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.
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