Development of Bone-Targeting Antibodies for Ewing Sarcoma Using Genetic Code Expansion

利用遗传密码扩展开发针对尤文肉瘤的骨靶向抗体

• 批准号: 10383663
• 负责人: Han Xiao
• 金额: $ 17.15万
• 依托单位: RICE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-05 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10383663
• 关键词: Adolescent and Young Adult; Adopted; Affinity; Alternative Therapies; Animal Model; Antibodies; Antibody Therapy; Antineoplastic Agents; Apoptosis; Binding; Biological Products; Biology; Bone Development; Bone Diseases; Bone Matrix; Breast Cancer Treatment; Cancer Patient; Cardiac; Cells; Charge; Chemicals; Childhood; Clinic; Collaborations; Collection; Combination Drug Therapy; Cytotoxic Chemotherapy; Data; Development; Diagnosis; Drug Kinetics; Environment; Ewings sarcoma; Exhibits; Generations; Genetic Code; Glycoproteins; Goals; Hydroxyapatites; Immunosuppression; Incidence; Injections; Lead; Learning; Life; Long-Term Effects; Malignant Bone Neoplasm; Malignant Childhood Neoplasm; Malignant Neoplasms; Medical; Medicine; Metastatic Neoplasm to the Bone; Minerals; Mission; Modeling; Modification; Operative Surgical Procedures; Osteoclasts; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Population; Pre-Clinical Model; Precision therapeutics; Preparation; Quality of life; Radiation therapy; Regimen; Relapse; Reporting; Research; Resistance; Rice; Risk; Salvage Therapy; Second Primary Cancers; Second Primary Neoplasms; Secondary to; Site; Technology; Testing; Therapeutic; Therapeutic antibodies; Tissues; Treatment Efficacy; Treatment Protocols; Treatment Side Effects; United States National Institutes of Health; Universities; Xenograft procedure; antibody conjugate; base; bisphosphonate; bone; cancer cell; chemotherapy; college; combinatorial; design; dosage; high risk; improved; improved outcome; in vitro Assay; in vivo; in vivo Model; in vivo evaluation; innovation; innovative technologies; malignant breast neoplasm; mortality; novel; novel therapeutic intervention; patient derived xenograft model; reproductive; sarcoma; scaffold; secondary infection; side effect; success; targeted treatment; therapeutically effective; treatment strategy; tumor; tumor microenvironment

PROJECT SUMMARY/ABSTRACT Ewing sarcoma (ES) is the second most common pediatric bone cancer with peak incidence during the adolescent and young adult period. ES is an extremely aggressive malignancy with the current treatment regimen relying on a combinatorial approach of chemotherapy, radiotherapy, and/or surgery. 65%-75% of ES patients can be cured with the current treatment strategies, but at a risk of suffering signficant systemic side effects. These include high risks for infection secondary to immunosuppression from cytotoxic chemotherapy to long term effects that can lead to serious cardiac, learning deficits, reproductive capabilities and even second malignancies. Therefore, it is essential to develop more precise, effective therapeutic approaches to maximize patient outcomes while minimizing devastating side effects. Our long-term goals are to design new therapeutic strategies against bone cancer cells through a synergistic collaborative effort between labs at Rice University and the Baylor College of Medicine. The overall goal of this proposal is to develop bone-targeting precision therapeutic biologics for the treatment of ES. To achieve this goal, the first research direction will focus on the generation of bone-targeting antibodies for ES using an innovative genetic code expansion technology we have recently pioneered. Bisphosphonates are a class of negatively charged molecules able to selectively bind to mineralized, positively charged bone matrix. Site-specific conjugation of bisphosphonates to antibodies will deliver a high concentration of therapeutic antibodies to the bone and activated within the acidic tumor microenvironment for better therapeutic efficacy and reduce adverse side effects associated with systemic delivery. To demonstrate the enhanced therapeutic profile of these bone-targeting antibodies for the treatment of ES, we will study their effects on the survival and progression of ES using ES cells or patient-derived xenograft- derived primary ES cells. Our efforts in this project will yield a collection of bone-targeting antibodies and demonstrate their enhanced therapeutic profile on Ewing sarcoma. Considering the growing success of antibody therapy in the clinic, selective delivery of therapeutic antibodies to the bone microenvironment will provide a promising avenue for different bone-associated primary and metastatic malignancies.

项目概要/摘要 尤文肉瘤 (ES) 是第二常见的儿童骨癌，发病率高峰期为 青春期和青年时期。根据目前的治疗方法，ES 是一种极具侵袭性的恶性肿瘤 依赖于化疗、放疗和/或手术的组合方法的治疗方案。 ES 的 65%-75% 患者可以通过当前的治疗策略治愈，但有遭受严重全身副作用的风险 影响。这些包括继发于细胞毒性化疗和免疫抑制的高感染风险。 长期影响可能导致严重的心脏、学习障碍、生殖能力甚至第二 恶性肿瘤。因此，有必要开发更精确、更有效的治疗方法，以最大限度地发挥作用。 患者的治疗效果，同时最大限度地减少毁灭性的副作用。我们的长期目标是设计新的治疗方法 通过莱斯大学实验室之间的协同合作，制定针对骨癌细胞的策略 和贝勒医学院。该提案的总体目标是提高骨靶向精度 用于治疗 ES 的治疗性生物制剂。为了实现这一目标，第一个研究方向将集中在 使用我们拥有的创新遗传密码扩展技术生成 ES 的骨靶向抗体 最近开创了。双膦酸盐是一类带负电荷的分子，能够选择性地结合 矿化的、带正电的骨基质。双膦酸盐与抗体的位点特异性缀合将 将高浓度的治疗抗体输送到骨骼并在酸性肿瘤内激活 微环境可提高治疗效果并减少与全身相关的不良副作用 送货。证明这些骨靶向抗体的增强治疗效果 对于ES，我们将使用ES细胞或患者来源的异种移植物来研究它们对ES存活和进展的影响- 衍生的原代ES细胞。我们在这个项目中的努力将产生一系列骨靶向抗体和 展示其对尤文肉瘤的增强治疗效果。考虑到抗体的日益成功 在临床治疗中，选择性地将治疗性抗体递送至骨微环境将提供 不同骨相关原发性和转移性恶性肿瘤的有希望的途径。