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2 results on '"Jemima Seidenberg"'

1. Fast-Track Discovery of SARS-CoV-2-Neutralizing Antibodies from Human B Cells by Direct Functional Screening

Author

Matthias Hillenbrand, Christoph Esslinger, Jemima Seidenberg, Marcel Weber, Andreas Zingg, Catherine Townsend, Barbara Eicher, Justina Rutkauskaite, Peggy Riese, Carlos A. Guzman, Karsten Fischer, and Simone Schmitt

Subjects
SARS-CoV-2, neutralizing antibodies, antibody discovery, monoclonal antibodies, viral variants, Microbiology, QR1-502
Abstract

As the COVID-19 pandemic revealed, rapid development of vaccines and therapeutic antibodies are crucial to guarantee a quick return to the status quo of society. In early 2020, we deployed our droplet microfluidic single-cell-based platform DROPZYLLA® for the generation of cognate antibody repertoires of convalescent COVID-19 donors. Discovery of SARS-CoV-2-specific antibodies was performed upon display of antibodies on the surface of HEK293T cells by antigen-specific sorting using binding to the SARS-CoV-2 spike and absence of binding to huACE2 as the sort criteria. This efficiently yielded antibodies within 3–6 weeks, of which up to 100% were neutralizing. One of these, MTX-COVAB, displaying low picomolar neutralization IC50 of SARS-CoV-2 and with a neutralization potency on par with the Regeneron antibodies, was selected for GMP manufacturing and clinical development in June 2020. MTX-COVAB showed strong efficacy in vivo and neutralized all identified clinically relevant variants of SARS-CoV-2 at the time of its selection. MTX-COVAB completed GMP manufacturing by the end of 2020, but clinical development was stopped when the Omicron variant emerged, a variant that proved to be detrimental to all monoclonal antibodies already approved. The present study describes the capabilities of the DROPZYLLA® platform to identify antibodies of high virus-neutralizing capacity rapidly and directly.

Published
2024
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2. The AP-1 Transcription Factor Fosl-2 Regulates Autophagy in Cardiac Fibroblasts during Myocardial Fibrogenesis

Author

Gabriela Kania, Przemyslaw Blyszczuk, Amela Hukara, Oliver Distler, Burkhard Ludewig, Mara Stellato, Jemima Seidenberg, Karin Klingel, University of Zurich, and Kania, Gabriela

Subjects
Male, Cardiac fibrosis, cardiac fibrosis, 1607 Spectroscopy, Fos-Related Antigen-2, lcsh:Chemistry, Mice, 0302 clinical medicine, lcsh:QH301-705.5, Spectroscopy, cardiac fibroblasts, 0303 health sciences, Chemistry, cardiac hypertrophy, 10051 Rheumatology Clinic and Institute of Physical Medicine, General Medicine, Middle Aged, 3. Good health, Computer Science Applications, AP-1 transcription factor, 030220 oncology & carcinogenesis, Female, 1606 Physical and Theoretical Chemistry, Myofibroblast, autophagy, Stromal cell, 1503 Catalysis, ATG5, Mice, Transgenic, 610 Medicine & health, Article, Catalysis, Inorganic Chemistry, 03 medical and health sciences, medicine, 1312 Molecular Biology, 1706 Computer Science Applications, Animals, Humans, Physical and Theoretical Chemistry, Molecular Biology, Fos-related antigen 2, 030304 developmental biology, Aged, Heart Failure, 1604 Inorganic Chemistry, Myocardium, Organic Chemistry, Autophagy, Fibroblasts, medicine.disease, Angiotensin II, Fibrosis, Transcription Factor AP-1, lcsh:Biology (General), lcsh:QD1-999, Gene Expression Regulation, Cancer research, Transforming growth factor, 1605 Organic Chemistry
Abstract

Background: Pathological activation of cardiac fibroblasts is a key step in development and progression of cardiac fibrosis and heart failure. This process has been associated with enhanced autophagocytosis, but molecular mechanisms remain largely unknown. Methods and Results: Immunohistochemical analysis of endomyocardial biopsies showed increased activation of autophagy in fibrotic hearts of patients with inflammatory cardiomyopathy. In vitro experiments using mouse and human cardiac fibroblasts confirmed that blockade of autophagy with Bafilomycin A1 inhibited fibroblast-to-myofibroblast transition induced by transforming growth factor (TGF)-β. Next, we observed that cardiac fibroblasts obtained from mice overexpressing transcription factor Fos-related antigen 2 (Fosl-2tg) expressed elevated protein levels of autophagy markers: the lipid modified form of microtubule-associated protein 1A/1B-light chain 3B (LC3BII), Beclin-1 and autophagy related 5 (Atg5). In complementary experiments, silencing of Fosl-2 with antisense GapmeR oligonucleotides suppressed production of type I collagen, myofibroblast marker alpha smooth muscle actin and autophagy marker Beclin-1 in cardiac fibroblasts. On the other hand, silencing of either LC3B or Beclin-1 reduced Fosl-2 levels in TGF-β-activated, but not in unstimulated cells. Using a cardiac hypertrophy model induced by continuous infusion of angiotensin II with osmotic minipumps, we confirmed that mice lacking either Fosl-2 (Ccl19CreFosl2flox/flox) or Atg5 (Ccl19CreAtg5flox/flox) in stromal cells were protected from cardiac fibrosis. Conclusion: Our findings demonstrate that Fosl-2 regulates autophagocytosis and the TGF-β-Fosl-2-autophagy axis controls differentiation of cardiac fibroblasts. These data provide a new insight for the development of pharmaceutical targets in cardiac fibrosis.

Published
2021
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