Novel injectable implants for long-term local controlled release of therapeutic monoclonal antibodies

PROJECT SUMMARY/ABSTRACT Delivery of monoclonal antibody (mAb) therapeutics to hard-to-reach areas of the body such as the eye, brain, joint and tumor tissues suffer from low drug concentrations at the target tissue, systemic side effects, or frequent local injections. One established approach to overcome these issues is local and sustained drug exposure, achievable with locally injectable polymer long-acting release (LAR) implants, particularly those prepared from biocompatible and biodegradable poly (lactic-co-glycolic acid) (PLGA). PLGA has been used in > 25 FDA approved commercial LARs. MAbs are a growing drug class with important applications in local delivery such as age-related macular degeneration in the eye, osteoarthritis in joints and solid tumors in the brain, lung, and pancreas. However, development of injectable PLGA LARs for mAbs is complicated by the instability of the protein, particularly during microencapsulation and long-term drug release, and achieving desirable slow and continuous drug release over substantial durations (>1 month). Here, we propose to develop novel and injectable pencil lead-type PLGA implants that is capable of stably microencapsulating a variety of therapeutic MAbs while retaining desirable release kinetics of stabilized protein in vivo for 6-12 weeks in between injection. The technology exploits a combination of anhydrous protein encapsulation, control of microclimate pH in PLGA, and controlling high osmotic pressures induced by necessary stabilizing disaccharide excipients. This proposal will focus on formulation and optimization of sterile mAb/PLGA implants, using model mAbs of important clinical significance (anti-VEGF and anti-PD1), for constant delivery of commercial therapeutic antibodies. These formulations will be tested for their pharmacokinetics after a single injection and the implants will be assessed for mAb stability/release directly in vivo by implant recovery.