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

基本信息

批准号：
10377398
负责人：
Ben Shen
金额：
$ 56.35万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-12 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10377398
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 base cancer therapy chronic lymphocytic leukemia cell clinical translation combinatorial cytotoxic cytotoxicity design dimer experimental study improved in vivo in vivo Model inhibitor kinase inhibitor leukemia male men mouse model new therapeutic target next generation novel overexpression patient derived xenograft model pre-clinical prototype receptor response selective expression small molecule targeted treatment trafficking

项目摘要

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)，旨在选择性且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， 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，每年就有超过 150,000 名男性和女性死亡，造成 4,500 多人死亡。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将追求两个独立的具体目标来严格检验这一假设。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 内化和这些 ADC 将基于 Selenoumab-药物缀合物平台，该平台利用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、离体的广泛验证，在体内，将评估一组 FCMR 靶向 Selenoumab 药物缀合物的稳定性， Aim 2 基于新型双可变结构域 (DVD)-IgG1-。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。将构建基于 ADC 的模型，该 ADC 可以同时结合 FCMR 和第二种 CLL 细胞表面抗原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在此过程中为高级临床前研究和最终的临床转化提供候选者。运动，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。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

Patient-derived Siglec-6-targeting antibodies engineered for T-cell recruitment have potential therapeutic utility in chronic lymphocytic leukemia.

患者衍生的用于 T 细胞募集的 Siglec-6 靶向抗体在慢性淋巴细胞白血病中具有潜在的治疗用途。

DOI：
发表时间：
2022-11
期刊：
影响因子：
0
作者：
Cyr, Matthew G;Mhibik, Maissa;Qi, Junpeng;Peng, Haiyong;Chang, Jing;Gaglione, Erika M;Eik, David;Herrick, John;Venables, Thomas;Novick, Scott J;Courouble, Valentine V;Griffin, Patrick R;Wiestner, Adrian;Rader, Christoph
通讯作者：
Rader, Christoph

Siglec-6 on Chronic Lymphocytic Leukemia Cells Is a Target for Post-Allogeneic Hematopoietic Stem Cell Transplantation Antibodies.

慢性淋巴细胞白血病细胞上的 Siglec-6 是同种异体造血干细胞移植后抗体的靶标。

DOI：
发表时间：
2018
期刊：
影响因子：
10.1
作者：
Chang, Jing;Peng, Haiyong;Shaffer, Brian C;Baskar, Sivasubramanian;Wecken, Ina C;Cyr, Matthew G;Martinez, Gustavo J;Soden, Jo;Freeth, Jim;Wiestner, Adrian;Rader, Christoph
通讯作者：
Rader, Christoph

Affinity maturation, humanization, and co-crystallization of a rabbit anti-human ROR2 monoclonal antibody for therapeutic applications.

用于治疗应用的兔抗人 ROR2 单克隆抗体的亲和力成熟、人源化和共结晶。

DOI：
发表时间：
2020-05-01
期刊：
影响因子：
0
作者：
Goydel, Rebecca S;Weber, Justus;Peng, Haiyong;Qi, Junpeng;Soden, Jo;Freeth, Jim;Park, HaJeung;Rader, Christoph
通讯作者：
Rader, Christoph

Site-Selective Antibody Functionalization via Orthogonally Reactive Arginine and Lysine Residues.

通过正交反应性精氨酸和赖氨酸残基进行位点选择性抗体功能化。

DOI：
发表时间：
2019
期刊：
影响因子：
8.6
作者：
Hwang, Dobeen;Nilchan, Napon;Nanna, Alex R;Li, Xiaohai;Cameron, Michael D;Roush, William R;Park, HaJeung;Rader, Christoph
通讯作者：
Rader, Christoph

ROR1-targeting switchable CAR-T cells for cancer therapy.

用于癌症治疗的 ROR1 靶向可切换 CAR-T 细胞。

DOI：
发表时间：
2022-08
期刊：
影响因子：
8
作者：
Peng, Haiyong;Nerreter, Thomas;Mestermann, Katrin;Wachter, Jakob;Chang, Jing;Hudecek, Michael;Rader, Christoph
通讯作者：
Rader, Christoph