Development of Human Asparaginase for Cancer Therapy

用于癌症治疗的人天冬酰胺酶的开发

• 批准号: 9344830
• 负责人: ARNON LAVIE
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 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 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9344830
• 关键词: Acute Lymphocytic Leukemia; Address; Adult; Adult Acute Lymphocytic Leukemia; Adverse effects; Antineoplastic Agents; Asparagine; Biological Markers; CRISPR/Cas technology; Cancer Patient; Cancer cell line; Cavia; Cell Culture Techniques; Childhood; Childhood Acute Lymphocytic Leukemia; Clinic; Clinical; Companions; Development; Disease; Distant; Drug Kinetics; Drug usage; Engineering; Enzymes; Exhibits; FDA approved; Funding; Genes; Genetic Screening; Glutaminase; Glutamine; Goals; Hematopoietic Neoplasms; Homologous Gene; Human; Image; Immunologics; Malignant Neoplasms; Medicine; Methods; Molecular; Molecular Profiling; Mus; Nature; Patients; Pharmaceutical Preparations; Pharmacodynamics; Population; Preparation; Property; Regimen; Research; Resistance; Safety; Sampling; Side; Solid Neoplasm; Source; Technology; Testing; Toxic effect; Treatment outcome; Variant; Veterans; Vision; Work; Xenograft Model; asparaginase; cancer cell; cancer therapy; cell killing; clinical efficacy; design; efficacy study; experimental study; immunogenic; immunogenicity; improved; in vivo; individualized medicine; killings; leukemia treatment; novel; novel therapeutics; patient population; patient subsets; personalized medicine; pre-clinical; predicting response; predictive marker; premature; prevent; response; response biomarker; success; tool

Project Summary: This application will address the unmet need for superior treatment outcomes for adults with acute lymphoblastic leukemia (ALL), and will develop the tools needed for personalized treatment to allow a more expanded use of the unique anti-cancer drug called L-asparaginase. Unlike pediatric ALL, a disease with a cure rate of >90%, the cure rate of adult ALL is <40%. One significant difference between the treatment of pediatric and adult ALL patients is that only the pediatric regimen always includes the drug L-asparaginase. Indeed, it was shown that cure rates are highly dependent on using this drug, and for the patient being able to complete the full course of treatment. Unfortunately, the side effects of L-asparaginase treatment often require prematurely stopping use of this drug. These L-asparaginase side effects can be traced directly to the bacterial origin and properties of all current FDA-approved L-asparaginases (and not to the anti-cancer asparagine depletion effect of drug). Being bacterial enzymes, currently approved drugs are highly immunogenic. Although a portion of this clinical problem has recently been addressed by pegylating the enzyme, the other source of side effects, the L- glutaminase co-activity of these bacterial enzymes, still remains. We propose a strategy that would address both the immunogenic and L-glutaminase-related side effects, in which the bacterial enzymes are replaced by human-like L-asparaginases that are devoid of L-glutaminase co-activity. The more similar a biologic is to a human sequence, the less likely it would be immunogenic. In our work to date, we identified a mammalian L-asparaginase (referred to as gpASNas1) that is 70% identical to the human enzyme (as compared to the mere 25% identity of the bacterial enzymes), and we have increased that percentage identity to 85% by employing a genetic screen and structural information. In our proposed work here, we have identified a path that will increase this percent identity to >95%. As importantly, gpASNase1 is devoid of the toxicity-causing L-glutaminase activity, so as a drug, it will also lack those side effects that are caused by glutamine depletion. Critically, in a mouse xenograft model of human T-ALL and B-ALL, we observed a potent anti-cancer effect of these human-like L-asparaginase drugs, which serves to demonstrate that the L-glutaminase activity is not required for killing the cancer cells. Moreover, as compared to the L- glutaminase containing FDA drug, our L-asparaginase version without this co-activity has exhibited reduced toxicity. Thus, the L-asparaginase variant that will be developed by the proposed work will have a high impact on ALL therapy, especially for adults, and thus with special relevance for veterans. In addition to impacting ALL treatment, our vision is to expand the use of L-asparaginases to other malignancies. A main factor that currently prevents the expanded use of L-asparaginases (in addition to aforementioned side effects that will be largely reduced by our variants) is the lack of a method to identity patients who would most benefit from this drug. To remedy this deficiency and to promote personalizing medicine, we will first identify the factors that determine whether a cancer cell is sensitive or resistant to L- asparaginase, and then use this understanding to develop a predictive screen for L-asparaginase. Success in the proposed work will be transformative, as it will expand the use of L-asparaginases beyond ALL to other blood cancers, through the combination of a drug that is safer (by being less immunogenic and by lacking L-glutaminase co-activity) with a companion biomarker that can predict a patient's response to this drug.

项目概要： 该应用程序将解决成人急性期患者对优质治疗结果的未满足需求 淋巴细胞白血病（ALL），并将开发个性化治疗所需的工具，以允许更多 扩大使用独特的抗癌药物 L-天冬酰胺酶。与儿科 ALL 不同，这种疾病具有 治愈率>90%，成人ALL治愈率<40%。治疗上的一个显着差异 儿童和成人 ALL 患者的主要区别在于，只有儿童治疗方案始终包含 L-天冬酰胺酶药物。 事实上，研究表明治愈率高度依赖于使用这种药物，并且患者能够 完成整个疗程。不幸的是，L-天冬酰胺酶治疗的副作用通常需要 提前停止使用这种药物。 这些 L-天冬酰胺酶的副作用可以直接追溯到细菌起源和当前所有细菌的特性。 FDA批准的L-天冬酰胺酶（并且不具有抗癌天冬酰胺消耗作用的药物）。存在 细菌酶，目前批准的药物具有高度免疫原性。虽然本临床研究的一部分 最近通过对酶进行聚乙二醇化解决了这个问题，这是副作用的另一个来源，L- 这些细菌酶的谷氨酰胺酶协同活性仍然存在。我们提出一项战略来解决 免疫原性和 L-谷氨酰胺酶相关的副作用，其中细菌酶被替换为 缺乏 L-谷氨酰胺酶共活性的类人 L-天冬酰胺酶。 生物制品与人类序列越相似，其具有免疫原性的可能性就越小。在我们的工作中 迄今为止，我们鉴定出了一种与人类 70% 相同的哺乳动物 L-天冬酰胺酶（称为 gpASNas1） 酶（与细菌酶只有 25% 的同一性相比），并且我们增加了 通过采用遗传筛选和结构信息，同一性百分比达到 85%。在我们提出的工作中 在这里，我们已经确定了一条途径，可以将同一性百分比提高到 > 95%。同样重要的是，gpASNase1 是 缺乏引起毒性的L-谷氨酰胺酶活性，因此作为药物，它也不会产生那些副作用 由谷氨酰胺缺乏引起。至关重要的是，在人类 T-ALL 和 B-ALL 的小鼠异种移植模型中，我们 观察到这些类人 L-天冬酰胺酶药物具有有效的抗癌作用，这证明了 L-谷氨酰胺酶活性并不是杀死癌细胞所必需的。此外，与L- 含有谷氨酰胺酶的 FDA 药物，我们的 L-天冬酰胺酶版本没有这种协同活性，表现出降低 毒性。因此，拟议工作将开发的 L-天冬酰胺酶变体将产生巨大影响 ALL 治疗，尤其是成人，因此与退伍军人特别相关。 除了影响 ALL 治疗之外，我们的愿景是将 L-天冬酰胺酶的使用扩展到其他领域 恶性肿瘤。目前阻碍L-天冬酰胺酶扩大使用的一个主要因素（除了 上述副作用将通过我们的变体大大减少）是缺乏识别方法 最能从该药物中受益的患者。为了弥补这一缺陷并促进个性化 医学上，我们首先要确定决定癌细胞对L-敏感还是耐药的因素 天冬酰胺酶，然后利用这一认识来开发 L-天冬酰胺酶的预测筛选。 拟议工作的成功将具有变革性，因为它将扩大 L-天冬酰胺酶的使用范围，使其超越所有疾病 与其他血癌相比，通过结合更安全的药物（通过免疫原性较低和通过 缺乏 L-谷氨酰胺酶协同活性）与可以预测患者对该药物反应的伴随生物标志物。