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，单抗(MAbbs)提供了无可挑战的特异性，代表着 1,500多亿美元的增长市场。然而，由于它们的结构复杂和稳定性差，它们仍然 在高浓度下难以配制，使静脉注射单抗成为“黄金标准”。IV 注射存在主要缺点，如患者不适、注射时间长和医疗费用高。 与医院内给药有关。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)，需要最低限度的技能(自我注射)，并允许 用于系统性的投放。将单抗重新表述为SC形式仍然是一个悬而未决的挑战。大多数单抗需要较大的 剂量要有效(&gt；300毫克)，SC给药量限制在1-2毫升，数百 比典型的静脉注射配方小一倍 使用水凝胶微粒(HMP)的SC注射提供了一种很有前途的包囊和递送方法 基于蛋白质的药物。HMP的组成、大小和机械性能可以广泛调整，以便于 他们通过针头注射进行皮下注射。基于海藻酸盐的MP正变得越来越受欢迎 由于它们的流变性和高度的生物相容性。此外，海藻酸盐的阴离子性质使 阳离子蛋白质的静电包埋与水凝胶孔隙率无关，使其成为一种候选 基于水凝胶的抗体制剂。然而，目前的制造技术仅限于低成本 聚合物浓度(&lt；5%)和低载货量，通常低于30 mg/ml的抗体，导致 机械和治疗性能不足。 通过对小型企业创新研究(SBIR)第一阶段项目的支持，我们的目标是改进 通过将静脉递送的单抗重新配制为SC形式，对数百万患者进行临床护理，这意味着患者可以 给他们服用救命药物，减轻疼痛和不适，成本只有他们的一小部分。 我们计划利用声光印迹(AP)来产生藻酸盐MP来稳定高浓度的mAbs 配方。这种平台技术能够在适度的剪切力下产生微粒子，而不需要 需要疏水载液，从而保护贵重货物并将污染降至最低。这个 技术特点：生物相容性高，不需要油或表面活性剂，使这项技术特别 适用于大蛋白质；高浓度货物(100 mg/ml)，包括海藻酸盐(10%)；低颗粒 差异(变异系数1-3%)减少了昂贵的筛选步骤、货物包装的一致性和 交付-因此显著改进了良好的制造规范-即使在极端负载下也是如此。 该项目的目标是：(1)制备单抗负载的水凝胶微粒，用于SC递送和 对它们进行体外表征，包括包封率、释放度和注射性。(2)在体内进行 研究以MP为基础的制剂在小鼠模型中的安全性、生物利用度和生物活性。