Next Article in Journal
Man-Made Synthetic Receptors for Capture and Analysis of Ochratoxin A
Previous Article in Journal
The Effects of Shiga Toxin 1, 2 and Their Subunits on Cytokine and Chemokine Expression by Human Macrophage-Like THP-1 Cells
Open AccessArticle

Mutagenic Deimmunization of Diphtheria Toxin for Use in Biologic Drug Development

University of Minnesota Masonic Cancer Center, Section of Molecular Cancer Therapeutics, Therapeutic Radiology-Radiation Oncology, University of Minnesota, Minneapolis, MN 55423, USA
Department for Hematology and Oncology, Department of Medicine 2, University Hospital of Tuebingen, Tuebingen 72076, Germany
Author to whom correspondence should be addressed.
Academic Editor: Sang Ho Choi
Toxins 2015, 7(10), 4067-4082;
Received: 6 July 2015 / Accepted: 9 September 2015 / Published: 10 October 2015
(This article belongs to the Section Bacterial Toxins)
Background: Targeted toxins require multiple treatments and therefore must be deimmunized. We report a method of protein deimmunization based on the point mutation of highly hydrophilic R, K, D, E, and Q amino acids on the molecular surface of truncated diphtheria-toxin (DT390). Methods: Based on their surface position derived from an X-ray-crystallographic model, residues were chosen for point mutation that were located in prominent positions on the molecular surface and away from the catalytic site. Mice were immunized with a targeted toxin containing either a mutated DT390 containing seven critical point mutations or the non-mutated parental toxin form. Results: Serum analysis revealed a significant 90% reduction in anti-toxin antibodies in mice immunized with the mutant, but not the parental drug form despite multiple immunizations. The experiment was repeated in a second strain of mice with a different MHC-haplotype to address whether point mutation removed T or B cell epitopes. Findings were identical indicating that B cell epitopes were eliminated from DT. The mutant drug form lost only minimal activity in vitro as well as in vivo. Conclusion: These findings indicate that this method may be effective for deimmunizing of other proteins and that discovery of a deimmunized form of DT may lead to the development of more effective targeted toxin. View Full-Text
Keywords: deimmunization; diphtheria; toxin; biologic drug; cancer; cancer treatment deimmunization; diphtheria; toxin; biologic drug; cancer; cancer treatment
Show Figures

Figure 1

MDPI and ACS Style

Schmohl, J.U.; Todhunter, D.; Oh, S.; Vallera, D.A. Mutagenic Deimmunization of Diphtheria Toxin for Use in Biologic Drug Development. Toxins 2015, 7, 4067-4082.

Show more citation formats Show less citations formats

Article Access Map by Country/Region

Only visits after 24 November 2015 are recorded.
Search more from Scilit
Back to TopTop