Collaborative Research: Integrative Adaptation of Dendrimer-peptide Conjugates for Cancer Immunotherapy

合作研究：树状聚合物-肽缀合物对癌症免疫治疗的综合适应

• 批准号: 2212123
• 负责人: Petr Kral
• 金额: $ 30万
• 依托单位: University of Illinois at Chicago
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2212123&HistoricalAwards=false
• 关键词: Collaborative; Research; Integrative; Adaptation; Dendrimer

Non-technical SummaryImmunotherapy, utilization of a patient’s own immune system to treat diseases, has revolutionized cancer treatment. Most of the immunotherapeutic drugs that are being used in the clinic are based on biologics, such as antibodies (proteins that bind to specific antigens only), that boost immune surveillance against tumor cells. However, such antibody-based drugs are expensive and often result in disappointing clinical outcomes, particularly when used alone. The use of peptides (macromolecules made from a chain of 20-30 amino acids) would be a promising alternative; however, their weaker binding than the corresponding antibodies has been recognized as a major weakness. Recently, the collaborative team proposing this work have demonstrated that small ball-shaped polymers (size of 1/10,000 of human hair thickness), called poly(amidoamine) (PAMAM) dendrimers, can be engineered to dramatically improve the binding strength of the peptides up to a million times. In this proposal, the team hypothesizes that dendrimers attached with computationally optimized peptides can boost up the immune system to attack tumor cells, thereby maximizing their immunotherapeutic effect. Upon successful completion of this project, the team will contribute to developing a new technology that would be compatible with various immunotherapeutic peptides. Integrated with the research effort, this project includes various educational activities that recruit graduate students, undergraduate students, and high school students. These activities will not only help advanced degree students be actively involved in cutting-edge science but also stimulate STEM interests of pre-college students, which will have profound impact on our nation to maintain the position as the world leader of science and engineering.Technical SummaryThe overarching goal of the research activities is to integrate computational and experimental methods to engineer a nanoparticle platform based on dendrimer-peptide conjugates for enhanced cancer immunotherapy. The collaborative team has demonstrated that poly(amidoamine) (PAMAM) dendrimers are excellent mediators for multivalent binding effects, as observed by dramatically enhanced binding avidities of small molecules, antibodies, and peptides. This nanoengineering approach for binding enhancement could be directly applicable for improving cancer immunotherapy that relies on efficient blocking of binding between immune and tumor cells. Given that strong binding to the target immune checkpoint proteins, such as programmed death-ligand 1 (PD-L1), programmed cell death protein-1 (PD-1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), is necessary to effectively induce the checkpoint blockade, all the FDA-approved immune checkpoint inhibitors (ICIs) to date are based on antibodies with strong binding affinities. Unfortunately, such antibody-based therapeutics are expensive and often result in disappointing clinical outcomes, particularly when used alone. The team hypothesizes that dendrimer conjugation with computationally optimized peptides that target multiple immune checkpoint receptors on T cells would substantially improve the binding strength of otherwise weakly binding peptides, which in turn would maximize their immunotherapeutic efficiency. The use of peptides would be advantageous, as they are cost-effective and amenable to various engineering strategies, in contrast to whole antibodies. The proposed dendrimer-peptide conjugate (DPC) systems, consisting of engineered PAMAM dendrimers functionalized with peptides, are relatively simple in comparison to other commonly used nanoparticle drug delivery systems. Yet, the DPC systems are unique and innovative in that: i) peptides can be adapted and optimized via a high-throughput computation; ii) dendrimers multimerize peptides to exploit strong multivalent binding effects (avidity); iii) folded peptides can be stabilized on the dendrimer surface, further contributing for binding enhancement; and iv) this approach is compatible with virtually any peptides, providing a modular platform for various combinations. Upon successful completion of this project, we will have obtained fundamental understanding in peptide design/synthesis, polymer engineering, and binding kinetics and biological behaviors of the DPCs. The project will broaden participation of underrepresented minorities and women in STEM research at various educational levels.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

非技术摘要免疫疗法，利用患者自身的免疫系统来治疗疾病，已经彻底改变了癌症治疗，临床上使用的大多数免疫治疗药物都是基于生物制剂，例如抗体（仅与特定抗原结合的蛋白质）。然而，这种基于抗体的药物价格昂贵，并且常常导致令人失望的临床结果，特别是在单独使用肽（由一系列肽组成的大分子时）。 20-30 个氨基酸）将是一个有前途的替代方案；然而，它们的结合力比相应的抗体弱已被认为是一个主要弱点，最近，提出这项工作的合作团队已经证明，小球形聚合物（大小为 1/ 10,000 根人类头发粗细的聚酰胺胺 (PAMAM) 树状聚合物经过改造后，可以将肽的结合强度显着提高一百万倍。附有经过计算优化的肽的树状聚合物可以增强免疫系统攻击肿瘤细胞，从而最大限度地发挥其免疫治疗效果。该项目成功完成后，该团队将有助于开发一种与各种免疫治疗肽相兼容的新技术。该项目包括招收研究生、本科生和高中生的各种教育活动，这些活动不仅可以帮助高级学位学生积极参与前沿科学，还可以激发学生对STEM的兴趣。预科学生，这将对我们国家保持世界科学和工程领导者的地位产生深远的影响。技术摘要研究活动的总体目标是整合计算和实验方法来设计基于树枝状聚合物的纳米颗粒平台用于增强癌症免疫治疗的肽缀合物已经证明，聚（酰胺基胺）（PAMAM）树状聚合物是多价结合效应的优秀介质，通过显着增强的小分子、抗体、这种结合增强的纳米工程方法可以直接应用于改善依赖于有效阻断免疫细胞和肿瘤细胞之间结合的癌症免疫疗法，因为它与目标免疫检查点蛋白（例如程序性死亡配体1（PD））有很强的结合力。 -L1)、程序性细胞死亡蛋白-1 (PD-1) 和细胞毒性 T 淋巴细胞相关蛋白 4 (CTLA-4) 是有效诱导检查点封锁所必需的，所有 FDA 批准的免疫检查点抑制剂迄今为止，这种基于抗体的疗法是基于具有强结合亲和力的抗体，并且常常导致令人失望的临床结果，特别是当单独使用时，该团队冒险将树状聚合物与针对多种免疫的计算优化的肽结合。 T细胞上的检查点受体将大大提高其他弱结合肽的结合强度，这反过来又会最大限度地提高其免疫治疗效率。肽的使用将是有利的，因为它们具有成本效益且有效。与完整抗体相比，所提出的树状聚合物-肽缀合物（DPC）系统由用肽功能化的工程化 PAMAM 树状聚合物组成，与其他常用的纳米颗粒药物递送系统相比相对简单。该系统的独特性和创新性在于：i) 肽可以通过高通量计算进行调整和优化；ii) 树枝状聚合物使肽多聚化，以利用强大的多价结合效应（亲和力）；iii）折叠肽可以稳定在树枝状聚合物表面，进一步促进结合增强；iv）这种方法几乎与任何肽兼容，为各种组合提供了模块化平台。将获得对 DPC 的肽设计/合成、聚合物工程以及结合动力学和生物行为的基本了解。该项目将扩大代表性不足的少数族裔和妇女对各种教育领域 STEM 研究的参与。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。