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

项目概要/摘要 尤文肉瘤（ES）是第二常见的儿科骨癌，发病率在20世纪达到高峰。 青春期和青年期。ES是目前治疗中一种极具侵袭性的恶性肿瘤 在一些实施方案中，化疗是依赖于化疗、放疗和/或手术的组合方法的治疗方案。ES的65%-75% 患者可以治愈与目前的治疗策略，但在遭受显着的全身性副作用的风险， 方面的影响.这些包括继发于细胞毒性化疗的免疫抑制的感染的高风险， 长期影响，可能导致严重的心脏，学习缺陷，生殖能力，甚至第二次 恶性肿瘤因此，有必要开发更精确、有效的治疗方法，以最大限度地 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， 和贝勒医学院该提案的总体目标是开发骨靶向精度 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 利用我们拥有的创新遗传密码扩展技术， 最近开创的。双膦酸盐是一类能够选择性结合至 矿化带正电荷的骨基质双膦酸盐与抗体的位点特异性缀合将 将高浓度的治疗性抗体递送到骨并在酸性肿瘤内活化 微环境，以获得更好的治疗效果，并减少与全身性疾病相关的不良副作用 交付.为了证明这些骨靶向抗体用于治疗的增强的治疗特征， 我们将使用ES细胞或患者来源的异种移植物研究它们对ES存活和进展的影响， 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， 证明了它们对尤文肉瘤的增强治疗作用。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一种有效的治疗方法。 这是治疗不同骨相关原发性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.