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Open AccessArticle

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