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Book ; Thesis: Ad5 for systemic vector delivery

Krutzke, Lea

studies on non-target interactions of Ad5 with non-cellular and cellular host blood components

2016

Author's details	Lea Krutzke
Keywords	Genetic therapy ; Adenoviridae
Language	English
Size	188 Blätter, Illustrationen, Diagramme
Publishing place	Ulm
Publishing country	Germany
Document type	Book ; Thesis
Thesis / German Habilitation thesis	Dissertation, Universität Ulm, 2016
HBZ-ID	HT019220938
Database	Catalogue ZB MED Medicine, Health

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Article ; Online: Chorioallantoic Membrane Tumor Model for Evaluating Oncolytic Viruses.

Krutzke, Lea / Allmendinger, Ellen / Hirt, Katja / Kochanek, Stefan

Human gene therapy

2020 Volume 31, Issue 19-20, Page(s) 1100–1113

Abstract: Oncolytic viruses are promising anticancer agents; however, regarding their clinical efficacy, there is still significant scope for improvement. ... ...

Abstract	Oncolytic viruses are promising anticancer agents; however, regarding their clinical efficacy, there is still significant scope for improvement. Preclinical
MeSH term(s)	Adenoviridae/genetics ; Animals ; Chickens ; Chorioallantoic Membrane/metabolism ; Chorioallantoic Membrane/pathology ; Genetic Therapy ; Genetic Vectors/administration & dosage ; Humans ; Lung Neoplasms/pathology ; Lung Neoplasms/therapy ; Mice ; Mice, Inbred BALB C ; Mice, Inbred NOD ; Mice, Nude ; Oncolytic Virotherapy/methods ; Virus Replication ; Xenograft Model Antitumor Assays
Language	English
Publishing date	2020-08-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	1028152-6
ISSN	1557-7422 ; 1043-0342
ISSN (online)	1557-7422
ISSN	1043-0342
DOI	10.1089/hum.2020.045
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Article ; Online: Process- and product-related impurities in the ChAdOx1 nCov-19 vaccine.

Krutzke, Lea / Rösler, Reinhild / Allmendinger, Ellen / Engler, Tatjana / Wiese, Sebastian / Kochanek, Stefan

eLife

2022 Volume 11

Abstract: ChAdOx1 nCov-19 and Ad26.COV2.S are approved vaccines inducing protective immunity against SARS-CoV-2 infection in humans by expressing the Spike protein of SARS-CoV-2. We analyzed protein content and protein composition of ChAdOx1 nCov-19 and Ad26.COV2 ... ...

Abstract	ChAdOx1 nCov-19 and Ad26.COV2.S are approved vaccines inducing protective immunity against SARS-CoV-2 infection in humans by expressing the Spike protein of SARS-CoV-2. We analyzed protein content and protein composition of ChAdOx1 nCov-19 and Ad26.COV2.S by biochemical methods and by mass spectrometry. Four out of four tested lots of ChAdOx1 nCoV-19 contained significantly higher than expected levels of host cell proteins (HCPs) and of free viral proteins. The most abundant contaminating HCPs belonged to the heat-shock protein and cytoskeletal protein families. The HCP content exceeded the 400 ng specification limit per vaccine dose, as set by the European Medicines Agency (EMA) for this vaccine, by at least 25-fold and the manufacturer's batch-release data in some of the lots by several hundred-fold. In contrast, three tested lots of the Ad26.COV2.S vaccine contained only very low amounts of HCPs. As shown for Ad26.COV2.S production of clinical grade adenovirus vaccines of high purity is feasible at an industrial scale. Correspondingly, purification procedures of the ChAdOx1 nCov-19 vaccine should be modified to remove protein impurities as good as possible. Our data also indicate that standard quality assays, as they are used in the manufacturing of proteins, have to be adapted for vectored vaccines.
MeSH term(s)	Ad26COVS1 ; COVID-19/prevention & control ; ChAdOx1 nCoV-19 ; Humans ; SARS-CoV-2
Chemical Substances	Ad26COVS1 ; ChAdOx1 nCoV-19 (B5S3K2V0G8)
Language	English
Publishing date	2022-07-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.78513
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Article ; Online: Human Monocytes Are Suitable Carriers for the Delivery of Oncolytic Herpes Simplex Virus Type 1 In Vitro and in a Chicken Embryo Chorioallantoic Membrane Model of Cancer.

Reale, Alberto / Krutzke, Lea / Cadamuro, Massimiliano / Vitiello, Adriana / von Einem, Jens / Kochanek, Stefan / Palù, Giorgio / Parolin, Cristina / Calistri, Arianna

International journal of molecular sciences

2023 Volume 24, Issue 11

Abstract: Oncolytic viruses (OVs) are promising therapeutics for tumors with a poor prognosis. An OV based on herpes simplex virus type 1 (oHSV-1), talimogene laherparepvec (T-VEC), has been recently approved by the Food and Drug Administration (FDA) and by the ... ...

Abstract	Oncolytic viruses (OVs) are promising therapeutics for tumors with a poor prognosis. An OV based on herpes simplex virus type 1 (oHSV-1), talimogene laherparepvec (T-VEC), has been recently approved by the Food and Drug Administration (FDA) and by the European Medicines Agency (EMA) for the treatment of unresectable melanoma. T-VEC, like most OVs, is administered via intratumoral injection, underlining the unresolved problem of the systemic delivery of the oncolytic agent for the treatment of metastases and deep-seated tumors. To address this drawback, cells with a tropism for tumors can be loaded ex vivo with OVs and used as carriers for systemic oncolytic virotherapy. Here, we evaluated human monocytes as carrier cells for a prototype oHSV-1 with a similar genetic backbone as T-VEC. Many tumors specifically recruit monocytes from the bloodstream, and autologous monocytes can be obtained from peripheral blood. We demonstrate here that oHSV-1-loaded primary human monocytes migrated in vitro towards epithelial cancer cells of different origin. Moreover, human monocytic leukemia cells selectively delivered oHSV-1 to human head-and-neck xenograft tumors grown on the chorioallantoic membrane (CAM) of fertilized chicken eggs after intravascular injection. Thus, our work shows that monocytes are promising carriers for the delivery of oHSV-1s in vivo, deserving further investigation in animal models.
MeSH term(s)	Chick Embryo ; Animals ; Humans ; Herpesvirus 1, Human/genetics ; Melanoma/therapy ; Oncolytic Virotherapy ; Chickens ; Monocytes ; Chorioallantoic Membrane ; Oncolytic Viruses/genetics
Language	English
Publishing date	2023-05-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24119255
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Evaluation of Human Mesenchymal Stromal Cells as Carriers for the Delivery of Oncolytic HAdV-5 to Head and Neck Squamous Cell Carcinomas.

Nilson, Robin / Krutzke, Lea / Wienen, Frederik / Rojewski, Markus / Zeplin, Philip Helge / Funk, Wolfgang / Schrezenmeier, Hubert / Kochanek, Stefan / Kritzinger, Astrid

Viruses

2023 Volume 15, Issue 1

Abstract: Human multipotent mesenchymal stromal cells (hMSCs) are of significant therapeutic interest due to their ability to deliver oncolytic adenoviruses to tumors. This approach is also investigated for targeting head and neck squamous cell carcinomas (HNSCCs). ...

Abstract	Human multipotent mesenchymal stromal cells (hMSCs) are of significant therapeutic interest due to their ability to deliver oncolytic adenoviruses to tumors. This approach is also investigated for targeting head and neck squamous cell carcinomas (HNSCCs). HAdV-5-HexPos3, a recently reported capsid-modified vector based on human adenovirus type 5 (HAdV-5), showed strongly improved infection of both hMSCs and the HNSCC cell line UM-SCC-11B. Given that, we generated life cycle-unmodified and -modified replication-competent HAdV-5-HexPos3 vector variants and analyzed their replication within bone marrow- and adipose tissue-derived hMSCs. Efficient replication was detected for both life cycle-unmodified and -modified vectors. Moreover, we analyzed the migration of vector-carrying hMSCs toward different HNSCCs. Although migration of hMSCs to HNSCC cell lines was confirmed in vitro, no homing of hMSCs to HNSCC xenografts was observed in vivo in mice and in ovo in a chorioallantoic membrane model. Taken together, our data suggest that HAdV-5-HexPos3 is a potent candidate for hMSC-based oncolytic therapy of HNSCCs. However, it also emphasizes the importance of generating optimized in vivo models for the evaluation of hMSC as carrier cells.
MeSH term(s)	Humans ; Mice ; Animals ; Squamous Cell Carcinoma of Head and Neck/therapy ; Adenoviruses, Human ; Adenoviridae ; Head and Neck Neoplasms/therapy ; Mesenchymal Stem Cells ; Cell Line, Tumor
Language	English
Publishing date	2023-01-13
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v15010218
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Article ; Online: Heterologous DNA-prime/protein-boost immunization with a monomeric SARS-CoV-2 spike antigen redundantizes the trimeric receptor-binding domain structure to induce neutralizing antibodies in old mice.

Pflumm, Dominik / Seidel, Alina / Klein, Fabrice / Groß, Rüdiger / Krutzke, Lea / Kochanek, Stefan / Kroschel, Joris / Münch, Jan / Stifter, Katja / Schirmbeck, Reinhold

Frontiers in immunology

2023 Volume 14, Page(s) 1231274

Abstract: A multitude of alterations in the old immune system impair its functional integrity. Closely related, older individuals show, for example, a reduced responsiveness to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccines. However, ... ...

Abstract	A multitude of alterations in the old immune system impair its functional integrity. Closely related, older individuals show, for example, a reduced responsiveness to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccines. However, systematic strategies to specifically improve the efficacy of vaccines in the old are missing or limited to simple approaches like increasing the antigen concentration or injection frequencies. We here asked whether the intrinsic, trimeric structure of the SARS-CoV-2 spike (S) antigen and/or a DNA- or protein-based antigen delivery platform affects priming of functional antibody responses particularly in old mice. The used S-antigens were primarily defined by the presence/absence of the membrane-anchoring TM domain and the closely interlinked formation/non-formation of a trimeric structure of the receptor binding domain (S-RBD). Among others, we generated vectors expressing prefusion-stabilized, cell-associated (TM
MeSH term(s)	Animals ; Mice ; Antibodies, Neutralizing ; SARS-CoV-2 ; COVID-19 ; Vaccines, DNA ; Blood Group Antigens ; Immunization
Chemical Substances	Antibodies, Neutralizing ; Vaccines, DNA ; Blood Group Antigens
Language	English
Publishing date	2023-09-11
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1231274
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Article ; Online: Human Monocytes Are Suitable Carriers for the Delivery of Oncolytic Herpes Simplex Virus Type 1 In Vitro and in a Chicken Embryo Chorioallantoic Membrane Model of Cancer

Alberto Reale / Lea Krutzke / Massimiliano Cadamuro / Adriana Vitiello / Jens von Einem / Stefan Kochanek / Giorgio Palù / Cristina Parolin / Arianna Calistri

International Journal of Molecular Sciences, Vol 24, Iss 9255, p

2023 Volume 9255

Abstract	Oncolytic viruses (OVs) are promising therapeutics for tumors with a poor prognosis. An OV based on herpes simplex virus type 1 (oHSV-1), talimogene laherparepvec (T-VEC), has been recently approved by the Food and Drug Administration (FDA) and by the European Medicines Agency (EMA) for the treatment of unresectable melanoma. T-VEC, like most OVs, is administered via intratumoral injection, underlining the unresolved problem of the systemic delivery of the oncolytic agent for the treatment of metastases and deep-seated tumors. To address this drawback, cells with a tropism for tumors can be loaded ex vivo with OVs and used as carriers for systemic oncolytic virotherapy. Here, we evaluated human monocytes as carrier cells for a prototype oHSV-1 with a similar genetic backbone as T-VEC. Many tumors specifically recruit monocytes from the bloodstream, and autologous monocytes can be obtained from peripheral blood. We demonstrate here that oHSV-1-loaded primary human monocytes migrated in vitro towards epithelial cancer cells of different origin. Moreover, human monocytic leukemia cells selectively delivered oHSV-1 to human head-and-neck xenograft tumors grown on the chorioallantoic membrane (CAM) of fertilized chicken eggs after intravascular injection. Thus, our work shows that monocytes are promising carriers for the delivery of oHSV-1s in vivo, deserving further investigation in animal models.
Keywords	oncolytic virus ; virotherapy ; HSV-1 ; monocytes ; carrier cells ; CAM model ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2023-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Affilin-based retargeting of adenoviral vectors to the epidermal growth factor receptor.

Wienen, Frederik / Nilson, Robin / Allmendinger, Ellen / Graumann, David / Fiedler, Erik / Bosse-Doenecke, Eva / Kochanek, Stefan / Krutzke, Lea

Biomaterials advances

2022 Volume 144, Page(s) 213208

Abstract: Introduction: Treatment of head and neck squamous cell carcinomas (HNSCC) by oncolytic adenoviral vectors holds promise as an efficient anti-cancer therapy. The epidermal growth factor receptor (EGFR) represents an attractive target receptor since it is ...

Abstract	Introduction: Treatment of head and neck squamous cell carcinomas (HNSCC) by oncolytic adenoviral vectors holds promise as an efficient anti-cancer therapy. The epidermal growth factor receptor (EGFR) represents an attractive target receptor since it is frequently overexpressed in many types of HNSCC. Methods: To achieve EGFR-specific targeting by human adenovirus type 5 (HAdV-5) based vectors, the EGFR affinity ligand Affilin was covalently attached in a position specific manner either to the fiber or the hexon protein of the vector capsid. In vitro and in vivo studies investigated EGFR-specific cancer cell transduction, susceptibility to natural sequestration mechanisms, pharmacokinetics and biodistribution profiles of Affilin-decorated vectors. Results: Affilin-decorated vectors showed strongly enhanced and EGFR-specific cancer cell transduction in vitro and less susceptibility to known sequestration mechanisms of HAdV-5 particles. However, in vivo neither systemic nor intratumoral vector administration resulted in an improved transduction of EGFR-positive tumors. Comprehensive analyses indicated hampered EGFR-targeting by Affilin-decorated vectors was caused by rapid vector particle consumption due to binding to the murine EGFR, insufficient tumor vascularization and poor target accessibility for Affilin in the solid tumor caused by a pronounced tumor stroma. Conclusion: In vitro studies yielded proof-of-concept results demonstrating that covalent attachment of a receptor-specific Affilin to the adenoviral capsid provides an effective and versatile tool to address cancer-specific target receptors by adenoviral vectors. Regarding EGFR as the vector target, off-target tissue transduction and low receptor accessibility within the tumor tissue prevented efficient tumor transduction by Affilin-decorated vectors, rendering EGFR a difficult-to-target receptor for adenoviral vectors.
Language	English
Publishing date	2022-11-23
Publishing country	Netherlands
Document type	Journal Article
ISSN	2772-9508
ISSN (online)	2772-9508
DOI	10.1016/j.bioadv.2022.213208
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Article ; Online: Vaccine-induced COVID-19 mimicry syndrome.

Kowarz, Eric / Krutzke, Lea / Külp, Marius / Streb, Patrick / Larghero, Patrizia / Reis, Jennifer / Bracharz, Silvia / Engler, Tatjana / Kochanek, Stefan / Marschalek, Rolf

eLife

2022 Volume 11

Abstract: To fight the COVID-19 pandemic caused by the RNA virus SARS-CoV-2, a global vaccination campaign is in progress to achieve the immunization of billions of people mainly with adenoviral vector- or mRNA-based vaccines, all of which encode the SARS-CoV-2 ... ...

Abstract	To fight the COVID-19 pandemic caused by the RNA virus SARS-CoV-2, a global vaccination campaign is in progress to achieve the immunization of billions of people mainly with adenoviral vector- or mRNA-based vaccines, all of which encode the SARS-CoV-2 Spike protein. In some rare cases, cerebral venous sinus thromboses (CVST) have been reported as a severe side effect occurring 4-14 days after the first vaccination and were often accompanied by thrombocytopenia. Besides CVST, splanchnic vein thromboses (SVT) and other thromboembolic events have been observed. These events only occurred following vaccination with adenoviral vector-based vaccines but not following vaccination with mRNA-based vaccines. Meanwhile, scientists have proposed an immune-based pathomechanism and the condition has been coined vaccine-induced immune thrombotic thrombocytopenia (VITT). Here, we describe an unexpected mechanism that could explain thromboembolic events occurring with DNA-based but not with RNA-based vaccines. We show that DNA-encoded mRNA coding for Spike protein can be spliced in a way that the transmembrane anchor of Spike is lost, so that nearly full-length Spike is secreted from cells. Secreted Spike variants could potentially initiate severe side effects when binding to cells via the ACE2 receptor. Avoiding such splicing events should become part of a rational vaccine design to increase safety of prospective vaccines.
MeSH term(s)	COVID-19/prevention & control ; COVID-19 Vaccines/adverse effects ; ChAdOx1 nCoV-19/adverse effects ; Drug-Related Side Effects and Adverse Reactions/etiology ; Humans ; Pandemics ; SARS-CoV-2 ; Sinus Thrombosis, Intracranial/etiology ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/metabolism ; Syndrome ; Thrombocytopenia/etiology ; Vaccination/adverse effects ; Vaccines, DNA/adverse effects ; Venous Thrombosis/etiology
Chemical Substances	COVID-19 Vaccines ; Spike Glycoprotein, Coronavirus ; Vaccines, DNA ; spike protein, SARS-CoV-2 ; ChAdOx1 nCoV-19 (B5S3K2V0G8)
Language	English
Publishing date	2022-01-27
Publishing country	England
Document type	Journal Article
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.74974
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Article ; Online: Vaccine-induced COVID-19 mimicry syndrome

Eric Kowarz / Lea Krutzke / Marius Külp / Patrick Streb / Patrizia Larghero / Jennifer Reis / Silvia Bracharz / Tatjana Engler / Stefan Kochanek / Rolf Marschalek

eLife, Vol

2022 Volume 11

Abstract	To fight the COVID-19 pandemic caused by the RNA virus SARS-CoV-2, a global vaccination campaign is in progress to achieve the immunization of billions of people mainly with adenoviral vector- or mRNA-based vaccines, all of which encode the SARS-CoV-2 Spike protein. In some rare cases, cerebral venous sinus thromboses (CVST) have been reported as a severe side effect occurring 4–14 days after the first vaccination and were often accompanied by thrombocytopenia. Besides CVST, splanchnic vein thromboses (SVT) and other thromboembolic events have been observed. These events only occurred following vaccination with adenoviral vector-based vaccines but not following vaccination with mRNA-based vaccines. Meanwhile, scientists have proposed an immune-based pathomechanism and the condition has been coined vaccine-induced immune thrombotic thrombocytopenia (VITT). Here, we describe an unexpected mechanism that could explain thromboembolic events occurring with DNA-based but not with RNA-based vaccines. We show that DNA-encoded mRNA coding for Spike protein can be spliced in a way that the transmembrane anchor of Spike is lost, so that nearly full-length Spike is secreted from cells. Secreted Spike variants could potentially initiate severe side effects when binding to cells via the ACE2 receptor. Avoiding such splicing events should become part of a rational vaccine design to increase safety of prospective vaccines.
Keywords	SARS-CoV-2 ; vaccines ; RNA ; splicing ; splice variants ; thrombosis ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	612
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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