Journal Of Pharmaceutical Sciences
Monoclonal antibodies continue to command a large market for treatment of a variety of diseases. In many cases, the doses required for therapeutic efficacy are large, limiting options for antibody delivery and administration. We report a novel formulation strategy based on dispersions of antibody nanoclusters that allows for subcutaneous injection of highly concentrated antibody ( 190 mg/mL). A solution of monoclonal antibody 1B7 was rapidly frozen and lyophilized using a novel spiral-wound in-situ freezing technology to generate amorphous particles. Upon gentle stirring, a translucent dispersion of approximately 430 nm protein clusters with low apparent viscosity ( 24 cp) formed rapidly in buffer containing the pharmaceutically acceptable crowding agents such as trehalose, polyethylene glycol, and n-methyl-2-pyrrolidone. Upon in vitro dilution of the dispersion, the nanoclusters rapidly reverted to monomeric protein with full activity, as monitored by dynamic light scattering and antigen binding. When administered to mice as an intravenous solution, subcutaneous solution, or subcutaneous dispersion at similar (4.6-7.3 mg/kg) or ultra-high dosages (51.6 mg/kg), the distribution and elimination kinetics were within error and the protein retained full activity. Overall, this method of generating high-concentration, low-viscosity dispersions of antibody nanoclusters could lead to improved administration and patient compliance, providing new opportunities for the biotechnology industry.