Coiled-coil assisted control of antibody quality, delivery and binding

卷曲螺旋辅助控制抗体质量、递送和结合

• 批准号: RGPIN-2020-07039
• 负责人: DeCrescenzo, Gregory
• 金额: $ 4.23万
• 依托单位: École Polytechnique de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=753733
• 关键词: Coiled; coil; assisted; control; antibody

The market of therapeutic recombinant proteins is now dominated by monoclonal antibodies (mAbs). With more than 60 mAbs approved and more than 350 undergoing clinical trials, this market now exceeds 50 billion dollars. Due to the complexity of mAb mode of production, mAb manufacturing still represent a significant economic burden to the public health care system. On the one hand, in the biopharmaceutical industry, the lack of cost-effective and high-throughput engineering solutions to assess mAb critical quality attributes severely impedes the improvement of current manufacturing processes relying on cell culture. First and foremost, the assessment of mAb glycosylation, a post translational modification performed by the cells, is crucial as glycosylation directly influences mAb stability and therapeutic efficacy. On the other hand, in the clinic, the mode of administration of mAbs via intravenous route, also needs improvement (more likely via materials engineering) to achieve maximal therapeutic efficacy. Indeed, intravenous administration forces the use of huge doses, in turn leading to patient inconvenience and high medical treatment costs. The lack of an efficient and versatile approach to promote the sustained local delivery of mAbs, alone or in combination with other drugs, severely impedes the development and implementation of the next-generation therapeutics. The focus of my ongoing research program is to develop versatile and efficient engineering strategies to control recombinant protein quality and delivery. Over the past years, my team has made significant progress on addressing these issues: we spearheaded the use of a grafting strategy relying on two distinct peptides, i.e., the E and K coils, to design better biosensing assays and control the capture of bioactive proteins into hydrogels. Because of the importance of mAbs, we will focus the next 5 years specifically on this class of biomolecules. Our short-term objectives for this Discovery Grant are to: 1) Develop the biosensing and numerical tools to characterize mAb glycosylation, and thus create an enhanced process analytical technology for mAb biomanufacturing 2) Design tunable, self-assembled hydrogels for the controlled release of mAbs and other entities, hence addressing the needs of the industry for platforms delivering combined therapies. 3) Further refine our grafting and delivery technological platform by fine-tuning the E and K coil peptide sequences, extending the characterization of their interactions to support the short and long-term objectives of this program. Overall, this Discovery Grant Program will contribute to the training of 10 undergraduate and 4 PhD students. Attaining our research objectives will not only yield insight into the fundamentals of mAb glycosylation and controlled release but facilitate technology transfer to our Canadian industrial partners, ultimately leading to more efficient and cost- effective treatment to Canadians.

目前，治疗性重组蛋白市场主要由单克隆抗体（mab）主导。目前，已有60多种单克隆抗体获得批准，350多种单克隆抗体正在进行临床试验，市场规模已超过500亿美元。由于单抗生产方式的复杂性，单抗制造仍然是公共卫生保健系统的重大经济负担。一方面，在生物制药行业，缺乏具有成本效益和高通量的工程解决方案来评估单克隆抗体的关键质量属性，严重阻碍了当前依赖细胞培养的制造工艺的改进。首先，单克隆抗体的糖基化（细胞在翻译后进行的修饰）的评估至关重要，因为糖基化直接影响单克隆抗体的稳定性和治疗效果。另一方面，在临床中，单克隆抗体的静脉给药方式也需要改进（更有可能是通过材料工程），以达到最大的治疗效果。事实上，静脉注射迫使使用大剂量，从而给病人带来不便和高昂的医疗费用。缺乏一种有效和通用的方法来促进单克隆抗体的持续局部递送，单独或与其他药物联合，严重阻碍了下一代治疗方法的开发和实施。我正在进行的研究项目的重点是开发通用和有效的工程策略来控制重组蛋白的质量和传递。在过去的几年里，我的团队在解决这些问题方面取得了重大进展：我们率先使用了依赖于两种不同肽的嫁接策略，即E和K线圈，以设计更好的生物传感检测并控制将生物活性蛋白捕获到水凝胶中。由于单克隆抗体的重要性，我们将在未来5年特别关注这类生物分子。我们的短期目标是：1)开发生物传感和数值工具来表征单抗糖基化，从而为单抗生物制造创造一种增强的过程分析技术；2)设计可调的、自组装的水凝胶，用于单抗和其他实体的控制释放，从而满足行业对提供联合疗法平台的需求。3)通过微调E和K线圈肽序列，进一步完善我们的嫁接和传递技术平台，扩展其相互作用的表征，以支持本项目的短期和长期目标。总体而言，该发现资助计划将有助于培养10名本科生和4名博士生。实现我们的研究目标不仅将使我们深入了解单抗糖基化和控释的基本原理，还将促进技术转让给我们的加拿大工业合作伙伴，最终为加拿大人带来更高效、更经济的治疗方法。