*For medical professionals only
This time, we have finally achieved a two-sided attack on cancer cells.
Robert T. Manguso, Kathleen B. Yates, and others at the Broad Institute at MIT and Harvard University have successfully developed an oral drug called ABBV-CLS-484 (AC484).
AC484 is the first small molecule inhibitor targeting the protein PTPN2/N1 to achieve a double effect, and the first active site phosphatase inhibitor. AC484 can not only enhance the anti-tumor activity of immune cells, but also make tumor cells more sensitive to immune attack.
It is equivalent to handing over the tumor cells and strengthening the firepower of immune cells! The article was recently published in the top issue of Nature [1].
Screenshot of the first page of the paper
Immunotherapy methods such as PD-1/PD-L1 inhibitors have been widely used in cancer treatment, but there are still many patients who do not benefit from them and face the problem of drug resistance.
In 2017, researchers at the Broad Institute revealed for the first time that the proteins PTPN2 and PTPN1 are targets for cancer immunotherapy, and that the absence of PTPN2/N1 in tumor cells can enhance their sensitivity to tumor killers such as IFN-γ, making tumors more sensitive to PD-1 inhibitors [2].
In other work, many research teams have found other bright spots in PTPN2/N1. Studies have shown that PTPN2/N1 is a negative regulator of immune cell activation, which can inhibit the anti-tumor ability of immune cells by dephosphorylating members of the JAK and STAT protein families, and knocking out PTPN2/N1 can improve anti-tumor activity.
In this way, by inhibiting PTPN2/N1, we can hold tumor cells in two bread clips. However, due to the physicochemical properties of PTPN2/N1, the road to the research and development of small molecule inhibitors is very bumpy, and it is even considered to be an "undruggable" target. PTPN2/N1 has a strong charge, so the small molecule drugs bound to it also need to carry a strong charge, but this will cause small molecules to be difficult to penetrate the cell membrane, and they cannot effectively function when administered in vivo, and there are currently no available PTPN2/N1 small molecule inhibitors.
Based on the optimization and exploration of the structure of small molecules that interact with PTPN2/N1, Robert T. Manguso, Kathleen B. Yates and others overcame the challenge to develop the drug AC484 targeting PTPN2/N1 and initially demonstrated its excellent effect in mouse experiments.
Robert T. Manguso（右）和Kathleen B. Yates（左）[3]
In vitro experimental results showed that AC484 had high affinity and high selectivity, and the half of the maximum inhibitory concentrations (IC50) of PTPN2 and PTPN1 were only 1.8 nM and 2.5 nM, respectively, and had no obvious non-specific effect on other proteases such as PTPN9. AC484 also has good pharmacokinetic properties, mostly in free form in plasma and slow clearance, suggesting that AC484 can achieve considerable efficacy in vivo by oral administration.
Molecular structure of AC484
Because inherited deletion variants of PTPN2/N1 are associated with human autoimmune diseases, caution is required in the AC484 dose range to avoid safety concerns associated with systemic suppression of PTPN2/N1.
In mouse experiments, the researchers found that when 3 mg/kg to 150 mg/kg once a day, the mice were well tolerated and did not have significant weight changes. At very high doses (such as 100mg/kg twice a day), it may lead to activation of the systemic immune system of mice, and increased levels of kidney, liver, and joint immune cell infiltration, but these phenomena disappear after 28 days of discontinuation, indicating that the systemic immune response caused by AC484 is reversible.
After the safety issues are resolved, let's take a look at the efficacy. The results showed that oral administration of AC484 at a dose of 150mg/kg once a day could significantly inhibit tumor growth in mouse models of melanoma, breast cancer, pancreatic cancer and other cancers, and inhibit the occurrence of tumor metastasis, improve the survival time of mice, and the efficacy of PD-1 inhibitors was comparable or even better, especially in tumor-bearing mouse models resistant to PD-1 inhibitors.
When AC484 is used in combination with PD-1 inhibitors, it exhibits a synergistic effect and further enhances the efficacy.
Efficacy of AC484 in mouse models of multiple cancer types
From the perspective of mechanism, AC484 attacks tumor cells and immune cells at the same time, reshapes the tumor microenvironment, and mobilizes various types of immune cells.
For tumor cells, AC484 can increase its sensitivity against tumor factors and achieve "breaking defense" for tumor cells.
For immune cells, AC484 treatment will cause a large number of immune cells such as macrophages, dendritic cells, T cells and NK cells to settle into the tumor, and enhance their respective anti-tumor activities, such as antigen presentation and antigen recognition. More importantly, by inhibiting PTPN2/N1 to enhance the signaling of the JAK-STAT pathway, AC484 can enhance and maintain the cytotoxic effect of anti-tumor workhorse CD8+ T cells, preventing their functional depletion.
In summary, the PTPN2/N1-targeting drug AC484 developed by Robert T. Manguso, Kathleen B. Yates et al. is the first small molecule drug to achieve anti-tumor effects that target tumor cells and immune cells at the same time. Given the good pharmacological properties and safety profile shown in preclinical trials, AC484 is currently in Phase I clinical trials for the treatment of solid tumors (NCT04777994) as monotherapy or in combination with PD-1 inhibitors.
In this way, breaking armor and increasing damage, AC484 has all done it. To date, this dual mechanism of action is unique compared to immunotherapies including PD-1 inhibitors[3].
#朋友们, in order not to miss the important research progress of the singularity cake push, you must remember to add a star 🌟 to us~
Bibliography:
[1]https://www.nature.com/articles/s41586-023-06575-7
[2] Manguso, R., Pope, H., Zimmer, M. et al. In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature 547, 413–418 (2017). https://doi.org/10.1038/nature23270
[3]https://www.broadinstitute.org/news/cancer-immunotherapy-candidate-provokes-powerful-dual-response-cancer-and-immune-cells
The author of this article 丨 Eddy Zhang