PD-1 antibody "new partner": fusion IL-21

Text | Li Yuan

PD-1 inhibitors can restore the vitality of tumor-reactive CD8+ T cells by eliminating the inhibitory effect induced by the interaction of PD-1 and PD-L1.

In a study published on Nature Communications on February 11, researchers from the Institute of Biophysics, Chinese Academy of Sciences developed a PD-1 antibody and IL-21 fusion protein (PD-1AB21), which can Targeting IL-21 to T cells expressing PD-1 while blocking the interaction between PD-1 and PD-L1.

Source: Nature Communications

The γc cytokine family plays an important role in the strength and function of CD8+ T cell response, and compared with other γc cytokines, tumor-reactive T cells (tumor-reactive T cells) produced under the regulation of IL-21 are in vivo It has a better anti-tumor effect in the experiment.

Based on this, the researchers developed a fusion protein that uses a non-covalent homodimer (diabody) of the PD-1 antibody single-chain antibody fragment (scFv).

The cloning strategy and domain assembly of PD-1Ab21 (Source: Nature Communications)

The researchers observed that PD-1AB21 completely blocked the binding of PD-L1IgFc after binding to EG7 lymphoma cells expressing PD-1 and activated CD8+ T cells.

This indicates that PD-1AB21 can bind to PD-1 on activated T cells, blocking the interaction of PD-1 and PD-L1, while maintaining the biological activity of IL-21.

The binding of PD-1Ab21 to cells expressing PD-1 (Source: Nature Communications)

After in-depth exploration, the researchers found that PD-1Ab21 can target IL-21 to activated T cells, and compared to recombinant IL-21, it can more effectively induce activated CD8+ T cells to differentiate into TSCM cells (memory stem T cells).

TSCM cells have strong proliferation potential, long-term survival ability and the ability to generate all memory and effector T cell subsets after exposure to antigen.

Tumor-bearing mice showed an increase in the frequency of TSCM and a large number of tumor-specific memory T cells after PD-1AB21 treatment, and the anti-tumor efficacy of this fusion protein was superior to the combination therapy of PD-1 antibody and IL-21.

PD-1Ab21 has excellent anti-tumor effects (Source: Nature Communications)

In general, this treatment strategy promotes the production of memory T cells in the body by simultaneously targeting cytokines to tumor-reactive T cells, thereby improving the therapeutic effect of immune checkpoint blockade.

Although the curative effect of PD-1AB21 is outstanding, there are still shortcomings, because the half-life of the single-chain PD-1 antibody in PD-1Ab21 is very short in the body.

Reference materials:

[1] Li, Y.