Boron Cluster based Star Polymers for Monoclonal Antibody Drug Formulations

• Lars Lefkowitz, Chemistry, University of Delaware

• Marco Messina, Department of Chemistry and Biochemistry, University of Delaware

Monoclonal antibody (mAbs) treatments are a rapidly developing class of biopharmaceuticals. The superior target specificity and minimal toxicity of mAbs have established their use in treatments for autoimmune disorders, cancers, and infectious diseases, with over 80 therapeutics garnering market approval. However, mAb therapies require specialized handling and cold storage conditions as exposure to environmental stressors leads to biomolecule aggregation and loss of activity. Additionally, intravenous administration remains the primary mode of mAb treatment, requiring multiple prolonged clinic visits with trained personnel, thus prompting interest in subcutaneous injection as an alternative form of drug delivery. However, subcutaneous delivery of mAb therapeutics remains challenging due to increased solution viscosity at required dosages. Formulations composed of small molecule excipients are deployed to combat these challenges, but high concentrations are needed. Recent work suggests that linear 2-dimensional (2D) polymers made from commonly used excipients offer greater stability at lower concentrations but do not address the viscosity challenge required for subcutaneous injection. Herein, our group aims to tackle this problem through the introduction of 3-dimensional (3D) star polymer stabilizers. We hypothesize that the 3D architecture will impose many unique features distinct from linear polymers including decreased solution viscosity and greater stabilization due to multivalent effects. We have designed boron-rich cluster core templates to access large varieties of distinct star polymer architectures in rapid fashion. B12(OCH2C6F5)12 enables rapid functionalization via SNAr chemistry with an array of thiol-terminated polymers or small molecule polymer initiators. Ongoing studies will utilize RAFT or ATRP to synthesize star polymers from boron-rich cluster core structures in a ‘graft-from’ strategy. Star polymer solution-state properties and biomolecule stabilization effects will be studied and compared with linear polymer derivatives. Ultimately, this work establishes new synthetic techniques and design principles within the realm of boron cluster chemistry while accessing new materials space in therapeutic formulations development.