A Drug Delivery Strategy for Targeted Therapy of Chronic Lymphocytic Leukemia

描述（由申请人提供）：我们的研究团队将生成，验证和提供新型载体-有效载荷缀合物，其设计用于选择性和有效地根除慢性淋巴细胞白血病（CLL），这是西方世界最常见的白血病，而不影响正常细胞和组织。CLL是一种惰性但不可治愈的B细胞恶性肿瘤，仅在美国每年就有大约150，000名患者受到折磨并导致4，500人死亡。目前没有允许选择性靶向恶性B细胞并且不伤害正常B细胞和其他正常细胞和组织的CLL治疗选择。我们假设最近发现的Fc？受体TOSO，单独或与在CLL中选择性表达的其它细胞表面受体组合，可以介导细胞毒性药物快速有效的细胞进入，用于CLL中的有效和特异性治疗干预。我们提出了两个具体目标来严格检验这一假设。在目标1中，我们将产生一系列分子定义的载体-有效载荷缀合物，其通过TOSO内化途径递送高细胞毒性药物。这些载体-有效负载缀合物将在体外、离体和体内进行严格验证，并将评估其稳定性、特异性、抗CLL活性和毒性。在整个活动中，我们将测试概念上新颖的载体-有效载荷缀合物的生物和化学成分。而目标1的研究将优化靶向TOSO的载体-有效载荷缀合物的效力，在目标2中，我们将提高这种药物递送策略的特异性。特别地，我们将引入第二种特异性，其由以高特异性和亲合力结合受体酪氨酸激酶ROR 1的抗体片段指导，我们已经显示其在CLL细胞中选择性表达，但不在正常B和T细胞中，也不在其他正常细胞或组织中。此外，我们将测试其他CLL细胞表面受体与TOSO组合用于双重靶向的效用。这些双特异性载体-有效负载缀合物的稳定性、特异性、亲合力、抗CLL活性和毒性将使用CLL的经验证的体外离体和体内模型进行测试。总的来说，我们的研究团队将提供一系列高度 特异性、安全性和有效性的试剂，将为CLL治疗的进一步临床前和临床研究奠定基础。值得注意的是，来自这些活动的概念上新颖的生物和化学组分可以容易且快速地用于产生远远超出CLL领域的其他载体-有效载荷缀合物。

DESCRIPTION (provided by applicant): Our research team will generate, validate, and deliver novel carrier-payload conjugates that are designed to selectively and potently eradicate chronic lymphocytic leukemia (CLL), the most common leukemia in the Western world, without affecting normal cells and tissues. CLL is an indolent yet incurable B-cell malignancy that afflicts approximately 150,000 patients and causes 4,500 deaths per year in the USA alone. There are currently no treatment options for CLL that allow for selective targeting of malignant B cells and that spare normal B cells and other normal cells and tissues. We hypothesize that the recently discovered Fc? receptor TOSO, on its own or in combination with other cell surface receptors that are selectively expressed in CLL, can mediate rapid and effective cellular entry of cytotoxic drugs for potent and specific therapeutic intervention in CLL. We propose two Specific Aims to rigorously test this hypothesis. In Aim 1 we will generate a series of molecularly defined carrier-payload conjugates that deliver highly cytotoxic drugs via the TOSO internalization pathway. These carrier-payload conjugates will be rigorously validated in vitro, ex vivo and in vivo and wil be assessed for their stability, specificity, anti-CLL activity, and toxicity. Throughout this campaign we will test conceptually novel biological and chemical components of carrier- payload conjugates. Whereas the studies of Aim 1 will optimize the potency of carrier-payload conjugates targeting TOSO, in Aim 2 we will improve the specificity of this drug delivery strategy. In particular, we will introduce a second specificity that is directed by an antibody fragment that binds with high specificity and avidity to the receptor tyrosine kinase ROR1, which we have shown is selectively expressed in CLL cells but not in normal B and T cells nor in other normal cells or tissues. Furthermore, we will test the utility of other CLL cell surface receptors for dual targeting in combination with TOSO. The stability, specificity, avidity, anti-CLL activity and toxicity of these bispecific carrier-payload conjugates will be tested using validated in vitro ex vivo, and in vivo models of CLL. Collectively, our research team will deliver a series of highly specific, safe, and potent reagents that will lay the foundation for further preclinical and clinicl investigations in the treatment of CLL. Notably, the conceptually novel biological and chemical components coming from these campaigns can be easily and rapidly exploited to generate other carrier-payload conjugates well beyond the realm of CLL.