Lower Gastrointestinal Tract Delivery of a Tetra-specific Antibody ABAB-IgG1 for the Treatment of Clostridium Difficile Infection (CDI)

Abstract

More than 246 protein or peptide therapeutics are on the market, including 47 monoclonal antibodies approved since early 1980s. Although most protein therapeutics are administered parentally, treatments for gastrointestinal diseases such as Clostridium difficile infection (CDI), ulcerative colitis and Crohn’s Disease would benefit from an oral delivery system that can target biologics to a site in the GI tract, with less systematic exposure and therefore less systematic toxicity, given the targets of disease are in the GI tract. This research focused on local delivery of a novel antibody therapeutic, ABAB-IgG1, for the treatment of CDI. The antibody was fabricated into a multi-particulate delivery system comprised of nonpareil beads and functional polymers using spray coating techniques. A proof-of-concept study was conducted using BSA as a model protein. BSA was first spray layered onto beads, then coated with pH sensitive polymers. There was no significant change in BSA conformation and aggregation profiles after the spray layering process. BSA multi-particulates were stable for at least 1 month stored at 4 ⁰C. In vitro dissolution testing showed that the enteric coated BSA beads remained intact in acidic media, while releasing BSA in higher pH buffers. A Design of Experiments strategy was used to understand how the formulation and process parameters impacted antibody stability during spray coating process and during accelerated stability studies. The formulation of novel structured antibody ABAB-IgG1 was also optimized based on the conformational and colloidal stabilities using various high throughput biophysical characterization techniques. The multi-particulate delivery system of ABAB-IgG1 was evaluated both in vitro and in vivo, and showed the feasibility of delivering ABAB-IgG1 to the lower GI tract using the multi-particulate system. The multi-particulate delivery system, which is well-studied for small molecule drugs, can be adopted to biologics without modification of existing fluid bed processing equipment, which implies the possibility of efficient scale up of this technique in existing industrial-scale equipment.