PD-1 inhibitors restore the activity of tumor-responsive CD8 + T cells by eliminating the inhibition induced by PD-1 and PD-L1 interaction. This therapy has brought great changes to cancer treatment, but only a few patients can benefit from this therapy. There is evidence that the lack of effective T cell activation may be one of the reasons.
In a study published in nature communications, researchers from the Institute of Biophysics, the Chinese Academy of Sciences developed a fusion protein (PD-1AB21) of PD-1 antibody and IL-21, which can block the interaction between PD-1 and PD-L1 and target IL-21 to T cells expressing PD-1. Studies have confirmed that this fusion protein has a strong anti-tumor effect in a variety of tumor models.
The γ C cytokine family plays an important role in the intensity and function of CD8 + T cell response, and compared with other γ C cytokines, tumor-reactive T cells regulated by IL-21 have better anti-tumor effects in vivo. Studies have shown that IL-21 can enhance the efficacy of CTLA-4 antibody or PD-1 antibody in the preclinical model.
Based on this, the researchers developed a fusion protein using the non-covalent homodimer form (diabody) of single-chain Fv fragment (scFv) of PD-1 antibody.
The researchers observed that PD-1AB21 completely blocked the binding of PD-L1 IGFC after binding to EG7 lymphoma cells expressing PD-1 and activated CD8 + T cells. In addition, the effect of PD-1AB21 on the proliferation of pro-B cell line Baf3 was the same as that of recombinant IL-21.
After in-depth exploration, researchers found that PD-1AB21 can target IL-21 to activated T cells, and can more effectively induce activated CD8+ T cells to differentiate into TSCM cells than recombinant IL-21.
TSCM cells have strong proliferative potential, long-term survival ability, and the ability to produce all memory and effector T cell subsets after exposure to antigens.
After PD-1AB21 treatment, tumor-bearing mice showed an increase in the frequency of TSCM and a large number of tumor-specific memory T cells, and the anti-tumor effect of this fusion protein was better than that of the combination therapy of PD-1 antibody and IL-21. In addition, PD-1AB21 significantly enhanced the therapeutic effect of the cancer vaccine.
In general, this strategy can promote the production of memory T cells by targeting cytokines to tumor-reactive T cells at the same time, so as to improve the therapeutic effect of immune checkpoint blockade.
Although the efficacy of PD-1AB21 is outstanding, there are still some shortcomings, because the half-life of PD-1 antibody in the single chain of PD-1AB21 is very short in vivo. Therefore, the authors believe that the fusion of PD-1 antibody with IL-21 will be more effective.
Ying Li, Yanni Cong, Mingming Jia, et al. Targeting IL-21 to tumor-reactive T cells enhances memory T cell responses and anti-PD-1 antibody therapy. Nat Commun. 2021 Feb 11;12(1):951. doi: 10.1038/s41467-021-21241-0.