Abstract Background Although biologics have higher rates of remission compared to conventional therapies, systemic toxicity is often associated with biotherapeutics (1). Therefore, the protein’s side effects must be weighed against its potential benefits for treating colitis in patient management. At the same time, the specific localisation of the disease to the colon encourages the use of local therapy that aims at having a high monoclonal antibody (mAb) dose only at the inflammation site with minimal exposure to healthy tissues (2). Therefore, exploring local applications via lipidic gel helps to develop more efficacious and safer therapies which can be self-applied, avoiding patients’ hospitalisation and multiple infusion-mediated administrations, thus increasing the patients’ compliance. Methods In vitro and in vivo experiments were used to develop the formulations and to test their efficacy. Specifically, a combination of imaging, pharmacokinetics and pharmacodynamics studies was used to evaluate the efficacy of our formulations in vivo. Moreover, a direct comparison with the available enteric-coated capsules and subcutaneous administration of the antibodies was performed. First, the formulations’ clearance profiles were evaluated, then the antibody pharmacokinetics and its colonic retention were estimated in the case of free mAb or mAb-loaded formulations. After these aims, the efficacy of the formulations was tested in an experimental model of chemically induced UC. In the experimental design, rats will receive different treatments administered either rectally or orally. Results Two formulations delivering infliximab (an anti-TNFα monoclonal antibody) have been developed and tested in vitro and in vivo. The oral dosage form and the rectal one are both made by a mixture of an FDA-approved lipid and water, and they can protect and release the antibody in a reasonable time frame. In vivo, the formulations adhere to the colon wall for more than 24 hours without any systemic adsorption while maintaining a consistent mAb concentration locally in the colonic tissue. Moreover, both the oral and the rectal formulations outperform their competitors (such as the subcutaneous administration of antibodies) in ameliorating the inflammation. Conclusion The local therapeutic approaches proposed aimed at shifting perspective in the field of biotherapeutic treatments. Indeed, mAb can cause unintended adverse effects on healthy tissue and require a trade-off between optimal disease treatment and patient quality of life. On the contrary, we designed, developed, and tested biocompatible drug delivery systems aimed to locally release the loaded mAb only at the inflammation site, minimising its side effects. References: 1. Rogler, G. Chronic ulcerative colitis and colorectal cancer. Cancer Lett. 345, 235–241 (2014). 2. Pache, I., Rogler, G. & Felley, C. TNF-α blockers in inflammatory bowel diseases: Practical consensus recommendations and a user’s guide. Swiss Medical Weekly (2009). doi:smw-12549 Conflict of interest: Dr. Aleandri, Simone: I actively collaborate with the PPM service and NograPharma. A semisolid formulation for treating proctitis has been patented. European Patent Application No 22197842.3.
Simone Aleandri (Thu,) studied this question.