Researchers at the Innovation Center for NanoMedicine (iCONM) have developed a novel method to stabilize protein complexes, paving the way for more effective cancer treatments. The team, led by Prof. Horacio Cabral, has discovered a polymer cloak that can enhance the stability and tumor-targeting ability of the IL-15/IL-15Rα complex, a powerful immunotherapeutic agent. This breakthrough could inspire further advancements in protein complex delivery and unlock new possibilities in cancer immunotherapy.
Stabilizing Protein Complexes
As the regulation of many biological processes relies on interactions between protein complexes, unique functions or druggable interaction sites are often found within the folds made by such complexes. For example, the IL-15/IL-15Rα complex can efficiently provide antitumoral immune activation via trans-presentation of IL-15 to immune cells. Nevertheless, such protein complexes tend to be bound by manner of non-covalent and therefore inherently individually unstable forces destabilizing them in vivo.
Seeking a solution to this problem, the team of researchers primary among whom was Prof Cabral have devised a polymer cloak for statin like functions which can help to avoid denaturing or degradation and said complex, thereby rendering the nanoconjugate ‘a nanosuperagonist’ since its ability exceeds natural IL 15 when unbound. A the polymer coating that contains and interlocks the complex also isolating it from any environmental resits must be established. This new method is unique and different from previous approaches that were based on the engineering of protein structures for provide stable fusion proteins, which goes a step towards that of simplifying the designing and manufacturing.
Delivery and Tumor-Selective Activation
In addition, the polymer overcoat made by the researchers stabilizes the protein complex and even possible to tumor-targeted delivery and activation. Since the cloak is pH-responsive, it can sense the slightly acidic environment of a tumor and release its cargo only there. They show that it is a targeted strategy, so the nanosuperagonist performs its potent antitumor effects at the site of the tumor and minimizes side effects in healthy tissues.
Indeed, in mouse models of colon cancer, the nanosuperagonist was shown to dramatically inflame the tumor and result in its elimination — with no detectable side effects associated with treatment other than anti-cancer immunity. This polymer cloak provided the nanosuperagonist with favorable stability and enhanced accumulation in tumors, which ultimately led to a more effective and less toxic therapy by contrast to conventional fusion protein-based IL-15 superagonist formulations.
Making the Most of Multi-Subunitiqué Protein Complexes
The polymer elucidates the multifunctional coated platform to deliver protein complexes that could be applicable for more than just IL-15/IL-15Rα complex, as demonstrated by the iCONM team. Stability to the complex from external environment proved that the cloak insulates the protein–protein interactions, which is a major issue in utilizing protein complexes as therapeutic agents.
Our study suggests that we can use materials to control protein complex assembly and offers a potential direction for polymer- and nano-based strategies to support the development of new therapies based on protein complexes. Compared to engineering stable fusion proteins, the polymer cloak strategy is easy designable and manufacturable which makes this technology accessible and scalable; as the researchers note in their report. This innovation can enable increased stabilization and tumor targeting properties for protein complexes, likely leading to improvements in cancer therapy and new horizons in the field of protein-based drug discovery.
