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

基本信息

批准号：
10600106
负责人：
Han Xiao
金额：
$ 17.15万
依托单位：
RICE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10600106
关键词：
Adolescent and Young Adult Adolescent and young adult cancer patients Adopted Affinity Alternative Therapies Animal Model Antibodies Antibody Therapy Antineoplastic Agents Apoptosis Binding Biological Response Modifier Therapy Biology Bone Development Bone Diseases Bone Matrix Breast Cancer Treatment Cancer Patient Cardiac Cells Charge Chemicals Childhood Clinic Collaborations Collection Combination Drug Therapy Creativeness Cytotoxic Chemotherapy Data Development Diagnosis Drug Kinetics Environment Ewings sarcoma Exhibits Generations Genetic Code Goals Hydroxyapatites Immunosuppression Incidence Injections Learning Life Long-Term Effects Malignant Bone Neoplasm Malignant Childhood Neoplasm Malignant Neoplasms Medical Medicine Membrane Glycoproteins Metastatic Neoplasm to the Bone 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 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 mineralization 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

项目摘要

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.

项目摘要/摘要尤因肉瘤（ES）是第二大的儿科骨癌，在青少年和年轻人时期。 ES是当前治疗的极具侵略性的恶性肿瘤依赖化学疗法，放疗和/或手术的组合方法的方案。 ES的65％-75％患者可以使用当前的治疗策略来治愈，但可能会遭受痛苦的全身方面效果。这些包括从细胞毒性化疗到免疫抑制继发于感染的高风险长期影响会导致严重的心脏，学习缺陷，生殖能力甚至第二恶性肿瘤。因此，必须开发更精确，有效的治疗方法以最大化是至关重要的患者的结果，同时最大程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性莱斯大学实验室之间的协同协作努力，针对骨癌细胞的策略和贝勒医学院。该提议的总体目标是开发靶向骨骼精度治疗ES的治疗生物制剂。为了实现这一目标，第一个研究方向将重点放在使用创新的遗传代码扩展技术，我们拥有的ES产生骨骼靶向抗体最近开创了。双膦酸盐是一类负电荷的分子，能够选择性结合矿化，带正电的骨基质。双膦酸盐与抗体的位点特异性共轭将向骨骼输送高浓度的治疗抗体并在酸性肿瘤中激活微环境可更好地治疗功效，并减少与全身性相关的不良副作用送货。为了证明这些骨骼靶向抗体的治疗概况的增强在ES中，我们将使用ES细胞或患者衍生的异种移植物研究它们对ES的生存和进展的影响衍生的原代ES细胞。我们在该项目中的努力将产生靶向骨靶向抗体的集合和展示了它们在尤因肉瘤上的增强治疗概况。考虑到抗体的增长诊所的治疗，选择性递送骨微环境的治疗性抗体将提供有希望的大道，用于不同骨相关的原发性和转移性恶性肿瘤。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Precision Modification of Native Antibodies.

DOI：
10.1021/acs.bioconjchem.1c00342
发表时间：
2021-09-15
期刊：
Bioconjugate chemistry
影响因子：
4.7
作者：
Wu KL;Yu C;Lee C;Zuo C;Ball ZT;Xiao H
通讯作者：
Xiao H

Advancing protein therapeutics through proximity-induced chemistry.

DOI：
10.1016/j.chembiol.2023.09.004
发表时间：
2023-10
期刊：
Cell chemical biology
影响因子：
8.6
作者：
Linqi Cheng;Yixian Wang;Yiming Guo;Sophie S. Zhang;Han Xiao
通讯作者：
Linqi Cheng;Yixian Wang;Yiming Guo;Sophie S. Zhang;Han Xiao

Biosynthesis and Genetic Incorporation of 3,4-Dihydroxy-L-Phenylalanine into Proteins in Escherichia coli.

DOI：
10.1016/j.jmb.2021.167412
发表时间：
2022-04-30
期刊：
JOURNAL OF MOLECULAR BIOLOGY
影响因子：
5.6
作者：
Chen, Yuda;Loredo, Axel;Chung, Anna;Zhang, Mengxi;Liu, Rui;Xiao, Han
通讯作者：
Xiao, Han

Unleashing the potential of noncanonical amino acid biosynthesis to create cells with precision tyrosine sulfation.

DOI：
10.1038/s41467-022-33111-4
发表时间：
2022-09-16
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Chen, Yuda;Jin, Shikai;Zhang, Mengxi;Wu, Kuan-lin;Chang, Anna;Wang, Shichao;Tian, Zeru;Wolynes, Peter G.;Xiao, Han
通讯作者：
Xiao, Han

Xanthone-based solvatochromic fluorophores for quantifying micropolarity of protein aggregates.