IL2 Cell Screening Model

Baijiein-2 (IL-2) is a T cell growth factor-induced by antigen-stimulated, and it is also a multi-effect cytokines that play a key role in the immune response. As a powerful induction of cytotoxic T cells and NK cells, IL-2 is one of the earliest immunotherapy drugs for the treatment of metastatic melanoma and renal cell cancer. Unfortunately, IL-2 immunotherapy has not been widely used after being approved due to its short period of half-life and severe toxicity in the treatment dose. In addition, IL-2 will also proliferate through binding to the IL-2 receptor α (IL-2RA). It is proven to enhance the anti-tumor immunity that can be enhanced by IL-2, which indicates that Treg may be the main obstacle of IL-2 mediated CTL amplification.

IL-2 uses the stimulus and adjustment function through binding with various types of IL-2 receptors, including monomers, di agents, and trimer IL-2 receptors. Some T cells, such as TREGS, express the high-end and heterogeneous trimer receptors composed of CD25 (IL-2RA), CD122 (IL-2RB), and CD132 (common cytokine receptor γ chain) subunit.

In contrast, the initial CD8 T cells, CD4/CD8 memory T -cells, and NK cells express a low -affinity diode receptor, and the receptor lacks CD25 sub -ina. There are obvious differences between the affinity between different types of IL-2 receptors and IL-2. When the heterogeneous triterom receptor is the highest-combined with IL2, the di-polytic receptor formed by CD122 (IL-2RB) and CD132 (common cytokine receptor γ chain), its affinity is second, about about the next, about about Only one percent of the trimer, and when the IL-2 receptor α sub-submall (IL-2RA) exists alone, its affinity is the lowest, and the separate IL-2ra does not conduct intracellular signals. It is necessary to rely on β/γ subunit, and the main role of α subunit is to promote the combination of IL-2. (As shown below)

It is precisely because of the difference between IL-2 and its different types of receptors that the effect of double-edged sword in tumor treatment in tumor treatment. On the one hand To achieve the effect of killing tumor cells; on the other hand, IL-2 can also be combined with the Sanya receptor of αβγ, thereby combining and activating other non-effect T cells, such as regulating T cells. The main reasons for cells to produce toxic side effects and are not conducive to the immunosuppressive effect of antitumor.

In order to reduce toxicity and prevent the targeted effect of TREG cells, people have always tried to use various methods to transform IL-2. Activation of non -effect T cells. Despite similar ideas, the technical routes adopted are endless:

For example, by adding multiple polyethylene glycol (PEG) molecules to the IL-2 molecules, the activity is closed. After injection of the patients, the PEG molecule in the body will gradually fall off to form a activity. 2 -PEG and 1-PEG IL-2 molecules, and the position of the PEG can just block the α chain of the receptor, make the drug specific binding to the beta chain, and realize the proliferation of T cells and NK cells while not interfere with TREGS. At the same time, PEG's modification is also conducive to increasing the half-life of IL-2 and making it longer in the body. The typical representative of this strategy is NKTR-214 and Sanofer's Thor-707.

The LTC002 developed by Zhidao Biological Development, by introducing additional sulfur bonds inside IL-2, makes IL-2 more structurally stable at the same time, can also form barriers, so that IL-2 molecules can achieve damage as possible as possible as possible as possible as possible. The binding plane with the alpha receptor makes it impossible for mutant molecules to be combined with alpha receptors, but it can be binding with β and γ receptor subcontraction.

A drug developed by Alkermes Nemvaleukin adopts the strategy of incorporating the C-end of the IL-2 molecule with an extracellular region of IL2Rα subunit. To achieve the purpose of blocking its IL-2Rαβγ subunit, it does not affect the purpose of binding with IL-2Rβγ subunit, thereby selecting a selective activation effect T cell.

Another tried strategy is to introduce IL-2 that introduces specific mutations and blends with antibodies that identify tumor special antigen. The antibody of the tumor-specific antigen is identified to position the IL-2 mutant to the tumor site. Combined with the T cell surface IL-2R β medical diometer in the tumor microe environment, thereby activating the immune effect of anti-tumor in the micro-environment. Roche developed RO6874281 and RG7813 are all products of this strategy.

In addition to the positioning of IL-2 specificity to the tumor site, you can also try to target the IL-2 specificity to specific immune cells. For example, RG6279 (RO7284755) developed by Roche is a PD1 antibody fusion IL-2 mutation. Body, it uses PD-1-specific targeting T cells to block PD-1-mediated immunosuppressing while activating T cells and kill tumors; AB248 developed by Asher Biotherapeutics is a target To the IL-2 drug that activates CD8 positive T cells, one of it can be combined with the IL-2 receptor on the cell surface, and the other is combined with the specific biomarkers expressed on the surface of CD8 positive T cells. Only these two are these two two. In part with the two different molecules on the cells at the same time, the effect of activating cells can be activated.

With the rapid development of biological informatics and AI technology in recent years, people have also tried to design the biased IL-2 drugs by computer design. In May 2022, Biolojic Design announced that the company's AU-007 launched clinical clinical clinical clinical was announced. Studies, this is an IL-2 antibody, and the first innovative antibody drug that enters the clinic that comes from computer design. This is finally obtained through computer design and in vitro evolution. The interaction of CD25 (that is, α subunit), which makes the endogenous IL-2 selective induction effect T cell activation without affecting other non-effect T cells.