Sustained Release Formulations of Therapeutic Antibodies

治疗性抗体的缓释制剂

• 批准号: 10255420
• 负责人: Chester Edward Markwalter
• 金额: $ 25.54万
• 依托单位: OPTIMEOS LIFE SCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-05 至 2023-12-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10255420
• 关键词: Address; Antibodies; Architecture; Arthritis; Beta Carotene; Biological; Biological Assay; Biological Products; Biological Sciences; Biophysics; Bolus Infusion; Chemical Structure; Chronic; Chronic Disease; Collaborations; Complex; Data; Development; Disease; Disease model; Dose; Emulsions; Encapsulated; Enzyme-Linked Immunosorbent Assay; Enzymes; Exhibits; Fab Immunoglobulins; Formulation; Frequencies; Funding; Goals; Grant; Horseradish Peroxidase; Hour; Hydrophobicity; Immunoglobulin Fragments; Immunoglobulin G; Injectable; Injections; Legal patent; Mass Spectrum Analysis; Measurement; Mechanics; Messenger RNA; Methods; Modeling; Molecular; Monitor; Muramidase; Office Visits; Patients; Peptides; Performance; Pharmacologic Substance; Phase; Polymers; Pore Proteins; Process; Production; Proteins; RNA delivery; Research; Rheumatoid Arthritis; Risk; Schedule; Serum; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Structure; TNF gene; Technology; Testing; Therapeutic; Therapeutic antibodies; Time; Translations; Universities; Vaccines; Water; Weight; Work; arthritis therapy; beta-Galactosidase; biodegradable polymer; chemical stability; commercialization; controlled release; design; enzyme replacement therapy; expectation; experience; improved; in vivo; innovation; insight; lipid nanoparticle; liraglutide; nanobodies; nanocomposite; nanoparticle; novel strategies; peptide drug; small molecule; success

This application seeks to develop a long-acting depot formulation for antibodies, using the inverse Flash NanoPrecipitation (iFNP) platform being commercialized by Optimeos Life Sciences. Microparticle depot formulations have been tested for decades to provide sustained release. The therapeutic is traditionally entrapped in a water-insoluble polymer matrix, with release proceeding as the polymer degrades. The traditional microparticle structure has significant limitations, including low therapeutic content and poor therapeutic stability. Consequently, there are currently no marketed microparticle depots for proteins. By contrast, the microparticles produced by Optimeos are formed by aggregating nanoparticles together to produce mechanically strong nanocomposite microparticles. The nanoparticles are produced by iFNP, a scalable and continuous process for encapsulating water-soluble compounds. The nanoparticle structure permits much higher loadings and forms a protective shell that will limit antibody instability during extended release. The iFNP technology has been extensively studied for peptide delivery, with demonstrated therapeutic weight content in the depot up to 10 times higher than currently possible with existing methods, and controlled release profiles ranging from 3 weeks to more than 3 months. The proposed research will extend the iFNP sustained release technology from peptides to proteins. Three Tumor Necrosis Factor alpha (TNFα) antibody formats will be evaluated to determine the scope of applicability of the technology. These constructs – a VHH single domain nanobody, a Fab fragment, and an IgG antibody – are of increasing complexity. This proposed study will enable the translation of the iFNP technology to more complex biologics by addressing the key process risks – chemical and structural instability of the encapsulated antibody during processing and release – through three aims: 1) Aim 1: Identify VHH microparticle formulations, produced using iFNP, with 20-40 wt% functional VHH. 2) Aim 2: Generate sustained release of active VHH over 1 and 3 months from microparticles, with weekly stability assessments indicating released VHH is > 90% native and functional. 3) Aim 3: Apply Aim 1 and Aim 2 findings to the encapsulation of Fab and IgG antibodies, producing sustained release over 1 and 3 months with released antibody > 90% native and functional. The performance of iFNP will be evaluated using VHH antibodies as an initial model because they are rapidly cleared following injection. Formulation design will build on the rules derived for peptide delivery using the iFNP process, produced under an STTR grant between Princeton University and Optimeos. Key stability measurements (ELISA, SEC, mass spectrometry) will be conducted via a collaboration with Integral Molecular. These results will be generalizable to other antibodies, allowing us to expand into the treatment of other diseases rapidly. Crucially, sustained delivery of proteins other than antibodies could enable vaccine or enzyme replacement applications using the same formulation principles identified by the proposed work.

该应用旨在使用反向 Flash 开发一种长效抗体储库制剂 NanoPrecipitation (iFNP) 平台由 Optimeos Life Sciences 进行商业化。 制剂经过数十年的测试以提供持续释放。 包埋在水不溶性聚合物基质中，随着聚合物降解而释放。 微粒结构具有显着的局限性，包括治疗含量低和治疗稳定性差。 经测试，目前还没有上市的蛋白质微粒储库。相比之下，微粒。 Optimeos 生产的纳米颗粒通过聚集在一起形成，具有机械强度 纳米复合微粒由 iFNP 生产，这是一种可扩展的连续工艺。 封装水溶性化合物。纳米颗粒结构允许更高的负载量并形成。 保护壳将限制抗体在延长释放过程中的不稳定性。 iFNP 技术主要用于肽递送研究，并已证明治疗重量 仓库中的含量比现有方法和受控释放的当前含量高出 10 倍 拟议的研究将延长 iFNP 的持续时间。 从肽到蛋白质的三种肿瘤坏死因子α（TNFα）抗体形式的释放技术。 进行评估以确定该技术的适用范围——VHH 单域。 纳米抗体、Fab 片段和 IgG 抗体的复杂性不断增加，这项拟议的研究将使之成为可能。 通过解决关键工艺风险（化学），将 iFNP 技术转化为更复杂的生物制剂 以及封装抗体在加工和释放过程中的结构不稳定性——通过三个目标： 1) 目标 1：鉴定使用 iFNP 生产的 VHH 微粒制剂，其中功能性 VHH 含量为 20-40 wt%。 2) 目标 2：在 1 到 3 个月内从微粒中持续释放活性 VHH，每周释放一次 发布的稳定性评估 VHH > 90% 是原生的和功能性的。 3) 目标 3：将目标 1 和目标 2 的发现应用于 Fab 和 IgG 抗体的封装，产生 持续释放超过 1 个月和 3 个月，释放的抗体 > 90% 是天然的和有功能的。 iFNP 的性能将使用 VHH 抗体作为初始模型进行评估，因为它们快速 注射后清除的制剂设计将基于使用 iFNP 进行肽递送的规则。 过程，由普林斯顿大学和 Optimeos 之间的 STTR 资助开发。 测量（ELISA、SEC、质谱）将通过与 Integral Molecular 合作进行。 这些结果将推广到其他抗体，使我们能够扩展到其他疾病的治疗 至关重要的是，持续输送抗体以外的蛋白质可以使疫苗或酶成为可能。 使用拟议工作确定的相同制定原则的替代应用程序。