Immunotoxins in bone marrow transplantation

描述（由申请人提供）：迫切需要药物难治性B细胞恶性肿瘤的替代疗法。我们利用上个周期的进展，开发了一类新的重组双特异性靶向毒素，其识别更广泛的B细胞癌的能力得到了扩展。在这笔资金的资助下，我们发现双特异性靶向毒素可以通过融合两个重复的scFv亚基产生双特异性配体导向毒素，并且它们比单特异性靶向毒素具有更好的活性。我们把这种药用于白血病的临床试验。研究结果令人鼓舞，但初步数据表明，正如预期的那样，毒素免疫原性将是一个问题。需要多次给药以获得持续的缓解，这会产生影响药物疗效的抗毒素抗体。为此，我们发现了一种重要的、新的、成功的方法来消除我们毒素的免疫，这可能对消除其他分子的免疫有影响。在目标1中，我们建议研究这种脱免疫。来自该提案的资金也导致了一种非常不同的靶向毒素的开发，这种毒素具有靶向癌症干细胞的能力。目前的理论认为癌细胞和正常细胞一样会分化。癌细胞群由一小群分化程度较低、自我更新、肿瘤起始的干细胞和一大群分化程度较高的肿瘤细胞组成。分化程度越高的细胞对化疗越敏感，少部分分化程度越低的癌症干细胞耐药程度越高，从而导致癌症的药物难治性复发。我们已经创造了一种新的靶向毒素，以癌症干细胞为目标，显然在系统性癌症小鼠模型中具有治疗效果。这种药物的优点是可以治疗多种不同的癌症。在目标2中，我们提出研究这种靶向肿瘤干细胞的新策略。Aim 1与Aim 2相关，因为脱免疫策略也用于构建抗干细胞靶向毒素。

DESCRIPTION (provided by applicant): Alternative therapies for drug refractory B cell malignancies are urgently needed. We used advances last cycle to develop a new class of recombinant bispecific targeted toxin with expanded ability to recognize a wider range of B cell cancers. With funding from this grant, we discovered that bispecific targeted toxins could be made by fusing two repeating scFv subunits creating a bispecific ligand directed toxin and they had superior activity over monospecific targeted toxins. We brought the drug to clinical trial for leukemia. Findings are encouraging, but preliminary data indicates that toxin immunogenicity will be a problem as anticipated. Multiple dosing is required to obtain sustained remissions and this generates anti-toxin antibodies that impact drug efficacy. To this end, we have found an important new and successful way to deimmunize our toxin that may have implications for deimmunizing other molecules. In aim 1, we propose to study this deimmunization. Funding from this proposal has also led to the development of a very different targeted toxin that has the ability to target cancer stem cells. Current theory dictates that cancer cells differentiate as do normal cells. The cancer cell population consists of a small cohort of less differentiated, self renewing, tumor initiating stem cells and a larger cohort of more differentiated tumor cells. More differentiated cells are more susceptible to chemotherapy and the minor fraction of less differentiated cancer stem cells are more drug resistant, thus contributing to drug refractory relapse in cancer. We have created a new targeted toxin that targets cancer stem cells and clearly has therapeutic efficacy in systemic mouse models of cancer. The agent has the advantage of working against a variety of different cancers. In aim 2, we propose to study this new strategy of targeting tumor stem cells. Aim 1 relates to Aim 2 since the deimmunization strategies are used to construct anti-stem cell targeted toxins as well.