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: 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
• 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

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.

项目总结/文摘

项目成果

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

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.

• DOI: 10.1039/d2sc05004h
• 发表时间: 2022-11-02
• 期刊: Chemical science
• 影响因子: 8.4