The Uab Research Foundation

Genentech, Inc.

Boehringer Ingelheim International Gmbh

The University of North Carolina at Chapel Hill

Other

University of Chicago

City of Hope

University of Alabama

University of Texas System

Washington University

Boehringer Ingelheim Gmbh

Genetech, Inc.

Unleash Immuno Oncolytics, Inc.

Curiel, David

David T Curiel

Matthew Cotten

Ernst Wagner

Max L Birnstiel

Donald J Buchsbaum

Berndt Oberhauser

Kurt Zatloukal

Murray A Stackhouse

Christian Plank

Victor N Krasnykh

Walter G Schmidt

De-Chu C Tang

Donald H Marks

Zhongkai Shi

Igor Dmitriev

Karen S Aboody

Maciej S Lesniak

Jeffrey Allen Engler

Alexander J Annala

Bryan Walter Tillman

Jessy Deshane

Joanne T Douglas

Kevin Paul Raisch

David Raben

James Alan Bonner

Andrew J Baird

Candelaria Gomez-Manzano

Barbara A Sosnowski

Glenn Francis Pierce

John D Mountz

Juan Fueyo-Margareto

Huang-Ge Zhang

Kent Rigby Van Kampen

Osvaldo Podhajcer

Walter G M Schmidt

Maria Veronica Lopez

Ramon Alemany

Ping-chuan Hu

Paul N Reynolds

Mohammad B Khazaeli

Mohammad B Khazaell

Kent R Van Kampen

Buck E Rogers

Lee C Pederson

Juan L Contreras

Guadalupe Bilbao

Provided herein is a conditionally-replicating serotype 5 adenovirus or adenoviral vector expressing a mutant E1A protein under control of a promoter that is responsive to hypoxia and inflammation and one or more immune modulators under control of a tumor-specific promoter. The adenovirus or adenoviral vector also comprises serotype 3 fiber and hexon proteins. Also provided is a method of inducing cytotoxicity in tumor cells using a composition containing the adenovirus or adenoviral vector.

Oncolytic adenoviral vector and methods of use

In some embodiments, methods of killing tumor cells are provided. The methods may include contacting the tumor cell with a tropic cell that carries a modified oncolytic virus, wherein the virus comprises a tumor selective element and/or a capsid protein that binds a tumor-specific cell surface molecule. In another embodiment, methods of treating cancer are provided. The methods may include administering a therapeutically effective amount of a pharmaceutical composition to a subject, wherein the pharmaceutical composition includes a tropic cell that carries a modified oncolytic virus, wherein the virus comprises a tumor selective promoter element and/or a capsid protein that binds a tumor-specific cell surface molecule.

Tropic cell based virotherapy for the treatment of cancer

A modified adenovirus capable of overcoming the problem of low level of coxsackie-adenovirus receptor (CAR) expression on tumor cells and methods of using such adenovirus are provided. The fiber protein of the adenovirus is modified by insertion or replacement so as to target the adenovirus to tumor cells, and the replication of the modified adenovirus is limited to tumor cells due to specific promoter control or mutations in E1a or E1b genes.

Infectivity-enhanced conditionally-replicative adenovirus and uses thereof

Disclosed are methods of transforming dendritic cells with a chimeric adenovirus-5 (Ad5). A chimeric adenovirus includes a fiber comprising a tail, a shaft and a knob, wherein the knob is a porcine knob, and a nucleic acid comprising a promoter operably linked to a heterologous sequence encoding an antigen peptide.

Porcine knob xenotype chimeric adenoviral vector for dendritic cell infection

The present invention provides means to modify the tropism of recombinant adenoviral vectors using genetic methods to alter the adenoviral fiber cell-binding protein. The present invention generates an adenovirus with modified fiber gene such that novel tropism is achieved. This recombinant adenovirus has a fiber gene modified in the HI loop domain.

Adenovirus vector containing a heterologous peptide epitope in the hi loop of the fiber knob

Human anti-epidermal growth factor receptor (EGFR) single-chain antibodies (scFvs) were isolated from a human IgM phage display library using purified epidermal growth factor receptor as antigen. Two isolates with different amino acid sequences were identified by ELISA as epidermal growth factor receptor-specific. The scFvs bind to the full length epidermal growth factor receptor and the truncated and/or mutated epidermal growth factor receptor on human cells. These anti-EGFR-scFvs are useful as therapeutic and/or diagnostic agents.

Human anti-epidermal growth factor receptor single-chain antibodies

The present invention describes recombinant adenoviral vectors modified by incorporating targeting ligands or label into viral capsid or structural proteins. In one embodiment, single-chain antibody was introduced into the minor capsid proteins pIIIa or pIX so that the adenoviral vector can be targeted to a particular cell type. In another embodiment, there is provided a noninvasive imaging strategy useful for monitoring the replication and spread of conditionally replicative adenoviral vectors. Viral structural proteins such as pIX capsid protein, core proteins mu, V and VII were expressed as fusion protein with a fluorescent label. Once incorporated into the virions, detection of the structural fusion protein label would indicate the localization of the disseminated viral progeny. The detected fluorescent signals also closely correlate with the level of viral replication and progeny production.

Capsid-modified recombinant adenovirus and methods of use

The present invention provides a CD40-targeted gene delivery system and a CD40-targeted recombinant adenoviral vector for genetic manipulation of dendritic cells and B cells. Also provided are methods of using this enhanced gene delivery to immune system cells and therefore, enhancing dendritic cell-based immunotherapy.

Immunomodulation by genetic modification of dendritic cells and B cells

A modified adenovirus capable of overcoming the problem of low level of coxsackle-adenovirus receptor (CAR) expression on tumor cells and methods of using such adenovirus are provided. The fiber protein of the adenovirus is modified by insertion or replacement so as to target the adenovirus to tumor cells, and the replication of the modified adenovirus is limited to tumor cells due to mutations in E1a or E1b genes.

The utility of adenovirus vectors (Ad) for gene therapy is restricted by their inability to selectively transduce disease-affected tissues. This limitation may be overcome by the derivation of vectors capable of interacting with receptors specifically expressed in the target tissue. Previous attempts to alter Ad tropism by genetic modification of the Ad fiber have had limited success due to structural conflicts between the fiber and the targeting ligand. The present invention presents a strategy to derive an Ad vector with enhanced targeting potential by a radical replacement of the fiber protein in the Ad capsid with a chimeric molecule containing a heterologous trimerization motif and a receptor-binding ligand.

Modified adenovirus containing a fiber replacement protein

Disclosed and claimed are methods of non-invasive genetic immunization in an animal and/or methods of inducing a systemic immune or therapeutic response in an animal, products therefrom and uses for the methods and products therefrom. The methods can include contacting skin of the animal with a vector in an amount effective to induce the systemic immune or therapeutic response in the animal. The vector can include and express an exogenous nucleic acid molecule encoding an epitope or gene product of interest. The systemic immune response can be to or from the epitope or gene product. The nucleic acid molecule can encode an epitope of interest and/or an antigen of interest and/or a nucleic acid molecule that stimulates and/or modulates an immunological response and/or stimulates and/or modulates expression, e.g., transcription and/or translation, such as transcription and/or translation of an endogenous and/or exogenous nucleic acid molecule; e.g., one or more of influenza hemagglutinin, influenza nuclear protein, influenza M2, tetanus toxin C-fragment, anthrax protective antigen, anthrax lethal factor, rabies glycoprotein, HBV surface antigen, HIV gp 120, HIV gp 160, human carcinoembryonic antigen, malaria CSP, malaria SSP, malaria MSP, malaria pfg, and mycobacterium tuberculosis HSP; and/or a therapeutic, an immunomodulatory gene, such as co-stimulatory gene and/or a cytokine gene. The immune response can be induced by the vector expressing the nucleic acid molecule in the animal's cells. The animal's cells can be epidermal cells. The immune response can be against a pathogen or a neoplasm. A prophylactic vaccine or a therapeutic vaccine or an immunological composition can include the vector. The animal can be a vertebrate, e.g., a mammal, such as human, a cow, a horse, a dog, a cat, a goat, a sheep or a pig; or fowl such as turkey, chicken or duck. The vector can be one or more of a viral vector, including viral coat, e.g., with some or all viral genes deleted therefrom, bacterial, protozoan, transposon, retrotransposon, and DNA vector, e.g., a recombinant vector; for instance, an adenovirus, such as an adenovirus defective in its E1 and/or E3 and/or E4 region(s). The method can encompass applying a delivery device including the vector to the skin of the animal, as well as such a method further including disposing the vector in and/or on the delivery device. The vector can have all viral genes deleted therefrom. The vector can induce a therapeutic and/or an anti-tumor effect in the animal, e.g., by expressing an oncogene, a tumor-suppressor gene, or a tumor-associated gene. Immunological products generated by the expression, e.g., antibodies, cells from the methods, and the expression products, are likewise useful in in vitro and ex vivo applications, and such immunological and expression products and cells and applications are disclosed and claimed. Methods for expressing a gene product in vivo and products therefor and therefrom including mucosal and/or intranasal administration of an adenovirus, advantageously an E1 and/or E3 and/or E4 defective or deleted adenovirus, such as a human adenovirus or canine adenovirus, are also disclosed and claimed.

Noninvasive genetic immunization, expression products therefrom, and uses thereof

The present invention provides a strategy that allows for selective switching off of both transgene and viral gene expression in tissues where such expression is undesirable. The present invention employs a vector containing a tissue specific promoter that drives expression of Cre recombinase gene in tissue where transgene expression is undesirable. As a result of Cre recombinase expression, the same or another vector that expresses the transgene in that tissue will be cut by the action of the Cre recombinase into several pieces due to LoxP sites that are strategically placed within the vector backbone. Consequently, unwanted transgene as well as viral gene expression are prevented.

Tissue-specific self-inactivating gene therapy vector

The present invention provides a method of inducing an immune response in a non-invasive mode, comprising the step of: contacting skin of an individual in need of such treatment topically by applying to said skin an immunologically effective concentration of a genetic vector encoding a gene of interest. Also provided is a method of inducing an anti-tumor immune response in an animal in need of such treatment, comprising the step of: contacting skin of said animal topically by applying to said skin an immunologically effective concentration of a vector encoding a gene which encodes an antigen which induces an anti-tumor effect in said animal following administration. The genetic vector may include adenovirus recombinants, DNA/adenovirus complexes, DNA/liposome complexes, or any other vectors capable of expressing transgenes. Topical application of geneticvectors may preferably include a device as designed therein.

Vaccination by topical application of genetic vectors

Growing community of inventors

St. Louis, MO, United States of America

David T Curiel