Sci Adv Tang Li's team uses chemical methods to achieve specific activation of immunomodulatory proteins in tumor tissues

Responsible Editor | Enzyme Co-stimulation is one of the necessary biological signals to activate T cell immune response, and it plays an irreplaceable and important role in tumor immune regulation
.

In recent years, immunotherapy represented by co-stimulatory agonist antibody and cytokine has shown great potential in pre-clinical experiments, but its clinical application has been severely restricted by its triggering in healthy tissues.
Systemic toxicity caused by non-specific immune response
.

To solve this problem, Tang Li's research group at the Federal Institute of Technology in Lausanne (EPFL) designed a new "Switchable Immune Modulator (Sw-IM)" program
.

This scheme uses special physiological conditions such as high reducibility and weak acidity in the tumor microenvironment, and connects PEG and other environmentally responsive chemical bonds such as disulfide bonds, maleimide and other environmentally responsive chemical bonds.
The polymer is modified to the amino group on the surface of the immunomodulatory protein to block its biological activity
.

When administered in vivo, the biological activity of Sw-IM remains "closed" in the blood circulation and healthy tissues, thereby greatly reducing the systemic toxicity of immunotherapy
.

When Sw-IM enters the tumor tissue with the blood circulation, the specific stimulation of the tumor microenvironment can effectively cut off the environmentally responsive chemical bond in the connection structure to remove the shielded polymer, thereby specifically "turning on" in the tumor tissue "The biological activity of immunomodulatory proteins
.

This result was published in Science Advances on September 11 under the title: Switchable immune modulator for tumor-specific activation of anticancer immunity
.

Sw-IM technology was first applied to the costimulatory antibody anti-4-1BB
.

Compared with ordinary anti-4-1BB antibodies, the "switched" anti-4-1BB antibody (Swredoxa4-1BB) with redox responsiveness can effectively avoid excessive activation of the spleen and spleen while maintaining the anti-tumor immune effect.
CD8+ T cells in healthy liver tissues and their toxicity and tissue damage
.

Since amino groups are generally present on the surface of proteins in large numbers, Sw-IM technology is also widely used in immunity including anti-PD-1, anti-CTLA-4 immune checkpoint blockers and IL-2, IL-15 and other cytokines.
Regulatory protein drugs
.

In clinical treatment, immunomodulatory proteins are often combined with adoptive T cell transfer (ACT) to enhance the treatment effect of the latter on solid tumors
.

However, in this type of combination therapy, the systemic toxicity caused by the massive expansion of immune cells in healthy tissues is usually more serious
.

Tang Li’s group used the “switch-type” IL-15 cytokine super agonist (SwredoxIL15) in combination with adoptive T cells, which not only achieved the anti-tumor effect of ordinary IL-15 super agonist combined with adoptive T cells, but also It effectively avoids the activation and expansion of CD8+ T cells and NK cells in healthy tissues, and significantly reduces liver damage indicators such as alanine aminotransferase (ALT) and aspartate transferase (AST) in serum, showing The huge application potential of Sw-IM technology
.

Thanks to the richness of environmentally responsive chemistry, the design of Sw-IM is highly modular
.

In addition to being suitable for various immunomodulatory proteins, Sw-IM can also be adapted to diverse tumor microenvironments by selecting different environmentally responsive chemical connection structures
.

In this work, Sw-IM can achieve "traceless release" of immunomodulatory proteins through the precisely designed "self-immolative structure"
.

On the other hand, by changing the type, molecular weight and modification density of the shielding polymer, the sensitivity of Sw-IM to specific stimuli in the tumor microenvironment can be designed and adjusted, so as to further balance and optimize the safety and anti-tumor activity of Sw-IM
.

At the end of this work, the team found and reported the general rules of Sw-IM design through screening of different shielding polymer molecular weights and modification densities
.

© LBI / EPFL / Yu Zhao This research is based on chemical methods, which opens up new ideas for improving the safety of co-stimulatory immune protein treatment, and also provides more feasibility for its clinical application
.

The first author of this work is Dr.
Zhao Yu from Tang Li's research group, and the corresponding author is Professor Tang Li
.

Introduction of Tang Li Laboratory: Engineering immunity-disease interactions for enhanced cancer immunotherapy.
Tang Li Laboratory at the Federal Institute of Technology in Lausanne, Switzerland, is committed to tumor immune engineering research, that is, integrating biology, chemistry, mechanics and other disciplines and methods to develop safe and effective tumor immunity Therapy
.

The laboratory has published papers in Nat.
Immunol.
, Nat.
Biotech.
, and ACS Cent.
Sci
.

Welcome doctoral students and postdoctoral fellows with relevant academic backgrounds to join.
For more information, please visit