Senior Principle Janssen Research and Development, LLC Spring House, Pennsylvania
Large therapeutic proteins are not given orally due to proteolysis, harsh conditions of GI tract, and large size, which limits absorption. Much speculation has surrounded intestinally expressed neonatal Fc Receptor (FcRn) as a means for transport and systemic uptake of orally administered immunoglobulin G (IgG). However, supporting data for this was limited to neonates or in FcRn expressing cells in vitro. We reported that IgG1 intestinal infusion in anesthetized cynomolgus resulted in detectable serum mAb levels, while orally administered mAb in PBS did not. Subsequently, we showed that IgG2 has greater protease resistance to intestinal enzymes in vitro and in vivo in mice, due to protease resistance in the hinge region. In this Proof-of-Concept study, IgG2 monoclonal antibody (mAb) was engineered for FcRn binding, optimally formulated, lyophilized and loaded into enteric-coated capsules for oral dosing in cynomolgus. Cynomolgus small intestinal pH 7.5 was selected for enteric release based on gastrointestinal pH profiling by operator-assisted IntelliCap System®. Lyophilization after formulation in 10 mM histidine, pH 5.7, 8.5% sucrose, 0.04% PS80 and milling did not alter the physico-chemical properties nor the molecular integrity compared to the batch released in PBS. Size 3 hard gel capsules (0.3 ml ; 23.2 API ~ 3 mg/kg) were coated with hydroxypropyl methylcellulose acetate succinate for rapid dissolution at pH 7.5. Initial dosing of capsules was by endoscopy into small intestine to ensure passage through pylorus but only achieved 0.2+0.1 ng/ml (n=5) peak at 24 hours. Weekly oral capsule dosing for 6 weeks achieved levels of 0.4+0.2 ng/ml. For weeks 7-10, the circulating levels remained below 1 ng/ml, despite increasing the dose and frequency In conclusion, lyophilized milled mAb retains FcRn binding and molecular integrity for small intestinal delivery. This has demonstrated the limitations of intestinal FcRn in non-human primates and the continuing challenges for obtaining therapeutic levels of full-length mAb, although local delivery and levels of mAb may be sufficient in intestinal diseases.
Upon completion, participants will be able to recognize the challenges to oral bioavailability for monoclonal antibody drugs
Upon completion, participants will be able to combine different technological approaches to surmount obstacles for oral delivery of mAbs
Upon completion, participants will be able to identify differences in the GI tract and how to exploit these for intestinally targeted delivery of mAbs
Upon completion, participants will be able to extrapolate the potential therapeutic outcomes, based on NHP Proof-of-Concept study demonstrating detectable full length mAb
Upon completion, participants will be able to debate the limitations based on using these technologies, such as cost-of goods.