Nature important finding: PD-1 antibody "new partner" - PCSK9 inhibitor

SOURCE: In a new study published In the journal Nature on Nov. 11, a team of researchers from Duke University Medical Center confirmed that PCSK9, a key protein that inhibits cholesterol metabolism, can improve tumor response to immunosuppressants through a mechanism that does not rely on PCSK9 cholesterol regulation.
using CRISPR technology to remove the PCSK9 gene from cancer cells in mice significantly weakens or prevents cancer cells from growing in mice by relying on cytotoxic T cells.
the PCSK9 gene also greatly enhances the efficacy of PD-1 antibodies.
addition, studies have confirmed that in cancer mouse models, approved PCSK9-listed antibodies and PD-1 antibodies have developed synergies in inhibiting tumor growth.
the new study is based on previous research by Professor Chuan-Yuan Li of Duke University Medical Center and colleagues.
they have found that lowering blood cholesterol appears to improve cancer immunotherapy.
considering that PCSK9 protein is a key regulator of serum cholesterol levels, Professor Li's team wanted to know whether PCSK9 protein was involved in regulating the tumor's response to immunotherapy.
to assess the effects of PCSK9 on tumor growth, the researchers used CRISPR-Cas9 technology to knock out the PCSK9 gene in four malignant mouse cancer cell linees (B16F10, 4T1, MC38, and CT26).
results found that although knocking out PCSK9 did not change the morphology or in-body growth rate of tumor cells, when PCSK9 defective cancer cells were inoculated into the host of the same source mice, their ability to form tumors decreased significantly compared to the control group.
In the same-origin mice, PCSK9 knock-out weakened tumor growth (Source: Nature) To determine that knocking out PCSK9 weakens tumor growth and is associated with the immune system, the team transplanted PCSK9 defective tumor cells into immunodeficiency mice that lacked T-cells, B-cells, and NK cells, and found that PCSK9 defects had no effect on tumor growth.
since PCSK9 regulates cholesterol levels by promoting lysosome degradation of low-density lipoprotein receptors (LDLR), the study also investigated whether LDLR was involved in regulating tumor formation in mice.
results showed that tumor growth and decay caused by PCSK9 defects were not affected by host LDLR status or cholesterol levels.
To assess whether PCSK9 defects worked in collaboration with immuno-checkpoint blocking therapy, the scientists used mouse anti-PD-1 immuno-checkpoint inhibitors in patients who were vaccinated against PCSK9 defects in B16F10, MC38, 4T1, or CT26 tumor cells.
results showed that in all four models, PD-1 antibodies and PCSK9 defects were able to inhibit tumor growth in concert.
inhibition of PCSK9 overcomes tumor resistance to PD-1 antibodies (Source: Nature) Professor Li's team investigated whether the two PCSK9 neutral antibodies approved for the treatment of hyperlipidemia, 1volocumab or alirocumab, could work in synergy with PD-1 antibodies.
both drugs have been shown to be effective in lowering cholesterol in mice.
results show that although PCSK9 antibody monotherapy can also delay the growth of MC38 tumors, when used in union with PD-1 antibodies, the effect is significantly improved, and some mice achieve long-term survival.
study also assessed whether PCSK9 antibodies also play a role in tumors that are resistant to immunosuppressants.
through 3 rounds of in vitro/in vitro screening, the researchers built a model of MC38R colon cancer resistant to PD-1 antibodies and treated them with PD-1 antibodies and/or evolocumab.
results showed that for MC38R tumors, evolocumab monotherapy or in combination with anti-PD-1 therapy showed anti-tumor activity.
PCSK9 deletion enhances in-tumor T-cell immersion (Source: Nature) Further studies have shown that inhibiting PCSK9 by removing genes or using PCSK9 antibodies can increase the expression of the main tissue compatible complex I (MHC I) molecules on the surface of tumor cells and promote cytotoxic T-cell immersion into tumors.
the mechanism, it has been found that PCSK9 can block the recycling of MHC Class I molecules on the cell surface by physically acting with MHC Class I molecules and promoting their repositioning and degradation in lysosomes.
normally, the identification of tumor antigens by cytotoxic T-cell surface T-cells (TCR) depends on the delivery of MHC-I molecules on the cancer cell surface.
increasingly large, the loss of the ability of MHC molecules to present tumor antigens is an explanation for cancer cells' escape from the immune system.
PCSK9 promotes the degradation of lysosome-mediated MHC Class I molecules in tumor cells (Source: Nature) Scientists believe that the study reveals an important role of PCSK9 in regulating MHC Class I molecular levels on cell surfaces, thereby affecting in-tumor immunoinfedulation, a new mechanism with great conversion potential.
results show that inhibition of PCSK9 is a promising method to enhance the efficacy of immunosupergent inhibitors.
PCSK9 may promote in-tumor immersion of T-cells, making tumors more sensitive to immuno-checkpoint therapy.
the study provides a compelling theoretical basis for future clinical trials in cancer patients to investigate the combined treatment strategy of "PCSK9 inhibitors and immunosuper inhibitors."
" is an important finding.
our study confirms that tumor growth slows by inhibiting the effects of the PCSK9 protein.
we have been tested in a number of different mouse tumor models and have observed effective anti-cancer effects in melanoma, breast cancer and colon cancer models.
addition, an analysis of previously published human data suggests that pcSK9 protein may also be a good target for several other cancers, including liver, lung and kidney cancers.
next step, we will conduct clinical studies to investigate the therapeutic potential of PCSK9 inhibitors such as evolocumab or alirocumab combined immunosuppressants.
," concludes Professor Li.
PCSK9 targeted drug is one of the most popular varieties in the field of pharmaceutical research and development in recent years, and has attracted much attention as a new generation of fat-lowering drugs.
PCSK9's ability to regulate cholesterol levels is based on its ability to lower LDLR levels on the cell surface, thereby reducing cholesterol metabolism (PCSK9 inhibits the recycling of LDLR on the cell surface by redirecting LDLR into the lysosome degradation pathway).
and PCSK9 targeted drugs can reduce LDL levels in the blood by inhibiting the binding of PCSK9 to LDL receptors, thereby increasing the number of available LDL receptors on the surface of liver cells to remove LDL, thereby reducing low-density lipoprotein cholesterol (LDL-C) levels in the blood (an increase in LDL-C is one of the important factors affecting cardiovascular disease). Part
Table 1 approved for listing and clinical development of PCSK9 targeted drugs adaptation certificate includes approved market adaptation certificate and adaptation certificate in research (source: NextPharma database) According to NextPharma database, in addition to the approved listing of evolocumab and alirocumab, there are currently several PCSK9 targeted drugs in clinical development worldwide.
there are several domestic companies in the phase II/III clinical, such as Junshi Bio's gongericimab (antibody), Cyntharma Bio's tafolecimab (antibody), Kangrong Oriental's ebronucimab (antibody), Siweier Pharmaceutical's CVI-LM001 (small molecule), Hengrui Pharmaceutical's SHR1209 (antibody).
it is worth mentioning that Junshi Bio, Xinda Bio and Hengrui Pharmaceuticals have PD-1 antibodies approved for the market.
the latest findings may be an important reference for their development of a new combined treatment called PD-1 Antibodies and PCSK9 Antibodies.
reference: 1' Spite-lowering Drugs Appear to Boost Cancer Cancer Immunotherapies (Source: Duke University Health System) 2# Xinjian Liu et al. Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer. Nature(2020).