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

描述(申请人提供)：用于放射增敏和癌症治疗的细胞穿透性抗DNA抗体。发现一种对癌细胞有选择性毒性或使肿瘤对放射或化疗敏感的新型治疗剂将是癌症研究的重要进展。我们发现，在细胞培养和体内肿瘤模型中，穿透细胞的抗DNA抗体(3E10)可以增加癌细胞对电离辐射和DNA靶向化疗药物的敏感性。初步研究表明，3E10通过阻断DNA修复发挥作用。3E10是从系统性红斑狼疮的小鼠模型中提取出来的，用于治疗人类的系统性红斑狼疮。重要的是，3E10单抗本身对BRCA2缺陷的癌细胞是合成致死的，但在其他方面对培养中的DNA修复熟练细胞或对 小鼠在活体内。在狼疮患者的I期试验中，该抗体在人体内也没有显示出可检测到的毒性。在初步工作中，3E10被发现大大增强了 在BRCA2缺乏的细胞中使用低剂量阿霉素，但在BRCA2熟练的细胞中不使用，提供了很大的治疗收益。我们认为3E10抗体在临床上可能是一种有效的治疗剂，我们假设它将对DNA修复缺陷的癌症特别有效，包括某些乳腺癌、卵巢癌、胰腺癌和脑癌。3E10穿透细胞和细胞核的能力使其有别于目前被批准用于癌症治疗的所有其他抗体；因此，3E10潜在地代表了一类新的癌症治疗药物。我们将通过细胞实验和体外实验探讨3E10对特定DNA修复途径的影响，从而探讨其作用机制。我们将定义3E10在DNA修复缺陷的癌细胞中潜在的合成致命相互作用，并将研究3E10与放射和其他癌症治疗相结合的效果。这些努力将使我们能够识别可能特别容易受到3E10感染的癌症，并将为设计优化的联合疗法提供基础，以实现治疗收益。我们还将使用人肿瘤异种移植瘤和原位肿瘤模型，在小鼠体内测试3E10单独和联合使用对肿瘤的有效性。还将进行体内试验，以评估正常的组织效应。这项工作将提供关键数据，以支持3E10在癌症治疗中的应用，确定获得治疗收益的机会，并确定最初有效的使用方法。由于3E10此前已被FDA批准用于狼疮的I期试验，因此已经有了开发这种药物用于临床的既定途径，但这一次是用于癌症治疗。因此，我们认为，拟议的工作具有非常高的潜力转化为临床，因此可能对人类健康产生直接和实质性的影响。

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.