A Drug Delivery Strategy for Targeted Therapy of Chronic Lymphocytic Leukemia

该项目生成、验证和交付新型抗体-药物结合物(ADC)，旨在 选择性和有效地根除慢性淋巴细胞白血病(CLL)，这是美国最常见的白血病， 而不影响健康的细胞和组织。慢性淋巴细胞性白血病是一种无痛但无法治愈的B细胞恶性肿瘤，它更多地困扰着 每年仅在美国就有超过15万名男性和女性死亡，导致4500多人死亡。确实有 目前还没有针对CLL的治疗选择，允许选择性靶向恶性B细胞和备用细胞 健康的B细胞和其他健康的细胞和组织。在这个前提下，项目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细胞表面结合 抗原，可以介导细胞毒药物快速有效地进入细胞内，进行有效和特异的治疗 干预。将追求两个独立的具体目标来严格检验这一假说。在目标1中，一个 将产生一系列分子定义的ADC，递送和释放高度细胞毒性的微管蛋白抑制物 和一种高度细胞毒性的DNA靶向药物，单独或组合，通过FCMR内化和 贩运路径。这些ADC将基于硒单抗-药物结合平台，该平台利用 设计的硒半胱氨酸残基用于特定部位的药物结合。通过广泛的体外、体外验证， 在体内，一组以FCMR为靶点的硒单抗药物结合物将被评估其稳定性， 特异性、效力、毒性和药代动力学。AIM 2建立在一种新型的双变构域(DVD)--IgG1--的基础上 基于ADC平台，利用独特的反应性赖氨酸残基进行特定部位的药物结合。DVD-IgM- 将建立能够同时结合FCMR和第二个CLL细胞表面抗原的ADC，并 经过广泛验证。除了高度模块化的研究策略外，该策略还系统地比较不同的 靶点，不同的抗体，不同的抗体形式，不同的连接物，不同的药物，体外和体内 在这两个特定目标上的活体实验将基于男性和 女性慢性淋巴细胞性白血病患者，而不是在细胞系上，共同取得稳健和公正的结果 为先进的临床前研究和最终的临床翻译提供候选人。在整个过程中 Campaign，概念上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.