Molecule packs dual punch for cancer immunotherapy

Scientists from AbbVie, the Broad Institute of MIT and Harvard, and Calico Life Sciences have discovered and characterized a molecule that works on two difficult-to-target immune checkpoint proteins to fight cancer (Nature 2023, DOI: 10.1038/s41586-023-06575-7). It’s the first drug candidate of its kind for cancer immunotherapy, the researchers say.

“Every step along the way where we were able to clear a hurdle that had previously impeded progress on these types of difficult targets was a little celebration,” says Philip Kym, AbbVie’s head of medicinal chemistry.

Genetic studies suggested that inhibiting the protein tyrosine phosphatases PTPN1 and PTPN2 in cancer and immune cells would make the tumor cells more visible to the immune system and mobilize the immune cells to fight the cancer.

But because their active sites are highly polar, phosphatases are notoriously challenging drug targets, so it’s hard to find bioavailable molecules that target them effectively. Other phosphatase drug development efforts have circumvented this problem by targeting allosteric sites. But PTPN2 doesn’t have a good allosteric site, says Jennifer Frost, the project’s medicinal chemistry lead at AbbVie, so the team had to tackle the active-site problem head-on.

The molecule that Frost and her team created, ABBV-CLS-484 (AC484), was optimized to be a potent yet bioavailable inhibitor. Experiments in mice showed that AC484 works well by itself as well as in combination with other immunotherapies such as PD-1 inhibitors. The team found that AC484 activates multiple types of immune cells against tumors—unlike anti-PD-1 therapies, which activate only T cells.

Anne Bertolotti of the MRC Laboratory of Molecular Biology was not involved in the study but says it is “likely to be a milestone for tyrosine phosphatase research.” She would like more work done to see if the results come solely from direct inhibition or if other mechanisms are involved.

“We’re excited about this work, and we really look forward to seeing it go forward and ultimately be evaluated in patients,” Kym says.

AbbVie and Calico are now testing the compound in a phase 1 clinical trial.