Enabling Subcutaneous Delivery of Therapeutic Monoclonal Antibodies via Hydrogel Microparticles

通过水凝胶微粒皮下输送治疗性单克隆抗体

• 批准号: 10761250
• 负责人: Daniele Foresti
• 金额: $ 32.45万
• 依托单位: ACOUSTICABIO, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10761250
• 关键词: Address; Alginates; Antibodies; Automobile Driving; Biological Availability; Blood capillaries; Brown Algae; Cells; Certification; Characteristics; Charge; Clinical; Consumption; Development; Diameter; Electrostatics; Encapsulated; Enzyme-Linked Immunosorbent Assay; Force of Gravity; Formulation; Frequencies; Future; Generations; Good Manufacturing Process; Home; Hospital Administration; Hospitals; Hydrogels; Hydrophobicity; Immunoglobulin G; In Vitro; Injectable; Injections; Intravenous; Ions; Life; Liquid substance; Marketing; Measures; Mechanics; Medical Care Costs; Methods; Molecular Weight; Monoclonal Antibodies; Mus; Nature; Needles; Oils; Pain; Particle Size; Patients; Pharmaceutical Preparations; Phase; Polymers; Polysaccharides; Printing; Process; Production; Property; Proteins; Route; Safety; Sampling; Self Administration; Serum; Small Business Innovation Research Grant; Specificity; Subcutaneous Injections; Surface; Technology; Testing; Therapeutic; Therapeutic Monoclonal Antibodies; Time; Travel; Variant; Viscosity; Visual; base; bevacizumab; biomaterial compatibility; clinical care; cost; crosslink; design; dosage; fluid flow; immunogenicity; improved; in vitro testing; in vivo; intravenous injection; irritation; manufacture; manufacturing technology; mechanical properties; meter; monoclonal antibody production; mouse model; pain reduction; particle; porous hydrogel; preservation; skills; small molecule; standard of care; subcutaneous; surfactant; technology platform; therapeutic protein

ABSTRACT Monoclonal antibodies (mAbs) provide unchallenged specificity compared to small molecules, representing a growing market of 150+ billion dollars. Due to their structural complexity and poor stability, however, they remain difficult to formulate at high concentrations, making intravenous (IV) delivery of mAbs the “gold standard”. IV injections present major drawbacks, such as patient discomfort, long injection times, and high medical costs associated with in-hospital administration. Subcutaneous (SC) delivery is a convenient route of administration for large molecules, as it allows for rapid injections (seconds), requires minimal skills (self-injection), and allows for systemic delivery. It remains an open challenge to reformulate mAbs to a SC form. Most mAbs requires large dosage to be effective (>300 mg), and SC administration volumes are constrained to only 1-2 ml, hundreds of times smaller than typical IV formulations SC injections using hydrogel microparticles (HMP) offer a promising method for encapsulating and delivering protein-based drugs. The composition, size, and mechanical properties of HMPs can be widely tuned to facilitate their injection through needles for subcutaneous delivery. Alginate-based MP are becoming increasingly popular due to their rheological properties and high biocompatibility. Additionally, the anionic nature of alginate enables electrostatic entrapment of cationic proteins independently of the hydrogel porosity, making it a candidate for hydrogel-based antibody formulations. However, current manufacturing technologies are limited to low concentration of polymer (<5%), and low cargo loading, typically below 30 mg/ml for antibodies, resulting in inadequate mechanical and therapeutic properties. Through the support of this Small Business Innovation Research (SBIR) Phase I project, we aim at improving clinical care of millions of patients by reformulating IV-delivered mAbs to a SC form, meaning patients could administer their life saving drugs with reduced pain and discomfort, at a fraction of the cost. We plan to leverage Acoustophoretic Printing (AP) to generate alginate MP to stabilize highly concentrated mAbs formulation. This platform technology enables microparticle generation under modest shear forces without the need for a hydrophobic carrier fluid, thereby protecting the valuable cargo and minimizing contamination. The technology features: high bio-compatibility with no oil or surfactant required, making this technology particularly suitable for large proteins; high concentrations of cargo (>100mg/ml), including alginate (>10%); low particle size variation (coefficient of variation of 1-3%) reducing costly sieving steps, consistency in cargo encapsulation and delivery - hence significantly improving Good Manufacturing Practices - even at extreme loading. This project aims to: (1) Manufacture mAbs loaded hydrogel-based microparticles for SC delivery and characterize them in-vitro, including encapsulation efficiency, release profile, and injectability. (2) Conduct In vivo study to investigate safety, bioavailability, and bioactivity of the MP-based formulations in murine models.

抽象的 与小分子相比，单克隆抗体 (mAb) 具有无可比拟的特异性，代表了 150+ 十亿美元的不断增长的市场。但由于其结构复杂、稳定性较差， 由于难以配制高浓度，因此静脉 (IV) 输送单克隆抗体成为“金标准”。四号 注射存在主要缺点，例如患者不适、注射时间长和医疗费用高 与院内管理有关。皮下（SC）给药是一种方便的给药途径 对于大分子，因为它允许快速注射（秒），需要最少的技能（自我注射），并且允许 用于全身输送。将 mAb 重新配制为 SC 形式仍然是一个公开的挑战。大多数单克隆抗体需要大 有效剂量（> 300 mg），SC 给药体积仅限于 1-2 ml，数百个 比典型静脉注射制剂小几倍 使用水凝胶微粒 (HMP) 的 SC 注射提供了一种有前途的封装和递送方法 基于蛋白质的药物。 HMP 的组成、尺寸和机械性能可以广泛调整，以促进 他们通过皮下注射针进行注射。基于海藻酸盐的 MP 越来越受欢迎 由于其流变特性和高生物相容性。此外，海藻酸盐的阴离子性质使得 独立于水凝胶孔隙率的阳离子蛋白质的静电捕获，使其成为 基于水凝胶的抗体制剂。然而，目前的制造技术仅限于低 聚合物浓度（<5%）和低负载量（抗体通常低于 30 mg/ml），导致 机械和治疗性能不足。 通过小企业创新研究 (SBIR) 第一阶段项目的支持，我们的目标是改善 通过将静脉注射的单克隆抗体重新配制为 SC 形式，为数百万患者提供临床护理，这意味着患者可以 以极低的成本管理他们的救生药物，减少疼痛和不适。 我们计划利用声泳印刷 (AP) 生成藻酸盐 MP 来稳定高浓度的 mAb 配方。该平台技术能够在适度的剪切力下生成微粒，而无需 需要疏水性载液，从而保护有价值的货物并最大限度地减少污染。这 技术特点：生物相容性高，无需油或表面活性剂，使该技术特别 适用于大蛋白质；高浓度货物（>100mg/ml），包括藻酸盐（>10%）；低粒径 变化（变化系数为 1-3%）减少了昂贵的筛分步骤，货物封装的一致性和 交付 - 从而显着改善良好制造规范 - 即使在极端负载下。 该项目的目标是：(1) 制造负载单克隆抗体的水凝胶微粒，用于 SC 输送和 对它们进行体外表征，包括封装效率、释放曲线和可注射性。 (2) 体内进行 研究旨在调查基于 MP 的制剂在小鼠模型中的安全性、生物利用度和生物活性。