The United States of America As Represented by the Department of Health

Peter J Nicholls

Richard J Youle

Susanna M Rybak

Dianne L Newton

Stephen H Leppla

Yogendra Singh

Naveen Arora

Kurt R Klimpel

The present invention relates to a selective cytotoxic RNase reagent. The reagent comprises a toxic moiety that is an RNase linked to a recognition moiety that binds a specific cell surface marker. Binding of the recognition moiety to a surface marker on a cell allows the toxic moiety to selectively kill the cell. To reduce immunogenicity, preferably the toxic moiety and the recognition moiety of the conjugate are endogenous to the species in which the reagent is intended for use. Cytotoxic reagents intended for use in humans preferably have as the toxic moiety a human ribonuclease, such as angiogenin, and as the recognition moiety as humanized chimeric antibody. The human ribonuclease and chimeric antibody preferably form a fused protein. The present invention also relates to pharmaceutical compositions including the cytotoxic reagent as well as treatment methods involving the use of the cytotoxic reagent.

Selective RNase cytotoxic reagents

The present invention provides a nucleic acid encoding a fusion protein, comprising a nucleotide sequence encoding the protective antigen (PA) binding domain of the native lethal factor (LF) protein and a nucleotide sequence encoding an activity inducing domain of a second protein. Also provided is a nucleic acid encoding a fusion protein, comprising a nucleotide sequence encoding the translocation domain and LF binding domain of the native PA protein and a nucleotide sequence encoding a ligand domain which specifically binds a cellular target. Proteins encoded by the nucleic acid of the invention, vectors comprising the nucleic acids and hosts capable of expressing the protein encoded by the nucleic acids are also provided. A composition comprising the PA binding domain of the native LF protein chemically attached to a non-LF activity inducing moiety is further provided. A method for delivering an activity to a cell is provided. The steps of the method include administering to the cell a protein comprising the translocation domain and the LF binding domain of the native PA protein and a ligand domain, and administering to the cell a product comprising the PA binding domain of the native LF protein and a non-LF activity inducing moiety, whereby the product administered is internalized into the cell and performs the activity within the cell.

Anthrax toxin fusion proteins, nucleic acid encoding same

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Berkshire, United Kingdom

Peter J Nicholls