor γ-/- (NSG) mouse model. In these animals, CD19 immunotoxins significantly prolonged the median survival from 31 days in controls to 34, 36, and 40 days in animals receiving the monovalent isoform, foldback diabody isoform, and bivalent isoform, respectively. The bivalent CD19 immunotoxin is a promising therapeutic drug candidate for targeting relapsing/refractory human CD19+ tumors.
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porcine treg depletion with a novel diphtheria toxin based anti human ccr4 immunotoxin
Veterinary Immunology and Immunopathology, 2016Co-Authors: Zhaohui Wang, Qi Huang, Huiping Zhang, Christene A. Huang, Joren C. Madsen, David H. Sachs, Qian Zheng, Nalu Navarroalvarez, Jigesh A Shah, Zhirui WangAbstract:Abstract Regulatory T cells (Tregs) are known to play an important role in immunoregulation and have been shown to facilitate induction of transplantation tolerance. Chemokine (C-C motif) receptor 4 (CCR4) is expressed on the surface of effector Tregs involved in controlling alloimmune and autoimmune responses. Recently we have developed a novel diphtheria-toxin based anti-human CCR4 immunotoxin for depleting CCR4 + cells in vivo. In this study, we have demonstrated that the anti-human CCR4 immunotoxin bound to porcine lymphocytes including CD4 + FoxP3 + Tregs. Anti-human CCR4 immunotoxin effectively depleted CCR4 + Foxp3 + porcine Tregs in vivo . We observed depletion of up to 70–85% of the CCR4 + Foxp3 + porcine Tregs in the peripheral blood and 85–91% in the lymph nodes following the anti-human CCR4 immunotoxin treatment in Massachusetts General Hospital (MGH) miniature swine. The depletion lasted for about one week with no significant reduction observed within CCR4 − cell populations including CD8α + T cells, CCR4 − CD4 + T cells and B cells. In summary, anti-human CCR4 immunotoxin effectively depleted CCR4 + Foxp3 + porcine Tregs in both peripheral blood and lymph nodes.
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recombinant anti monkey cd3 immunotoxin depletes peripheral lymph node t lymphocytes more effectively than rabbit anti thymocyte globulin in naive baboons
Transplant Immunology, 2013Co-Authors: Isaac Wamala, Christene A. Huang, Zhirui Wang, Abraham J Matar, Evan A Farkash, David H. SachsAbstract:Abstract T cell depletion is an important procedure for both experimental and therapeutic immune modulation. Rabbit anti-thymocyte globulin (ATG), which is a commonly used T cell depletion antibody in clinical organ and cell transplantation protocols, is effective in temporarily depleting peripheral blood T lymphocytes but only moderately effective in depleting peripheral lymph node T cells which comprise the majority of T lymphocytes. A recombinant anti-CD3 immunotoxin, A-dmDT390-scfbDb (C207), has been developed and shown in an initial study to retain the lymph node depleting properties of conjugated CD3 immunotoxin. This agent could potentially be used synergistically with or as a replacement for rabbit ATG in preclinical primate models of transplantation. We directly compared the peripheral blood and lymph node depleting abilities of this recombinant anti-CD3 immunotoxin and rabbit ATG in naive animals at clinically tolerated doses. Baboons were treated with a full course of either rabbit ATG (n = 2) or CD3 immunotoxin (n = 3). Peripheral blood and lymph node T lymphocytes were measured before and following treatment. Peripheral blood CD3 + cells fell below 100 cells/μL in every animal. In the two animals receiving ATG, CD3 + cells represented 53% and 68% of lymph node cells two days following a full course of rabbit ATG. In contrast, CD3 + cells represented 3%, 5%, and 38% in lymph nodes following a full course of CD3-IT. Thus, recombinant anti-monkey CD3 immunotoxin showed improved peripheral lymph node T lymphocyte depletion to rabbit ATG and spared other immune cells.
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development of a diphtheria toxin based antiporcine cd3 recombinant immunotoxin
Bioconjugate Chemistry, 2011Co-Authors: Zhirui Wang, David M Neville, David H. Sachs, Raimon Duranstruuck, R Crepeau, Abraham J Matar, Isabel Hanekamp, Srimathi Srinivasan, Christene A. HuangAbstract:Anti-CD3 immunotoxins, which induce profound but transient T-cell depletion in vivo by inhibiting eukaryotic protein synthesis in CD3+ cells, are effective reagents in large animal models of transplantation tolerance and autoimmune disease therapy. A diphtheria toxin based antiporcine CD3 recombinant immunotoxin was constructed by fusing the truncated diphtheria toxin DT390 with two identical tandem single chain variable fragments (scFv) derived from the antiporcine CD3 monoclonal antibody 898H2-6-15. The recombinant immunotoxin was expressed in a diphtheria-toxin resistant yeast Pichia pastoris strain under the control of the alcohol oxidase promoter. The secreted recombinant immunotoxin was purified sequentially with hydrophobic interaction chromatography (Butyl 650 M) followed by strong anion exchange (Poros 50 HQ). The purified antiporcine CD3 immunotoxin was tested in vivo in four animals; peripheral blood CD3+ T-cell numbers were reduced by 80% and lymph node T-cells decreased from 74% CD3+ cells pretreatment to 24% CD3+ cells remaining in the lymph node following 4 days of immunotoxin treatment. No clinical toxicity was observed in any of the experimental swine. We anticipate that this conjugate will provide an important tool for in vivo depletion of T-cells in swine transplantation models.