Engineering Diptheria Toxin Towards the Development of Therapeutics against Breast Cancer
Abstract
The goal of this project is to design a cytotoxic protein using diphtheria toxin as a template that will recognize and bind to a cell that overproduces heregulin (HRG) precursor on the cell surface. HRG is an activating growth factor ligand for HER-4, whose overexpression is correlated with breast cancer cells. Given the recent success with the humanized monoclonal antibody (herceptin) against erb-B receptors as therapeutics against breast cancer, we hypothesize that the downregulation of the production of this ligand will lead to the inhibition of the growth of breast cancer cells. In 1997, we have completed the crystal structure of diphtheria toxin (DT) complexed with an extracellular fragment of its receptor protein, a membrane- bound precursor of human heparin-binding EGF (HBEGF). HBEGF is structurally homologous to HRG, thus providing a point of departure for molecular design of diphtheria toxin in order to divert to a new target receptor, HRG. The engineered toxin will be tested in vivo for its efficiency in targeted delivery of cytotoxicity.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 1998
- Accession Number
- ADA377811
Entities
People
- Senyon Choe
Organizations
- Salk Institute for Biological Studies