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

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

The United States of America as Represented by the Secretary of

David J Fitzgerald

Ira H Pastan

Mark C Willingham

Cary L Queen

Thomas Alexander Waldmann

Waldemar Debinski

Vijay Kumar Chaudhary

Prior Trevor

Clay Siegall

The present invention describes recombinant antibody toxin fusion proteins which selectively kill cells bearing appropriate antigens or receptors.

Recombinant antibody-toxin fusion protein

This invention relates to the production and use of recombinant Pseudomonas-derived toxins modified to increase their toxicity and potency in therapy. More particularly, the invention relates to certain deletions in domain II of the amino acid sequence of Pseudomonas exotoxin the domain which relates to the toxin's natural proteolytic processing.

Recombinant pseudomonas exotoxin with increased activity

Proteins that are impermeable and foreign to the eukaryotic cells can now be delivered across cellular membranes into the cytosol of target cells by making a chimeric protein having specific attributes. A method of making such chimeric proteins is disclosed. As an example, a chimeric protein PE-Bar with dual enzymatic activity has been made. The chimeric proteins can be used for cytotoxic, diagnostic or therapeutic purposes, such as for compensating the deficiency or defect of an enzyme or a protein which may be causative of a disease or an abnormality.

Recombinant chimeric proteins deliverable across cellular membranes into

Monoclonal antibodies are produced which specifically bind to human ovarian cancer cells. These antibodies are conjugated to Pseudomonas exotoxin in order to produce an immunotoxin suitable for the chemotherapeutic treatment of human ovarian cancer.

Monoclonal antibody against ovarian cancer cells (OVB-3)

A method of modifying Pseudomonas exotoxin (PE) with methyl-4-mercaptobutyrimidate is disclosed so that after conjugating the exotoxin to a monoclonal antibody (ab) such as the antibody to the transferrin receptor, the PE-ab conjugate becomes a highly potent immunotoxin suitable for use against human tumor cells. This same method has been used to conjugate PE to epidermal growth factor (EGF) to create a highly potent growth factor-toxin conjugate for use against cells having large numbers of EGF receptors. Also disclosed are the immunotoxin conjugates for Pseudomonas exotoxin coupled to anti-TFR (antibody to the transferrin receptor) and anti-TAC (antibody to the human T-cell growth factor receptor) and to EGF.

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Silver Springs, MD, United States of America

David J Fitzgerald