A small molecule from AbbVie and Calico Life Sciences currently in early-stage clinical trials for solid tumors appears to improve the response to PD-1 inhibitors in mice with solid tumors. It also incurs a survival benefit when used on its own.
In the results of a study published Oct. 4 in Nature, researchers from AbbVie, Calico and the Broad Institute at Harvard and MIT reported that mice with pancreatic, breast and metastatic cancer who were treated with an orally-administered small molecule, ABBV-CLS-484, alongside a PD-1 inhibitor outlived controls and had slower tumor growth. Mice that received the drug by itself had a smaller but still statistically significant survival benefit.
Importantly, ABBV-CLS-484 also appeared to reduce T cell exhaustion in mice and reinvigorate exhausted human T cells, a sign that the drug may be able to stave off a major pathway of resistance for immunotherapies.
“Resistance to PD-1 blockade is a major problem in oncology, as the majority of patients show primary resistance to [immune checkpoint blockade],” study co-lead Robert Manguso, Ph.D., of the Broad Institute, told Fierce Biotech Research in an email. “Even among responders, the majority of patients will develop adaptive or secondary resistance. We need new immunotherapies and combinations to improve overall response rates and treat resistant tumors.”
ABBV-CLS-484 inhibits the activity of PTPN1 and PTPN2, both types of enzymes known as protein tyrosine phosphatases. Typically, they act as immune checkpoints by interfering with molecules along JAK/STAT signaling pathways, crucial elements of inflammation. This is helpful for keeping the immune system under control when it’s warding off pathogens, but not so much when it needs all hands on deck to destroy malignant cells, as Manguso explained. Inhibiting PTPN1 and PTPN2 unleashes that portion of the immune response, giving the body another weapon in its anticancer arsenal.
Until recently, though, fighting cancer this way was wishful thinking. Protein tyrosine phosphatases like PTPN1 and PTPN2 were dismissed as “undruggable” targets for a number of reasons, one of which was an electrical problem, so to speak: Since the binding site was positively charged, it would only bind to negatively charged molecules—which usually can’t cross the outer membrane to get into the cell. Previous attempts to develop phosphatase inhibitors that could overcome this had failed.
Still, the case for targeting PTPN1 and PTPN2 was growing. The results of CRISPR screening, published by Manguso’s lab in 2017, suggested that PTPN2 could improve responses to immunotherapy. Around the same time, work from other labs that suggested targeting PTPN1 and PTPN2 together could have a one-two punch of making T cells more effective against cancer while also sensitizing tumor cells to immunotherapy.
“We knew that drugging a phosphatase would be challenging,” Manguso recalled. His lab partnered with AbbVie and Calico to find a solution, which ultimately came in the form of ABBV-CLS-484.“The medicinal chemistry lab at AbbVie did groundbreaking work on this project, and their belief in the promise of the target and the culture of optimism around it were big drivers of the eventual success,” Manguso said.
Besides demonstrating that it’s possible to target a phosphatase—and that doing so can potentially both make immunotherapy more effective and overcome a major source of resistance—the drug may also provoke the pharmaceutical industry to look beyond biologics for immunotherapy, Manguso noted. Small molecules have more flexible dosing options, lower production costs and are easier to distribute and store, he said.
“The development of small molecule immunotherapies could help this type of treatment reach even more patients in need of better treatment options,” Manguso said.
ABBV-CLS-484 is a product of AbbVie’s ongoing partnership with Calico to find therapies for age-related diseases. The companies first signed a deal in 2014 where each party could co-invest up to $1.5 billion, with an original investment of $250,000 each and the possibility of an additional $500,000 each. They extended it twice since, adding another $1 billion each time.