Immunotoxins in bone marrow transplantation

治疗B细胞恶性肿瘤的替代疗法迫在眉睫。我们在上个周期使用先进技术开发了一种 新型重组双特异性免疫毒素(IT)对多种B细胞的识别能力 细胞癌。我们发现，这种IT可以通过融合两个重复的SFV亚基识别 人CD19和人CD22剪接成截短的DT。这种名为DT2219的分子是独一无二的 研究表明，杂合分子与恶性B细胞株的结合效果好于单独的抗CD19和 抗CD22抗体，功能较好。DT2219显示出令人印象深刻的抗癌活性 建立了感染SCID小鼠的血液性人类癌症。这项提案的目标将是更好地界定 DT2219的生物学、药理学和毒理学为了确定sFv是否完全完整， 并确定DT2219在体内清除和分布的方式。此外，我们还将 充分确定其体内抗肿瘤活性和毒性。尽管我们的发现和进展令人鼓舞，但有两个 主要问题仍然存在，毒性和免疫原性。幸运的是，因为DT2219是遗传的 可修改的，我们将继续探索我们上个周期开始的重要修改的研究。这些 强调通过添加Ig恒定区的分解代谢抑制序列和工作来降低毒性 人源化降低SFV区免疫原性及降低毒素免疫原性的研究 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.