Extending the in vivo half-life of a novel engineered mammalian asparaginase via its binding to human serum albumin

通过与人血清白蛋白的结合延长新型工程哺乳动物天冬酰胺酶的体内半衰期

基本信息

批准号：
10075744
负责人：
Amanda M Schalk
金额：
$ 40万
依托单位：
ENZYME BY DESIGN, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10075744
关键词：
Acute Acute Lymphocytic Leukemia Acute Myelocytic Leukemia Adoption Adult Adult Acute Lymphocytic Leukemia Affinity Albumins Amino Acids Amylases Antibodies Asparagine Bilirubin Binding Biological Blood Blood Chemical Analysis Blood Circulation Blood Circulation Time Body Weight Changes Bone Marrow Breast Cavia Cell Line Cells Childhood Acute Lymphocytic Leukemia Chimera organism Clinic Clinical Clinical Data Clinical Trials Data Data Reporting Distant Dose Drug Kinetics Drug Targeting Drug toxicity Drug usage Engineering Enzymes Erwinia Escherichia coli Eye FDA approved Fatty acid glycerol esters Feedback Formulation Frequencies Glutaminase Half-Life Hematologic Neoplasms Histology Histopathology Homologous Gene Hospitals Human Immunologics Laboratories Lead Liver Malignant Neoplasms Measurable Modeling Mus Myelogenous Ovarian PTPRC gene Pancreas Patients Pegaspargase Pharmaceutical Preparations Phase Plasma Proteins Posture Process Production Property Recurrence Renal function Rivers Safety Serum Albumin Signal Transduction Solid Neoplasm Spleen Stains Technology The Jackson Laboratory Time TimeLine Toxic effect Toxicology Treatment Efficacy Urea Nitrogen Vacuole Variant Xenograft Model Xenograft procedure asparaginase base bioluminescence imaging clinical application clinical efficacy clinical practice clinically relevant commercialization cost design efficacy study head-to-head comparison immunogenic immunogenicity in vivo novel pediatric patients peripheral blood phase 1 study prevent side effect standard of care stem therapeutic candidate triple-negative invasive breast carcinoma

项目摘要

PROJECT SUMMARY: Enzyme by Design (EbD) is developing a safer L-asparaginase (ASNase) to maximize the potential clinical applications of this unique drug. ASNases are enzyme drugs that systematically deplete L- asparagine from the blood. In the US, the 1st-line ASNase is Oncaspar, a PEGylated version of the E. coli ASNase (EcA). Patients intolerant of Oncaspar switch to the naked Erwinia ASNase (ErA, Erwinaze). Despite being key drugs in pediatric acute lymphoblastic leukemia (ALL), the side effects of current FDA-approved ASNases are so pronounced in adults that their use is largely avoided. These side effects also prevent the use of ASNases in other hematological malignancies (e.g. acute myeloid leukemia) and in solid tumors (e.g. pancreatic, ovarian or triple-negative breast cancers), despite strong evidence that ASNases would be effective in treating those cancers. Side effects of EcA/ErA stem from i) their immunogenicity, due to their bacterial origin and ii) their L-glutaminase co-activity. To expand the use of this drug to adult ALL patients and to other indications, there is a need for an ASNase with (i) reduced immunogenicity, (ii) lack of L-glutaminase co- activity, combined with (iii) long in vivo persistence. To mitigate the immunogenicity, EbD is developing the first mammalian ASNase. In sharp contrast to the bacterial EcA/ErA, which are very distant from the human homolog, EbD is developing the guinea pig ASNase (GpA), which is much closer in identity to the human ASNase. Moreover, by following a humanization process, EbD increased GpA’s % sequence identity to the human homolog. Together, this humanized enzyme, referred to as GpAhum, is predicted to be much less immunogenic compared to the bacterial ASNases. An added advantage of this enzyme is that it is intrinsically GLNase-free, thereby reducing off-target drug toxicity. We have extensive data that shows strong in vivo anti-ALL potency of GpAhum with little toxicity. However, the half-life (t1/2) of GpAhum is not optimal for clinical use. Whereas PEGylation offers one solution for increasing the t1/2, as seen in Oncaspar, recent clinical data reporting anti-PEG antibodies in patients previously treated with Oncaspar made it clear that PEGylation is not a viable path to the clinic for any new ASNase. Therefore, to achieve an increased t1/2, we pivoted to human serum albumin (HSA)-binding technology via fusing our ASNase to an immunologically neutral human serum albumin binding domain (ABD). The product, ABD-GpAhum, more than doubled the parental GpAhum’s blood circulation time with excellent HSA binding affinity. In vivo efficacy in mouse xenograft models confirms its superior potency: 1 dose of ABD-GpAhum is equivalent to 3 doses of GpAhum, allowing similar therapeutic efficacy with reduced dosing frequency and total amount of drug injected. This predicts less accumulated toxicity in patients, lowered drug-related therapy cost and ease of use for hospital-related staffs. This proposal will further evaluate the anti-ALL efficacy of ABD-GpAhum and supply proof-of-concept toxicity data to confirm that ABD-GpAhum is indeed a viable, safe and competitive therapeutic candidate, thus providing the rationale for advancing it through IND-enabling studies.

项目摘要：Enzyme by Design (EbD) 正在开发一种更安全的 L-天冬酰胺酶 (ASNase)，以最大限度地提高这种独特药物的潜在临床应用是系统性消耗 L- 的酶药物。在美国，第一线 ASNase 是 Oncaspar，它是大肠杆菌的聚乙二醇化版本。 ASNase (EcA)。尽管如此，不耐受 Oncaspar 的患者转而使用裸欧文氏菌 ASNase (ErA、Erwinaze)。作为小儿急性淋巴细胞白血病 (ALL) 的关键药物，目前 FDA 批准的副作用 ASNase 在成人中非常明显，因此在很大程度上避免使用它们，这些副作用也阻碍了其使用。其他血液恶性肿瘤（例如急性髓性白血病）和实体瘤（例如骨髓瘤）中 ASNase 的作用胰腺癌、卵巢癌或三阴性乳腺癌），尽管有强有力的证据表明 ASNase 有效在治疗这些癌症时，EcA/ErA 的副作用源于 i) 由于其细菌而具有免疫原性。起源和 ii) 它们的 L-谷氨酰胺酶共同活性将这种药物的用途扩大到成人 ALL 患者和其他患者。适应症，需要一种具有以下特征的 ASNase：(i) 免疫原性降低，(ii) 缺乏 L-谷氨酰胺酶辅酶活性，与 (iii) 体内持久性相结合，为了减轻免疫原性，EbD 正在开发第一个哺乳动物的 ASNase 与细菌 EcA/ErA 形成鲜明对比，后者与人类相距甚远。同源物，EbD 正在开发豚鼠 ASNase (GpA)，它与人类 ASNase 的特性更加接近。此外，通过遵循人源化过程，EbD 增加了 GpA 与人类的序列同一性百分比总之，这种被称为 GpAhum 的人源化酶的免疫原性预计要低得多。与细菌 ASNase 相比，这种酶的另一个优点是它本质上不含 GLNase，我们有大量数据表明，其具有强大的体内抗 ALL 功效。 GpAhum 毒性很小，但 GpAhum 的半衰期 (t1/2) 并不适合临床使用。提供了一种增加 t1/2 的解决方案，如 Oncaspar 中所示，最近报告抗 PEG 抗体的临床数据先前接受过 Oncaspar 治疗的患者的研究表明，聚乙二醇化并不是进入临床的可行途径因此，为了提高 t1/2，我们转向人血清白蛋白 (HSA) 结合。通过将我们的 ASNase 与免疫中性人血清白蛋白结合域 (ABD) 融合的技术。该产品ABD-GpAhum，具有优异的HSA，使亲本GpAhum的血液循环时间延长了一倍以上小鼠异种移植模型的体内功效证实了其卓越的效力：1 剂 ABD-GpAhum 相当于 3 剂 GpAhum，可实现相似的治疗效果，同时减少给药频率和总剂量这预示着患者体内累积的毒性会减少，从而降低药物相关的治疗成本。该提案将进一步评估 ABD-GpAhum 的抗 ALL 功效。并提供概念验证毒性数据，以确认 ABD-GpAhum 确实是一种可行、安全且具有竞争力的药物治疗候选药物，从而为通过 IND 支持研究推进它提供了理由。