Abstract
A high percentage of human breast and ovarian tumors display amplified c-erbB-2 gene copies, leading to overexpression of the growth factor receptor. Its membrane location and elevated expression make the erbB-2 protein an appropriate target for a directed tumor therapy. We have used recombinant DNA technology to produce a single-chain antibody-exotoxin A (scFv-ETA) fusion protein which specifically binds the human erbB-2 receptor. The scFv portion is composed of the heavy- and light-chain variable domains of a monoclonal antibody which recognizes the extracellular domain of the human erbB-2 receptor. The bacterially produced scFv-ETA protein was shown to bind specifically to cells expressing the human erbB-2 protein. The scFv-ETA inhibits protein synthesis in erbB-2-expressing tumor cells at doses ranging from 2 to 200 ng/ml and is cytotoxic for these cells at equivalent doses. In athymic nude mice, administration of the scFv-ETA inhibited the growth of erbB-2-overexpressing human ovarian carcinoma cells.
MeSH terms
-
ADP Ribose Transferases*
-
Amino Acid Sequence
-
Animals
-
Antibodies, Monoclonal / immunology
-
Antibody Specificity
-
Bacterial Toxins*
-
Base Sequence
-
Carrier Proteins / genetics
-
Carrier Proteins / pharmacology*
-
Cell Division / drug effects
-
Chimera / genetics
-
DNA, Recombinant / genetics
-
Exotoxins / genetics
-
Exotoxins / pharmacology*
-
Female
-
Humans
-
Immunotoxins / pharmacology*
-
Mammary Neoplasms, Experimental / drug therapy
-
Mammary Neoplasms, Experimental / immunology
-
Mammary Neoplasms, Experimental / therapy*
-
Mice
-
Mice, Nude
-
Molecular Sequence Data
-
Neoplasm Proteins / biosynthesis
-
Neoplasm Transplantation
-
Ovarian Neoplasms / drug therapy
-
Ovarian Neoplasms / immunology
-
Ovarian Neoplasms / therapy*
-
Proto-Oncogene Proteins / genetics
-
Proto-Oncogene Proteins / immunology*
-
Proto-Oncogene Proteins / physiology
-
Pseudomonas aeruginosa Exotoxin A
-
Receptor, ErbB-2
-
Recombinant Fusion Proteins / genetics
-
Recombinant Fusion Proteins / pharmacology*
-
Recombinant Proteins
-
Transplantation, Heterologous
-
Virulence Factors*
Substances
-
Antibodies, Monoclonal
-
Bacterial Toxins
-
Carrier Proteins
-
DNA, Recombinant
-
Exotoxins
-
Immunotoxins
-
Neoplasm Proteins
-
Proto-Oncogene Proteins
-
Recombinant Fusion Proteins
-
Recombinant Proteins
-
Virulence Factors
-
single-chain antigen-binding protein B6.2-212
-
ADP Ribose Transferases
-
Receptor, ErbB-2