Genvec, Inc.

Cornell Research Foundation Inc.

Other

The United States of America, As Represented by the Secretary, Department of Health and Human Services

Thomas J Wickham

Gary J Nabel

Imre Kovesdi

Petrus W Roelvink

Douglas E Brough

Joseph T Bruder

Duncan L McVey

Ronald G Crystal

C Richter King

Jason G D Gall

Erik S Falck-Pedersen

Jason Gall

Mohammed Zuber

Joseph T Brader

William J Enright

The present invention provides a library of viral vectors, wherein each member comprises a first heterologous DNA encoding a first gene product and a second heterologous DNA encoding a second gene product. The first heterologous DNA is common to each member of the library, while the second heterologous DNA varies between members of the library. The present invention additionally provides a method of constructing a library of viral vectors. The method comprises carrying out homologous recombination between a first DNA molecule and a second DNA molecule to form a pool of intermediate viral vector genomes. One or more linear third DNA molecules are ligated into the pool of intermediate viral genomes to produce a library of viral vector genomes. Alternatively, homologous recombination between linear DNA molecules and recipient DNA molecules produces a library of viral vector genomes. The library of viral vector genomes is converted into a library of viral vectors.

Methods of preparing and using a viral vector library

The present invention provides a recombinant adenovirus comprising coat proteins that lack native binding. In particular, the present invention provides a recombinant adenovirus comprising a penton base protein and a fiber protein, wherein the penton base protein and the fiber protein lack native binding. The present invention further provides a recombinant adenovirus comprising (a) a penton base protein that lacks native binding and (b) a nonnative amino acid sequence that binds a cell-surface binding site.

Vectors and methods for gene transfer

The present invention provides a complex that includes a virion having a ligand that recognizes an epitope present on an immune effector cell surface and at least a first nucleic acid encoding a first non-native antigen. The invention also provides a library including a plurality of such complexes, in which antigens of at least two of the plurality are different. Using such reagents, the invention provides a method of precipitating an immune response within an immune effector cell, wherein such a complex is delivered to the cell under conditions sufficient for the cell to mount an immune response to the antigen. When applied in vivo, the method can serve to immunize an animal from the pathogen. Moreover, using a library including a plurality of complexes, which contains at least one test antigen, the invention provides a method of assessing the antigenicity of the test antigen.

Antigenic complexes and methods

The present invention provides a chimeric protein IX (pIX). The chimeric pIX protein has an adenoviral pIX domain and also a non-native amino acid. Where the non-native amino acid is a ligand that binds to a substrate present on the surface cells, the chimeric pIX can be used to target vectors containing such proteins to desired cell types. Thus, the invention provides vector systems including such chimeric pIX proteins as well as methods of infecting cells using such vector systems.

Adenoviral capsid containing chimeric protein IX

The present invention provides a chimeric adenovirus fiber protein, which differs from the wild-type coat protein by the introduction of a nonnative amino acid sequence in a conformationally-restrained manner. Such a chimeric adenovirus fiber protein according to the invention is able to direct entry into cells of a vector comprising the chimeric fiber protein that is more efficient than entry into cells of a vector that is identical except for comprising a wild-type adenovirus fiber protein rather than the chimeric adenovirus fiber protein. The nonnative amino acid sequences encodes a peptide motif that comprises an epitope for an antibody, or a ligand for a cell surface receptor, that can be employed in cell targeting. The present invention also pertains to vectors comprising such a chimeric adenovirus fiber protein, and to methods of using such vectors.

Targeting adenovirus with use of constrained peptide motifs

The invention provides a chimeric adenovirus fiber protein including a nonnative amino acid sequence, and a chimeric adenovirus fiber protein lacking a native amino acid receptor-binding sequence. The chimeric protein trimerizes when produced in a mammalian cell.

Chimeric adenovirus fiber protein

The present invention provides a chimeric adenovirus coat protein, which differs from the wild-type coat protein by the introduction of a nonnative amino acid sequence. Such a chimeric adenovirus coat protein according to the invention is able to direct entry into cells of a vector comprising the coat protein that is more efficient than entry into cells of a vector that is identical except for comprising a wild-type adenovirus coat protein rather than the chimeric adenovirus coat protein. The chimeric coat protein preferably is a fiber, hexon, or penton protein. The present invention also provides an adenoviral vector that comprises the chimeric adenovirus coat protein, as well as methods of constructing and using such a vector.

Vectors and methods for gene transfer to cells

The present invention provides a recombinant protein having an amino terminus of an adenoviral fiber protein and having a trimerization domain. A fiber incorporating such a protein exhibits reduced affinity for a native substrate than does a wild-type adenoviral fiber trimer. The present invention further provides an adenovirus incorporating the recombinant protein of the present invention.

Alternatively targeted adenovirus

Targetting adenovirus with use of constrained peptide motifs

The present invention provides a chimeric adenoviral coat protein (particularly a chimeric adenovirus hexon and/or fiber protein). The chimeric adenovirus coat protein has a decreased ability or inability to be recognized by a neutralizing antibody directed against the corresponding wild-type adenovirus coat protein. The invention also provides an adenovirus comprising a chimeric adenovirus coat protein, and methods of constructing and using such an adenovirus, for instance, in gene therapy.

Nucleic acid that encodes a chimeric adenoviral coat protein

Chimeric adenoviral coat protein and methods of using same

The present invention provides a short-shafted adenoviral fiber, a recombinant adenovirus comprising a short-shafted fiber, a vector comprising a short-shafted adenoviral fiber gene, and a method of targeting attachment of a short-shafted recombinant adenovirus to a cell so as to effect entry of the short-shafted recombinant adenovirus into the cell.

Growing community of inventors

Germantown, MD, United States of America

Thomas J Wickham