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Toxins 2015, 7(10), 4067-4082; doi:10.3390/toxins7104067

Mutagenic Deimmunization of Diphtheria Toxin for Use in Biologic Drug Development

1
University of Minnesota Masonic Cancer Center, Section of Molecular Cancer Therapeutics, Therapeutic Radiology-Radiation Oncology, University of Minnesota, Minneapolis, MN 55423, USA
2
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
Received: 6 July 2015 / Accepted: 9 September 2015 / Published: 10 October 2015
(This article belongs to the Section Bacterial Toxins)
View Full-Text   |   Download PDF [1704 KB, uploaded 10 October 2015]   |  

Abstract

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
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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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.

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