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: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=718662
• 关键词: Coiled; coil; assisted; control; antibody; 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.

治疗性重组蛋白的市场现在由单克隆抗体（MABS）主导。该市场已有60多个MAB批准，并经过350多个正在进行临床试验，现在超过500亿美元。由于MAB生产模式的复杂性，MAB制造仍然代表了公共卫生保健系统的重大经济负担。 一方面，在生物制药行业中，缺乏具有成本效益和高通量工程解决方案来评估MAB的关键质量属性，严重阻碍了依赖细胞文化的当前制造过程的改善。首先，最重要的是，通过细胞进行的翻译后修饰的mAb糖基化评估至关重要，因为糖基化直接影响mAb稳定性和治疗功效。 另一方面，在诊所中，通过静脉内路线对mAb的给药方式也需要改进（更有可能通过材料工程）来达到最大的治疗效果。实际上，静脉管理迫使使用大剂量，进而导致患者不便和高昂的医疗费用。缺乏一种有效且多才多艺的方法来促进单独或与其他药物联合使用MAB的持续局部交付，从而严重阻碍了下一代治疗剂的发展和实施。 我正在进行的研究计划的重点是制定多功能有效的工程策略，以控制重组蛋白质质量和交付。在过去的几年中，我的团队在解决这些问题方面取得了重大进展：我们率先使用了一种依靠两种不同的肽，即E和K线圈的使用，即E和K线圈，以设计更好的生物传感测定法，并控制将生物活性蛋白捕获为水凝胶中的生物活性蛋白。由于mAB的重要性，我们将在接下来的5年中专门针对这类生物分子。我们对这项发现赠款的短期目标是： 1）开发生物传感和数值工具来表征mAb糖基化，从而创建增强的工艺分析技术，以用于mab生物制造 2）设计可调节的，自组装的水凝胶，用于控制mAB和其他实体的受控释放，因此满足了该行业对提供合并疗法的平台的需求。 3）通过微调E和K线圈肽序列，进一步完善我们的嫁接和交付技术平台，扩展其相互作用的表征，以支持该程序的短期和长期目标。 总体而言，该发现赠款计划将有助于对10名本科生和4名博士学位学生的培训。实现我们的研究目标不仅会深入了解mAb糖基化和受控释放的基本原理，而且可以促进技术转移到我们的加拿大工业伙伴，最终导致对加拿大人的效率和成本效益更高。