A fully human antitumor immunoRNase selective for ErbB-2-positive carcinomas.

Abstract

We report the preparation and characterization of a novel, fully human antitumor immunoRNase (IR). The IR, a human RNase and fusion protein made up of a human single chain variable fragment (scFv), is directed to the ErbB-2 receptor and overexpressed in many carcinomas. The anti-ErbB-2 IR, named hERB-hRNase, retains the enzymatic activity of the wild-type enzyme (human pancreatic RNase) and specifically binds to ErbB-2-positive cells with the high affinity (K(d) = 4.5 nm) of the parental scFv. hERB-hRNase behaves as an immunoprotoxin and on internalization by target cells becomes selectively cytotoxic in a dose-dependent manner at nanomolar concentrations. Administered in five doses of 1.5 mg/kg to mice bearing an ErbB-2-positive tumor, hERB-hRNase induced a dramatic reduction in tumor volume. hERB-hRNase is the first fully human antitumor IR produced thus far, with a high potential as a poorly immunogenic human drug devoid of nonspecific toxicity, directed against ErbB-2-positive malignancies.

• Authors: Claudia De Lorenzo, Angela Arciello, Rosanna Cozzolino, Donald B Palmer, Paolo Laccetti, Renata Piccoli, Giuseppe D'Alessio
• Journal: Cancer research (Cancer Res) Vol. 64 Issue 14 Pg. 4870-4 (Jul 15 2004) ISSN: 0008-5472 [Print] United States
• PMID: 15256457 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Immunotoxins
• Recombinant Fusion Proteins
• Receptor, ErbB-2
• Ribonucleases

Topics

• Amino Acid Sequence
• Animals
• Breast Neoplasms (drug therapy, metabolism)
• Cell Line, Tumor
• Drug Stability
• Female
• Humans
• Immunotoxins (genetics, metabolism, pharmacokinetics, pharmacology)
• Mice
• Mice, Inbred BALB C
• Molecular Sequence Data
• Neoplasms, Experimental (drug therapy, metabolism)
• Receptor, ErbB-2 (biosynthesis, genetics, metabolism)
• Recombinant Fusion Proteins (biosynthesis, genetics, pharmacokinetics, pharmacology)
• Ribonucleases (genetics, metabolism, pharmacology)