JEM: Fu Yangxin/Peng Hua collaborated to develop a new generation of tumor-specific anti-PD-1-IL-15 immunotherapy drugs

As a new method of tumor treatment that has developed rapidly in recent years, tumor immunotherapy has made the situation of tumor treatment look new by mobilizing the body's own immune system to fight tumors
.
In particular, immune checkpoint blocking treatment has benefited a large number of cancer patients, and its discoverers have won the Nobel Prize
in Physiology and Medicine in 2018.
Nevertheless, there are still problems such as low response rate and tumor recurrence in immune checkpoint blockade therapy, so more and more effective immunotherapy methods are
still needed.

As an important molecule in the body's immune regulatory network, cytokines also have a very important impact on
the body's anti-tumor response.
Among them, interleukin 15 (IL-15) can effectively promote the proliferation and cytotoxicity of effector cells, including effector CD8+ T cells and NK cells, so it has great potential
in anti-tumor therapy.
However, IL-15 is often accompanied by serious toxic side effects in the process of circulatory system drug administration, which greatly limits the clinical application
of IL-15.

Therefore, finding effective modification or modification methods so that IL-15 can safely and effectively play anti-tumor functions is the key
to solving the dilemma of IL-15 application.
In response to this problem, the basic transformation strategy is: limit the activity of IL-15 in peripheral tissues to avoid serious toxicity, and selectively release the activity of IL-15 in tumor tissues to exert effective anti-tumor effects
.

The "pro-cytokine" prodrug strategy previously proposed by Peng Hua's research group of the Institute of Biophysics of the Chinese Academy of Sciences can effectively reduce toxicity (Cell Res, 2021
).

Recently, Professor Fu Yangxin's team of Tsinghua University School of Medicine, in collaboration with the team of researcher Peng Hua of the Institute of Biophysics of the Chinese Academy of Sciences, published an article in the Journal of Experimental Medicine titled: An engineered concealed IL-15-R elicits tumor-specific CD8+T cell responses through Research paper on PD-1-cis delivery
.

The study proposes another new modification strategy different from "pro-cytokine", according to the structural analysis of IL-15 and its receptor interaction, IL-15 is placed at the carboxyl end of the antibody Fc, forming a steric hindrance, so that Fc physically hinders the binding of IL-15 to the receptor, effectively reducing the activity
of IL-15.
When injected intraperitoneally into mice, the toxicity of IL-15 was significantly reduced, ensuring the safety
of IL-15 use.

To ensure that the masked IL-15 can effectively activate effector cells within the tumor and exert anti-tumor effects, the researchers added PD-1 antibody (aPD-1) to build a aPD-1-IL-15 fusion protein
.
When administered systematically, aPD-1 antibodies can target tumor tissue on the one hand, and bring IL-15 more to the tumor site; On the other hand, aPD-1 antibodies are able to anchor the masked IL-15 to effector cells that highly express PD-1 molecules within the tumor, especially PD-1+CD8+ T cells
.
The researchers found that when the aPD-1 antibody binds to PD-1+ cells, the activity of the masked IL-15 is completely restored
.
In general, the toxicity and antitumor activity of IL-15 are dependent on the activity of IL-15 itself, so it is often accompanied, one wins and one loses
.
The new transformation strategy proposed by the researchers effectively separates the toxicity and antitumor activity of IL-15 spatially, reduces the activity of IL-15 and thereby reduces the toxicity of peripheral tissues by physically covering the formation of steric hindrance, and specifically restores the activity of IL-15 on PD-1+ CD8+ T cells in the tumor by means of PD-1 auxiliary targeting and auxiliary binding, and effectively exerts anti-tumor function
.

Limited by limited fused protein structure information, the mechanism by which masked IL-15 regains activity is unclear
.
The researchers also put forward two hypotheses, one is that when the aPD-1 antibody binds to the PD-1 molecule on the cell, the structure between Fc and IL-15 changes conformationally, so that the originally covered IL-15 is no longer covered, and the activity of IL-15 is completely released
.
The other is that the aPD-1 antibody anchors IL-15 to the cell surface, increases the local concentration of the fusion protein, enhances the binding probability of IL-15 to the receptor, and thus greatly recovers
the activity.
The engineered aPD-1-IL-15 fusion protein exhibits significant inhibition of tumor growth in a variety of mouse tumor models without any toxic side effects
.
In terms of mechanism, the CD8+ T cells pre-existing in the tumor are the main effector cells of the fusion protein to exert anti-tumor function, and the fusion protein can significantly promote the proliferation of CD8+ T cells and enhance the effector ability of CD8+ T cells, which can not only inhibit the growth of in situ tumor, but also inhibit the distal metastasis of the tumor, and provide long-term immune memory protection
.

Anti-PD-1-IL-15-R delivered IL-15-R cis through PD-1, specifically binding and activating PD-1+CD8+ T cells in tumors to exert anti-tumor function pattern diagram Doctoral
students Shen Jiao and Zou Zhuangzhi of the Institute of Biophysics, Chinese Academy of Sciences are co-first authors of this paper; Professor Fu Yangxin of Tsinghua University School of Medicine and Professor Peng Hua of the Institute of Biophysics of the Chinese Academy of Sciences are co-corresponding authors
of this paper.
The research was funded by the national science and technology major special project
.
The Institute of Biophysics laboratory animal platform provided important technical support
for the study.

Paper link: https://doi.
org/10.
1084/jem.
20220745
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