Manguso and Kathleen Yates at the Broad co-direct TIDE, which uses CRISPR screens and other tools in animals to systematically uncover genes such as PTPN2 that cancers use to evade immunotherapy. Hakimeh Ebrahimi-Nik, a senior research scientist in TIDE, and Christina Baumgartner, a senior principal research scientist at AbbVie, were co-first authors on the study. In addition to Manguso and Yates, Jennifer Frost, a research fellow at AbbVie, and Philip Kym, vice president of Global Medicinal Chemistry at AbbVie, co-led the study in collaboration with scientists at Calico.

“It still sort of stuns me that we went from discovering a target in 2017 to testing drugs in patients starting in 2020,” Yates said. “The ability to leverage these partnerships, resources, technology like CRISPR, and AbbVie’s medicinal chemistry — it’s just been this confluence of factors that has felt like a fast-forward button.”

“Discovering a mechanism that has the potential to make a difference in someone’s life is one of the most exciting and rewarding parts about being a drug discovery scientist,” Baumgartner said. “We work every day with a sense of urgency and dedication knowing that patients are waiting. By collaborating with our partners at Calico and the Broad, we were able to quickly discover, characterize, and develop these innovative molecules.”

“The challenge of identifying orally bioavailable small molecule therapeutics targeting the active site of a phosphatase drug class was significant. In fact, previous work across the pharmaceutical industry targeting active site phosphatase inhibitors was unsuccessful, leading to the general conclusion that this was an ‘undruggable’ target class,” added Kym. “Therefore, it was very exciting to see the collaborative work of the combined discovery team be successful in delivering this first-in-class clinical candidate.” 

“This three-way collaboration among Calico, the Broad Institute, and AbbVie demonstrates the power of combining the best features of academia with the best of industry to accelerate scientific advances — in this case, translating early biology and target discovery into a clinical compound that is the first known active site phosphatase inhibitor of any kind,” said Marcia Paddock, co-author and director of oncology new target development at Calico.

Keeping cancer in check

In 2017, in an experiment that would become the foundation of TIDE, Manguso and researchers including W. Nicholas Haining (then at the Dana-Farber Cancer Institute and now at Arsenal Bio) systematically combed through almost 2,400 cancer genes in mice, looking for those that made melanoma tumors more or less sensitive to treatment with PD-1 inhibitors. They homed in on the PTPN2 gene and found that deleting it made tumor cells strikingly more sensitive to anti-PD-1 therapy.

But Manguso and Yates had another reason to be hopeful: PTPN2 is highly expressed in T cells, and previous research had shown that deleting it helped activate those cells, which could improve their ability to keep tumors in check. PTPN2 and a closely related gene called PTPN1 both encode phosphatases that inhibit signaling in an important immune pathway called JAK-STAT. 

However, drug companies had historically struggled to make inhibitors that bind to the active site of these phosphatases because they have a strong electric charge. This means that drugs that bind to them must also be highly charged, making it difficult for them to cross the cell membrane and enter the cell.

“There was evidence in the literature that this was going to be very difficult, but AbbVie just tackled the problem in a pretty fearless way,” Manguso said. “That culture of optimism was really important for the project’s eventual success.”

AbbVie scientists succeeded in designing a small molecule that enters the cell and binds to the PTPN2 and PTPN1 phosphatases, and the team then tested the molecule in tumor-bearing mice. Animals treated with the molecule showed slower tumor growth and survived longer than untreated animals, suggesting that ABBV-CLS-484 may work on its own, unlike many other emerging immunotherapies. The team also found that mice treated with both the molecule and an anti-PD-1 drug showed an even greater benefit, suggesting that the molecule may work in combination with other immunotherapies in patients.

Orchestrating efficacy