A Drug Delivery Strategy for Targeted Therapy of Chronic Lymphocytic Leukemia

该项目生成、验证和提供新型抗体-药物缀合物（ADC）， 选择性和有效地根除慢性淋巴细胞白血病（CLL），在美国最常见的白血病， 而不影响健康的细胞和组织。CLL是一种无痛但无法治愈的B细胞恶性肿瘤， 仅在美国，每年就有超过150，000名男性和女性死亡，并导致超过4，500人死亡。有 目前没有允许选择性靶向恶性B细胞并避免 健康的B细胞和其它健康的细胞和组织。有了这个假设，这个项目就建立在假设的基础上。 Fcµ受体FCMR单独或与其他选择性表达的CLL细胞表面 抗原，可以介导细胞毒性药物快速有效地进入细胞，用于有效和特异性的治疗 干预两个独立的具体目标将追求严格检验这一假设。在目标1中，a 将产生一系列分子定义的ADC，其递送并释放高细胞毒性微管蛋白抑制剂 和高细胞毒性DNA靶向药物，单独或组合，通过FCMR内化， 贩运途径。这些ADC将基于硒诺单抗-药物缀合物平台，其利用半导体器件。 用于位点特异性药物缀合的工程化硒代半胱氨酸残基。通过体外、离体、 并且在体内，将评估一组靶向FCMR的硒单抗-药物缀合物的稳定性， 特异性、效力、毒性和药代动力学。目的2建立在一个新的双可变结构域（DVD）-IgG 1- 基于ADC的平台，其利用独特的反应性赖氨酸残基用于位点特异性药物缀合。DVD-IgM- 可以同时接合FCMR和第二CLL细胞表面抗原的基于ADC将被构建， 广泛验证。除了高度模块化的研究策略，系统地比较不同的 靶点、不同抗体、不同抗体形式、不同接头和不同药物，离体和体内的抗体可以是不同的。 两种特定目的的体内实验将基于来自男性和女性的外周血单核细胞。 女性CLL患者，而不是细胞系，共同实现稳健和无偏倚的结果， 为先进的临床前研究和最终的临床翻译提供候选人。贯穿本 概念新颖的生物和化学成分，广泛适用于下一代 将开发用于癌症治疗的ADC。

This project generates, validates, and delivers novel antibody-drug conjugates (ADCs) that are designed to selectively and potently eradicate chronic lymphocytic leukemia (CLL), the most common leukemia in the U.S., without affecting healthy cells and tissues. CLL is an indolent yet incurable B-cell malignancy that afflicts more than 150,000 men and women and causes more than 4,500 deaths per year in the U.S. alone. There are currently no treatment options for CLL that allow for selective targeting of malignant B cells and that spare healthy B cells and other healthy cells and tissues. With this Premise, the project is built on the Hypothesis that the Fcµ receptor FCMR, on its own or in combination with other selectively expressed CLL cell surface antigens, can mediate rapid and effective cellular entry of cytotoxic drugs for potent and specific therapeutic intervention. Two independent Specific Aims will be pursued to rigorously test this hypothesis. In Aim 1, a series of molecularly defined ADCs will be generated that deliver and release a highly cytotoxic tubulin inhibitor and a highly cytotoxic DNA-targeting drug, on their own or in combination, via the FCMR internalization and trafficking pathway. These ADCs will be based on the selenomab-drug conjugate platform which utilizes an engineered selenocysteine residue for site-specific drug conjugation. By extensive validation in vitro, ex vivo, and in vivo, a panel of FCMR-targeting selenomab-drug conjugates will be assessed for their stability, specificity, potency, toxicity, and pharmacokinetics. Aim 2 builds on a novel dual variable domain (DVD)-IgG1- based ADC platform that utilizes a unique reactive lysine residue for site-specific drug conjugation. DVD-IgM- based ADCs that can simultaneously engage FCMR and a second CLL cell surface antigen will be built and extensively validated. In addition to a highly modular research strategy that systematically compares different targets, different antibodies, different antibody formats, different linkers, and different drugs, the ex vivo and in vivo experiments in both Specific Aims will be based on peripheral blood mononuclear cells from male and female CLL patients rather than on cell lines to collectively achieve Robust and Unbiased Results toward delivering a candidate for advanced preclinical investigations and eventual clinical translation. Throughout this campaign, conceptually novel biological and chemical components with broad applicability to next-generation ADCs for cancer therapy will be developed.