A Drug Delivery Strategy for Targeted Therapy of Chronic Lymphocytic Leukemia

描述(申请人提供)：我们的研究团队将产生、验证和交付新型载体-有效载荷结合物，旨在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是一种无痛但无法治愈的B细胞恶性肿瘤，仅在美国每年就有大约150,000名患者受到影响，并导致4,500人死亡。目前还没有针对CLL的治疗方案，可以选择性地靶向恶性B细胞，而不包括正常B细胞和其他正常细胞和组织。我们假设最近发现的FC？Toso受体单独或与CLL中选择性表达的其他细胞表面受体结合，可介导细胞毒药物快速有效地进入细胞内，从而对CLL进行有效和特异的治疗干预。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-有效载荷结合物，通过Toso内化途径输送高度细胞毒性的药物。这些载体-有效载荷结合物将在体外、体外和体内进行严格的验证，并将评估它们的稳定性、特异性、抗CLL活性和毒性。在整个活动中，我们将从概念上测试运载器-有效载荷连接物的新颖生物和化学成分。虽然目标1的研究将优化针对Toso的载体-有效载荷结合物的效力，但在目标2中，我们将提高这种药物递送策略的特异性。特别是，我们将引入第二个特异性，它是由与受体酪氨酸激酶ROR1高度特异性和亲和力结合的抗体片段指导的，我们已经证明，ROR1在CLL细胞中选择性表达，但在正常B和T细胞或其他正常细胞或组织中不表达。此外，我们将测试其他CLL细胞表面受体与Toso结合用于双靶向的效用。这些双特异性载体-有效载荷结合物的稳定性、特异性、亲和力、抗CLL活性和毒性将通过验证的体外和体内CLL模型进行测试。总体而言，我们的研究团队将提供一系列高度 特异、安全和有效的试剂，将为进一步的临床前和临床研究治疗CLL奠定基础。值得注意的是，来自这些战役的概念新颖的生物和化学成分可以很容易和快速地被利用来产生远远超出CLL领域的其他载体-有效载荷共轭化合物。

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.