Cell-Penetrating Anti-DNA Antibody for Radiosensitization and Cancer Therapy

用于放射增敏和癌症治疗的细胞穿透性抗 DNA 抗体

• 批准号: 8500076
• 负责人: PETER M GLAZER
• 金额: $ 34.52万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8500076
• 关键词: Anti-DNA Antibodies; Antibodies; Antineoplastic Agents; BRCA2 gene; Basic Science; Biological Assay; Brain; Breast; Breast Cancer Model; CDC2 Protein Kinase; Cancerous; Cell Culture Techniques; Cell Cycle Progression; Cell Nucleus; Cells; Chemosensitization; Clinic; Clinical; Clinical Treatment; Combined Modality Therapy; DNA; DNA Repair; DNA Repair Disorder; DNA Repair Pathway; Data; Disease; Dose; Doxorubicin; Effectiveness; FDA approved; Goals; Health; Human; Hypoxia; Immune; Ionizing radiation; Knowledge; Lupus; Malignant - descriptor; Malignant Neoplasms; Modeling; Monoclonal Antibodies; Mus; Normal tissue morphology; Nude Mice; Ovary; Pancreas; Pathway interactions; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Radiation; Radiosensitization; Systemic Lupus Erythematosus; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Translations; Work; Xenograft procedure; anticancer research; base; cancer cell; cancer therapy; cell killing; chemotherapy; clinical application; design; high throughput screening; in vitro Assay; in vivo; inhibitor/antagonist; mouse model; novel therapeutics; oncology; public health relevance; subcutaneous; time use; tumor; tumor growth; tumor xenograft; validation studies

DESCRIPTION (provided by applicant): Cell-Penetrating Anti-DNA Antibody for Radiosensitization and Cancer Therapy. Identification of a novel therapeutic agent that is selectively toxic to cancer cells or that sensitizes tumors to radiation or chemotherapy would be an important advance in cancer research. We have discovered that a cell- penetrating, anti-DNA antibody (3E10) can increase the sensitivity of cancer cells to ionizing radiation and to DNA-targeted chemotherapy agents both in cell culture and in vivo in mouse tumor models. Preliminary work suggests that 3E10 exerts its effects by blocking DNA repair. 3E10 was derived from a mouse model of systemic lupus erythematosus for treating that disease in humans. Importantly, the 3E10 monoclonal antibody, by itself, is synthetically lethal to BRCA2-deficient cancer cells, but is otherwise non-toxic to DNA repair- proficient cells in culture or to mice in vivo. The antibody also showed no detectable toxicity in humans when tested in a phase I trial in lupus patients. In preliminary work, 3E10 was found to greatly potentiate the effects of low-dose doxorubicin in BRCA2-deficient cells but not in BRCA2-proficient cells, providing a large therapeutic gain. We believe that the 3E10 antibody may be an effective therapeutic agent in the clinic, and we hypothesize that it will be particularly effective against cancers deficient in DNA repair, including certain malignancies of the breast, ovary, pancreas, and brain. The ability of 3E10 to penetrate into cells and nuclei distinguishes it from all other antibodies currently approved for cancer therapy; as such, 3E10 potentially represents a new class of cancer therapy agents. We will investigate the mechanism of action of 3E10 by probing its effects on specific DNA repair pathways via both cell-based and in vitro assays. We will define potential synthetic lethal interactions of 3E10 in DNA repair-deficient cancer cells, and we will study the effects of 3E10 in combination with radiation and other cancer therapies. These efforts will allow us to identify cancers that may be especially vulnerable to 3E10 and will provide the basis for designing optimized combination therapies in order to achieve therapeutic gain. We will also test the effectiveness of 3E10, alone and in combination, against tumors in vivo in mice using human tumor xenografts and orthotopic tumor models. In vivo assays to evaluate normal tissue effects will also be carried out. This work will provide key data to support the utility of 3E10 in cancer therapy, to identify opportunities for therapeutic gain, and to define initial effective means of use. Because 3E10 has previously been approved by the FDA for a phase I trial for treatment of lupus, there is already an established pathway to develop this agent for clinical use, but this time for cancer therapy. Consequently, we believe that the proposed work has a very high potential for translation into the clinic and so could have a direct and substantia impact on human health.

描述（由申请方提供）：用于放射增敏和癌症治疗的细胞穿透性抗DNA抗体。 鉴定一种对癌细胞有选择性毒性或使肿瘤对放射或化学疗法敏感的新型治疗剂将是癌症研究的一个重要进展。我们已经发现，细胞穿透性抗DNA抗体（3E 10）可以在细胞培养物中和在小鼠肿瘤模型中体内增加癌细胞对电离辐射和DNA靶向化疗剂的敏感性。初步研究表明，3E 10通过阻断DNA修复发挥作用。3E 10来源于用于治疗人类疾病的系统性红斑狼疮小鼠模型。重要的是，3E 10单克隆抗体本身对BRCA 2缺陷型癌细胞是合成致死的，但对培养物中的DNA修复能力强的细胞或培养物中的细胞是无毒的。 小鼠体内。在狼疮患者的I期试验中，该抗体在人体中也没有检测到毒性。在初步工作中，发现3E 10大大增强了 低剂量阿霉素在BRCA 2缺陷细胞中，但在BRCA 2熟练细胞中则不然，从而提供了巨大的治疗收益。 我们相信3E 10抗体可能是临床上有效的治疗剂，我们假设它对DNA修复缺陷的癌症特别有效，包括乳腺癌、卵巢癌、胰腺癌和脑癌。3E 10渗透到细胞和细胞核中的能力将其与目前批准用于癌症治疗的所有其他抗体区分开来;因此，3E 10可能代表一类新的癌症治疗剂。 我们将通过基于细胞的和体外试验探索3E 10对特定DNA修复途径的影响，研究3E 10的作用机制。我们将确定3E 10在DNA修复缺陷癌细胞中的潜在合成致死相互作用，并研究3E 10与放射和其他癌症疗法联合使用的效果。这些努力将使我们能够识别可能特别容易受到3E 10影响的癌症，并为设计优化的联合疗法提供基础，以实现治疗增益。我们还将使用人肿瘤异种移植物和原位肿瘤模型测试3E 10单独和组合在小鼠体内抗肿瘤的有效性。还将进行评价正常组织效应的体内试验。这项工作将提供关键数据，以支持3E 10在癌症治疗中的效用，以确定治疗增益的机会，并定义初始有效的使用方法。 由于3E 10此前已被FDA批准用于治疗狼疮的I期试验，因此已经有了一个开发这种药物用于临床的既定途径，但这次是用于癌症治疗。因此，我们认为，拟议的工作有很大的潜力转化为临床，因此可能对人类健康产生直接和实质性的影响。