A Drug Delivery Strategy for Targeted Therapy of Chronic Lymphocytic Leukemia

慢性淋巴细胞白血病靶向治疗的给药策略

• 批准号: 10021283
• 负责人: CHRISTOPH RADER
• 金额: $ 9.25万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-12 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10021283
• 关键词: Address; Affect; Antibodies; Antibody-drug conjugates; Antigens; Autologous; B lymphoid malignancy; B-Lymphocytes; Binding; Biological; C-terminal; Cell Line; Cell surface; Cells; Cessation of life; Chemicals; Chronic Lymphocytic Leukemia; Combination Drug Therapy; Confocal Microscopy; Cytotoxic agent; DNA; Development; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Engineering; Fc Immunoglobulins; Female; Fluorescein; Funding; Goals; Human; IgG1; Immunoglobulin G; Immunoglobulin M; In Vitro; Indolent; Investigation; Lysine; Lysosomes; Malignant - descriptor; Malignant Neoplasms; Mediating; Molecular; Monoclonal Antibodies; Mus; Mutation; Names; Oryctolagus cuniculus; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Phage Display; Pharmaceutical Preparations; Property; Protein Fragment; ROR1 gene; Research; Selenocysteine; Series; Site; Specificity; Surface Antigens; T-Lymphocyte; Technology; Testing; Therapeutic Intervention; Tissues; Toxic effect; Tubulin; Validation; Woman; Work; Xenograft procedure; base; cancer therapy; chronic lymphocytic leukemia cell; clinical translation; combinatorial; cytotoxic; cytotoxicity; design; dimer; experimental study; improved; in vivo; in vivo Model; inhibitor/antagonist; kinase inhibitor; leukemia; male; men; mouse model; new therapeutic target; next generation; novel; overexpression; pre-clinical; prototype; receptor; response; selective expression; small molecule; targeted treatment; trafficking

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.

该项目生成、验证并提供新型抗体药物偶联物 (ADC)，旨在 选择性地、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。 CLL 是一种惰性但无法治愈的 B 细胞恶性肿瘤，影响更多人 仅在美国，每年就造成超过 150,000 名男性和女性死亡，并导致超过 4,500 人死亡。有 目前还没有针对 CLL 的治疗方案可以选择性靶向恶性 B 细胞并保留 健康的 B 细胞和其他健康的细胞和组织。在此前提下，该项目建立在假设之上 Fcμ受体 FCMR，单独或与其他选择性表达的 CLL 细胞表面组合 抗原，可以介导细胞毒性药物快速有效地进入细胞，以实现有效和特异性的治疗 干涉。将追求两个独立的具体目标来严格检验这一假设。在目标 1 中， 将产生一系列分子定义的 ADC，用于传递和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 内化和 贩运途径。这些 ADC 将基于 Selenomab-药物结合平台，该平台利用 工程化的硒代半胱氨酸残基用于位点特异性药物缀合。通过体外、离体的广泛验证， 在体内，将评估一组 FCMR 靶向硒抗体药物缀合物的稳定性， 特异性、效力、毒性和药代动力学。 Aim 2 建立在新型双可变域 (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位点特异性药物缀合。 DVD-IgM- 将构建基于 ADC 的可同时参与 FCMR 和第二种 CLL 细胞表面抗原的技术 得到广泛验证。除了系统地比较不同的高度模块化的研究策略之外 靶点、不同的抗体、不同的抗体形式、不同的接头和不同的药物、体外和体内 两个特定目标的体内实验将基于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公正的结果 为先进的临床前研究和最终的临床转化提供候选人。纵观这一切 活动，概念新颖的生物和化学成分，具有广泛适用于下一代 将开发用于癌症治疗的 ADC。