National Institutes of Health, a Component of the US Dept. of Health & Human Services

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

Other

Immunomedics, Inc.

Dianne L Newton

Susanna M Rybak

Richard J Youle

Peter J Nicholls

David M Goldenberg

Andrea Cara

Alexander Wlodawer

Gabriele Luca Gusella

Lluis Boque

This invention provides for new recombinant ribonuclease proteins which are active when expressed by bacteria. This allows the recombinant ribonucleases of this invention to be fused in-frame with ligand binding moieties to form cytotoxic fusion proteins. Furthermore, these proteins are more active than ribonucleases currently available even though the proteins of this invention lack an N-terminal pyroglutamic acid, which has been found to be necessary for ribonucleolytic activity. Because these proteins are recombinant proteins, mutations which increase cytotoxicity can be engineered.

Recombinant anti-tumor RNAse

This invention provides RNase A superfamily polypeptides with modified amino terminal which can be used to selectively kill target Kaposi's sarcoma cells, neoplastic endothelial cells, and non-neoplastic endothelial cells. In certain embodiments of the invention, the amino terminal modification consists of an addition of 4 amino acid sequence consisting of the SLHV sequence at position &#x2212;4 to &#x2212;1 to the eosinophil derived neurotoxin protein. The amino terminal addition is capable of directing the claimed RNase A superfamily polypeptides to proliferating endothelial cells, such as Kaposi's sarcoma cells, and selectively killing these cells.

Selective toxicity of amino-terminal modified rnase a superfamily polypeptides

Cell transformation vectors for inhibiting HIV and tumor growth are provided. Optionally, the vectors encode RNAses such as EDN. Cells transduced by the vectors and methods of transforming cells (in vitro and in vivo) using the vectors are also provided.

Vectors for delivering viral and oncogenic inhibitors

The present invention relates to immunotoxins, that effectively kill malignant cells having a given surface marker and nucleic acid constructs encoding them. These reagents comprise a toxic moiety that is derived from a protein having ribonucleolytic activity linked to an antibody capable of specific binding with a chosen tumor cell.

Immunotoxins directed against malignant cells

Recombinant ribonuclease proteins

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.

Growing community of inventors

Rockville, MD, United States of America

Dianne L Newton