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

项目摘要/摘要 尤文肉瘤(Ewing Saroma，ES)是儿童第二常见的骨癌，发病率最高的是 青春期和青壮年时期。ES是一种极具侵袭性的恶性肿瘤，目前的治疗方法 方案依赖于化疗、放射治疗和/或手术的组合方法。65%-75%的ES 患者可以用目前的治疗策略治愈，但有遭受明显全身副作用的风险。 效果。这些包括细胞毒性化疗引起的免疫抑制继发感染的高风险 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，必须开发更精确、更有效的治疗方法，以最大限度地 患者预后，同时将破坏性副作用降至最低。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来对抗骨癌细胞的策略 和贝勒医学院。这项提议的总体目标是发展骨靶向精确度。 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 使用创新的遗传密码扩展技术生成ES的骨靶向抗体 最新的先驱者。双膦酸盐是一类带负电荷的分子，能够选择性地与 矿化的带正电的骨基质。双膦酸类与抗体的定点结合将 将高浓度的治疗性抗体输送到骨骼，并在酸性肿瘤内激活 提供更好的治疗效果和减少与全身相关的不良副作用的微环境 送货。为了证明这些骨靶向抗体在治疗中的增强治疗效果 我们将使用ES细胞或患者来源的异种移植来研究它们对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 展示他们对尤文肉瘤的增强治疗方案。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输送到骨骼微环境将提供 治疗不同骨相关原发和转移性恶性肿瘤的有希望的途径。

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.