Cancer immunotherapy drugs called PD-1 inhibitors are widely used to stimulate the immune system to fight cancer, but many patients either do not respond to these drugs or develop resistance. A novel small-molecule drug candidate called ABBV-CLS-484 being tested in an early-stage clinical trial aims to improve patient response to such immunotherapies.
Now, in a new study, researchers from The Broad Institute, AbbVie, and Calico Life Sciences report that the small-molecule drug ABBV-CLS-484 slows tumor growth and improves survival in experimental mice through two different mechanisms - making tumors more sensitive to immune attack and boosting the activity of immune cells. The findings were published online Oct. 4, 2023, in Nature under the title "The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumor immunity ".
The molecule works by blocking the PTPN2 and PTPN1 proteins, which normally shut down a cell's ability to sense signals that activate immune cells. These authors found that by inhibiting PTPN2/N1, the molecule turns immune cells called T cells and NK cells into more effective tumor cell killers, while also making tumor cells more vulnerable to attack. Blocking PTPN2/N1 also helps reduce T-cell exhaustion, which is a type of T-cell dysfunction thought to be at the root of resistance to certain cancer immunotherapies.
The molecule works by blocking the PTPN2 and PTPN1 proteins, which normally shut down a cell's ability to sense signals that activate immune cells. These authors found that by inhibiting PTPN2/N1, the molecule turns immune cells called T cells and NK cells into more effective tumor cell killers, while also making tumor cells more vulnerable to attack. Blocking PTPN2/N1 also helps reduce T-cell exhaustion, which is a type of T-cell dysfunction thought to be at the root of resistance to certain cancer immunotherapies.
The molecule's dual mechanism of action - targeting both tumor cells and immune cells - is unique compared to other cancer immunotherapies, including PD-1 drugs, which these authors believe may explain why the molecule is so effective in animal models and may not even need to be used in combination with other drugs, such as anti-PD-1 therapies.
AbbVie and Calico Life Sciences discovered the molecule, called ABBV-CLS-484, in 2017, after researchers from The Broad Institute's Tumor Immunotherapy Discovery Engine (TIDE) found the PTPN2 gene to be a promising cancer immunotherapy target (Nature, 2017, doi:10.1038/nature23270). The companies are currently conducting Phase 1 clinical trials of this molecule and another related molecule called ABBV-CLS-579, also developed by them.
Dr. Robert Manguso of the Broad Institute, co-corresponding author of the paper, said, "This is an unprecedented opportunity to assess how the immune response works. The ability to further explore this signaling pathway in clinical studies is really important."
Manguso and Kathleen Yates co-lead the TIDE program at the Broad Institute, which uses CRISPR screens and other tools to systematically identify genes such as PTPN2 in animals that cancers use to evade immune therapies.TIDE Senior Research Scientist Hakimeh Ebrahimi-Nik and AbbVie's Christina Baumgartner, senior principal research scientist at AbbVie, are co-first authors of the paper. In addition to Manguso and Yates, Jennifer Frost, an AbbVie researcher, and Philip Kym, vice president of global medicinal chemistry at AbbVie, co-led the study in collaboration with Calico Life Sciences scientists.
Yates said, "It still kind of dazzles me that we went from discovering a target in 2017 to starting to test the drug in patients in 2020. Utilizing these partnerships, resources, technologies like CRISPR, and the capabilities of AbbVie's medicinal chemistry - all of these factors come together and it feels like hitting the fast-forward button."
Discovery of the PTPN2/N1 active site inhibitor ABBV-CLS-484.
Image from Nature, 2023, doi:10.1038/s41586-023-06575-7.
Image from Nature, 2023, doi:10.1038/s41586-023-06575-7.
Discovering a mechanism that has the potential to change people's lives is one of the most exciting and rewarding parts of being a drug discovery scientist," Baumgartner said. We work every day with a sense of urgency and dedication because we know that patients are waiting for us. By working with our partners at Calico Life Sciences and the Broad Institute, we are able to rapidly discover, characterize and develop these innovative molecules."
Kym added, "Identifying orally bioavailable small molecule drugs that target the active site of phosphatase analogs is a major challenge. Indeed, previous efforts by the pharmaceutical industry to develop inhibitors targeting the active site of phosphatases have been unsuccessful, and as a result, it is widely recognized as a class of 'undruggable' targets. It is therefore very exciting to see this collaboration succeed in launching this first-in-class clinical candidate."
Marcia Paddock, co-author of the paper and head of new target development in oncology at Calico Life Sciences, said, "This three-way collaboration between Calico Life Sciences, The Broad Institute, and AbbVie demonstrates that the best features of academia combined with the best features of industry can accelerate scientific progress - in this case, translating early biological and target discoveries into clinical compounds, the first known inhibitors of the phosphatase active site."
Controlling cancer
In 2017, in an experiment that would later become the basis for TIDE, Manguso and researchers including W. Nicholas Haining (then at the Dana-Farber Cancer Institute, now at Arsenal Bio) systematically combed through nearly 2,400 cancer genes in mice, looking for genes that made melanoma tumors more or less sensitive to PD-1 inhibitor PD-1 inhibitors. They targeted the PTPN2 gene and found that knocking out the gene made tumor cells more sensitive to anti-PD-1 therapy.
But Manguso and Yates had another reason for hope: PTPN2 is highly expressed in T cells, and previous studies have shown that knocking it out can help activate those cells, thereby improving their ability to control tumors. which inhibits signaling in an important immune pathway called JAK-STAT.
However, because these phosphatases are so strongly charged, pharmaceutical companies have struggled to create inhibitors that bind to the phosphatase active site. This means that the drugs that bind to them must also be strongly charged, which makes it difficult for them to cross the cell membrane and enter the cell.
There was evidence in the literature that this would be very difficult, but AbbVie solved this problem in a very fearless way," Manguso says. This culture of optimism was very important to the ultimate success of the project."
AbbVie scientists succeeded in designing a small molecule called ABBV-CLS-484 that enters cells and binds to the PTPN2 and PTPN1 phosphatases. Tumors in animals treated with the molecule grew more slowly and survived longer than in untreated animals, suggesting that ABBV-CLS-484, unlike many other emerging immunotherapies, may work on its own.
These authors also found that mice treated with both the molecule and an anti-PD-1 drug showed greater benefit, suggesting that the molecule may be used in combination with other immunotherapies in patients.
Harmonizing efficacy
Led by Ebrahimi-Nik of the Broad Institute and Baumgartner of AbbVie, these authors, along with scientists at Calico, discovered the mechanism of action of the small-molecule drug, which may explain why it is so effective in experimental animals. They found that inhibiting PTPN2 and PTPN1 in tumor cells made these cells more susceptible to certain cell-killing signals produced by immune cells, and also made cancer-fighting NK and T cells more active in animal tumors and human blood samples.
In addition, ABBV-CLS-484 appears to reduce T cell exhaustion. T cells treated with this molecule stay functional and divide, helping to control cancer growth even in situations where T cells normally struggle to do their job, such as in tumors where immune cell infiltration is not evident or has spread to other parts of the body.
These authors found that ABBV-CLS-484 leads to an increase in JAK-STAT signaling, which may help keep T cells active and prevent them from failing.Ebrahimi-Nik said this strong effect on T cells has not been observed in other immunotherapies, including anti-PD-1 drugs.
She said, "When we treated the animals with our small-molecule inhibitors, we observed that specific CD8+ T-cell populations in the tumors were more active - they were more efficient, more proliferative, and less depleted. We were very impressed with this."
TIDE researchers are currently working with scientists from AbbVie, Calico Life Sciences and other teams to design a new phase of clinical trials and identify markers of patient response to ABBV-CLS-484.
Yates said, "Eliminating inhibition of JAK-STAT signaling in these T cells makes them extremely effective frontline fighters, while also greatly reducing T cell exhaustion. To our knowledge, this has not been observed before with small molecule immunotherapeutics. We are very much looking forward to learning how this will improve patient response."
