Novel Enediyne-Based Antibody-Drug Conjugates for Cancers

用于癌症的新型烯二炔抗体药物偶联物

基本信息

批准号：
9402588
负责人：
CHRISTOPH RADER
金额：
$ 65.9万
依托单位：
SCRIPPS FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-15 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9402588
关键词：
Address Affinity Anabolism Antibodies Antibody-drug conjugates Antigen Targeting Antineoplastic Agents Benchmarking Biochemical Breast Cancer Patient Breast Cancer cell line Categories Cessation of life Chemistry Clinical Trials Cysteine DNA Damage Data Development Disease Drug Kinetics ERBB2 gene Engineering Evaluation Exhibits FDA approved Family Fermentation Fibrinogen Goals Grant Heterogeneity In Vitro Iodoacetamide Lysine Malignant Neoplasms Microtubules Monoclonal Antibodies Mus Natural Products Outcome Pharmaceutical Preparations Pharmacology Production Property ROR1 gene Recombinants Research Rest Safety Selenocysteine Side Site Specificity Streptomyces Structure-Activity Relationship Technology Therapeutic Therapeutic Index Toxic effect Validation Xenograft procedure analog base cancer therapy cancer type clinical development cytotoxic cytotoxicity drug discovery effective therapy falls functional group genetic manipulation improved in vivo in vivo Model inhibitor/antagonist innovation malignant breast neoplasm member microbial next generation novel oncology program scaffold small molecule success technology development therapy outcome treatment response tumor virtual

项目摘要

Both the two FDA-approved antibody-drug conjugates (ADCs) (Adcetris® and Kadcyla®) and nearly all ADCs in clinical trials are prepared by randomly conjugating drugs to lysine or cysteine residues in the antibody, affording a heterogeneous ADC mixture. Site-specific conjugation is a major recent improvement to ADC development, yielding homogeneous ADCs with greatly improved therapeutic index. Among the 60+ ADCs currently in clinical development, nearly 50 of them use auristatin and maytansine, the two payloads used in Adcetris® or Kadcyla®, respectively, with the rest using one of only five other drugs. The ADC field is in critical need of new, highly potent, and rapidly acting cytotoxic payloads that are active in many tumor types. We propose in this application to develop new enediyne-based site-specific ADCs for cancer therapy. Specifically, we will focus on tiancimycins (TNMs), which we recently discovered as novel members of the enediyne family of natural products. Our hypotheses are: (i) TNMs are outstanding ADC payload candidates owing to their exquisite potency and validated mode of action, (ii) genetic manipulation of TNM biosynthesis provides outstanding opportunities to produce the most promising TNM analogues to develop the linker chemistry and facilitate site-specific conjugation, (iii) site-specific conjugation of TNMs to engineered thiomabs and selenomabs will generate homogeneous ADCs with defined drug-to-antibody ratios (DARs), and (iv) complementary targeting of HER2 and ROR1 will help evaluate the novel enediyne-based ADCs against current benchmarks and improve therapeutic outcomes for breast cancer patients. The specific aims for this grant are: (i) manipulation of TNM biosynthesis in Streptomyces sp. CB03234 to produce the most promising TNMs for site-specific conjugation, (ii) production and purification of anti-HER2 and anti-ROR1 thiomabs and selenomabs with 2 engineered cysteine (Cys) and 2 or 1 engineered selenocysteine (Sec) residues, respectively, (iii) development of linker chemistry for site-specific conjugation and delivery of a panel of anti- HER2 and anti-ROR1 thiomab-TNM and selenomab-TNM conjugates, and (iv) evaluation of selectivity and potency of the anti-HER2 and anti-ROR1 thiomab-TNM and selenomab-TNM conjugates against HER2+ and HER2−/ROR1+ breast cancers in both in vitro and in vivo models. The outcomes of this application include (i) fundamental contributions to ADCs and (ii) a panel of anti-HER2 and anti-ROR1 thiomab-TNM and selenomab- TNM conjugates as next-generation ADC therapeutics for cancers. The long-term goal of our research is to discover novel microbial natural products and harness their exquisite cytotoxicity as ADC payloads for anticancer drug discovery.

FDA 批准的两种抗体药物偶联物 (ADC)（Adcetris® 和 Kadcyla®）以及几乎所有 ADC 临床试验是通过将药物随机缀合到抗体中的赖氨酸或半胱氨酸残基来准备的，提供异质 ADC 混合物是 ADC 最近的一项重大改进。开发，产生同质 ADC，在 60 多个 ADC 中显着提高了治疗指数。目前正在临床开发中，其中近 50 个使用 auristatin 和 maytansine，这两种有效载荷用于分别是 Adcetris® 或 Kadcyla®，其余仅使用其他五种药物中的一种。 ADC 领域至关重要。需要在许多肿瘤类型中具有活性的新型、高效且快速起效的细胞毒性有效负载。特别建议，我们将重点关注天赐霉素 (TNM)，我们最近发现它是烯二炔家族的新成员我们的假设是：(i) TNM 因其出色的 ADC 有效负载候选者而闻名。精致的效力和经过验证的作用模式，(ii) TNM 生物合成的基因操作提供了生产最有前途的 TNM 类似物以开发连接化学的绝佳机会促进位点特异性缀合，(iii) TNM 与工程 thiomab 的位点特异性缀合，以及 Selenomab 将产生具有确定的药物与抗体比率 (DAR) 的同质 ADC，以及 (iv) HER2 和 ROR1 的互补靶向将有助于评估新型基于烯二炔的 ADC 当前的基准并改善乳腺癌患者的治疗结果。资助的内容是：(i) 操纵链霉菌 CB03234 中的 TNM 生物合成，以产生最有前途的药物。用于位点特异性缀合的 TNM，(ii) 抗 HER2 和抗 ROR1 thiomab 的生产和纯化，以及具有 2 个工程化半胱氨酸 (Cys) 和 2 或 1 个工程化硒代半胱氨酸 (Sec) 残基的硒化抗体，分别，（iii）开发用于位点特异性缀合和递送一组抗- HER2 和抗 ROR1 thiomab-TNM 和 Selenomab-TNM 缀合物，以及 (iv) 选择性和抗 HER2 和抗 ROR1 thiomab-TNM 和 Selenomab-TNM 缀合物针对 HER2+ 和体外和体内模型中的 HER2−/ROR1+ 乳腺癌的结果包括 (i) 对 ADC 的基本贡献以及 (ii) 一组抗 HER2 和抗 ROR1 thiomab-TNM 和 Selenomab- TNM 结合物作为下一代癌症 ADC 疗法我们研究的长期目标是发现新型微生物天然产物并利用其精致的细胞毒性作为 ADC 有效负载抗癌药物的发现。