Anti-cancer Protein

Development of Oral delivery-based optimized therapeutic proteins for cancer and infection treatment.

Protein-based therapeutics are considered a safer alternative to conventional drug therapies due to its high specificity and efficacy, while imposing minimal burden to the patient’s bodily function. However, the administration of such proteins often requires invasive procedures while requiring the assistance of professional medical care experts. Additionally, the widespread use of conventional protein-based anticancer treatments is limited by the poor absorption and instability issues, requiring higher dosage of the administered therapeutic protein to elicit a desired response. Additionally, the bioactivity of protein-based anticancer agents is dependent on the protein-protein interactions, governed by the protein-size, binding pocket depth, contiguous binding sites and ligand availability.    

This research proposes the development of a stable oral-delivery system, carried out through three main foci. First, the development protein-tags for efficient protein therapeutics across the intestinal barrier. Second, the optimization of therapeutic proteins to survive the harsh gastro-intestinal environment. Third, increasing protein target specificity towards specific ailments. Basing on currently known proteins that facilitate intestinal barrier permeability, such as human lactoferrin, this study aims to investigate the protein domains that facilitate natural bio-absorption of this protein into the host blood stream. Additionally, through sequence comparison and protein modelling using various platforms, such as the Enzyme Function Initiative-Enzyme Similarity Tools, we intend to further optimize these proteins to increase the bio-absorption and stability of the protein tags. Similarly, through mathematical modelling and rational design, the study aims to increase the therapeutic protein payload tolerance towards the harsh gastro-intestinal environment, such as extreme pH conditions, and proteolytic digestion by the host and its microbiota. In order to further improve the specificity and efficacy of these proteins, the therapeutic protein is subjected to the Design-Build-Test-Learn cycle looking specifically on surface-biomarker binding tags for target specific delivery of the therapeutics and increasing the therapeutic protein bioactivity. The study aims to improve the bioactivity of these therapeutic proteins by at least two to three orders of magnitude. This study aims to target two main ailments, cancer and infection. As a proof-of-concept, the study specifically looks into targeting pancreatic and breast cancer, and infiltrative microbial infections such as Helicobacter pylori and Fusobacterium nucleatum.

The development of these proteins has a two-pronged function. First, the direct use of these therapeutic protein as a bench-to-bedside therapy. Second, as an effector tool for sustainable delivery of therapeutic proteins using gut-residing probiotic and commensal microbes.

Developing intestinal permeable tags for efficient orally-administered therapeutic proteins, and engineering therapeutic proteins to improve stability, specificity and efficacy against cancer and infections. The study aims to increase the bioactivity of these proteins in the host body by increasing the specificity and efficacy by at least two to three orders of magnitude. This work will provide an alternative to orally-administered conventional therapeutic drugs by exerting the desired bioactivity on the target, while leaving minimal metabolic burden to the host body.