Immunotoxins in bone marrow transplantation

迫切需要B细胞恶性肿瘤的替代疗法。我们利用上个周期的进展， 一类新的重组双特异性免疫毒素（IT），具有扩展的识别更宽范围B的能力 细胞癌我们发现这种IT可以通过融合两个重复的sFv亚基来实现， 人CD 19和人CD 22剪接到截短的DT上。这种被称为DT 2219的分子是独一无二的， 研究表明，杂交分子比单独的抗-CD 19和抗-CD 19更好地结合恶性B细胞系。 抗CD 22抗体，功能更好。DT 2219显示出令人印象深刻的抗癌活性， 建立了感染scid小鼠的血液学人类癌症。该提案的目标是更好地界定 DT 2219的生物学、药理学和毒理学，以确定sFv是否完全完整， 并确定DT 2219在体内清除和分布的方式。我们亦会 充分确定其体内抗肿瘤活性和毒性。尽管我们取得了令人鼓舞的发现和进展， 仍然存在毒性和免疫原性的主要问题。幸运的是，由于DT 2219在基因上是 我们将继续探索我们上一个周期开始的重要修改的研究。这些 强调通过添加来自IG恒定区的分解代谢抑制序列来降低毒性， 通过人源化降低sFv区的免疫原性和降低毒素的免疫原性 通过使用人类来源的促凋亡毒素。

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.