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Article ; Online: CT109-SN-38, a Novel Antibody-drug Conjugate with Dual Specificity for CEACAM5 and 6, Elicits Potent Killing of Pancreatic Cancer Cells.

Arias Cardenas, Kelly C / Enos, Clinton W / Spear, Mark R / Austin, Dana E / Almofeez, Raghad / Kortchak, Stephanie / Pincus, Lauren / Guo, Hua-Bei / Dolezal, Samuel / Pierce, J Michael / Furth, Emma / Gineste, Cyrille / Kwon, Yongjun / Gelber, Cohava

Current cancer drug targets

2024

Abstract: Background: CEACAM5 and CEACAM6 are glycosylphosphatidylinositol (GPI)- linked members of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family, which are frequently upregulated in epithelial cancers where they contribute to ... ...

Abstract	Background: CEACAM5 and CEACAM6 are glycosylphosphatidylinositol (GPI)- linked members of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family, which are frequently upregulated in epithelial cancers where they contribute to invasion, metastasis, immune evasion, and resistance to anoikis. CT109 is a novel antibody with dual specificity to both CEACAM5 and 6. Objective: In this study, we aimed to perform the preclinical characterization of CT109 and antibody- drug conjugate (ADCs) derivatives of CT109, focusing on CT109-SN-38. Methods: CT109's cognate epitope was characterized by scanning mutagenesis. CT109 specificity and internalization kinetics were assessed by immunoblot and flow cytometry, respectively. Cognate antigen expression prevalence in colorectal cancer and normal tissue arrays was determined by immunohistochemistry. CT109 conjugations were generated by the reaction of reduced CT109 cysteines with maleimide-functionalized payload linkers. In vitro cytotoxic activity of CT109 ADCs was characterized on antigen-positive and negative pancreatic ductal adenocarcinoma cell (PDAC) lines using a luminometric viability assay. In vivo efficacy of CT109-SN-38 was assessed on a PDAC tumor xenograft model at 10 and 25 mg/kg concentrations. Results: CT109 showed to bind a glycoepitope centered on N309. CT109 is internalized in the CEACAM5+/CEACAM6+ double-positive PDAC line, BxPC-3, with a t1/2 of 2.3 hours. CT109 ADCs elicit a dose and antigen-dependent cytotoxic effect, with CT109-SN-38 exhibiting an IC50 value of 21 nM in BxPC-3 cells. In a BxPC-3 tumor xenograft model, CT109-SN-38 reduced tumor growth and induced regression in 3/10 mice at 25 mg/kg concentration. Conclusions: These data suggest that further preclinical and clinical development of CT109-SN-38 is warranted.
Language	English
Publishing date	2024-01-04
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2064824-8
ISSN	1873-5576 ; 1568-0096
ISSN (online)	1873-5576
ISSN	1568-0096
DOI	10.2174/0115680096260614231115192343
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Efficacy of FDA-Approved Anti-Inflammatory Drugs Against Venezuelan Equine Encephalitis Virus Infection.

Risner, Kenneth / Ahmed, Aslaa / Bakovic, Allison / Kortchak, Stephanie / Bhalla, Nishank / Narayanan, Aarthi

Viruses

2019 Volume 11, Issue 12

Abstract: Venezuelan equine encephalitis virus (VEEV) is a category B select agent pathogen that can be aerosolized. Infections in murine models and humans can advance to an encephalitic phenotype which may result in long-term neurological complications or death. ... ...

Abstract	Venezuelan equine encephalitis virus (VEEV) is a category B select agent pathogen that can be aerosolized. Infections in murine models and humans can advance to an encephalitic phenotype which may result in long-term neurological complications or death. No specific FDA-approved treatments or vaccines are available for the treatment or prevention of VEEV infection. Neurotropic viral infections have two damaging components: neuronal death caused by viral replication, and damage from the subsequent inflammatory response. Reducing the level of inflammation may lessen neurological tissue damage that often arises following VEEV infection. In this study, three commercially available anti-inflammatory drugs, Celecoxib, Rolipram, and Tofacitinib, were evaluated for antiviral activity in an astrocyte and a microglial model of VEEV infection. The inhibitors were tested against the vaccine strain VEEV TC-83, as well as the wild-type VEEV Trinidad donkey strain. Celecoxib, Tofacitinib, and Rolipram significantly decreased viral titers both after pre-treatment and post-treatment of infected cells. VEEV Trinidad Donkey (TrD) titers were reduced 6.45-fold in cells treated with 50 µM of Celecoxib, 2.45-fold when treated with 50 µM of Tofacitinib, and 1.81-fold when treated with 50 µM of Rolipram. Celecoxib was also shown to decrease inflammatory gene expression in the context of TC-83 infection. Overall, Celecoxib demonstrated potency as a countermeasure strategy that slowed VEEV infection and infection-induced inflammation in an in vitro model.
MeSH term(s)	Animals ; Anti-Inflammatory Agents/pharmacology ; Antiviral Agents/pharmacology ; Astrocytes/drug effects ; Cell Line ; Cell Survival/drug effects ; Cytokines/metabolism ; Drug Approval ; Drug Repositioning ; Encephalitis Virus, Venezuelan Equine/drug effects ; Encephalomyelitis, Venezuelan Equine/drug therapy ; Encephalomyelitis, Venezuelan Equine/virology ; Humans ; Microglia/drug effects ; United States ; United States Food and Drug Administration ; Virus Replication/drug effects
Chemical Substances	Anti-Inflammatory Agents ; Antiviral Agents ; Cytokines
Language	English
Publishing date	2019-12-12
Publishing country	Switzerland
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v11121151
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Venezuelan Equine Encephalitis Virus nsP3 Phosphorylation Can Be Mediated by IKKβ Kinase Activity and Abrogation of Phosphorylation Inhibits Negative-Strand Synthesis.

Bakovic, Allison / Bhalla, Nishank / Kortchak, Stephanie / Sun, Chengqun / Zhou, Weidong / Ahmed, Aslaa / Risner, Kenneth / Klimstra, William B / Narayanan, Aarthi

Viruses

2020 Volume 12, Issue 9

Abstract: Venezuelan equine encephalitis virus (VEEV), a mosquito transmitted alphavirus of ... ...

Abstract	Venezuelan equine encephalitis virus (VEEV), a mosquito transmitted alphavirus of the
MeSH term(s)	Aedes ; Animals ; Antiviral Agents/pharmacology ; Cell Line ; Chlorocebus aethiops ; Encephalitis Virus, Venezuelan Equine/drug effects ; Encephalitis Virus, Venezuelan Equine/genetics ; Encephalitis Virus, Venezuelan Equine/metabolism ; Encephalomyelitis, Venezuelan Equine ; Humans ; I-kappa B Kinase/metabolism ; Mutation ; NF-kappa B/metabolism ; Phosphorylation ; Vero Cells ; Viral Nonstructural Proteins/genetics ; Viral Nonstructural Proteins/metabolism ; Virus Replication/drug effects
Chemical Substances	Antiviral Agents ; NF-kappa B ; Viral Nonstructural Proteins ; I-kappa B Kinase (EC 2.7.11.10)
Language	English
Publishing date	2020-09-13
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v12091021
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Direct and indirect pro-inflammatory cytokine response resulting from TC-83 infection of glial cells.

Keck, Forrest / Kortchak, Stephanie / Bakovic, Allison / Roberts, Brian / Agrawal, Nitin / Narayanan, Aarthi

Virulence

2018 Volume 9, Issue 1, Page(s) 1403–1421

Abstract: Venezuelan equine encephalitis virus (VEEV) is a neurotropic arbovirus that is highly infectious as an aerosol and can result in an encephalitic phenotype in infected individuals. VEEV infections are known to be associated with robust inflammation that ... ...

Abstract	Venezuelan equine encephalitis virus (VEEV) is a neurotropic arbovirus that is highly infectious as an aerosol and can result in an encephalitic phenotype in infected individuals. VEEV infections are known to be associated with robust inflammation that eventually contributes to neurodegenerative phenotypes. In this study, we utilize the TC-83 strain of VEEV, which is known to induce the expression of IL-6, IL-8, and other pro-inflammatory cytokines. We had previously demonstrated that TC-83 infection resulted in changes in mitochondrial function, eventually resulting in mitophagy. In this manuscript, we provide data that links upstream mitochondrial dysfunction with downstream pro-inflammatory cytokine production in the context of microglia and astrocytoma cells. We also provide data on the role of bystander cells, which significantly contribute to the overall inflammatory load. Use of a mitochondrial-targeted antioxidant, mitoquinone mesylate, greatly reduced the inflammatory cytokine load and ameliorated bystander cell inflammatory responses more significantly than a broad-spectrum anti-inflammatory compound (BAY 11-7082). Our data suggest that the inflammatory mediators, especially IL-1β, may prime naïve cells to infection and lead to increased infection rates in microglial and astrocytoma cells. Cumulatively, our data suggest that the interplay between mitochondrial dysfunction and inflammatory events elicited in a neuronal microenvironment during a TC-83 infection may contribute to the spread of infection.
MeSH term(s)	Animals ; Astrocytes/immunology ; Astrocytes/virology ; Astrocytoma/immunology ; Astrocytoma/virology ; Cell Line, Tumor ; Cytokines/immunology ; Encephalitis Virus, Venezuelan Equine/immunology ; Encephalomyelitis, Venezuelan Equine/immunology ; Humans ; Inflammation ; Membrane Potential, Mitochondrial ; Microglia/immunology ; Microglia/virology ; Mitochondria/drug effects ; Mitochondria/immunology ; Mitochondria/pathology ; Neuroglia/immunology ; Organophosphorus Compounds/pharmacology ; Ubiquinone/analogs & derivatives ; Ubiquinone/pharmacology
Chemical Substances	Cytokines ; Organophosphorus Compounds ; Ubiquinone (1339-63-5) ; mitoquinone (47BYS17IY0)
Language	English
Publishing date	2018-08-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	2657572-3
ISSN	2150-5608 ; 2150-5594
ISSN (online)	2150-5608
ISSN	2150-5594
DOI	10.1080/21505594.2018.1509668
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Venezuelan Equine Encephalitis Virus nsP3 Phosphorylation Can Be Mediated by IKKβ Kinase Activity and Abrogation of Phosphorylation Inhibits Negative-Strand Synthesis

Bakovic, Allison / Bhalla, Nishank / Kortchak, Stephanie / Sun, Chengqun / Zhou, Weidong / Ahmed, Aslaa / Risner, Kenneth / Klimstra, William B / Narayanan, Aarthi

Viruses. 2020 Sept. 13, v. 12, no. 9

2020

Abstract: Venezuelan equine encephalitis virus (VEEV), a mosquito transmitted alphavirus of the Togaviridae family, can cause a highly inflammatory and encephalitic disease upon infection. Although a category B select agent, no FDA-approved vaccines or ... ...

Abstract	Venezuelan equine encephalitis virus (VEEV), a mosquito transmitted alphavirus of the Togaviridae family, can cause a highly inflammatory and encephalitic disease upon infection. Although a category B select agent, no FDA-approved vaccines or therapeutics against VEEV currently exist. We previously demonstrated NF-κB activation and macromolecular reorganization of the IKK complex upon VEEV infection in vitro, with IKKβ inhibition reducing viral replication. Mass spectrometry and confocal microscopy revealed an interaction between IKKβ and VEEV non-structural protein 3 (nsP3). Here, using western blotting, a cell-free kinase activity assay, and mass spectrometry, we demonstrate that IKKβ kinase activity can directly phosphorylate VEEV nsP3 at sites 204/5, 142, and 134/5. Alanine substitution mutations at sites 204/5, 142, or 134/5 reduced VEEV replication by >30-100,000-fold corresponding to a severe decrease in negative-strand synthesis. Serial passaging rescued viral replication and negative-strand synthesis, and sequencing of revertant viruses revealed reversion to the wild-type TC-83 phosphorylation capable amino acid sequences at nsP3 sites 204/5, 142, and 135. Generation of phosphomimetic mutants using aspartic acid substitutions at site 204/5 resulted in rescue of both viral replication and negative-strand RNA production, whereas phosphomimetic mutant 134/5 rescued viral replication but failed to restore negative-strand RNA levels, and phosphomimetic mutant 142 did not rescue VEEV replication. Together, these data demonstrate that IKKβ can phosphorylate VEEV nsP3 at sites 204/5, 142, and 134/5, and suggest that phosphorylation is essential for negative-strand RNA synthesis at site 204/5, but may be important for infectious particle production at site 134/5.
Keywords	Culicidae ; RNA ; Venezuelan equine encephalitis virus ; Western blotting ; alanine ; amino acid sequences ; aspartic acid ; confocal microscopy ; enzyme activity ; enzymes ; mass spectrometry ; mutants ; mutation ; phosphorylation ; therapeutics ; transcription factor NF-kappa B ; vaccines ; viral nonstructural proteins ; virus replication ; viruses
Language	English
Dates of publication	2020-0913
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2516098-9
ISSN	1999-4915
ISSN	1999-4915
DOI	10.3390/v12091021
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Synthetic Host Defense Peptides Inhibit Venezuelan Equine Encephalitis Virus Replication and the Associated Inflammatory Response.

Ahmed, Aslaa / Bakovic, Allison / Risner, Kenneth / Kortchak, Stephanie / Der Torossian Torres, Marcelo / de la Fuente-Nunez, Cesar / Lu, Timothy / Bhalla, Nishank / Narayanan, Aarthi

Scientific reports

2020 Volume 10, Issue 1, Page(s) 21491

Abstract: Venezuelan equine encephalitis virus (VEEV), a New World alphavirus of the Togaviridae family of viruses causes periodic outbreaks of disease in humans and equines. Disease following VEEV infection manifests as a febrile illness with flu-like symptoms, ... ...

Abstract	Venezuelan equine encephalitis virus (VEEV), a New World alphavirus of the Togaviridae family of viruses causes periodic outbreaks of disease in humans and equines. Disease following VEEV infection manifests as a febrile illness with flu-like symptoms, which can progress to encephalitis and cause permanent neurological sequelae in a small number of cases. VEEV is classified as a category B select agent due to ease of aerosolization and high retention of infectivity in the aerosol form. Currently, there are no FDA-approved vaccines or therapeutics available to combat VEEV infection. VEEV infection in vivo is characterized by extensive systemic inflammation that can exacerbate infection by potentially increasing the susceptibility of off-site cells to infection and dissemination of the virus. Hence, a therapeutic targeting both the infection and associated inflammation represents an unmet need. We have previously demonstrated that host defense peptides (HDPs), short peptides that are key components of the innate immune response, exhibit antiviral activity against a multitude of viruses including VEEV. In this study, we designed synthetic peptides derived from indolicidin, a naturally occurring HDP, and tested their efficacy against VEEV. Two candidate synthetic peptides inhibited VEEV replication by approximately 1000-fold and decreased the expression of inflammatory mediators such as IL1α, IL1β, IFNγ, and TNFα at both the gene and protein expression levels. Furthermore, an increase in expression levels of genes involved in chemotaxis of leukocytes and anti-inflammatory genes such as IL1RN was also observed. Overall, we conclude that our synthetic peptides inhibit VEEV replication and the inflammatory burden associated with VEEV infection.
MeSH term(s)	Animals ; Anti-Inflammatory Agents/pharmacology ; Antimicrobial Cationic Peptides/chemical synthesis ; Antimicrobial Cationic Peptides/chemistry ; Antimicrobial Cationic Peptides/pharmacology ; Antiviral Agents/pharmacology ; Cell Line ; Chlorocebus aethiops ; Disease Models, Animal ; Encephalitis Virus, Venezuelan Equine/genetics ; Encephalitis Virus, Venezuelan Equine/metabolism ; Horses ; Humans ; Inflammation ; Mice ; Vero Cells ; Virus Replication/drug effects
Chemical Substances	Anti-Inflammatory Agents ; Antimicrobial Cationic Peptides ; Antiviral Agents ; indolicidin (073SBV429N)
Language	English
Publishing date	2020-12-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-77990-3
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Human cathelicidin peptide LL-37 as a therapeutic antiviral targeting Venezuelan equine encephalitis virus infections.

Ahmed, Aslaa / Siman-Tov, Gavriella / Keck, Forrest / Kortchak, Stephanie / Bakovic, Allison / Risner, Kenneth / Lu, Timothy K / Bhalla, Nishank / de la Fuente-Nunez, Cesar / Narayanan, Aarthi

Antiviral research

2019 Volume 164, Page(s) 61–69

Abstract: Venezuelan equine encephalitis virus (VEEV), a new world alphavirus belonging to the Togaviridae family, causes periodic disease outbreaks in humans and equines with high associated mortality and morbidity. VEEV is highly infectious via the aerosol route ...

Abstract	Venezuelan equine encephalitis virus (VEEV), a new world alphavirus belonging to the Togaviridae family, causes periodic disease outbreaks in humans and equines with high associated mortality and morbidity. VEEV is highly infectious via the aerosol route and so has been developed as a biological weapon (Hawley and Eitzen, 2001). Despite its current classification as a category B select agent, there are no FDA approved vaccines or therapeutics to counter VEEV infections. Here we utilize a naturally occurring host defense peptide, LL-37, as a therapeutic strategy to inhibit VEEV multiplication in infected cells. LL-37 has previously demonstrated activity against several viruses by directly interacting with viral particles and indirectly by establishing an antiviral state in the host cell. We show that LL-37 exhibited potent antiviral activity against VEEV by inhibiting viral replication. Genomic RNA copies of the TC-83 strain of VEEV and viral titers were significantly reduced compared to non-treated controls. LL-37 also inhibited the virulent Trinidad Donkey (TrD) strain of VEEV. Entry assays revealed a robust reduction of viral RNA copies at the early stages of TC-83 infection. Pre-incubation of cells with LL-37 and TC-83 resulted in a strong inhibitory response, indicating that LL-37 impacts early stages of the infectious process. Confocal and electron microscopy images confirmed the aggregation of viral particles, which potentially accounts for entry prevention and hence reduced viral infection. LL-37 treatment also modulated type I interferon (IFN) expression in infected cells. LL-37 treatment dramatically increased IFNβ1 expression in treated cells in a time-dependent manner. Our results establish LL-37 as a relevant and novel potential therapeutic strategy for the treatment of VEEV infections.
MeSH term(s)	Antimicrobial Cationic Peptides/pharmacology ; Antiviral Agents/pharmacology ; Cell Line ; Encephalitis Virus, Venezuelan Equine/drug effects ; Encephalitis Virus, Venezuelan Equine/physiology ; Humans ; Viral Load ; Virus Replication/drug effects
Chemical Substances	Antimicrobial Cationic Peptides ; Antiviral Agents ; ropocamptide (3DD771JO2H)
Language	English
Publishing date	2019-02-08
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	306628-9
ISSN	1872-9096 ; 0166-3542
ISSN (online)	1872-9096
ISSN	0166-3542
DOI	10.1016/j.antiviral.2019.02.002
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 1627: Show issues

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bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
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ab Jg. 2022: Lesesaal (EG)

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Article ; Online: CT109-SN-38, a Novel Antibody-drug Conjugate with Dual Specificity for CEACAM5 and 6, Elicits Potent Killing of Pancreatic Cancer Cells.

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Article ; Online: Efficacy of FDA-Approved Anti-Inflammatory Drugs Against Venezuelan Equine Encephalitis Virus Infection.

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Article ; Online: Venezuelan Equine Encephalitis Virus nsP3 Phosphorylation Can Be Mediated by IKKβ Kinase Activity and Abrogation of Phosphorylation Inhibits Negative-Strand Synthesis.

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Article ; Online: Direct and indirect pro-inflammatory cytokine response resulting from TC-83 infection of glial cells.

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Article: Venezuelan Equine Encephalitis Virus nsP3 Phosphorylation Can Be Mediated by IKKβ Kinase Activity and Abrogation of Phosphorylation Inhibits Negative-Strand Synthesis

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Kategorien

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Article ; Online: Synthetic Host Defense Peptides Inhibit Venezuelan Equine Encephalitis Virus Replication and the Associated Inflammatory Response.

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Article ; Online: Human cathelicidin peptide LL-37 as a therapeutic antiviral targeting Venezuelan equine encephalitis virus infections.

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In stock of ZB MED Cologne/Königswinter

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