Enabling subcutaneous delivery of antibodies via microgel-based, ultra-high concentration formulations

About This Grant

ABSTRACT Monoclonal antibodies (mAbs) provide unchallenged specificity compared to small molecules, representing a growing market of 220+ 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 require large dosages 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 microgels offer a promising method for encapsulating and delivering protein-based drugs. The composition, size, and mechanical properties of microgels 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 cargo loading for antibodies, or use of oils and solvents that can cause significant drawbacks including hypertonicity of the formulation and increased injection site pain. Through the support of this Small Business Innovation Research (SBIR) Phase II project, we aim at improving clinical care of millions of patients by reformulating IV-delivered mAbs to a SC form. We plan to leverage Acoustophoretic Printing (AP) to generate alginate microgels 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 (>300mg/ml); low particle size variation (coefficient of variation of <5%) reducing costly sieving steps, consistency in cargo encapsulation and delivery - hence significantly improving Good Manufacturing Practices - even at extreme loading. In our prior work, we demonstrated the viability of this approach by (1) Manufacturing mAbs loaded microgels for SC delivery and characterize them in-vitro, including encapsulation efficiency, release profile, and injectability and by (2) demonstrating its in-vivo safety, bioavailability, and bioactivity of the microgel-based formulations in murine models. In this Phase II, we plan to build upon these achievements by working towards a pre-clinical formulation with scaled-up manufacturing capabilities and a customer-driven product development.