Search

Your search keyword '"Siegel, Robert W."' showing total 11 results
Start Over Author "Siegel, Robert W." Publication Year Range Last 3 years
11 results on '"Siegel, Robert W."'

2. Carboxyl-terminal sequences in APOA5 are important for suppressing ANGPTL3/8 activity

Author

Chen, Yan Q., primary, Yang, Ye, additional, Zhen, Eugene Y., additional, Beyer, Thomas P., additional, Li, Hongxia, additional, Wen, Yi, additional, Ehsani, Mariam, additional, Jackson, Nicholas, additional, Xie, Katherine, additional, Jung, Hyesoo, additional, Scheithauer, Julia L., additional, Kumari, Anni, additional, Birrane, Gabriel, additional, Russell, Anna M., additional, Balasubramaniam, Deepa, additional, Liao, Zhongping, additional, Siegel, Robert W., additional, Qian, Yuewei, additional, Ploug, Michael, additional, Young, Stephen G., additional, and Konrad, Robert J., additional

Published
2024
Full Text
View/download PDF

3. Essential role of pre-existing humoral immunity in TLR9- mediated type I IFN response to recombinant AAV vectors in human whole blood.

Author

Alakhras, Nada S., Moreland, Christopher A., Li Chin Wong, Raut, Priyam, Kamalakaran, Sid, Yi Wen, Siegel, Robert W., and Malherbe, Laurent P.

Subjects
HUMORAL immunity, TYPE I interferons, GENE therapy, IMMUNE response, ADENO-associated virus
Abstract

Recombinant adeno-associated virus (AAV) vectors have emerged as the preferred platform for gene therapy of rare human diseases. Despite the clinical promise, host immune responses to AAV vectors and transgene remain a major barrier to the development of successful AAV-based human gene therapies. Here, we assessed the human innate immune response to AAV9, the preferred serotype for AAV-mediated gene therapy of the CNS. We showed that AAV9 induced type I interferon (IFN) and IL-6 responses in human blood from healthy donors. This innate response was replicated with AAV6, required full viral particles, but was not observed in every donor. Depleting CpG motifs from the AAV transgene or inhibiting TLR9 signaling reduced type I IFN response to AAV9 in responding donors, highlighting the importance of TLR9-mediated DNA sensing for the innate response to AAV9. Remarkably, we further demonstrated that only seropositive donors with preexisting antibodies to AAV9 capsid mounted an innate immune response to AAV9 in human whole blood and that anti-AAV9 antibodies were necessary and sufficient to promote type I IFN release and plasmacytoid dendritic (pDC) cell activation in response to AAV9. Thus, our study reveals a previously unidentified requirement for AAV preexisting antibodies for TLR9-mediated type I IFN response to AAV9 in human blood. [ABSTRACT FROM AUTHOR]

Published
2024
Full Text
View/download PDF

8. LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants

Author

Westendorf, Kathryn, primary, Žentelis, Stefanie, additional, Wang, Lingshu, additional, Foster, Denisa, additional, Vaillancourt, Peter, additional, Wiggin, Matthew, additional, Lovett, Erica, additional, van der Lee, Robin, additional, Hendle, Jörg, additional, Pustilnik, Anna, additional, Sauder, J. Michael, additional, Kraft, Lucas, additional, Hwang, Yuri, additional, Siegel, Robert W., additional, Chen, Jinbiao, additional, Heinz, Beverly A., additional, Higgs, Richard E., additional, Kallewaard, Nicole L., additional, Jepson, Kevin, additional, Goya, Rodrigo, additional, Smith, Maia A., additional, Collins, David W., additional, Pellacani, Davide, additional, Xiang, Ping, additional, de Puyraimond, Valentine, additional, Ricicova, Marketa, additional, Devorkin, Lindsay, additional, Pritchard, Caitlin, additional, O’Neill, Aoise, additional, Dalal, Kush, additional, Panwar, Pankaj, additional, Dhupar, Harveer, additional, Garces, Fabian A., additional, Cohen, Courtney A., additional, Dye, John M., additional, Huie, Kathleen E., additional, Badger, Catherine V., additional, Kobasa, Darwyn, additional, Audet, Jonathan, additional, Freitas, Joshua J., additional, Hassanali, Saleema, additional, Hughes, Ina, additional, Munoz, Luis, additional, Palma, Holly C., additional, Ramamurthy, Bharathi, additional, Cross, Robert W., additional, Geisbert, Thomas W., additional, Menachery, Vineet, additional, Lokugamage, Kumari, additional, Borisevich, Viktoriya, additional, Lanz, Iliana, additional, Anderson, Lisa, additional, Sipahimalani, Payal, additional, Corbett, Kizzmekia S., additional, Yang, Eun Sung, additional, Zhang, Yi, additional, Shi, Wei, additional, Zhou, Tongqing, additional, Choe, Misook, additional, Misasi, John, additional, Kwong, Peter D., additional, Sullivan, Nancy J., additional, Graham, Barney S., additional, Fernandez, Tara L., additional, Hansen, Carl L., additional, Falconer, Ester, additional, Mascola, John R., additional, Jones, Bryan E., additional, and Barnhart, Bryan C., additional

Published
2022
Full Text
View/download PDF

9. An anti-ANGPTL3/8 antibody decreases circulating triglycerides by binding to a LPL-inhibitory leucine zipper-like motif

Author

Balasubramaniam, Deepa, primary, Schroeder, Oliver, additional, Russell, Anna M., additional, Fitchett, Jonathan R., additional, Austin, Aaron K., additional, Beyer, Thomas P., additional, Chen, Yan Q., additional, Day, Jonathan W., additional, Ehsani, Mariam, additional, Heng, Aik Roy, additional, Zhen, Eugene Y., additional, Davies, Julian, additional, Glaesner, Wolfgang, additional, Jones, Bryan E., additional, Siegel, Robert W., additional, Qian, Yue-Wei, additional, and Konrad, Robert J., additional

Published
2022
Full Text
View/download PDF

10. The HLA class-II immunopeptidomes of AAV capsids proteins.

Author

Brito-Sierra CA, Lannan MB, Siegel RW, and Malherbe LP

Subjects
Humans, Dependovirus, Peptides metabolism, HLA Antigens metabolism, Capsid Proteins genetics, Capsid
Abstract

Introduction: Gene therapies are using Adeno-associated viruses (AAVs) as vectors, but immune responses against the capsids pose challenges to their efficiency and safety. Helper T cell recognition of capsid-derived peptides bound to human leukocyte antigen (HLA) class II molecules is an essential step in the AAV-specific adaptive immunity., Methods: Using MHC-associated peptide proteomics, we identified the HLA-DR and HLA-DQ immunopeptidomes of the capsid proteins of three different AAV serotypes (AAV2, AAV6, and AAV9) from a panel of healthy donors selected to represent a majority of allele usage., Results: The identified sequences span the capsids of all serotypes, with AAV2 having the highest peptide count. For all the serotypes, multiple promiscuous peptides were identified and displayed by both HLA-DR and -DQ. However, despite high sequence homology, there were few identical peptides among AAV2, AAV6, and AAV9 immunopeptidomes, and none were promiscuous., Discussion: Results from this work represent a comprehensive immunopeptidomics research of potential CD4+ T cell epitopes and provide the basis for immunosurveillance efforts for safer and more efficient AAV-based gene therapies., Competing Interests: All authors are employees and stockholders of Eli Lilly and Company., (Copyright © 2022 Brito-Sierra, Lannan, Siegel and Malherbe.)

Published
2022
Full Text
View/download PDF

11. LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants.

Author

Westendorf K, Žentelis S, Wang L, Foster D, Vaillancourt P, Wiggin M, Lovett E, van der Lee R, Hendle J, Pustilnik A, Sauder JM, Kraft L, Hwang Y, Siegel RW, Chen J, Heinz BA, Higgs RE, Kallewaard NL, Jepson K, Goya R, Smith MA, Collins DW, Pellacani D, Xiang P, de Puyraimond V, Ricicova M, Devorkin L, Pritchard C, O'Neill A, Dalal K, Panwar P, Dhupar H, Garces FA, Cohen CA, Dye JM, Huie KE, Badger CV, Kobasa D, Audet J, Freitas JJ, Hassanali S, Hughes I, Munoz L, Palma HC, Ramamurthy B, Cross RW, Geisbert TW, Menacherry V, Lokugamage K, Borisevich V, Lanz I, Anderson L, Sipahimalani P, Corbett KS, Yang ES, Zhang Y, Shi W, Zhou T, Choe M, Misasi J, Kwong PD, Sullivan NJ, Graham BS, Fernandez TL, Hansen CL, Falconer E, Mascola JR, Jones BE, and Barnhart BC

Abstract

SARS-CoV-2 neutralizing monoclonal antibodies (mAbs) can reduce the risk of hospitalization when administered early during COVID-19 disease. However, the emergence of variants of concern has negatively impacted the therapeutic use of some authorized mAbs. Using a high throughput B-cell screening pipeline, we isolated a highly potent SARS-CoV-2 spike glycoprotein receptor binding domain (RBD)-specific antibody called LY-CoV1404 (also known as bebtelovimab). LY-CoV1404 potently neutralizes authentic SARS-CoV-2 virus, including the prototype, B.1.1.7, B.1.351 and B.1.617.2). In pseudovirus neutralization studies, LY-CoV1404 retains potent neutralizing activity against numerous variants including B.1.1.7, B.1.351, B.1.617.2, B.1.427/B.1.429, P.1, B.1.526, B.1.1.529, and the BA.2 subvariant and retains binding to spike proteins with a variety of underlying RBD mutations including K417N, L452R, E484K, and N501Y. Structural analysis reveals that the contact residues of the LY-CoV1404 epitope are highly conserved with the exception of N439 and N501. Notably, the binding and neutralizing activity of LY-CoV1404 is unaffected by the most common mutations at these positions (N439K and N501Y). The breadth of reactivity to amino acid substitutions present among current VOC together with broad and potent neutralizing activity and the relatively conserved epitope suggest that LY-CoV1404 has the potential to be an effective therapeutic agent to treat all known variants causing COVID-19., In Brief: LY-CoV1404 is a potent SARS-CoV-2-binding antibody that neutralizes all known variants of concern and whose epitope is rarely mutated., Highlights: LY-CoV1404 potently neutralizes SARS-CoV-2 authentic virus and known variants of concern including the B.1.1.529 (Omicron), the BA.2 Omicron subvariant, and B.1.617.2 (Delta) variantsNo loss of potency against currently circulating variantsBinding epitope on RBD of SARS-CoV-2 is rarely mutated in GISAID databaseBreadth of neutralizing activity and potency supports clinical development.

Published
2022
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results