Polymer cloak stabilizes cytokine complexes to generate tumor-targeted nanosuperagonists
A group led by Professor Horacio Cabral has discovered a new way to build therapeutics based on protein complexes.
Professor Cabral is a visiting researcher at the Innovation Center for Nanomedicine (iCONM) and an associate professor at the Department of Biotechnology, Graduate School of Engineering, University of Tokyo.
The paper, titled “Nano-enabled IL-15 superagonist via conditionally stabilized protein-protein interactions eradicates solid tumors through precise immunomodulation,” was published on October 2, 2024. Published in the Journal of the American Chemical Society.
Protein complexes are important regulators of diverse biological processes and exhibit unique features that make them promising candidates for therapeutic applications. For example, interlukin-15 (IL-15) can bind to its receptor alpha domain (IL-15Rα) to form a hyperagonistic complex, which enhances the transduction of IL-15 into immune cells. presentation and can effectively activate anti-tumor immunity.
However, protein complexes are formed primarily through dynamic noncovalent interactions, resulting in instability and transient shelf life in biological environments. Therefore, delivery strategies are required to mediate stable delivery of protein complexes.
In the present study, we present a polymeric cloak designed to support the use of protein conjugates as therapeutic agents, as demonstrated in a prototype formulation loading the IL-15/IL-15Rα complex.
Polymer coating stabilizes the protein-protein interaction between IL-15 and IL-15Rα, effectively immobilizing the complex and isolating the complex from its surroundings, producing an IL-15 nanosuperagonist with improved efficacy. did. In mouse models, nanosuperagonists showed improved pharmacokinetics and stably delivered intact protein complexes upon intravenous injection.
Moreover, the pH sensitivity of the polymeric cloak allows nanosuperagonists to sense the acidic tumor microenvironment and ensure tumor-selective activation. In a mouse colon cancer model, the nanosuperagonist deeply inflamed the tumor and eliminated cancer cells without inducing immune-related side effects.
As shown in this study, the IL-15/IL-15Rα complex can be disrupted by monomeric IL-15 and external reactive species such as proteases, leading to rapid disintegration of the complex in vivo. There is.
In contrast, the polymeric cloak linked the complex and protected its integrity even in harsh environments such as the bloodstream. Therefore, the polymer cloak may promote protein complex stability and function in in vivo conditions, which is important for achieving therapeutic activity.
While reported methods for delivering protein complexes have focused on manipulating the structure of proteins to create stable fusion proteins, this polymeric cloak has been developed through the design and fabrication of protein engineering techniques. It bypasses the complexity of
Furthermore, this system can be easily extended to apply to other protein complex payloads beyond the illustrated IL-15/IL-15Rα complex, serving as a universal platform. Moreover, benefiting from the pH-sensitive nature of the polymeric cloak, this system not only mediated the stable delivery of intact protein complexes throughout the body, but also achieved further tumor-targeted cargo release. .
In the case of IL-15-based nanosuperagonists, the polymer coating stabilizes the IL-15/IL-15Rα complex to provide antitumor superagonism, and pH-controlled polymer uncoating provides tumor-specific activation is now possible. Reduced toxicity.
Therefore, compared with conventional fusion protein-based IL-15 superagonist formulations, nanosuperagonists achieved safer treatment. In summary, polymer cloaks provide a streamlined platform for tumor-targeted delivery of protein conjugates and stimulate further investigation of polymer- and nano-based approaches to facilitate translation of protein conjugates as therapeutic agents. Probably.
Further information: Pengwen Chen et al., Nanoenabled IL-15 Superagonist via Conditionally Stabilized Protein-Protein Interactions Eradicates Solid Tumors by Precise Immunomodulation, Journal of the American Chemical Society (2024). DOI: 10.1021/jacs.4c08327
Provided by: Nanomedicine Innovation Center
Citation: Polymeric cloak stabilizes cytokine complexes and generates tumor-targeting nanosuperagonists (October 4, 2024) https://phys.org/news/2024-10-polymeric-cloak-stabilizes- Retrieved October 4, 2024 from cytokine-complex.html
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