33 results on '"Steven Eck"'
Search Results
2. Best practices for the development and fit-for-purpose validation of biomarker methods: a conference report
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Joel Mathews, Lakshmi Amaravadi, Steven Eck, Lauren Stevenson, Yow-Ming C. Wang, Viswanath Devanarayan, John Allinson, Kelly Lundsten, Michele Gunsior, Yan G. Ni, Marc-Olivier Pepin, Audrey Gagnon, Curtis Sheldon, Paul C. Trampont, and Virginia Litwin
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Biomarker ,Validation ,Fit-for-purpose ,Flow cytometry ,Drug development ,Therapeutics. Pharmacology ,RM1-950 ,Pharmacy and materia medica ,RS1-441 - Abstract
Abstract This conference report summarized a full-day workshop, “best practices for the development and fit-for-purpose validation of biomarker methods,” which was held prior to the American Association of Pharmaceutical Scientists (AAPS) PharmSci360 Congress, San Antonio, TX, November 2019. The purpose of the workshop was to bring together thought leaders in biomarker assay development in order to identify which assay parameters and key statistical measures need to be considered when developing a biomarker assay. A diverse group of more than 40 scientists participated in the workshop. The workshop and subsequent working dinner stimulated robust discussion. While a consensus on best practices was not achieved, some common themes and major points to consider for biomarker assay development have been identified and agreed on. The focus of this conference report is to summarize the presentations and discussions which occurred at the workshop. Biomarker assay validation is a complex and an evolving area with discussions ongoing.
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- 2022
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3. First-in-human study of oleclumab, a potent, selective anti-CD73 monoclonal antibody, alone or in combination with durvalumab in patients with advanced solid tumors
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Johanna Bendell, Patricia LoRusso, Michael Overman, Anne M. Noonan, Dong-Wan Kim, John H. Strickler, Sang-We Kim, Stephen Clarke, Thomas J. George, Peter S. Grimison, Minal Barve, Manik Amin, Jayesh Desai, Trisha Wise-Draper, Steven Eck, Yu Jiang, Anis A. Khan, Yuling Wu, Philip Martin, Zachary A. Cooper, Nairouz Elgeioushi, Nancy Mueller, Rakesh Kumar, and Sandip Pravin Patel
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Cancer Research ,Oncology ,Immunology ,Immunology and Allergy - Abstract
Background CD73 upregulation in tumors leads to local immunosuppression. This phase I, first-in-human study evaluated oleclumab (MEDI9447), an anti-CD73 human IgG1λ monoclonal antibody, alone or with durvalumab in patients with advanced colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), or epidermal growth factor receptor-mutant non-small-cell lung cancer (NSCLC). Methods Patients received oleclumab 5–40 mg/kg (dose-escalation) or 40 mg/kg (dose-expansion) intravenously every 2 weeks (Q2W), alone (escalation only) or with durvalumab 10 mg/kg intravenously Q2W. Results 192 patients were enrolled, 66 during escalation and 126 (42 CRC, 42 PDAC, 42 NSCLC) during expansion. No dose-limiting toxicities occurred during escalation. In the monotherapy and combination therapy escalation cohorts, treatment-related adverse events (TRAEs) occurred in 55 and 54%, respectively, the most common being fatigue (17 and 25%). In the CRC, PDAC, and NSCLC expansion cohorts, 60, 57, and 45% of patients had TRAEs, respectively; the most common were fatigue (15%), diarrhea (9%), and rash (7%). Free soluble CD73 and CD73 expression on peripheral T cells and tumor cells showed sustained decreases, accompanied by reduced CD73 enzymatic activity in tumor cells. Objective response rate during escalation was 0%. Response rates in the CRC, PDAC, and NSCLC expansion cohorts were 2.4% (1 complete response [CR]), 4.8% (1 CR, 1 partial response [PR]), and 9.5% (4 PRs), respectively; 6-month progression-free survival rates were 5.4, 13.2, and 16.0%. Conclusions Oleclumab ± durvalumab had a manageable safety profile, with pharmacodynamic activity reflecting oleclumab’s mechanism of action. Evidence of antitumor activity was observed in tumor types that are generally immunotherapy resistant. Clinical trial registration Clinicaltrials.gov, NCT02503774; date of registration, July 17, 2015.
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- 2023
4. Figure S4 from Potent Immune Modulation by MEDI6383, an Engineered Human OX40 Ligand IgG4P Fc Fusion Protein
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Scott A. Hammond, Andrew Weinberg, Nicholas P. Morris, Louis Picker, Michael K. Axthelm, Andrew Sylwester, Haesun Park, Andrew J. Pierce, Lolke de Haan, Nicholas Buss, Steven Eck, Hui Feng, Melissa Damschroder, Qun Du, Shino Hanabuchi, James Hair, Kelly McGlinchey, Kathy Mulgrew, Stacy Kentner, Chad Morris, Catherine Augé, and Michael D. Oberst
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Expression of cell surface Fc gamma receptors on human cells
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- 2023
5. Supplementary Methods from Potent Immune Modulation by MEDI6383, an Engineered Human OX40 Ligand IgG4P Fc Fusion Protein
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Scott A. Hammond, Andrew Weinberg, Nicholas P. Morris, Louis Picker, Michael K. Axthelm, Andrew Sylwester, Haesun Park, Andrew J. Pierce, Lolke de Haan, Nicholas Buss, Steven Eck, Hui Feng, Melissa Damschroder, Qun Du, Shino Hanabuchi, James Hair, Kelly McGlinchey, Kathy Mulgrew, Stacy Kentner, Chad Morris, Catherine Augé, and Michael D. Oberst
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Supplementary Methods
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- 2023
6. Data from Potent Immune Modulation by MEDI6383, an Engineered Human OX40 Ligand IgG4P Fc Fusion Protein
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Scott A. Hammond, Andrew Weinberg, Nicholas P. Morris, Louis Picker, Michael K. Axthelm, Andrew Sylwester, Haesun Park, Andrew J. Pierce, Lolke de Haan, Nicholas Buss, Steven Eck, Hui Feng, Melissa Damschroder, Qun Du, Shino Hanabuchi, James Hair, Kelly McGlinchey, Kathy Mulgrew, Stacy Kentner, Chad Morris, Catherine Augé, and Michael D. Oberst
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Ligation of OX40 (CD134, TNFRSF4) on activated T cells by its natural ligand (OX40L, CD252, TNFSF4) enhances cellular survival, proliferation, and effector functions such as cytokine release and cellular cytotoxicity. We engineered a recombinant human OX40L IgG4P Fc fusion protein termed MEDI6383 that assembles into a hexameric structure and exerts potent agonist activity following engagement of OX40. MEDI6383 displayed solution-phase agonist activity that was enhanced when the fusion protein was clustered by Fc gamma receptors (FcγRs) on the surface of adjacent cells. The resulting costimulation of OX40 on T cells induced NFκB promoter activity in OX40-expressing T cells and induced Th1-type cytokine production, proliferation, and resistance to regulatory T cell (Treg)-mediated suppression. MEDI6383 enhanced the cytolytic activity of tumor-reactive T cells and reduced tumor growth in the context of an alloreactive human T cell:tumor cell admix model in immunocompromised mice. Consistent with the role of OX40 costimulation in the expansion of memory T cells, MEDI6383 administered to healthy nonhuman primates elicited peripheral blood CD4 and CD8 central and effector memory T-cell proliferation as well as B-cell proliferation. Together, these results suggest that OX40 agonism has the potential to enhance antitumor immunity in human malignancies. Mol Cancer Ther; 17(5); 1024–38. ©2018 AACR.
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- 2023
7. Figures S5-S6 from Potent Immune Modulation by MEDI6383, an Engineered Human OX40 Ligand IgG4P Fc Fusion Protein
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Scott A. Hammond, Andrew Weinberg, Nicholas P. Morris, Louis Picker, Michael K. Axthelm, Andrew Sylwester, Haesun Park, Andrew J. Pierce, Lolke de Haan, Nicholas Buss, Steven Eck, Hui Feng, Melissa Damschroder, Qun Du, Shino Hanabuchi, James Hair, Kelly McGlinchey, Kathy Mulgrew, Stacy Kentner, Chad Morris, Catherine Augé, and Michael D. Oberst
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Supplementary Figure 5. Lack of NK cell mediated ADCC and complement protein C1q binding by MEDI6383. Supplementary Figure 6. MEDI6383 mediated release of cytokines from primary human T cells.
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- 2023
8. 2021 White Paper on Recent Issues in Bioanalysis: ISR for Biomarkers, Liquid Biopsies, Spectral Cytometry, Inhalation/Oral & Multispecific Biotherapeutics, Accuracy/LLOQ for Flow Cytometry (<u>Part 2</u> – Recommendations on Biomarkers/CDx Assays Development & Validation, Cytometry Validation & Innovation, Biotherapeutics PK LBA Regulated Bioanalysis, Critical Reagents & Positive Controls Generation)
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Sarah Hersey, Steve Keller, Joel Mathews, Lindsay King, Abbas Bandukwala, Flora Berisha, Mary Birchler, Joe Bower, Valerie Clausen, Jose Duarte, Fabio Garofolo, Shirley Hopper, Sumit Kar, Omar Mabrouk, Jean-Claude Marshall, Kristina McGuire, Michael Naughton, Yoshiro Saito, Imelda Schuhmann, Gizette Sperinde, Priscila Teixeira, Alessandra Vitaliti, Yow-Ming Wang, Richard Wnek, Yan Zhang, Sue Spitz, Vilma Decman, Steven Eck, Jose Estevam, Polina Goihberg, Enrique Gómez Alcaide, Christèle Gonneau, Michael Nathan Hedrick, Gregory Hopkins, Fabian Junker, Sandra Nuti, Ulrike Sommer, Nathan Standifer, Chad Stevens, Erin Stevens, Carrie Hendricks, Meenu Wadhwa, Albert Torri, Mark Ma, Shannon Harris, Seema Kumar, Michael A Partridge, Teresa Caiazzo, Shannon Chilewski, Isabelle Cludts, Kelly Coble, Boris Gorovits, Christine Grimaldi, Gregor Jordan, John Kamerud, Beth Leary, Meina Liang, Hanjo Lim, Andrew Mayer, Ellen O'Connor, Nisha Palackal, Johann Poetzl, Sandra Prior, Mohsen Rajabi Abhari, Natasha Savoie, Catherine Soo, Mark Ware, Bonnie Wu, Yang Xu, Tong-Yuan Yang, and Jad Zoghbi
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Medical Laboratory Technology ,Clinical Biochemistry ,General Medicine ,General Pharmacology, Toxicology and Pharmaceutics ,Analytical Chemistry - Abstract
The 15th edition of the Workshop on Recent Issues in Bioanalysis (15th WRIB) was held on 27 September to 1 October 2021. Even with a last-minute move from in-person to virtual, an overwhelmingly high number of nearly 900 professionals representing pharma and biotech companies, contract research organizations (CROs), and multiple regulatory agencies still eagerly convened to actively discuss the most current topics of interest in bioanalysis. The 15th WRIB included three Main Workshops and seven Specialized Workshops that together spanned 1 week in order to allow exhaustive and thorough coverage of all major issues in bioanalysis, biomarkers, immunogenicity, gene therapy, cell therapy and vaccines. Moreover, in-depth workshops on biomarker assay development and validation (BAV) (focused on clarifying the confusion created by the increased use of the term “context of use” [COU]); mass spectrometry of proteins (therapeutic, biomarker and transgene); state-of-the-art cytometry innovation and validation; and critical reagent and positive control generation were the special features of the 15th edition. This 2021 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2021 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 2) covers the recommendations on ISR for Biomarkers, Liquid Biopsies, Spectral Cytometry, Inhalation/Oral & Multispecific Biotherapeutics, Accuracy/LLOQ for Flow Cytometry. Part 1A (Endogenous Compounds, Small Molecules, Complex Methods, Regulated Mass Spec of Large Molecules, Small Molecule, PoC), Part 1B (Regulatory Agencies' Inputs on Bioanalysis, Biomarkers, Immunogenicity, Gene & Cell Therapy and Vaccine) and Part 3 (TAb/NAb, Viral Vector CDx, Shedding Assays; CRISPR/Cas9 & CAR-T Immunogenicity; PCR & Vaccine Assay Performance; ADA Assay Comparability & Cut Point Appropriateness) are published in volume 14 of Bioanalysis, issues 9 and 11 (2022), respectively.
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- 2022
9. Figure S5 from Safety and Clinical Activity of MEDI0562, a Humanized OX40 Agonist Monoclonal Antibody, in Adult Patients with Advanced Solid Tumors
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Sandip Pravin Patel, Danielle M. Townsley, Katie Streicher, Matthew Gribbin, Steven Eck, Yanan Zheng, Jennifer Burton, James P. Ohr, Sanjay Goel, Reva Schneider, Bhumsuk Keam, Naiyer A. Rizvi, John Powderly, Robert L. Ferris, Rom S. Leidner, and Bonnie S. Glisson
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Figure S5: Dual MoA of MEDI0562
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- 2023
10. Data from Safety and Clinical Activity of MEDI0562, a Humanized OX40 Agonist Monoclonal Antibody, in Adult Patients with Advanced Solid Tumors
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Sandip Pravin Patel, Danielle M. Townsley, Katie Streicher, Matthew Gribbin, Steven Eck, Yanan Zheng, Jennifer Burton, James P. Ohr, Sanjay Goel, Reva Schneider, Bhumsuk Keam, Naiyer A. Rizvi, John Powderly, Robert L. Ferris, Rom S. Leidner, and Bonnie S. Glisson
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Purpose:Immune checkpoint blockade has demonstrated clinical benefits across multiple solid tumor types; however, resistance and relapse often occur. New immunomodulatory targets, which are highly expressed in activated immune cells, are needed. MEDI0562, an agonistic humanized mAb, specifically binds to the costimulatory molecule OX40. This first-in-human study evaluated MEDI0562 in adults with advanced solid tumors.Patients and Methods:In this phase I, multicenter, open-label, single-arm, dose-escalation (3+3 design) study, patients received 0.03, 0.1, 0.3, 1.0, 3.0, or 10 mg/kg MEDI0562 through intravenous infusion every 2 weeks, until confirmed disease progression or unacceptable toxicity. The primary objective evaluated safety and tolerability. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics.Results:In total, 55 patients received ≥1 dose of MEDI0562 and were included in the analysis. The most common tumor type was squamous cell carcinoma of the head and neck (47%). Median duration of treatment was 10 weeks (range, 2–48 weeks). Treatment-related adverse events (TRAEs) occurred in 67% of patients, most commonly fatigue (31%) and infusion-related reactions (14%). Grade 3 TRAEs occurred in 14% of patients with no apparent dose relationship; no TRAEs resulted in death. Two patients had immune-related partial responses per protocol and 44% had stable disease. MEDI0562 induced increased Ki67+ CD4+ and CD8+ memory T-cell proliferation in the periphery and decreased intratumoral OX40+ FOXP3+ cells.Conclusions:MEDI0562 was safely administered at doses up to 10 mg/kg in heavily pretreated patients. On-target pharmacodynamic effects were suggested in this setting. Further evaluation with immune checkpoint inhibitors is ongoing.
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- 2023
11. 2021 White Paper on Recent Issues in Bioanalysis: ISR for Biomarkers, Liquid Biopsies, Spectral Cytometry, Inhalation/OralMultispecific Biotherapeutics, Accuracy/LLOQ for Flow Cytometry (
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Sarah, Hersey, Steve, Keller, Joel, Mathews, Lindsay, King, Abbas, Bandukwala, Flora, Berisha, Mary, Birchler, Joe, Bower, Valerie, Clausen, Jose, Duarte, Fabio, Garofolo, Shirley, Hopper, Sumit, Kar, Omar, Mabrouk, Jean-Claude, Marshall, Kristina, McGuire, Michael, Naughton, Yoshiro, Saito, Imelda, Schuhmann, Gizette, Sperinde, Priscila, Teixeira, Alessandra, Vitaliti, Yow-Ming, Wang, Richard, Wnek, Yan, Zhang, Sue, Spitz, Vilma, Decman, Steven, Eck, Jose, Estevam, Polina, Goihberg, Enrique Gómez, Alcaide, Christèle, Gonneau, Michael Nathan, Hedrick, Gregory, Hopkins, Fabian, Junker, Sandra, Nuti, Ulrike, Sommer, Nathan, Standifer, Chad, Stevens, Erin, Stevens, Carrie, Hendricks, Meenu, Wadhwa, Albert, Torri, Mark, Ma, Shannon, Harris, Seema, Kumar, Michael A, Partridge, Teresa, Caiazzo, Shannon, Chilewski, Isabelle, Cludts, Kelly, Coble, Boris, Gorovits, Christine, Grimaldi, Gregor, Jordan, John, Kamerud, Beth, Leary, Meina, Liang, Hanjo, Lim, Andrew, Mayer, Ellen, O'Connor, Nisha, Palackal, Johann, Poetzl, Sandra, Prior, Mohsen Rajabi, Abhari, Natasha, Savoie, Catherine, Soo, Mark, Ware, Bonnie, Wu, Yang, Xu, Tong-Yuan, Yang, and Jad, Zoghbi
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Liquid Biopsy ,Humans ,Indicators and Reagents ,Flow Cytometry ,Biomarkers ,Mass Spectrometry - Abstract
The 15th edition of the Workshop on Recent Issues in Bioanalysis (15th WRIB) was held on 27 September to 1 October 2021. Even with a last-minute move from in-person to virtual, an overwhelmingly high number of nearly 900 professionals representing pharma and biotech companies, contract research organizations (CROs), and multiple regulatory agencies still eagerly convened to actively discuss the most current topics of interest in bioanalysis. The 15th WRIB included three Main Workshops and seven Specialized Workshops that together spanned 1 week in order to allow exhaustive and thorough coverage of all major issues in bioanalysis, biomarkers, immunogenicity, gene therapy, cell therapy and vaccines. Moreover, in-depth workshops on biomarker assay development and validation (BAV) (focused on clarifying the confusion created by the increased use of the term "context of use" [COU]); mass spectrometry of proteins (therapeutic, biomarker and transgene); state-of-the-art cytometry innovation and validation; and critical reagent and positive control generation were the special features of the 15th edition. This 2021 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2021 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 2) covers the recommendations on ISR for Biomarkers, Liquid Biopsies, Spectral Cytometry, Inhalation/OralMultispecific Biotherapeutics, Accuracy/LLOQ for Flow Cytometry. Part 1A (Endogenous Compounds, Small Molecules, Complex Methods, Regulated Mass Spec of Large Molecules, Small Molecule, PoC), Part 1B (Regulatory Agencies' Inputs on Bioanalysis, Biomarkers, Immunogenicity, GeneCell Therapy and Vaccine) and Part 3 (TAb/NAb, Viral Vector CDx, Shedding Assays; CRISPR/Cas9CAR-T Immunogenicity; PCRVaccine Assay Performance; ADA Assay ComparabilityCut Point Appropriateness) are published in volume 14 of Bioanalysis, issues 9 and 11 (2022), respectively.
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- 2022
12. 2020 White Paper on Recent Issues in Bioanalysis: BAV Guidance, CLSI H62, Biotherapeutics Stability, Parallelism Testing, CyTOF and Regulatory Feedback (<u>Part 2A</u> – Recommendations on Biotherapeutics Stability, PK LBA Regulated Bioanalysis, Biomarkers Assays, Cytometry Validation & Innovation <u>Part 2B</u> – Regulatory Agencies’ Inputs on Bioanalysis, Biomarkers, Immunogenicity, Gene & Cell Therapy and Vaccine)
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Andrew P Mayer, Jinhui Zhang, Sam Haidar, Sandra Nuti, Shyam Sarikonda, Therese Solstad, Megan McCausland, Fabian Junker, Elana Cherry, Susan M. Spitz, Tahseen Mirza, Anna Edmison, Patrick Faustino, Yan Zhang, Rafiq Islam, Steven Eck, Christèle Gonneau, Fabio Garofolo, Nilufer Tampal, Kevin Maher, Lisa Patti-Diaz, Kun Peng, Alberto Robert, Yow-Ming Wang, Rachel Palmer, Marcela Araya, Lakshmi Amaravadi, Alison Joyce, Daniela Verthelyi, Giane Sumner, Andrew Exley, Sally Fischer, Gustavo Mendes Lima Santos, Michael McGuinness, Yoshiro Saito, Alessandra Vitaliti, Naveen Dakappagari, Daniel Baltrukonis, Christina Satterwhite, Gregory Hopkins, Gregor Jordan, Akiko Ishii-Watabe, Arindam Dasgupta, David Lanham, Priscila Camillo Teixeira, Mitra Azadeh, Stephen Vinter, Sumit Kar, Lucia Zhang, Linda Terry, Michael Nathan Hedrick, João Pedras-Vasconcelos, Shabnam Tangri, Florian Neff, Natasha Savoie, Weili Yan, Matthew Andisik, Mohsen Rajabi Abhari, Richard Siggers, Lindsay King, Diaa Shakleya, Isabelle Cludts, Nisha Palackal, Meiyu Shen, Ulrike Sommer, Sylvie Bertholet, Susan Kirshner, Cherie Green, Christine Grimaldi, Susan Stojdl, Kristina McGuire, Vilma Decman, Jose Estevam, Suman Dandamudi, Seema Kumar, Richard Wnek, Catherine Soo, Haoheng Yan, Jan Welink, Rebecca Elliott, and Abbas Bandukwala
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0303 health sciences ,Bioanalysis ,Immunogenicity ,010401 analytical chemistry ,Clinical Biochemistry ,Scientific excellence ,Harmonization ,General Medicine ,01 natural sciences ,0104 chemical sciences ,Analytical Chemistry ,Regulatory authority ,03 medical and health sciences ,Medical Laboratory Technology ,Engineering management ,Biopharmaceutical ,White paper ,Business ,General Pharmacology, Toxicology and Pharmaceutics ,030304 developmental biology - Abstract
The 14th edition of the Workshop on Recent Issues in Bioanalysis (14th WRIB) was held virtually on June 15-29, 2020 with an attendance of over 1000 representatives from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations, and regulatory agencies worldwide. The 14th WRIB included three Main Workshops, seven Specialized Workshops that together spanned 11 days in order to allow exhaustive and thorough coverage of all major issues in bioanalysis, biomarkers, immunogenicity, gene therapy and vaccine. Moreover, a comprehensive vaccine assays track; an enhanced cytometry track and updated Industry/Regulators consensus on BMV of biotherapeutics by LCMS were special features in 2020. As in previous years, this year's WRIB continued to gather a wide diversity of international industry opinion leaders and regulatory authority experts working on both small and large molecules to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance and achieving scientific excellence on bioanalytical issues. This 2020 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the Global Bioanalytical Community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2020 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication covers the recommendations on (Part 2A) BAV, PK LBA, Flow Cytometry Validation and Cytometry Innovation and (Part 2B) Regulatory Input. Part 1 (Innovation in Small Molecules, Hybrid LBA/LCMS & Regulated Bioanalysis), Part 3 (Vaccine, Gene/Cell Therapy, NAb Harmonization and Immunogenicity) are published in volume 13 of Bioanalysis, issues 4, and 6 (2021), respectively.
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- 2021
13. High‐sensitivity flow cytometric assays: Considerations for design control and analytical validation for identification of Rare events
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Thomas W. McCloskey, Ulrike Sommer, Cherie Green, Jennifer J. Stewart, Teri Oldaker, Virginia Litwin, Laura Marszalek, Jolene Bradford, Alessandra Vitaliti, and Steven Eck
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0301 basic medicine ,Histology ,Computer science ,Event (computing) ,Equipment Design ,Cell Biology ,Flow Cytometry ,Design control ,Predictive value ,Lower limit ,Pathology and Forensic Medicine ,Reliability engineering ,03 medical and health sciences ,Identification (information) ,030104 developmental biology ,0302 clinical medicine ,Flow (mathematics) ,030220 oncology & carcinogenesis ,Rare events ,Humans ,Sensitivity (control systems) - Abstract
The current consensus recommendation papers dealing with the unique requirements for the analytical validation of assays performed by flow cytometry address the validation of sensitivity (both analytical and functional) only in general terms. In this paper, a detailed approach for designing and validating the sensitivity of rare event methods is described. The impact of panel design and optimization on the lower limit of quantification (LLOQ) and suggestions for reporting data near, or below, the LLOQ are addressed. This paper serves to provide best practices for the development, optimization, and analytical validation of flow cytometric assays designed to assess rare events. Note that this paper does not discuss clinical sensitivity validation, which addresses the positive and negative predictive value of the test result.
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- 2020
14. Abstract CT183: First-in-human study of MEDI1191 (mRNA encoding IL-12) plus durvalumab in patients (pts) with advanced solid tumors
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Benedito A. Carneiro, Dmitriy Zamarin, Thomas Marron, Inderjit Mehmi, Sandip P. Patel, Vivek Subbiah, Anthony El-Khoueiry, David Grand, Kirema Garcia-Reyes, Sanjay Goel, Phillip Martin, Jixin Wang, Yuling Wu, Steven Eck, Benjamin Ridgway, Nairouz Elgeioushi, Jim Eyles, Nicholas Durham, Analia Azaro, and Omid Hamid
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Cancer Research ,Oncology - Abstract
Background: IL-12 is a key mediator of antitumor immune response. In preclinical models, IT IL-12 mRNA led to IFNγ release and CD8+ T cell-dependent tumor regression and potentiated PD-L1 blockade. MEDI1191, a lipid nanoparticle-formulated mRNA encoding IL-12 delivered by IT injection, drives IL-12 production and enhances antitumor immune response with improved tolerability. We hypothesized that combining MEDI1191 with PD-L1 blockade would augment antitumor immunity in vivo. Here we report updated results from the dose-escalation phase of the first-in-human study of IT MEDI1191 and IV durvalumab (D; anti-PD-L1) for advanced/metastatic solid tumors (NCT03946800). Methods: In this multicenter, open-label study, MEDI1191 was dosed sequentially (seq, Part 1A) or concurrently (conc, Part 1B) with D. In Part 1A, MEDI1191 was given IT on Days 1 and 22 followed by D 1500 mg on day 43 and then Q4W IV. In Part 1B, MEDI1191 was given IT on Days 1, 29, 57 and then Q8W, along with D on Day 1 and then Q4W. Treatment continued until progression or unacceptable toxicity for up to 2 years. Eligible adult pts had any solid tumor with cutaneous or subcutaneous lesions suitable for IT injection and progression on standard therapy for recurrent/metastatic disease. Primary objectives were safety and tolerability and determination of maximum tolerated dose (MTD); secondary objectives included preliminary antitumor activity by RECIST v1.1. Results: Starting in May 2019, 31 pts received seq MEDI1191 with D (Part 1A cohorts 0.1-12 μg; n=20) or conc MEDI1191 with D (Part 1B cohorts 1.0-3.0 μg; n=11); 23 pts had received prior anti-PD-1/PD-L1 therapy. Most common tumor types were melanoma, n=8; head and neck cancer, n=4; and breast cancer, n=4. At the data cutoff of Dec 7, 2021, there were no dose-limiting toxicities and no MTD was identified. One pt (3.2%) had a Gr ≥3 MEDI1191-related AE (Gr 3 pyrexia, resolved within 24 hr) and 1 (3.2%) had a MEDI1191-related serious AE (SAE; Gr 2 confusion). Two pts had Gr 3 D-related AEs (6.5%, pyrexia also related to MEDI1191 and pruritus; each n=1); none had a D-related SAE. There were no Gr 4 related AEs. 3 pts had partial responses (PR): 1 with head and neck cancer (unconfirmed, off study) and 2 with anti-PD-1 resistant melanoma (1 confirmed, >12 months on treatment; 1 unconfirmed, off study); 10 pts had stable disease (including the 2 unconfirmed PRs). Among pts with available biomarker data (up to 3 μg in Part 1A and 1 μg in Part 1B), MEDI1191 increased serum IL-12 in 15/17 pts, increased CD8+ T cell tumor infiltration by >2-fold in 8/14 pts and increased tumor PD-L1 expression in 6/14 pts. Conclusions: IT MEDI1191 plus systemic anti-PD-L1 was safe and feasible. Preliminary antitumor efficacy and pharmacodynamics, including tumor CD8+ T cell recruitment, were consistent with expected mechanism of action. Pts with injectable deep visceral and superficial lesions are being recruited. Citation Format: Benedito A. Carneiro, Dmitriy Zamarin, Thomas Marron, Inderjit Mehmi, Sandip P. Patel, Vivek Subbiah, Anthony El-Khoueiry, David Grand, Kirema Garcia-Reyes, Sanjay Goel, Phillip Martin, Jixin Wang, Yuling Wu, Steven Eck, Benjamin Ridgway, Nairouz Elgeioushi, Jim Eyles, Nicholas Durham, Analia Azaro, Omid Hamid. First-in-human study of MEDI1191 (mRNA encoding IL-12) plus durvalumab in patients (pts) with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT183.
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- 2022
15. Humanised effector-null FcγRIIA antibody inhibits immune complex-mediated proinflammatory responses
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Sean Turman, Benjamin Kemp, Ronald Herbst, Janet Griffiths, Jennifer Cann, Mary Jane Hinrichs, M. Jack Borrok, Lisa Marie Kitching Vinall, D. Gareth Rees, David Howe, Yue Wang, Carlos Gonzalez, Shu Wang, Steven Eck, Hong Sun, Brian Naiman, Katherine A. Vousden, Koshu Okubo, Roland Kolbeck, Antonio DiGiandomenico, Tanya N. Mayadas, Gary P. Sims, Ethan Grant, Neang Ly, Ximing Xiong, Yebin Zhou, Srinath Kasturiangan, Holly Koelkebeck, Weiguang Zhao, Christopher Morehouse, and Bo Chen
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0301 basic medicine ,Neutrophils ,immune complex ,Arthritis ,Antigen-Antibody Complex ,Mice ,0302 clinical medicine ,antibody ,Immunology and Allergy ,Connective Tissue Diseases ,medicine.diagnostic_test ,biology ,Immune complex ,Antibodies, Anti-Idiotypic ,medicine.symptom ,Antibody ,Immunology ,Mice, Transgenic ,Inflammation ,General Biochemistry, Genetics and Molecular Biology ,Antibodies, Antineutrophil Cytoplasmic ,Autoimmune Diseases ,Flow cytometry ,Proinflammatory cytokine ,03 medical and health sciences ,Immune system ,Rheumatology ,medicine ,Animals ,Immunologic Factors ,Humans ,Immune Complex Diseases ,030203 arthritis & rheumatology ,FcγRIIA ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,business.industry ,Receptors, IgG ,Autoantibody ,Dendritic Cells ,medicine.disease ,Macaca fascicularis ,030104 developmental biology ,inflammation ,Immunoglobulin G ,biology.protein ,Reactive Oxygen Species ,business - Abstract
ObjectiveImmune complexes (ICs) play a critical role in the pathology of autoimmune diseases. The aim of this study was to generate and characterise a first-in-class anti-FcγRIIA antibody (Ab) VIB9600 (previously known as MEDI9600) that blocks IgG immune complex-mediated cellular activation for clinical development.MethodsVIB9600 was humanised and optimised from the IV.3 Ab. Binding affinity and specificity were determined by Biacore and ELISA. Confocal microscopy, Flow Cytometry-based assays and binding competition assays were used to assess the mode of action of the antibody. In vitro cell-based assays were used to demonstrate suppression of IC-mediated inflammatory responses. In vivo target suppression and efficacy was demonstrated in FcγRIIA-transgenic mice. Single-dose pharmacokinetic (PK)/pharmacodynamic study multiple dose Good Laboratory Practice (GLP) toxicity studies were conducted in non-human primates.ResultsWe generated a humanised effector-deficient anti-FcγRIIA antibody (VIB9600) that potently blocks autoantibody and IC-mediated proinflammatory responses. VIB9600 suppresses FcγRIIA activation by blocking ligand engagement and by internalising FcγRIIA from the cell surface. VIB9600 inhibits IC-induced type I interferons from plasmacytoid dendritic cells (involved in SLE), antineutrophil cytoplasmic antibody (ANCA)-induced production of reactive oxygen species by neutrophils (involved in ANCA-associated vasculitis) and IC-induced tumour necrosis factor α and interleukin-6 production (involved in rheumatoid arthritis). In FcγRIIA transgenic mice, VIB9600 suppressed antiplatelet antibody-induced thrombocytopaenia, acute anti-GBM Ab-induced nephritis and anticollagen Ab-induced arthritis. VIB9600 also exhibited favourable PK and safety profiles in cynomolgus monkey studies.ConclusionsVIB9600 is a specific humanised antibody antagonist of FcγRIIA with null effector function that warrants further clinical development for the treatment of IC-mediated diseases.
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- 2018
16. 2020 White Paper on Recent Issues in Bioanalysis: BAV Guidance, CLSI H62, Biotherapeutics Stability, Parallelism Testing, CyTOF and Regulatory Feedback (
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Susan, Spitz, Yan, Zhang, Sally, Fischer, Kristina, McGuire, Ulrike, Sommer, Lakshmi, Amaravadi, Abbas, Bandukwala, Steven, Eck, Fabio, Garofolo, Rafiqul, Islam, Gregor, Jordan, Lindsay, King, Yoshiro, Saito, Giane, Sumner, Linda, Terry, Alessandra, Vitaliti, Yow-Ming, Wang, Christine, Grimaldi, Alison, Joyce, Rachel, Palmer, Matthew, Andisik, Marcela, Araya, Mitra, Azadeh, Daniel, Baltrukonis, Rebecca, Elliott, Sam, Haidar, Seema, Kumar, Andrew, Mayer, Florian, Neff, Nisha, Palackal, Kun, Peng, Mohsen Rajabi, Abhari, Christina, Satterwhite, Natasha, Savoie, Catherine, Soo, Stephen, Vinter, Jan, Welink, Weili, Yan, Kevin, Maher, David, Lanham, Sylvie, Bertholet, Naveen, Dakappagari, Christèle, Gonneau, Cherie, Green, Fabian, Junker, Sumit, Kar, Lisa, Patti-Diaz, Shyam, Sarikonda, Megan, McCausland, Priscila Camillo, Teixeira, Vilma, Decman, Jose, Estevam, Michael, Hedrick, Alberto Hidalgo, Robert, Gregory, Hopkins, Sandra, Nuti, Shabnam, Tangri, Richard, Wnek, Suman, Dandamudi, Arindam, Dasgupta, Anna, Edmison, Patrick, Faustino, Michael, McGuinness, Gustavo Mendes, Lima Santos, Tahseen, Mirza, Diaa, Shakleya, Susan, Stojdl, Nilufer, Tampal, Jinhui, Zhang, Elana, Cherry, Isabelle, Cludts, Andrew, Exley, Akiko, Ishii-Watabe, Susan, Kirshner, Joao, Pedras-Vasconcelos, Meiyu, Shen, Richard, Siggers, Therese, Solstad, Daniela, Verthelyi, Haoheng, Yan, and Lucia, Zhang
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Research Report ,Cell- and Tissue-Based Therapy ,Humans ,Biological Assay ,Genetic Therapy ,Biomarkers ,Biotechnology - Abstract
The 14
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- 2021
17. Best practices for the development, analytical validation and clinical implementation of flow cytometric methods for chimeric antigen receptor T cell analyses
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Paul C Trampont, Ghanashyam Sarikonda, Virginia Litwin, Laïla-Aïcha Hanafi, Vilma Decman, Anil Pahuja, Yongliang S Sun, Mélissa Mathieu, Michael Nathan Hedrick, Susan Reynolds, Steven Eck, Qiong Xue, Naveen Dakappagari, Jennifer J. Stewart, Shabnam Tangri, Mahwish Natalia, and Piotr L Pierog
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0301 basic medicine ,Multiple stages ,Histology ,Best practice ,T cell ,T-Lymphocytes ,Computational biology ,Immunotherapy, Adoptive ,Pathology and Forensic Medicine ,Flow cytometry ,Blood cancer ,03 medical and health sciences ,0302 clinical medicine ,Medicine ,Humans ,Receptors, Chimeric Antigen ,medicine.diagnostic_test ,business.industry ,Cell Biology ,Flow Cytometry ,Chimeric antigen receptor ,Clinical trial ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Car t cells ,business - Abstract
Chimeric Antigen Receptor (CAR) T cells are recognized as efficacious therapies with demonstrated ability to produce durable responses in blood cancer patients. Regulatory approvals and acceptance of these unique therapies by patients and reimbursement agencies have led to a significant increase in the number of next generation CAR T clinical trials. Flow cytometry is a powerful tool for comprehensive profiling of individual CAR T cells at multiple stages of clinical development, from product characterization during manufacturing to longitudinal evaluation of the infused product in patients. There are unique challenges with regard to the development and validation of flow cytometric methods for CAR T cells; moreover, the assay requirements for manufacturing and clinical monitoring differ. Based on the collective experience of the authors, this recommendation paper aims to review these challenges and present approaches to address them. The discussion focuses on describing key considerations for the design, optimization, validation and implementation of flow cytometric methods during the clinical development of CAR T cell therapies.
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- 2020
18. Potent Immune Modulation by MEDI6383, an Engineered Human OX40 Ligand IgG4P Fc Fusion Protein
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Andrew W. Sylwester, James Hair, Scott A. Hammond, Qun Du, Nicholas Buss, Lolke de Haan, Michael Oberst, Kathy Mulgrew, Louis J. Picker, Michael K. Axthelm, Melissa Damschroder, Hui Feng, Andrew D. Weinberg, Haesun Park, Shino Hanabuchi, Steven Eck, Stacy R. Kentner, Chad Morris, Kelly McGlinchey, Nicholas P. Morris, Andrew J. Pierce, and Catherine Auge
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Cytotoxicity, Immunologic ,0301 basic medicine ,Cancer Research ,Regulatory T cell ,Recombinant Fusion Proteins ,T-Lymphocytes ,medicine.medical_treatment ,T cell ,OX40 Ligand ,Lymphocyte Activation ,T-Lymphocytes, Regulatory ,Article ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Animals ,Humans ,CD134 ,Receptor ,Chemistry ,Effector ,Receptors, OX40 ,Macaca mulatta ,Fusion protein ,Immunoglobulin Fc Fragments ,Cell biology ,HEK293 Cells ,030104 developmental biology ,medicine.anatomical_structure ,Cytokine ,Oncology ,Immunoglobulin G ,Cytokines ,Female ,Protein Multimerization ,CD8 - Abstract
Ligation of OX40 (CD134, TNFRSF4) on activated T cells by its natural ligand (OX40L, CD252, TNFSF4) enhances cellular survival, proliferation, and effector functions such as cytokine release and cellular cytotoxicity. We engineered a recombinant human OX40L IgG4P Fc fusion protein termed MEDI6383 that assembles into a hexameric structure and exerts potent agonist activity following engagement of OX40. MEDI6383 displayed solution-phase agonist activity that was enhanced when the fusion protein was clustered by Fc gamma receptors (FcγRs) on the surface of adjacent cells. The resulting costimulation of OX40 on T cells induced NFκB promoter activity in OX40-expressing T cells and induced Th1-type cytokine production, proliferation, and resistance to regulatory T cell (Treg)-mediated suppression. MEDI6383 enhanced the cytolytic activity of tumor-reactive T cells and reduced tumor growth in the context of an alloreactive human T cell:tumor cell admix model in immunocompromised mice. Consistent with the role of OX40 costimulation in the expansion of memory T cells, MEDI6383 administered to healthy nonhuman primates elicited peripheral blood CD4 and CD8 central and effector memory T-cell proliferation as well as B-cell proliferation. Together, these results suggest that OX40 agonism has the potential to enhance antitumor immunity in human malignancies. Mol Cancer Ther; 17(5); 1024–38. ©2018 AACR.
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- 2018
19. Safety and Clinical Activity of MEDI0562, a Humanized OX40 Agonist Monoclonal Antibody, in Adult Patients with Advanced Solid Tumors
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Bonnie S. Glisson, Yanan Zheng, Bhumsuk Keam, Steven Eck, Sandip Pravin Patel, Sanjay Goel, Matthew Gribbin, James Ohr, Naiyer A. Rizvi, Danielle M. Townsley, Katie Streicher, Reva Schneider, John D. Powderly, Jennifer Burton, Rom Leidner, and Robert L. Ferris
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0301 basic medicine ,Adult ,Male ,Cancer Research ,Programmed Cell Death 1 Receptor ,Pharmacology ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Pharmacokinetics ,Neoplasms ,Medicine ,Humans ,CTLA-4 Antigen ,Adverse effect ,Aged ,Neoplasm Staging ,Dose-Response Relationship, Drug ,business.industry ,Immunogenicity ,FOXP3 ,Antibodies, Monoclonal ,Middle Aged ,Antigens, Differentiation ,Immune checkpoint ,030104 developmental biology ,Oncology ,Tolerability ,030220 oncology & carcinogenesis ,Pharmacodynamics ,Female ,Neoplasm Recurrence, Local ,business - Abstract
Purpose: Immune checkpoint blockade has demonstrated clinical benefits across multiple solid tumor types; however, resistance and relapse often occur. New immunomodulatory targets, which are highly expressed in activated immune cells, are needed. MEDI0562, an agonistic humanized mAb, specifically binds to the costimulatory molecule OX40. This first-in-human study evaluated MEDI0562 in adults with advanced solid tumors. Patients and Methods: In this phase I, multicenter, open-label, single-arm, dose-escalation (3+3 design) study, patients received 0.03, 0.1, 0.3, 1.0, 3.0, or 10 mg/kg MEDI0562 through intravenous infusion every 2 weeks, until confirmed disease progression or unacceptable toxicity. The primary objective evaluated safety and tolerability. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics. Results: In total, 55 patients received ≥1 dose of MEDI0562 and were included in the analysis. The most common tumor type was squamous cell carcinoma of the head and neck (47%). Median duration of treatment was 10 weeks (range, 2–48 weeks). Treatment-related adverse events (TRAEs) occurred in 67% of patients, most commonly fatigue (31%) and infusion-related reactions (14%). Grade 3 TRAEs occurred in 14% of patients with no apparent dose relationship; no TRAEs resulted in death. Two patients had immune-related partial responses per protocol and 44% had stable disease. MEDI0562 induced increased Ki67+ CD4+ and CD8+ memory T-cell proliferation in the periphery and decreased intratumoral OX40+ FOXP3+ cells. Conclusions: MEDI0562 was safely administered at doses up to 10 mg/kg in heavily pretreated patients. On-target pharmacodynamic effects were suggested in this setting. Further evaluation with immune checkpoint inhibitors is ongoing.
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- 2019
20. Cyt-Geist: Current and Future Challenges in Cytometry: Reports of the CYTO 2018 Conference Workshops
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Kamila Czechowska, Giacomo Vacca, Cherie Green, Ruth M Barnard, Jaroslav Icha, Michael Nathan Hedrick, Gelo Victoriano Dela Cruz, Nicole E. Paul, Judith Arcidiacono, Andrew Filby, Jakob Zimmermann, Jonni S. Moore, Steven R. Bauer, Ruben Props, Jakub Nedbal, Yongliang Sun, Soren Ulrik Sonder, Christopher Hall, Caryn van Vreden, Cláudia Bispo, Paul K. Wallace, Rachel J. Errington, Jenny Molloy, Joanne Lannigan, Frederik Hammes, Johanna Ivaska, Thomas M. Ashhurst, Frederiek-Maarten Kerckhof, Michael Lee, Hyun-Dong Chang, Christian Kukat, Attila Tárnok, Nao Nitta, Robert S. Hoffman, Gert Van Isterdael, Lina Chakrabarti, John Sharpe, Michael Weber, Raluca Niesner, Christopher Groves, Peter Rubbens, Samson Rogers, Yanli Liu, Dominic Gagnon, Alessandra Vitaliti, Radhika Rayanki, Matthias Schiemann, Lili Wang, Robert Salomon, Grace Chojnowski, Rui Gardner, Bunny Cotleur, Derek H. Jones, John T. Elliott, Betsy Ohlsson-Wilhelm, Stefan Radtke, Maciej Cabanski, Ryan R. Brinkman, Michael Gregory, Henning Ulrich, Jennifer J. Stewart, Sheng Lin-Gibson, Dominic C. Jenner, Heba A. Degheidy, Virginia Litwin, Ziv Portat, Silas J. Leavesley, David Lanham, Susann Müller, Stephen P. Perfetto, Steven Eck, Aja M. Rieger, and Diana L. Bonilla
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Histology ,Drug development ,Geist ,Immunology ,570 Life sciences ,biology ,Cell Biology ,Computational biology ,Biomarker discovery ,Biology ,500 Science ,Cytometry ,Pathology and Forensic Medicine - Published
- 2019
21. A CD40L-targeting protein reduces autoantibodies and improves disease activity in patients with autoimmunity
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Isharat Yusuf, Stacey Drabic, Albulescu Marius, Melissa de los Reyes, Rachel Ettinger, Manuel Baca, Jodi L. Karnell, Li Yan, Ximing Xiong, Thomas Thisted, L. Wang, Ulf Müller-Ladner, David Howe, Jing Li, Jorn Drappa, Steven Eck, Rachel Moate, Ronald Herbst, Michele Gunsior, Katie Streicher, and Vaheh Oganesyan
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0301 basic medicine ,Platelet Aggregation ,CD40 Ligand ,Autoimmunity ,Plasma cell ,medicine.disease_cause ,Arthritis, Rheumatoid ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Plasma cell differentiation ,medicine ,Humans ,Rheumatoid factor ,CD40 Antigens ,Autoantibodies ,Cell Proliferation ,Autoimmune disease ,B-Lymphocytes ,CD40 ,biology ,business.industry ,Autoantibody ,General Medicine ,medicine.disease ,Healthy Volunteers ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Immunology ,biology.protein ,business - Abstract
The CD40/CD40L axis plays a central role in the generation of humoral immune responses and is an attractive target for treating autoimmune diseases in the clinic. Here, we report the generation and clinical results of a CD40L binding protein, VIB4920, which lacks an Fc domain, therefore avoiding platelet-related safety issues observed with earlier monoclonal antibody therapeutics that targeted CD40L. VIB4920 blocked downstream CD40 signaling events, resulting in inhibition of human B cell activation and plasma cell differentiation, and did not induce platelet aggregation in preclinical studies. In a phase 1 study in healthy volunteers, VIB4920 suppressed antigen-specific IgG in a dose-dependent fashion after priming and boosting with the T-dependent antigen, KLH. Furthermore, VIB4920 significantly reduced circulating Ki67+ dividing B cells, class-switched memory B cells, and a plasma cell gene signature after immunization. In a phase 1b proof-of-concept study in patients with rheumatoid arthritis, VIB4920 significantly decreased disease activity, achieving low disease activity or clinical remission in more than 50% of patients in the two higher-dose groups. Dose-dependent decreases in rheumatoid factor autoantibodies and Vectra DA biomarker score provide additional evidence that VIB4920 effectively blocked the CD40/CD40L pathway. VIB4920 demonstrated a good overall safety profile in both clinical studies. Together, these data demonstrate the potential of VIB4920 to significantly affect autoimmune disease and humoral immune activation and to support further evaluation of this molecule in inflammatory conditions.
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- 2019
22. OP0331 A novel humanized effector-deficient fcyriia antibody inhibits immune complex mediated proinflammatory responses
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Shu Wang, Roland Kolbeck, Ronald Herbst, Benjamin Kemp, Gary P. Sims, Steven Eck, Sean Turman, Ximing Xiong, Bo Chen, D. Close, Katherine A. Vousden, S Kasturiangan, Antonio DiGiandomenico, Mary Jane Hinrichs, Hong Sun, Lisa Marie Kitching Vinall, Janet Griffiths, and Ethan Grant
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biology ,business.industry ,Autoantibody ,Humanized antibody ,Fragment crystallizable region ,Immune complex ,Proinflammatory cytokine ,Immune system ,Immunology ,biology.protein ,Medicine ,Antibody ,business ,Receptor - Abstract
Background Collectively, the cell surface Fc region of IgG receptors (FcγRs) engage soluble IgG and IgG containing immune complexes and trigger activation or inhibtory signals that play a critical role in the regulation of immune responses. The low affinity FcγRIIA (CD32A) is the most widely expressed activating FcγR in humans and appears to drive autoantibody and immune complex mediated autoimmune disorders. So far a therapeutic targeting this receptor has not been developed. Objectives To generate and characterize a novel humanized effector-deficient FcγRIIA antibody (MEDI9600) for clinical development. Methods The mode of action of MEDI9600 was assessed by confocal microscopy, whole blood internalization, and binding competition assays. Multiple cell based assays were used to measure autoantibody and immune complex mediated responses. The safety of MEDI9600 was assessed in in vitro by neutrophil migration, activation and opsonophagocytic killing assays. Safety and pharmacokinetics were examined in vivo in a single-dose PK/PD study in cynomolgus monkey. Results We generated a humanized effector-deficient FcγRIIA antibody (MEDI9600) that potently blocks both autoantibody and immuno complex-mediated proinflammatory responses from a variety of cell types. This includes the inhibition of Toll-like receptor stimulatory immune complexes that induce type I Interferons from pDC, and the inhibition of anti-neutrophil cytoplasmic antibody (ANCA) induced production of reactive oxygen species from neutrophils, which are associated with the pathogenesis of systemic lupus and ANCA vasculitis respectively. MEDI9600 specifically binds FcγRIIA and its suppressive activity is attributed to its capacity to block ligand engagement and to internalize the receptor from the cell surface. Moreover, in vivo studies indicate that MEDI9600 has a favorable pharmacokinetic and safety profile. Conclusions We have generated MEDI9600, a specific humanized antibody antagonist of FcγRIIA with null effector function that may provide a novel therapeutic approach in the treatment of immune complex mediated diseases. Disclosure of Interest None declared
- Published
- 2017
23. Flow Cytometry Method Validation Protocols
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Steven Eck, Cherie Green, Virginia Litwin, Jennifer J. Stewart, Nithianandan Selliah, Teri Oldaker, and Alessandra Vitaliti
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Quality Control ,0301 basic medicine ,Protocol (science) ,Histology ,Computer science ,Reproducibility of Results ,General Medicine ,Flow Cytometry ,Biochemistry ,03 medical and health sciences ,Medical Laboratory Technology ,030104 developmental biology ,0302 clinical medicine ,Limit of Detection ,Systems engineering ,Animals ,Humans ,030215 immunology - Abstract
Analytical method validation provides a means to ensure that data are credible and reproducible. This unit will provide a brief introduction to analytical method validation as applied to cellular analysis by flow cytometry. In addition, the unit will provide practical procedures for three different types of validation. The first is a limited validation protocol that is applicable for research settings and non-regulated laboratories. The second is validation protocol that presents the minimum validation requirements in regulated laboratories. The third is a transfer validation protocol to be used when methods are transferred between laboratories. The recommendations presented in this unit are consistent with the white papers published by the American Association of Pharmaceutical Scientists and the International Clinical Cytometry Society, as well as with Clinical Laboratory Standards Institute Guideline H62: Validation of Assays Performed by Flow Cytometry (currently in preparation). © 2018 by John Wiley & Sons, Inc.
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- 2018
24. Modeling a 3-D multiscale blood-flow and heat-transfer framework for realistic vascular systems
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Rohan Amare, Erlend Hodneland, Jeremy A. Roberts, Amir A. Bahadori, and Steven Eckels
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Medicine ,Science - Abstract
Abstract Modeling of biological domains and simulation of biophysical processes occurring in them can help inform medical procedures. However, when considering complex domains such as large regions of the human body, the complexities of blood vessel branching and variation of blood vessel dimensions present a major modeling challenge. Here, we present a Voxelized Multi-Physics Simulation (VoM-PhyS) framework to simulate coupled heat transfer and fluid flow using a multi-scale voxel mesh on a biological domain obtained. In this framework, flow in larger blood vessels is modeled using the Hagen–Poiseuille equation for a one-dimensional flow coupled with a three-dimensional two-compartment porous media model for capillary circulation in tissue. The Dirac distribution function is used as Sphere of Influence (SoI) parameter to couple the one-dimensional and three-dimensional flow. This blood flow system is coupled with a heat transfer solver to provide a complete thermo-physiological simulation. The framework is demonstrated on a frog tongue and further analysis is conducted to study the effect of convective heat exchange between blood vessels and tissue, and the effect of SoI on simulation results.
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- 2022
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25. Safety and disease response to MEDI-551, an anti-CD19 antibody, in chronic lymphocytic leukemia patients previously treated with rituximab
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Naresh Bellam, Ronald Herbst, Bruce D. Cheson, Meina Liang, Mehdi Hamadani, Nairouz Elgeioushi, Michelle A. Fanale, Steven Eck, Andres Forero, Antonio Cuneo, Trishna Goswami, Jaime Pérez de Oteyza, Thomas J. Kipps, Marc André, Amy Schneider, Ramy Ibrahim, and Douglas E. Gladstone
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Bendamustine ,Cancer Research ,medicine.medical_specialty ,Nausea ,Chronic lymphocytic leukemia ,Immunology ,Neutropenia ,Gastroenterology ,Sepsis ,Internal medicine ,parasitic diseases ,medicine ,Immunology and Allergy ,Adverse effect ,Pharmacology ,business.industry ,medicine.disease ,Surgery ,Oncology ,Poster Presentation ,Molecular Medicine ,Rituximab ,Chills ,medicine.symptom ,business ,medicine.drug - Abstract
and 13 had stable disease. Commonly reported adverse events (AEs) in MEDI-551 pts were infusion-related reactions (IRRs; 62%), nausea (23%), pyrexia (23%), and neutropenia (23%) in the 26 ph 1/2 pts; in the 29 ph 2 pts, they were nausea (62%), IRRs (31%), pyrexia (28%), chills (28%), and fatigue (28%). 11 pts had ≥ grade 3 AEs in the ph 1/2 study and 16 in the ph 2. Common treatmentrelated AEs: IRRs (58%) and nausea (12%) in the ph 1/2; nausea (52%), IRRs (28%), chills (24%), and fatigue (24%) in the ph 2. Three treatment-unrelated AEs of general health deterioration (ph 1/2), subarachnoid hemorrhage (ph 1/2), and sepsis (ph 2), resulted in death. Conclusions MEDI-551 as a single agent demonstrated B-cell depletion, increased serum BAFF levels, clinical activity, and an acceptable risk-benefit profile in relapsed/refractory CLL pts. Preliminary results of the ongoing ph 2 study of MEDI-551+bendamustine demonstrated an acceptable safety profile.
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- 2013
26. Effect of human OX40 ligand fusion protein (MEDI6383) on immune cells of the humoral and cell-mediated immune response in a non-human primate model
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Haesun Park, Andrew D. Weinberg, Andrew W. Sylwester, Steven Eck, Nicholas Buss, Hyewon Kim, Michael Axhelm, Louis J. Picker, Michael Oberst, Andrew J. Pierce, Scott A. Hammond, and Lolke de Haan
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Agonist ,Cancer Research ,education.field_of_study ,Non human primate ,medicine.drug_class ,Cell-mediated immune response ,Biology ,Fusion protein ,In vitro ,OX40 ligand ,Cell biology ,Immune system ,Oncology ,Immunology ,medicine ,education - Abstract
3052 Background: MEDI6383 is a human OX40 ligand fusion protein currently in clinical development for the treatment of advanced solid malignancies. In vitro, this OX40 agonist binds and activates t...
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- 2015
27. Human OX40 ligand fusion protein (MEDI6383) as a potent OX40 agonist and immuno-modulator in vitro and in vivo
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Melissa Damschroder, Christina Stracener, Scott A. Hammond, Qun Du, Andrew D. Weinberg, Michael Oberst, Steven Eck, Nicholas Buss, Kathy Mulgrew, Catherine Auge, Chad Morris, Kelly McGlinchey, James Hair, and Lolke de Haan
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Agonist ,Cancer Research ,education.field_of_study ,medicine.drug_class ,Effector ,business.industry ,Fusion protein ,In vitro ,OX40 ligand ,Human tumor ,Oncology ,In vivo ,medicine ,Cancer research ,education ,business ,Tumor necrosis factor receptor - Abstract
3056 Background: OX40 is a tumor necrosis factor receptor found primarily on activated T effector (Teff) cells and regulatory T (Treg) cells including lymphocytes infiltrating mouse and human tumor...
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- 2015
28. A Structured Cleaving Mesh for Bioheat Transfer Application
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Rohan Amare, Amir A. Bahadori, and Steven Eckels
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Cartesian grid method ,image-based modeling ,finite-volume method ,human thermal modeling ,voxel-based mesh ,volumetric mesh ,Computer applications to medicine. Medical informatics ,R858-859.7 ,Medical technology ,R855-855.5 - Abstract
Goal: The thermoregulation mechanism is a complex system that executes vital processes in the human body. Various models have been proposed to simulate the thermoregulatory response of an adult human to environmental stimuli. However, these models generally rely on stylized phantoms that lack the anatomical details of voxel phantoms used in radiation dosimetry and shielding research. The goal of this work is to introduce voxel phantoms to thermoregulation research by modeling the physical energy exchange between tissue and its surroundings, discuss a specific challenge associated with voxel phantoms, propose a method to address this challenge, and demonstrate its application. Method: One of the major challenges in using voxel phantoms is the stair-step effect on the surface of the voxelized domain. This effect causes over-estimation of surface area, accurate knowledge of which is critical for modeling heat exchanging systems. A methodology to generate a voxel domain from medical imaging data and reduce error in the surface area caused by the stair-step effect is presented. The methodology, based on a structured mesh and finite-volume method, is demonstrated with tumors generated from magnetic resonance imaging (MRI) scans of mice. Results: The methodology discussed in the paper shows a decrease in surface area over-estimation from 50% to 15% for a sphere and 47% to 17% for tumor models generated directly from MRI scans. Conclusion: This work provides a direct method to generate a smoother domain from medical imaging data and reducing surface area error in a voxelized domain. The technique presented is independent of domain material, including tissue type, and can be extended to any homogeneous or inhomogeneous domain. The increase in surface area accuracy obtained by smoothing the voxel domain results in more accurate temperature estimates in heat transfer simulation.
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- 2020
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29. MEDI-551, an anti-CD19 antibody active in chronic lymphocytic leukemia (CLL) patients previously treated with rituximab
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Douglas E. Gladstone, Nairouz Elgeioushi, Jaime Pérez de Oteyza, Andres Forero, Bruce D. Cheson, Steven Eck, Thomas J. Kipps, Mehdi Hamadani, Ronald Herbst, Ramy Ibrahim, Antonio Cuneo, Michelle A. Fanale, Meina Liang, and Trishna Goswami
- Subjects
Oncology ,Antibody-dependent cell-mediated cytotoxicity ,Cancer Research ,medicine.medical_specialty ,biology ,business.industry ,Chronic lymphocytic leukemia ,medicine.disease ,Refractory ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,Immunology ,medicine ,biology.protein ,Biomarker (medicine) ,Rituximab ,Antibody ,B-cell activating factor ,business ,Adverse effect ,medicine.drug - Abstract
7045 Background: Anti-CD20 mAb therapy has provided survival advantage to patients (pts) with CLL; but pts invariably relapse after anti-CD20 therapy and new approaches are needed. The CLL cells of most pts express CD19, which are upregulated following anti-CD20 therapy. MEDI-551, an affinity-optimized anti-CD19 antibody, destroys malignant cells by Ab-dependent cellular cytotoxicity (ADCC) once bound to CD19. Methods: The activity and toxicity of single-agent MEDI-551 in CLL pts with prior rituximab administration was assessed in a phase 1/2, open-label, dose-escalation and expansion study (NCT00983619). Response was assessed using the 2008 Intl Working Group criteria. B-cell depletion was assessed with flow cytometry and confirmed with biomarker analyses (BAFF). Safety assessments included laboratory parameters and adverse events (AEs and serious AEs [SAEs]). Results: Of 91 pts with refractory B-cell malignancies included in the study, 26 had CLL. CLL pts had received a median of 6 prior therapies: 89% with chemotherapy, 27% with single-agent biologics. Within 3 cycles of MEDI-551 (3 mos), >60% of assessable pts achieved CD20+ B-cell depletion to + and CD22+B cells were associated with concomitant increases in serum BAFF concentrations. Of 20 pts evaluable for response, 4 achieved partial response and 13 had stable disease. Commonly reported AEs were generally grade 1/2 and included infusion reactions (62%), nausea (23%), pyrexia (23%), and neutropenia (23%). Six SAEs were noted in 3 pts: 1 had infusion reaction and general health deterioration, another had subarachnoid hemorrhage (SAH), and a third had dyspnea, pyrexia, and back pain. Only infusion reaction was considered treatment related. Two treatment-unrelated events of general health deterioration and SAH resulted in death. Conclusions: Single-agent activity with a manageable toxicity profile was seen in CLL pts treated in this phase 1/2 study of MEDI-551. An ongoing phase 2 study of MEDI-551 in combination with bendamustine in relapsed CLL patients (NCT01466153) is evaluating clinical response to MEDI-551 and chemotherapy. This study was sponsored by MedImmune, LLC.
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- 2013
30. A review of drag reduction and heat transfer enhancement by riblet surfaces in closed and open channel flow
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Shima Soleimani and Steven Eckels
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Riblet ,Turbulence ,Fluid drag reduction ,Heat transfer enhancement ,Turbulent structures ,Heat ,QC251-338.5 - Abstract
Turbulence and heat transfer are two critical factors in the chain of world energy consumption. Hence, development of more efficient energy transfer techniques in engineering applications through control and optimization of the thermal turbulent boundary layer and turbulence continues to be a subject of intense interest. This is why reviewing a passive flow control technique with a focus on unique characteristics of heat transfer in devices called riblets is beneficial as technology pushes to revolutionize design and manufacturing of heat exchanger equipment. Riblet surfaces are considered beneficial to many commercial applications as they reduce forces between surface and fluid, and in some cases can enhance heat transfer in the turbulent flow regime. As there is no literature study that focuses on heat transfer and riblets, the current study reports experimental and numerical investigations reviewing both drag reduction and heat transfer using riblets in closed and open channels. Drag reduction studies are limited to water and oil flow studies, and heat transfer studies are expanded to air flow studies as there are none on water or oil flow. In addition, physical mechanisms of fluid drag and convective heat transfer are discussed. This paper outlines the challenges of fabricating riblets and provides a design summary for optimal drag reduction and heat transfer. This review also looks at applied numerical methods and their accuracy in evaluating drag reduction and heat transfer over riblet surfaces. The important findings and a possible future optimization approach on riblet surfaces are highlighted as well.
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- 2021
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31. X-ray Imaging-Based Void Fraction Measurement in Saturated Flow Boiling Experiments with Seawater Coolant
- Author
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Seth Eckels, Zayed Ahmed, Molly Ross, Daniel Franken, Steven Eckels, and Hitesh Bindra
- Subjects
X-ray imaging ,flow boiling ,seawater ,void fraction ,flow regimes ,pressure drop ,Technology ,Electrical engineering. Electronics. Nuclear engineering ,TK1-9971 - Abstract
Recent studies have shown that the presence of dissolved salts in water can exhibit peculiar flow boiling and two-phase flow regimes. Two-phase flow and convective flow boiling are typically characterized with the help of void fraction measurements. To quantitatively improve our understanding of two-phase flow and boiling phenomenon with seawater coolant, void fraction data are needed, which can not be obtained from optical imaging. In this paper, we present experimental void fraction measurements of saturated flow boiling of tap water and seawater using X-ray radiography. X-rays with a maximum energy level of 40 KeV were used for imaging the exit region of the heated test section. At lower heat flux levels, the two phase flow in seawater was bubbly and homogeneous in nature, resulting in higher void fractions as compared to tap water. With an increase in heat flux, the flow regime was similar to slug flow, and void fraction measurements approached similarity with tap water. The predicted pressure drop using the measured void faction shows good agreement with the measured total pressure drop across the test section, demonstrating the validity of the measurement process.
- Published
- 2021
- Full Text
- View/download PDF
32. A Novel Penetration System for in situ Astrobiological Studies
- Author
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Yang Gao, Alex Ellery, Mustafa Jaddou, Julian Vincent, and Steven Eckersley
- Subjects
Planetary penetration ,drilling ,astrobiological studies ,bio-inspired systems ,Electronics ,TK7800-8360 ,Electronic computers. Computer science ,QA75.5-76.95 - Abstract
Due to ultraviolet flux in the surface layers of most solar bodies, future astrobiological research is increasingly seeking to conduct subsurface penetration and drilling to detect chemical signature for extant or extinct life. To address this issue, we present a micro-penetrator concept (mass < 10 kg) that is suited for extraterrestrial planetary deployment and in situ investigation of chemical and physical properties. The instrumentation in this concept is a bio-inspired drill to access material beneath sterile surface layer for biomarker detection. The proposed drill represents a novel concept of two-valve-reciprocating motion, inspired by the working mechanism of wood wasp ovipositors. It is lightweight (0.5 kg), driven at low power (3 W), and able to drill deep (1-2 m). Tests have shown that the reciprocating drill is feasible and has potential of improving drill efficiency without using any external force. The overall penetration system provides a small, light and energy efficient solution to in situ astrobiological studies, which is crucial for space engineering. Such a micro-penetrator can be used for exploration of terrestrial-type planets or other small bodies of the solar system with the minimum of modifications.
- Published
- 2008
33. A Novel Penetration System for in Astrobiological Studies
- Author
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Yang Gao, Alex Ellery, Mustafa Jaddou, Julian Vincent, and Steven Eckersley
- Subjects
Electronics ,TK7800-8360 ,Electronic computers. Computer science ,QA75.5-76.95 - Abstract
Due to ultraviolet flux in the surface layers of most solar bodies, future astrobiological research is increasingly seeking to conduct subsurface penetration and drilling to detect chemical signature for extant or extinct life. To address this issue, we present a micro-penetrator concept (mass < 10 kg) that is suited for extraterrestrial planetary deployment and in situ investigation of chemical and physical properties. The instrumentation in this concept is a bio-inspired drill to access material beneath sterile surface layer for biomarker detection. The proposed drill represents a novel concept of two-valve-reciprocating motion, inspired by the working mechanism of wood wasp ovipositors. It is lightweight (0.5 kg), driven at low power (3 W), and able to drill deep (1-2 m). Tests have shown that the reciprocating drill is feasible and has potential of improving drill efficiency without using any external force. The overall penetration system provides a small, light and energy efficient solution to in situ astrobiological studies, which is crucial for space engineering. Such a micro-penetrator can be used for exploration of terrestrial-type planets or other small bodies of the solar system with the minimum of modifications.
- Published
- 2005
- Full Text
- View/download PDF
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