7 results on '"Kermer V"'
Search Results
2. mRNA vaccine development during the COVID-19 pandemic: a retrospective review from the perspective of the Swiss affiliate of a global biopharmaceutical company.
- Author
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Killeen T, Kermer V, and Troxler Saxer R
- Abstract
The coronavirus disease 2019 (COVID-19) pandemic has been the defining public health emergency of our time. In Switzerland, messenger RNA (mRNA) vaccines were and still are widely utilized as a critical component of the Federal Office of Public Health (FOPH)'s preventative mitigation strategy. The development, conditional approval and worldwide roll-out of mRNA vaccines against COVID-19 proceeded at an unprecedented pace and presented myriad challenges for manufacturers. In this review, we discuss, from the perspective of the Swiss affiliate of a global biopharmaceutical company, the clinical, regulatory, pharmacovigilance and logistical considerations of making a mRNA COVID-19 vaccine available to the Swiss population during a pandemic as rapidly as possible while ensuring strict adherence to safety and quality standards., (© 2023. Pfizer Inc.)
- Published
- 2023
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3. Combining antibody-directed presentation of IL-15 and 4-1BBL in a trifunctional fusion protein for cancer immunotherapy.
- Author
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Kermer V, Hornig N, Harder M, Bondarieva A, Kontermann RE, and Müller D
- Subjects
- 4-1BB Ligand genetics, 4-1BB Ligand therapeutic use, Animals, Cell Line, Tumor, Cell Proliferation, Humans, Interleukin-15 genetics, Interleukin-15 immunology, Interleukin-15 urine, Lymphocyte Activation immunology, Mice, Neoplasms immunology, Receptors, Tumor Necrosis Factor immunology, Receptors, Tumor Necrosis Factor metabolism, Recombinant Fusion Proteins immunology, Recombinant Fusion Proteins therapeutic use, Single-Chain Antibodies immunology, Single-Chain Antibodies therapeutic use, T-Lymphocytes, Cytotoxic immunology, 4-1BB Ligand immunology, Immunotherapy, Interleukin-15 therapeutic use, Neoplasms therapy
- Abstract
Influencing the cytokine receptor network that modulates the immune response holds great potential for cancer immunotherapy. Although encouraging results have been obtained by focusing on individual members of the common γ-chain (γc) receptor family and TNF receptor superfamily so far, combination strategies might be required to further improve the effectiveness of the antitumor response. Here, we propose the combination of interleukin (IL)-15 and 4-1BBL in a single, tumor-directed molecule. Therefore, a trifunctional antibody fusion protein was generated, composed of a tumor-specific recombinant antibody, IL-15 linked to a fragment of the IL-15Rα chain (RD) and the extracellular domain of 4-1BBL. In soluble and targeted forms, the trifunctional antibody fusion protein RD_IL-15_scFv_4-1BBL was shown to stimulate activated T-cell proliferation and induce T-cell cytotoxicity to a similar degree as the bifunctional scFv_RD_IL-15 fusion protein. On the other hand, in targeted form, the trifunctional fusion protein was much more effective in inducing T-cell proliferation and IFN-γ release of unstimulated peripheral blood mononuclear cells (PBMC). Here, the additional signal enhancement could be attributed to the costimulatory activity of 4-1BBL, indicating a clear benefit for the simultaneous presentation of IL-15 and 4-1BBL in one molecule. Furthermore, the trifunctional antibody fusion protein was more effective than the corresponding bifunctional fusion proteins in reducing metastases in a tumor mouse model in vivo. Hence, the targeted combination of IL-15 and 4-BBL in the form of a trifunctional antibody-fusion protein is a promising new approach for cancer immunotherapy.
- Published
- 2014
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4. Evaluating combinations of costimulatory antibody-ligand fusion proteins for targeted cancer immunotherapy.
- Author
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Hornig N, Reinhardt K, Kermer V, Kontermann RE, and Müller D
- Subjects
- 4-1BB Ligand genetics, 4-1BB Ligand immunology, Animals, Antibodies, Bispecific genetics, Antibodies, Bispecific immunology, B7-1 Antigen genetics, B7-1 Antigen immunology, Cell Line, Tumor, Cell Proliferation drug effects, Cells, Cultured, Drug Evaluation, Preclinical, Granzymes immunology, Granzymes metabolism, HEK293 Cells, Humans, Interferon-gamma immunology, Interferon-gamma metabolism, Ligands, Lung Neoplasms immunology, Lung Neoplasms secondary, Lung Neoplasms therapy, Mice, Mice, Inbred C57BL, Neoplasms, Experimental immunology, Neoplasms, Experimental pathology, Programmed Cell Death 1 Receptor immunology, Programmed Cell Death 1 Receptor metabolism, Recombinant Fusion Proteins immunology, Recombinant Fusion Proteins pharmacokinetics, T-Lymphocytes drug effects, T-Lymphocytes immunology, T-Lymphocytes metabolism, Treatment Outcome, Tumor Burden drug effects, Tumor Burden immunology, Immunotherapy methods, Neoplasms, Experimental therapy, Recombinant Fusion Proteins therapeutic use
- Abstract
Combinatory strategies are becoming of increasing interest in cancer immunotherapy. Costimulation by individual members of the immunoglobulin-like (Ig)- and TNF superfamily have already shown promising antitumor potential, thus prompting the exploration of their synergistic abilities in combinatorial approaches. Here, we pursued a targeted strategy with antibody-fusion proteins composed of a tumor-directed antibody and the extracellular domain of the costimulatory ligand B7.1, 4-1BBL, OX40L, GITRL or LIGHT, respectively. Costimulatory activity was assessed in an experimental setting where initial T cell activation was induced by a bispecific antibody (tumor-related antigen × CD3). Advantage of combined targeted costimulation was shown for either B7.1 or 4-1BBL with OX40L, GITRL, LIGHT and 4-1BBL in terms of T cell proliferation and IFN-γ release. Since encouraging results were obtained by the combination of B7.1 and 4-1BBL, we adapted the model system for a time-shift setting. Here, enhanced proliferation and granzyme B expression as well as reduced PD-1 expression on the T cell population demonstrated the benefit of costimulation-assisted restimulation. Finally, the antitumor potential of this combinatorial setting was confirmed in vivo in a lung metastasis mouse model. Thus, combinatorial approaches with costimulatory antibody-ligand fusion proteins seem a promising strategy to be further investigated for cancer immunotherapy.
- Published
- 2013
- Full Text
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5. Combination of a bispecific antibody and costimulatory antibody-ligand fusion proteins for targeted cancer immunotherapy.
- Author
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Hornig N, Kermer V, Frey K, Diebolder P, Kontermann RE, and Müller D
- Subjects
- Antibodies, Bispecific immunology, Antigens, CD genetics, Antigens, CD immunology, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes immunology, Cell Proliferation drug effects, Cells, Cultured, Endoglin, Endopeptidases, Gelatinases genetics, Gelatinases immunology, HEK293 Cells, Humans, Interferon-gamma biosynthesis, Interferon-gamma immunology, Interleukin-2 biosynthesis, Interleukin-2 immunology, Interleukin-2 Receptor alpha Subunit biosynthesis, Interleukin-2 Receptor alpha Subunit immunology, Ligands, Lymphocyte Activation, Membrane Proteins genetics, Membrane Proteins immunology, Molecular Targeted Therapy, Receptors, Cell Surface genetics, Receptors, Cell Surface immunology, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins immunology, Serine Endopeptidases genetics, Serine Endopeptidases immunology, T-Lymphocytes, Regulatory drug effects, T-Lymphocytes, Regulatory immunology, Transfection, Antibodies, Bispecific pharmacology, Recombinant Fusion Proteins pharmacology
- Abstract
Initiation of a tumor-directed immune response and appropriate modulation of its progress are key issues in cancer immunotherapy. Combinatorial strategies addressing both aspects might therefore be especially suitable. Here, we report a targeted approach combining a bispecific antibody with 2 costimulatory antibody-ligand fusion proteins. According to the concept, the bispecific antibody (scDbFAP×CD3) retargets T cells in a MHC-independent manner to tumor cells, providing an artificial first signal that allows the costimulatory antibody-ligand fusion proteins (B7.2-Db and scFv-4-1BBL) likewise targeted to the tumor cells to modulate the T-cell response. In our model system, the target cells coexpress the fibroblast activation protein (FAP) and endoglin as antigens. ScDbFAPCD3 and B7.2-Db are targeted to FAP although by different antibody moieties, whereas scFv-4-1BBL is directed against endoglin. ScDbFAPCD3-induced T-cell stimulation could be enhanced by the addition of either B7.2-Db or scFv-4-1BBL and even further by the combination of both as shown in terms of cytokine release (interleukin-2/interferon γ), proliferation and activation marker expression (CD25). By combined costimulation, overall T-cell population strongly increased in activation-experienced memory phenotype accompanied by a decrease in naive phenotype. ScFv-4-1BBL-mediated costimulation of naive CD8+ T cells promoted the expansion and development of cytotoxic T cells with strong effector potential. Thus, combining a bispecific antibody with antibody-ligand fusion protein-mediated CD28 and 4-1BB costimulation in a targeted approach shows great potential to generate and shape an immune response at the tumor site. Therefore, the adaptation of this approach to other immune modulatory ligands and tumor-relevant targets seems to be promising.
- Published
- 2012
- Full Text
- View/download PDF
6. An antibody fusion protein for cancer immunotherapy mimicking IL-15 trans-presentation at the tumor site.
- Author
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Kermer V, Baum V, Hornig N, Kontermann RE, and Müller D
- Subjects
- Animals, Antigen Presentation, Antineoplastic Agents pharmacokinetics, Cell Line, Tumor, Cell Proliferation, Endopeptidases, Gelatinases immunology, Gelatinases metabolism, Humans, Immunotherapy, Interleukin-15 metabolism, Interleukin-15 Receptor alpha Subunit metabolism, Lung Neoplasms immunology, Lung Neoplasms prevention & control, Lung Neoplasms secondary, Membrane Proteins immunology, Membrane Proteins metabolism, Mice, Mice, Inbred C57BL, Molecular Mimicry, Molecular Targeted Therapy, Neoplasm Transplantation, Protein Structure, Tertiary, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins pharmacokinetics, Serine Endopeptidases immunology, Serine Endopeptidases metabolism, T-Lymphocytes drug effects, T-Lymphocytes immunology, T-Lymphocytes pathology, Antineoplastic Agents pharmacology, Interleukin-15 immunology, Interleukin-15 Receptor alpha Subunit genetics, Recombinant Fusion Proteins pharmacology, Single-Chain Antibodies genetics
- Abstract
Cytokines driving the immune response are powerful tools for cancer immunotherapy, but their application is generally limited by severe systemic toxicity. Targeted approaches by means of antibody-cytokine fusion proteins might enable focus on the cytokine activity to the tumor site, thereby reducing unwanted side effects. Here, we investigated the possibility to improve the efficiency of interleukin (IL)-15 presentation in a targeted approach by the incorporation of an IL-15Rα chain fragment, mimicking physiologic trans-presentation. Therefore, an antibody cytokine fusion protein (scFv_RD_IL-15) composed of an antibody moiety targeting the tumor stromal fibroblast activation protein (FAP), an extended IL-15Rαsushi domain (RD) and IL-15 was generated, exhibiting antibody-mediated specific binding and cytokine activity in soluble and targeted form. Comparative analysis with a corresponding antibody fusion protein devoid of RD (scFv_IL-15) showed for scFv_RD_IL-15 in solution enhanced stimulatory activity on Mo7e (IL-15Rβγ) cells and reduced proliferation response on CTLL-2 (IL-15Rαβγ) cells, while in FAP-targeted, that is, membrane-bound form, comparable proliferation of CTLL-2 (IL-15Rαβγ) cells was obtained. In addition, scFv_RD_IL-15 achieved in its soluble and target-bound form stronger proliferation and cytotoxicity on unstimulated and activated T cells, respectively. Furthermore, in vivo analysis in a lung metastasis tumor mouse model revealed a superior antitumor effect for scFv_RD_IL-15 in comparison with that obtained by an untargeted or RD missing version of IL-15 fusion protein. Thus, tumor-directed trans-presentation of IL-15 in association with RD in form of an antibody fusion protein seems to be a promising approach to further improve the antitumor effect of IL-15., (©2012 AACR)
- Published
- 2012
- Full Text
- View/download PDF
7. Knockdown of tissue nonspecific alkaline phosphatase impairs neural stem cell proliferation and differentiation.
- Author
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Kermer V, Ritter M, Albuquerque B, Leib C, Stanke M, and Zimmermann H
- Subjects
- Alkaline Phosphatase physiology, Animals, Blotting, Western, Cell Adhesion physiology, Cells, Cultured, Immunohistochemistry, Mice, Mice, Transgenic, Multipotent Stem Cells physiology, Neurons physiology, Oligodendroglia physiology, RNA Interference, RNA, Messenger biosynthesis, RNA, Messenger genetics, RNA, Small Interfering biosynthesis, RNA, Small Interfering genetics, Alkaline Phosphatase genetics, Cell Differentiation genetics, Cell Differentiation physiology, Cell Proliferation, Neural Stem Cells enzymology, Neural Stem Cells physiology
- Abstract
In the adult mammalian brain the subependymal layer of the lateral ventricles houses neural stem cells giving rise to young neurons migrating towards the olfactory bulb. The molecular cues controlling essential functions within the neurogenesis pathway such as proliferation, short and long distance migration, differentiation and functional integration are poorly understood. Neural progenitors in situ express the tissue nonspecific form of alkaline phosphatase (TNAP), a cell surface-located nonspecific phosphomonoesterase capable of hydrolyzing extracellular nucleotides. To gain insight into the functional role of TNAP in cultured multipotent neural stem cells we applied a knockdown protocol using RNA interference with shRNA and retroviral infection. We show that TNAP knockdown reduces cell proliferation and differentiation into neurons or oligodendrocytes. This effect is abrogated by addition of alkaline phosphatase to the culture medium. Our results suggest that TNAP is essential for NSC proliferation and differentiation in vitro and possibly also in vivo., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
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