Alternative therapies for B cell malignancies are urgently needed. We used advances last cycle to develop a new class of recombinant bispecific immunotoxin (IT) with expanded ability to recognize a wider range of B cell cancers. We discovered that this IT could be made by fusing two repeating sFv subunits recognizing human CD19 and human CD22 spliced to truncated DT. This molecule called DT2219 was unique since studies indicated that the hybrid molecule bound better to malignant B cell lines than separate anti-CD19 and anti-CD22 antibodies and was functionally better. DT2219 showed impressive anti-cancer activity against established hematologic human cancer infecting scid mice. The goal of this proposal will be to better define the biology, pharmacology, and toxicology of DT2219 in order to determine whether the sFvs are fully intact, and to determine the manner in which DT2219 is cleared and distributed throughout the body. Also, we will fully define its in vivo anti-tumor activity and toxicity. Despite our encouraging findings and progress, two major problems still exist, toxicity and immunogenicity. Fortunately, because DT2219 is genetically modifiable, we will continue to explore the study of important modifications that we began last cycle. These emphasize reducing toxicity by adding catabolism-inhibiting sequences from Ig constant regions and working on reducing immunogenicity of the sFv region by humanization and reducing the immunogenicity of the toxin by using proapoptotic toxins of human origin.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA036725-25
Application #
7799824
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Welch, Anthony R
Project Start
1984-01-01
Project End
2011-06-30
Budget Start
2010-05-01
Budget End
2011-06-30
Support Year
25
Fiscal Year
2010
Total Cost
$236,154
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Schmohl, Joerg U; Todhunter, Deborah; Oh, Seung et al. (2015) Mutagenic Deimmunization of Diphtheria Toxin for Use in Biologic Drug Development. Toxins (Basel) 7:4067-82
Bachanova, Veronika; Frankel, Arthur E; Cao, Qing et al. (2015) Phase I study of a bispecific ligand-directed toxin targeting CD22 and CD19 (DT2219) for refractory B-cell malignancies. Clin Cancer Res 21:1267-72
Waldron, Nate N; Barsky, Sanford H; Dougherty, Phillip R et al. (2014) A bispecific EpCAM/CD133-targeted toxin is effective against carcinoma. Target Oncol 9:239-49
Gleason, Michelle K; Ross, Julie A; Warlick, Erica D et al. (2014) CD16xCD33 bispecific killer cell engager (BiKE) activates NK cells against primary MDS and MDSC CD33+ targets. Blood 123:3016-26

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