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.

该应用程序旨在使用逆闪光灯开发抗体的长效库公式 由Optimeos Life Sciences商业化的纳米沉淀（IFNP）平台。微粒沉积 公式已经测试了数十年以提供持续释放。该理论在传统上是 被加入了不脱水的聚合物基质，随着聚合物降解，释放程序。传统 微粒结构具有显着的局限性，包括较低的治疗含量和较差的治疗稳定性。 因此，目前尚无蛋白质的销售微粒沉积物。相比之下，微粒 OptimeOS产生的是通过将纳米颗粒聚集在一起形成的，以产生机械强的 纳米复合微粒。纳米颗粒是由IFNP生成的，这是一个可扩展且连续的过程 封装水溶性化合物。纳米颗粒结构允许更高的负载并形成A 保护性壳会限制在延长释放期间抗体不稳定性。 IFNP技术已广泛研究肽的递送，并具有治疗重量 库中的内容使用现有方法比当前可能高10倍，并受控发行 剖面范围从3周到3个月不等。拟议的研究将扩大IFNP的持续 将技术从Petides释放到蛋白质。三种肿瘤坏死因子α（TNFα）抗体格式将 进行评估以确定技术的适用范围。这些结构 - VHH单个域 纳米机构，FAB片段和IgG抗体 - 复杂性增加。这项拟议的研究将使 通过解决关键过程的风险来将IFNP技术转换为更复杂的生物制剂 - 化学 在加工和释放过程中封装抗体的结构不稳定 - 通过三个目的： 1）目标1：识别使用IFNP产生的VHH微粒公式，具有20-40 wt％的功能VHH。 2）AIM 2：从微粒生成1和3个月的活动VHH的持续释放，每周 表明释放VHH的稳定性评估> 90％的天然和功能。 3）目标3：应用AIM 1和AIM 2调查结果，以封装Fab和IgG抗体，产生 在1和3个月内持续释放，释放抗体> 90％的天然和功能。 IFNP的性能将使用VHH抗体作为初始模型进行评估，因为它们是迅速的 注射后清除。配方设计将建立在使用IFNP的肽传递的规则上 流程，根据普林斯顿大学和Optimos之间的STTR赠款生产。关键稳定性 测量（ELISA，SEC，质谱法）将通过与整合分子的合作进行。 这些结果将推广到其他抗体，从而使我们能够扩展到其他疾病的治疗 迅速。十字形，抗体以外的蛋白质的持续递送可以启用疫苗或酶 使用拟议工作确定的相同公式原则的替换申请。