Pharmacological and toxicological testing of a novel L-asparaginase

新型L-天冬酰胺酶的药理和毒理测试

基本信息

批准号：
10454879
负责人：
ARNON LAVIE
金额：
--
依托单位：
JESSE BROWN VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10454879
关键词：
Acute Lymphocytic Leukemia Acute Myelocytic Leukemia Address Adult Adult Acute Lymphocytic Leukemia Affect Amino Acids Antineoplastic Agents Apoptosis Asparagine Biological Blood Blood Circulation C-terminal Cancer Patient Canis familiaris Catalytic Domain Cavia Cells Childhood Acute Lymphocytic Leukemia Clinic Clinical Clinical Data Crystallization Data Disease Drug Kinetics Drug usage Enzymes Escherichia coli Exhibits FDA approved Glutaminase Glutamine Goals Hematologic Neoplasms Homologous Gene Human Hydrolysis Immune system Immunologics Investigational Drugs Investigational New Drug Application Kinetics Lead Legal patent Leukocytes Life Malignant Neoplasms Malignant neoplasm of pancreas Mus Pancreas Patients Pectobacterium chrysanthemi Pegaspargase Pharmaceutical Preparations Pharmacology and Toxicology Property Protocols documentation Publishing Rattus Reaction Reporting Risk Safety Side Site Solid Solid Neoplasm Source Structure Testing Therapeutic Time Toxic effect Variant Work acute lymphoblastic leukemia cell anti-cancer asparaginase base cell killing clinical efficacy drug development drug efficacy experimental study humanized mouse immunogenic immunogenicity improved in vivo leukemia treatment mortality mouse model neoplastic cell novel novel therapeutics pancreatic cancer patients patient population pre-clinical preclinical efficacy preclinical study preclinical toxicity prevent reconstitution side effect standard of care success

项目摘要

Project Summary: The goal of this proposal is to perform IND-enabling studies of a significantly safer variant of the anti-cancer biologic drug L-asparaginase. L-asparaginases are enzyme drugs that act to deplete the amino acid asparagine from the blood. Due to toxicity, which is especially pronounced in adults, L- asparaginase treatment is limited to acute lymphoblastic leukemia (ALL), a cancer of white blood cells. One source of toxicity of L-asparaginases is due to their bacterial origin (either from E. coli (Elspar) or Erwinia chrysanthemi (Erwinaze)), making the naked drugs highly immunogenic. The current standard of care is a PEGylated version of Elspar called Oncaspar. While PEGylation reduces, but does not eliminate the immunological challenge of using these drugs, the other toxicity-causing factor remains - this being their L- glutaminase coactivity. Therefore, Oncaspar is limited to ALL, where even its use to treat adult ALL patients is highly limited. Of note, L-asparaginase-associated side effects prevent the use of this unique cancer drug in other hematological malignancies (e.g. acute myeloid leukemia) and in solid tumors (e.g. pancreatic cancer), despite strong evidence that L-asparaginases would be effective in treating those cancers. Hence, there is a clear unmet need for an L-asparaginase with reduced immunogenicity and that lacks L-glutaminase coactivity. Recently, we characterized a guinea pig L-asparaginase (GpA) that possesses the required low KM property for clinical efficacy and that exhibits in vivo tumor cell-killing. Notably, we also discovered that GpA is devoid of the toxicity-causing L-glutaminase co-activity. With ~70% sequence identity to human L- asparaginase, GpA should be less immunogenic compared to the bacterial enzymes that share only ~25% sequence identity with the human enzyme. We recently identified the lead biologic GpA369 which is a stable and active C-terminal truncation of GpA comprising the catalytic domain. Here we will perform the required studies required to bring this novel enzyme drug to patients. In Aim 1 we will increase its sequence identity to the human homolog using a structure-guided approach and identify the optimal PEGylation strategy. Aim 2 will determine the pharmacokinetic properties of the top 3 optimized leads from Aim 1, as well as confirm their anti- cancer efficacy in a human ALL mouse model. In Aim 3, the top variant (optimal combination of PK and anti- cancer efficacy) will proceed to toxicity studies, first in mice, followed by more extensive studies in rats and dogs. Finally, Aim 4 will evaluate the immunogenicity of our enzyme drug in a novel mouse model that has a reconstituted human immune system, and compare our drug to Oncaspar. Together, these studies will bring us to the cusp of submitting an IND application for testing this novel L-asparaginase in patients. Impact is predicted to extend beyond ALL, since the improved safety profile of our L-asparaginase variant would enable its use in multiple cancers for which effective options are sorely lacking and which strong data suggests that an L-asparaginase drug would be effective but is not used due to the unacceptable toxicity profile of current L- asparaginase options.

项目摘要：该提案的目的是对更安全的变体进行辅助研究抗癌生物药物L-天冬酰胺酶L-天冬酰胺酶是作用于耗尽的酶药物血液中的氨基酸天冬酰胺。由于毒性，在成年人中特别明显，l- 天冬酰胺酶处理仅限于急性淋巴细胞白血病（ALL），白细胞癌。一 L-天冬酰胺酶的毒性来源是由于其细菌起源（来自大肠杆菌（Elspar）或Erwinia 菊花（Erwinaze），使裸药具有高度免疫原性。当前的护理标准是 Elspar的PegyPation版本称为Oncaspar。而耶和华却减少了，但没有消除使用这些药物的免疫学挑战，另一个引起毒性的因素仍然存在 - 这是他们的L- 谷氨酰胺酶的共同。因此，Oncaspar仅限于所有人，即使是治疗成人所有患者高度有限。值得注意的是，L-天冬酰胺酶相关的副作用阻止了这种独特的癌症药物在其他血液恶性肿瘤（例如急性髓样白血病）和实体瘤（例如胰腺癌），尽管有强有力的证据表明L-天冬酰胺酶将有效地治疗这些癌症。因此，有一个对具有降低免疫原性的L-天冬酰胺酶的明确需求，并且缺乏L-谷氨酰胺酶相抗性。最近，我们表征了具有所需低的豚鼠L-天冬酰胺酶（GPA） KM临床功效的特性，并在体内肿瘤细胞中表现出。值得注意的是，我们还发现GPA 没有引起毒性的L-谷氨酰胺酶共同活性。对人L-具有约70％的序列身份与只有〜25％的细菌酶相比，天冬酰胺酶的免疫原性应较低与人酶的序列同一性。我们最近确定了铅生物GPA369，这是一个稳定的以及包括催化域的GPA的主动C末端截断。在这里，我们将执行所需的需要将这种新型酶药物带给患者所需的研究。在AIM 1中，我们将将其序列身份提高到使用结构引导的方法的人类同源物并确定最佳的同性恋策略。 AIM 2意志确定来自AIM 1的前3个优化导线的药代动力学特性，并确认其抗人类所有小鼠模型中的癌症功效。在AIM 3中，顶级变体（PK和抗 - 的最佳组合癌症功效）将继续进行毒性研究，首先在小鼠中进行，然后在大鼠和狗。最后，AIM 4将在具有新型小鼠模型中评估我们的酶药物的免疫原性重构人类免疫系统，并将我们的药物与Oncaspar进行比较。这些研究将带给我们提交IND应用程序以测试患者中这种新型L-天冬酰胺酶的尖端。影响是预计将超出所有内容，因为我们的L-天冬酰胺酶变体的安全性提高将启用它在多种癌症中的使用，这些癌症严重缺乏有效的选择，哪些强大的数据表明 L-天冬酰胺酶药物将是有效的，但由于电流L-的不可接受的毒性特征而未使用天冬氨酸酶选项。