Science Immunology: Peng Hua/Fu Yangxin collaborate to develop a new generation of high-efficiency, low-toxicity tumor-specific IL-12 prodrugs

Interleukin 12 (IL-12) is a heterodimer composed of P35 and P40 subunits and is one of the main cytokines that induce cellular immunity
.

In the tumor microenvironment, IL-12 stimulates activated T cells and natural killer (NK) cells to release toxic enzymes or secrete effector cytokines such as IFNγ, which are critical for tumor clearance

With the strong antitumor activity of IL-12, the upsurge of IL-12 clinical research was set off in the 1990s
.

Because of the short half-life of IL-12 in the body, in order to achieve sufficient blood concentration, IL-12 is often administered intravenously for multiple times in clinical treatment, resulting in IL-12 stimulating immune cells in the activated blood circulation before reaching the tumor site , while also producing serious side effects such as dose-related cytokine storm or liver or other organ tissue damage

On January 7, 2022, Peng Hua's team from the Institute of Biophysics, Chinese Academy of Sciences and Fu Yangxin's team from the University of Texas Southwestern Medical Center published a paper entitled: A tumor-specific pro-IL-12 activates preexisting cytotoxic T cells in the journal Science Immunology Research paper to control established tumors
.

For the first time, the research team designed a prodrug of IL-12 (pro-IL-12) that can specifically release activity in the tumor microenvironment, and further explored this new-generation, low-toxicity tumor-specific interleukin-12 prodrug.
This design strategy can also be applied to the modification or transformation of other cytokine drugs
.

For the first time, a prodrug of IL-12 (pro-IL-12) that can specifically release activity in the tumor microenvironment was designed, and this new-generation, low-toxicity tumor-specific prodrug of interleukin-12 was further explored.
Molecular anti-tumor mechanism, the design strategy can also be applied to the modification or transformation of other cytokine drugs.
For the first time, a prodrug of IL-12 (pro-IL-12) that can specifically release activity in the tumor microenvironment was designed.
, and further explored the anti-tumor mechanism of this new-generation, low-toxicity tumor-specific interleukin-12 prodrug molecule.
This design strategy can also be applied to the modification or transformation of other cytokine drugs.

In order to prolong the half-life of IL-12, the research team first constructed a recombinant IL-12-Fc fusion protein
.

On this basis, pro-IL-12 was further designed: the activity of IL-12 was blocked with the extracellular binding domain of the IL-12 natural cell receptor, and the receptor and IL-12 were connected by a cleavable matrix metalloproteinase substrate.

Further mechanism studies have found that pro-IL-12 can directly act on killer T cells (CTL) in tumors and promote their secretion of IFNγ to play an anti-tumor effect
.

Tumors driven by proto-oncogenes in the clinic often fail to respond to immunotherapy.

How to overcome resistance to immune checkpoint blockade drugs (ICBs) is a challenge for clinical immunotherapy
.

The research team proposed and demonstrated that pro-IL-12 provides the third signal of T cell activation, which enhances its activity while releasing T cell immunosuppression, and finally overcomes anti-PDL1 resistance

Proposed and demonstrated that the third signal of T cell activation provided by pro-IL-12, enhances its activity while relieving T cell immunosuppression, and finally overcomes anti-PDL1 resistance Proposed and demonstrated that pro-IL-12 provides The third signal of T cell activation, enhances its activity while lifting T cell immunosuppression, and finally overcomes anti-PDL1 resistance

Diyuan Xue, Ph.
D.
, Institute of Biophysics, Chinese Academy of Sciences, and Benjamin Moon, Ph.
D.
, University of Texas Southwestern Medical Center, are the co-first authors of this paper; Hua Peng, researcher, Institute of Biophysics, Chinese Academy of Sciences, University of Texas Southwestern Medicine Professor Fu Yangxin from the center is the co-corresponding author of this paper
.

The research was funded by the National Science and Technology Major Project

Original source:

Original source:

DIYUAN XUE, et al.

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