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.

摘要 与小分子相比，单克隆抗体（mAb）提供了未受到挑战的特异性，代表了 1500多亿美元的增长市场。然而，由于其结构复杂性和稳定性差， 难以以高浓度配制，使得静脉内（IV）递送mAb成为“金标准”。IV 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 与住院管理有关。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），并允许 用于全身性递送。将mAb重新配制成SC形式仍然是一个开放的挑战。大多数mAb需要大的 有效剂量（>300 mg），而SC给药体积仅限于1-2 ml，数百个 比典型IV制剂小1倍 使用水凝胶微粒（HMP）的SC注射提供了一种有前途的包封和递送方法， 蛋白质类药物HMP的组成、尺寸和机械性能可以广泛地调节，以促进 它们通过针头注射用于皮下递送。基于藻酸盐的MP越来越受欢迎 这是由于它们的流变特性和高生物相容性。另外，藻酸盐的阴离子性质使得能够 阳离子蛋白质的静电捕获独立于水凝胶孔隙率，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%）和低负荷，对于抗体通常低于30 mg/ml，导致 机械和治疗性能不足。 通过支持这个小企业创新研究（SBIR）第一阶段项目，我们的目标是提高 通过将IV递送的mAb重新配制为SC形式，数百万患者的临床护理，这意味着患者可以 以低廉的成本服用救生药物，减轻疼痛和不适。 我们计划利用声泳印刷（AP）产生藻酸盐MP来稳定高浓度的mAb 公式化。该平台技术能够在适度的剪切力下产生微粒，而不需要在微流体中产生微粒。 因此，需要疏水载体流体，从而保护有价值的货物并使污染最小化。的 技术特点：高生物相容性，不需要油或表面活性剂，使该技术特别适合于 适用于大蛋白质;高浓度的货物（> 100 mg/ml），包括藻酸盐（>10%）;低粒度 变化（变化系数为1-3%）减少了昂贵的筛选步骤，货物封装的一致性， 因此，即使在极端负载下，也能显著改善良好生产规范。 该项目旨在：（1）制造用于SC递送的负载mAb的基于水凝胶的微粒， 在体外对其进行表征，包括包封效率、释放曲线和可注射性。(2)进行体内 在鼠模型中研究基于MP的制剂的安全性、生物利用度和生物活性的研究。